TW202527955A - Bifunctional compounds containing 2,5-substituted pyrimidine derivatives for degrading cyclin-dependent kinase 2 and cyclin-dependent kinase 4 via ubiquitin proteasome pathway - Google Patents

Abstract

The present disclosure provides certain bifunctional compounds that cause degradation of Cyclin-dependent kinase 2 (CDK2) and Cyclin-dependent kinase 4 (CDK4)via ubiquitin proteasome pathway and are therefore useful for the treatment of diseases mediated by CDK2 and/or CDK4. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Description

Translated fromChinese

用於經由泛素蛋白酶體途徑降解週期蛋白依賴性激酶2和週期蛋白依賴性激酶4的含有2,5-取代的嘧啶衍生物的雙功能化合物Bifunctional compounds containing 2,5-substituted pyrimidine derivatives for degradation of cyclin-dependent kinase 2 and cyclin-dependent kinase 4 via the ubiquitin-proteasome pathway

本揭露提供了某些含有2,5-取代的嘧啶衍生物的雙功能化合物，其經由泛素蛋白酶體途徑引起週期蛋白依賴性激酶2（CDK2）和週期蛋白依賴性激酶2（CDK4）的降解，因此可用於治療由CDK2和/或CDK4介導的疾病。還提供了含有此類化合物的藥物組成物以及用於製備此類化合物的方法。The present disclosure provides certain bifunctional compounds containing 2,5-substituted pyrimidine derivatives that induce degradation of cyclin-dependent kinase 2 (CDK2) and cyclin-dependent kinase 4 (CDK4) via the ubiquitin-proteasome pathway and are therefore useful for treating diseases mediated by CDK2 and/or CDK4. Also provided are pharmaceutical compositions containing such compounds and methods for preparing such compounds.

週期蛋白依賴性激酶（CDK）係必需的細胞絲胺酸/蘇胺酸激酶，在協調傳訊事件（如DNA複製和蛋白質合成）中發揮重要作用，以確保真核細胞的準確分裂和增殖。CDK活性的調節受到各種週期蛋白水平波動的嚴格控制，該等週期蛋白與CDK形成異二聚物複合物以活化它們。在已鑒定的21種CDK中，CDK1/週期蛋白B、CDK2/週期蛋白E、CDK2/週期蛋白A、CDK4/週期蛋白D、CDK6/週期蛋白D複合物係熟知的細胞週期進程的重要調節劑。其他CDK參與調節基因轉錄、DNA修復、分化和細胞凋亡（參見Morgan, D. O.Annu.Rev. Cell. Dev. Biol.[細胞與發育生物學年度評論] (1997) 13: 261-291）。Cyclin-dependent kinases (CDKs) are essential cellular serine/threonine kinases that play a crucial role in coordinating signaling events, such as DNA replication and protein synthesis, to ensure the accurate division and proliferation of eukaryotic cells. Regulation of CDK activity is tightly controlled by fluctuations in the levels of various cyclins, which form heterodimeric complexes with CDKs to activate them. Of the 21 identified CDKs, the CDK1/cyclin B, CDK2/cyclin E, CDK2/cyclin A, CDK4/cyclin D, and CDK6/cyclin D complexes are well-known as key regulators of cellular cycle processes. Other CDKs are involved in regulating gene transcription, DNA repair, differentiation, and apoptosis (see Morgan, DOAnnu.Rev. Cell. Dev. Biol. (1997) 13: 261-291).

在細胞週期的典型模型中，促有絲分裂傳訊（mitogenic signaling）上調D型週期蛋白，其直接結合並活化CDK4/6。活性CDK4/6-週期蛋白D複合物部分磷酸化Rb，從而破壞Rb/E2F相互作用並解除對E2F活性的抑制，導致週期蛋白E（一種CDK2活化劑）的上調。Cdk2-週期蛋白E進一步過度磷酸化Rb，從而釋放E2F來轉錄進入S期所需的基因。在S期期間，週期蛋白E被降解，並且CDK2與週期蛋白A形成複合物，以促進DNA複製必需底物的磷酸化和E2F失活，從而完成S期（Asghar等人Nat.Rev. Drug. Discov.[自然評論：藥物發現] (2015) 14: 130-146）。CDK1-週期蛋白A和CDK1-週期蛋白B複合物分別在S期晚期和G2期被活化，以推動向有絲分裂的過渡和有絲分裂的完成（Katsuno等人, 2009；Lindqvist等人, 2009；Lohka等人, 1988）。In the canonical model of cell cycle, mitogenic signaling upregulates D-type cyclin, which directly binds and activates CDK4/6. The active CDK4/6-cyclin D complex partially phosphorylates Rb, disrupting the Rb/E2F interaction and releasing inhibition of E2F activity, leading to upregulation of cyclin E, a CDK2 activator. Cdk2-cyclin E further hyperphosphorylates Rb, releasing E2F to transcribe genes required for S phase entry. During S phase, cyclin E is degraded, and CDK2 forms a complex with cyclin A to promote phosphorylation of essential substrates for DNA replication and inactivation of E2F, thereby completing S phase (Asghar et al. Nat.Rev. Drug. Discov. (2015) 14: 130-146). The CDK1-cyclin A and CDK1-cyclin B complexes are activated in late S phase and G2 phase, respectively, to drive the transition to mitosis and completion of mitosis (Katsuno et al., 2009; Lindqvist et al., 2009; Lohka et al., 1988).

由於CDK在調節細胞週期和其他必需細胞過程中發揮著重要作用，已證實CDK活性的增加或暫時異常活化會促進腫瘤形成和疾病進展（Cordon-Cardo C.Am. J. Pathol.[美國病理學雜誌] (1995) 147:545-560；Karp JE, Broder S.Nat. Med.[自然醫學] (1995) 1:309-320；Hall M, Peters G.Adv. Cancer Res.[癌症研究進展] (1996) 68:67-108）。CDK-週期蛋白複合物及調節它們的蛋白質的基因變化在各種癌症中廣泛存在，並且通常與不良的臨床結果有關。常見的改變包括週期蛋白D、週期蛋白E、CDK4和CDK6的擴增/過表現；Rb的缺失；CDK抑制調節劑（如p16、p21、p27）的缺乏；以及FBXW7（負責週期蛋白E降解的SCF^Fbw7泛素E3連接酶的組分）的功能喪失突變（Smalley等人.Cancer Res.[癌症研究] (2008) 68: 5743-52）。Because CDKs play a crucial role in regulating cell cycling and other essential cellular processes, increased or transiently abnormal CDK activity has been shown to promote tumor formation and disease progression (Cordon-Cardo C.Am. J. Pathol. (1995) 147:545-560; Karp JE, Broder S.Nat. Med. (1995) 1:309-320; Hall M, Peters G.Adv. Cancer Res. (1996) 68:67-108). Genetic alterations in CDK-cyclin complexes and the proteins that regulate them are widespread in various cancers and are often associated with adverse clinical outcomes. Common alterations include amplification/overexpression of cyclin D, cyclin E, CDK4, and CDK6; loss of Rb; deficiency of CDK inhibitory regulators (such as p16, p21, and p27); and loss-of-function mutations in FBXW7, a component of the SCF^Fbw7 ubiquitin E3 ligase responsible for cyclin E degradation (Smalley et al.Cancer Res . (2008) 68: 5743-52).

在過去的二十年裡，人們對開發用於治療目的的CDK抑制劑產生了濃厚的興趣。與內分泌療法相組合，CDK4和CDK6的選擇性可逆抑制劑（例如帕博西尼、瑞博西尼和阿貝西利）徹底改變了激素受體陽性（HR+）轉移性乳腺癌（MBC）的治療管理。正在進行的臨床試驗也在研究該等CDK4/6抑制劑作為單一藥劑或與其他治療劑組合用於各種癌症。（O'Leary等人Nature Reviews[自然評論] (2016) 13:417-430）。Over the past two decades, there has been intense interest in developing CDK inhibitors for therapeutic purposes. Selective, reversible inhibitors of CDK4 and CDK6 (such as palbociclib, ribociclib, and abemaciclib) have revolutionized the management of hormone receptor-positive (HR+) metastatic breast cancer (MBC) when combined with endocrine therapy. Ongoing clinical trials are also investigating these CDK4/6 inhibitors as single agents or in combination with other therapies in various cancers (O'Leary et al.,Nature Reviews (2016) 13:417-430).

儘管CDK4/6抑制劑對ER陽性轉移性乳腺癌具有顯著的臨床功效，但也存在一些局限性。一個主要的缺點係隨著時間的推移，會產生原發性或獲得性耐藥性。耐藥性的一個重要機制涉及CDK2的異常活化。這可能是由於週期蛋白E表現升高導致CDK2/週期蛋白E複合物過度活化（Asghar, U.等人.Clin.Cancer Res.[臨床癌症研究] (2017) 23:5561），或由於響應CDK4/6抑制而形成了非典型CDK2/週期蛋白D1複合物（Herrera-Abreu MT等人,Cancer Res.[癌症研究] (2006) 15: 2301），從而繞過了細胞週期再進入（cell cycle reentry）對CDK4/6的需要。另外，CDK4/6抑制劑帕博西尼和瑞博西尼表現出相對較高的血液學毒性，主要是嗜中性球減少症。CDK6在血液系統中高度表現，起到調節造血細胞生長的作用。因此，一般認為，由於乳腺癌細胞主要依賴CDK4進行增殖，CDK6的抑制會導致嗜中性球減少症。阿貝西利對CDK6的抑制作用比對CDK4的抑制作用弱，因此血液學毒性較低。Despite their remarkable clinical efficacy in ER-positive metastatic breast cancer, CDK4/6 inhibitors have several limitations. A major drawback is the development of either primary or acquired resistance over time. A key mechanism of resistance involves aberrant CDK2 activation. This may be due to elevated cyclin E expression, leading to overactivation of the CDK2/cyclin E complex (Asghar, U. et al.Clin.Cancer Res. (2017) 23:5561), or to the formation of an atypical CDK2/cyclin D1 complex in response to CDK4/6 inhibition (Herrera-Abreu MT et al.Cancer Res. (2006) 15:2301), thereby bypassing the requirement for CDK4/6 for cell cycle reentry. Furthermore, the CDK4/6 inhibitors palbociclib and ribociclib exhibit relatively high hematologic toxicity, primarily neutropenia. CDK6 is highly expressed in the blood system and plays a role in regulating hematopoietic cell growth. Therefore, it is generally believed that because breast cancer cells primarily rely on CDK4 for proliferation, inhibition of CDK6 leads to neutropenia. Abecib's inhibitory effect on CDK6 is weaker than its effect on CDK4, resulting in less hematologic toxicity.

考慮到該等因素，開發一種專門針對CDK4和CDK2兩者的小分子抑制劑或蛋白水解靶向嵌合分子（PROTAC）可以帶來降低毒性且提高整體治療功效的治療機會。Taking these factors into consideration, the development of a small molecule inhibitor or proteolysis-targeting chimeric molecule (PROTAC) that specifically targets both CDK4 and CDK2 may provide therapeutic opportunities that reduce toxicity and improve overall therapeutic efficacy.

PROTAC係由靶蛋白募集部分和E3連接酶的配位基（二者藉由生物相容性連接基連接）組成的雙功能分子。PROTAC使目的蛋白和E3連接酶緊密接近，並誘導靶蛋白的泛蛋白化和隨後靶蛋白被蛋白酶體降解。PROTACs are bifunctional molecules composed of a target protein recruitment moiety and an E3 ligase ligand, connected by a biocompatible linker. PROTACs bring the target protein and E3 ligase into close proximity, inducing ubiquitination and subsequent proteasomal degradation of the target protein.

與通常結合疾病相關蛋白並抑制其功能的小分子藥物相比，PROTAC顯示出幾種獨特且有吸引力的特徵，使其成為理想的藥物候選物。例如，PROTAC已被證明比其抑制劑對應物更具選擇性，這可能會降低脫靶毒性。此外，PROTAC可以進行多輪靶標泛蛋白化和降解。由於這種催化作用模式，PROTAC可以在亞化學計量的受體佔用率下起作用。在PROTAC中使用的E3連接酶主要包括小腦蛋白（cereblon，CRBN）、含Von Hippel-Lindau的複合物（VHL）、凋亡蛋白抑制劑（IAP）和小鼠雙微體2（MDM2）。Compared to small-molecule drugs that typically bind to disease-associated proteins and inhibit their function, PROTACs exhibit several unique and attractive features that make them ideal drug candidates. For example, PROTACs have been shown to be more selective than their inhibitory counterparts, which may reduce off-target toxicity. Furthermore, PROTACs can undergo multiple rounds of target ubiquitination and degradation. Due to this catalytic mode of action, PROTACs can function at substoichiometric receptor occupancy. E3 ligases used in PROTACs include cereblon (CRBN), von Hippel-Lindau complex (VHL), inhibitor of apoptosis protein (IAP), and mouse double minute 2 (MDM2).

因此，需要能夠將CDK2和CDK4兩者募集到泛素連接酶，從而引起CDK2和CDK4兩者的泛蛋白化和蛋白酶體降解的PROTAC。本揭露滿足此需求及相關需求。Therefore, there is a need for PROTACs that can recruit both CDK2 and CDK4 to ubiquitin ligases, thereby causing ubiquitination and proteasomal degradation of both CDK2 and CDK4. The present disclosure satisfies this and related needs.

在第一方面，提供了一種經由泛素蛋白酶體途徑降解CDK2和CDK4蛋白的方法，該方法包括使細胞與以下接觸：具有式 (IA) 的化合物：(IA) 其中： Q係CH或N； R^1a係氫、氘、烷基、鹵代、鹵代烷基、烷氧基、羥基或氰基； Het選自1) 含有一或兩個氮環原子的5員或6員雜芳基環，其中該5員或6員雜芳基環視需要地與雜環基^A或螺雜環基^A稠合，2) 含有一至五個氮環原子的9員或10員稠合雙環雜芳基環，其中該9員或10員稠合雙環雜芳基環視需要地與雜環基^A或不飽和雜環基^A稠合，以及3) 部分飽和的9員或10員稠合雙環雜芳基，其視需要地與含有一或兩個氮環原子的5員雜芳基^A稠合，其中該5員或6員雜芳基、該9員或10員稠合雙環雜芳基、和該部分飽和的9員或10員稠合雙環雜芳基的至少一個氮環原子與形成到-NH-的鍵的Het環的碳原子鄰位並且Het中之每個環被R^x、R^y和R^z取代，其中R^x和R^y獨立地選自氫、烷基、烷氧基、鹵代、鹵代烷基、鹵代烷氧基、羥基、氰基、氰基烷基、氰基烷基氧基、胺基羰基、烷基胺基羰基、二烷基胺基羰基和烷基羰基胺基，並且R^z係氫、烷基、烯基、炔基、鹵代、羥基、環烷基、橋接環烷基、環烷基烷基、螺環烷基、苯基、雜芳基、雜環基、橋接雜環基、螺雜環基或稠合雜環基，其中每個上述R^z環視需要地被1至3個獨立地選自氫、烷基、環烷基、鹵代、氰基、羥基或胺基的取代基取代； 降解決定子（Degron）係E3泛素連接酶配位基；並且 Z係-O-、-NR³-（其中R³係氫或烷基）、伸炔基、環伸烷基、伸苯基、單環雜伸芳基、不飽和雜亞環基、雜亞環基、橋接雜亞環基或螺雜亞環基，其中每個環被獨立地選自氫、氘、烷基、烷氧基、鹵代、鹵代烷基、鹵代烷氧基和氰基的R^d和R^e取代； alk係被選自氫、氟和氰基的R^f取代的C₃至C₆伸烯基；C₃至C₆伸烷基或C₃至C₆雜伸烷基，其中該C₃至C₆伸烷基和C₃至C₆雜伸烷基被R^g、R^h和Rⁱ取代，其中R^g係氫、氘或鹵代，R^h係氫、氘、環烷基、環烷基氧基、橋接環烷基、鹵代、鹵代烷氧基、烷氧基、羥基、氰基、氰基烷基、氰基烷基氧基、胺基羰基、烷基胺基羰基、二烷基胺基羰基、烷基羰基胺基、苯基、雜芳基、雜環基、雜環基氧基、雜環基羰基、或橋接雜環基（其中環烷基——本身或作為環烷基氧基的一部分、橋接環烷基、苯基、雜芳基、雜環基——本身或作為雜環基氧基或雜環基羰基的一部分、和橋接雜環基被獨立地選自氫、氘、烷基、烷氧基、鹵代、鹵代烷基、鹵代烷氧基、羥基、烷基羰基、烷基氧基羰基、胺基、烷基胺基、二烷基胺基和氰基的R⁷和R⁸取代）；或者當R^g和R^h附接至該C₃至C₆伸烷基或C₃至C₆雜伸烷基的直鏈部分的相同碳或相鄰碳原子時，R^g和R^h可與它們所附接的碳原子一起形成環伸烷基或雜亞環基（其中由R^g和R^h形成的該環伸烷基和雜亞環基被獨立地選自氫、氘、烷基、烷氧基、鹵代、鹵代烷基、鹵代烷氧基、羥基、烷基羰基、烷基氧基羰基、胺基、烷基胺基、二烷基胺基和氰基的R⁹和R¹⁰取代），並且Rⁱ係氫或鹵代；並且附接Ar和Z的C₃至C₆伸烯基、C₃至C₆伸烷基和C₃至C₆雜伸烷基的直鏈部分含有至少三個原子； Ar係伸苯基、單環雜伸芳基、雜亞環基、橋接雜亞環基或螺雜亞環基，其中上述環中之每一個被獨立地選自氫、氘、烷基、烷氧基、鹵代、鹵代烷基、鹵代烷氧基和氰基的R^j、R^k和R^m取代；或 其藥學上可接受的鹽。In a first aspect, a method is provided for degrading CDK2 and CDK4 proteins via the ubiquitin proteasome pathway, the method comprising contacting a cell with a compound having formula (IA): (IA) wherein: Q is CH or N; R^1a is hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxyl, or cyano; Het is selected from 1) a 5- or 6-membered heteroaryl ring containing one or two nitrogen ring atoms, wherein the 5- or 6-membered heteroaryl ring is optionally fused to a heterocyclic group^A or a spiroheterocyclic group^A , 2) a 9- or 10-membered fused bicyclic heteroaryl ring containing one to five nitrogen ring atoms, wherein the 9- or 10-membered fused bicyclic heteroaryl ring is optionally fused to a heterocyclic group^A or an unsaturated heterocyclic group^A , and 3) A partially saturated 9- or 10-membered fused bicyclic heteroaryl group, which is optionally fused to a 5-membered heteroaryl group^A containing one or two nitrogen ring atoms, wherein the 5- or 6-membered heteroaryl group, the 9- or 10-membered fused bicyclic heteroaryl group, and at least one nitrogen ring atom of the partially saturated 9- or 10-membered fused bicyclic heteroaryl group are adjacent to the carbon atom of the Het ring that forms a bond to -NH- and each ring in Het is substituted by^Rx ,^Ry , and^Rz , wherein^Rx and R^y is independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, cyanoalkyl, cyanoalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, and alkylcarbonylamino, and^Rz is hydrogen, alkyl, alkenyl, alkynyl, halo, hydroxy, cycloalkyl, bridged cycloalkyl, cycloalkylalkyl, spiroalkyl, phenyl, heteroaryl, heterocyclic group, bridged heterocyclic group, spiroheterocyclic group, or fused heterocyclic group, wherein each of the above^Rz rings is optionally substituted with 1 to 3 substituents independently selected from hydrogen, alkyl, cycloalkyl, halo, cyano, hydroxy, or amino; Degron is an E3 ubiquitin ligase ligand; and Z is -O-, -NR³ - (wherein R³ is hydrogen or alkyl), alkynyl, cycloalkylene, phenylene, monocyclic heteroaryl, unsaturated heterocycloene, heterocycloene, bridged heterocycloene, or spiroheterocycloene, wherein each ring is independently substituted with R d and R e selected from hydrogen, deuterium, alkyl, alkoxy, halogen, halogenated alkyl, halogenated alkoxy, and cyano; alk is C₃ to C^6alkenyl substituted with R^f selected from hydrogen,_fluorine , and cyano; C₃ to C₆ alkylene or C₃ to C₆ heteroalkylene, wherein the C₃ to C₆ alkylene and C₃ to C₆ heteroalkylene groups are substituted by^Rg ,^Rh and^Ri , wherein^Rg is hydrogen, deuterium or halogenated, and^Rh is hydrogen, deuterium, cycloalkyl, cycloalkyloxy, bridged cycloalkyl, halogenated, halogenated alkoxy, alkoxy, hydroxyl, cyano, cyanoalkyl, cyanoalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, phenyl, heteroaryl, heterocyclo, heterocyclooxy, heterocyclocarbonyl, or bridged heterocyclo (wherein cycloalkyl—itself or R as part of a cycloalkyloxy group, a bridged cycloalkyl group, a phenyl group, a heteroaryl group, a heterocyclo group, itself or as part of a heterocyclooxy group or a heterocyclocarbonyl group, and a bridged heterocyclo group independently selected from hydrogen, deuterium, an alkyl group, an alkoxy group, a halogenated group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, an alkylcarbonyl group, an alkyloxycarbonyl group, an amino group, an alkylamino group, a dialkylamino group, and a cyano group^{or when R g and R hareattached} to the same carbon or adjacent carbon atoms of the linear portion of the C₃ to C₆ alkylene or^C₃ to C₆ heteroalkylene, R^g and R^h may form together with the carbon atoms to which they are attached a cycloalkylene or heterocycloene group (wherein the cycloalkylene and heterocycloene group formed by R^g and R^h are substituted with R 9 and R 10 independently selected from hydrogen, deuterium, alkyl, alkoxy, halogenated, halogenated alkyl, halogenated alkoxy, hydroxy, alkylcarbonyl, alkyloxycarbonyl, amino, alkylamino, dialkylamino, and cyano groups), and Rⁱ is hydrogen or halogenated; and the C₃ to C⁶ alkenylene, C₃ to C₆ alkylene, and C 3 to C₆ heteroalkylene group attached to Ar and Z are substituted with R g and R^h_; wherein the straight chain portion of the_heteroaryl group contains at least three atoms; Ar is a phenylene group, a monocyclic heteroaryl group, a heterocycloene group, a bridged heterocycloene group, or a spiroheterocycloene group, wherein each of the above rings is substituted with^Rj ,^Rk, and^Rm independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, halogenated alkyl, halogenated alkoxy, and cyano; or a pharmaceutically acceptable salt thereof.

在第二方面，提供了一種具有式 (IB) 的化合物：(IB) 其中： R¹係烷基、烯基、炔基、環烷基、環烷基氧基（其中環烷基——單獨的或作為環烷氧基的一部分，被一至三個鹵代取代）、鹵代、鹵代烷基、鹵代烷氧基、烷氧基、芳基氧基、或氰基； R²和R^2a獨立地是氫或氘； Hy係環伸烷基、伸芳基、雜伸芳基、雜亞環基、雙環雜亞環基、螺雜亞環基、橋接雜亞環基或稠合雜亞環基，其中上述環中之每一個被獨立地選自氫、氘、烷基、鹵代、鹵代烷基、烷氧基、羥基和氰基的R^a、R^b和R^c取代； 降解決定子係選自以下的E3泛素連接酶配位基： (a) 具有式 (i) 的基團：(i)；   或者 (b) 具有式 (ii) 的基團：(ii)； Y^a係CH或N； Z^a係鍵、-CH₂-、-NH-、-O-或-NHC(O)-，其中-NHC(O)-的NH附接至Y^a； 環A係具有式 (a) 或 (b) 的基團：； 其中： R^aa、R^bb、R^cc和R^dd獨立地選自氫、烷基、烷氧基、鹵代、鹵代烷基、鹵代烷氧基和氰基； R⁴和R⁵獨立地是氫或烷基；或R⁴和R⁵與它們所附接的碳一起形成＞C=O； M係-O-或-NR⁶-；並且 R⁶係氫或烷基； 環B係伸苯基、環亞胺基、5員或6員單環雜伸芳基、或9員或10員稠合雙環雜伸芳基，其中每個雜伸芳基環含有一至三個環原子，該等環原子係獨立地選自氮、氧或硫的雜原子，並且進一步地，其中該伸苯基、環亞胺基和每個雜伸芳基獨立地被獨立地選自氫、烷基、環烷基、烷氧基、鹵代、鹵代烷基、鹵代烷氧基和氰基的R^ee和R^ff取代；並且 Z係-O-、-NR³-（其中R³係氫或烷基）、伸炔基、環伸烷基、伸苯基、單環雜伸芳基、不飽和雜亞環基、雜亞環基、橋接雜亞環基或螺雜亞環基，並且其中每個環被獨立地選自氫、氘、烷基、烷氧基、鹵代、鹵代烷基、鹵代烷氧基和氰基的R^d和R^e取代； alk係被選自氫、氟和氰基的R^f取代的C₃至C₆伸烯基；C₃至C₆伸烷基或C₃至C₆雜伸烷基，其中該C₃至C₆伸烷基和C₃至C₆雜伸烷基被R^g、R^h和Rⁱ取代，其中R^g係氫、氘或鹵代，R^h係氫、氘、環烷基、環烷基氧基、橋接環烷基、鹵代、鹵代烷氧基、烷氧基、羥基、氰基、氰基烷基、氰基烷基氧基、胺基羰基、烷基胺基羰基、二烷基胺基羰基、烷基羰基胺基、苯基、雜芳基、雜環基、雜環基氧基、雜環基羰基、或橋接雜環基（其中環烷基——本身或作為環烷基氧基的一部分、橋接環烷基、苯基、雜芳基、雜環基——本身或作為雜環基氧基或雜環基羰基的一部分、和橋接雜環基被獨立地選自氫、氘、烷基、烷氧基、鹵代、鹵代烷基、鹵代烷氧基、羥基、烷基羰基、烷基氧基羰基、胺基、烷基胺基、二烷基胺基和氰基的R⁷和R⁸取代）；或者當R^g和R^h附接至該C₃至C₆伸烷基或C₃至C₆雜伸烷基的直鏈部分的相同碳或相鄰碳原子時，R^g和R^h可與它們所附接的碳原子一起形成環伸烷基或雜亞環基（其中由R^g和R^h形成的該環伸烷基和雜亞環基被獨立地選自氫、氘、烷基、烷氧基、鹵代、鹵代烷基、鹵代烷氧基、羥基、烷基羰基、烷基氧基羰基、胺基、烷基胺基、二烷基胺基和氰基的R⁹和R¹⁰取代），並且Rⁱ係氫或鹵代；並且附接Ar和Z的C₃至C₆伸烯基、C₃至C₆伸烷基和C₃至C₆雜伸烷基的直鏈部分含有至少三個原子； Ar係伸苯基、單環雜伸芳基、雜亞環基、不飽和雜亞環基^X、橋接雜亞環基或螺雜亞環基，其中上述環中之每一個被獨立地選自氫、氘、烷基、烷氧基、鹵代、鹵代烷基、鹵代烷氧基和氰基的R^j、R^k和R^m取代；或 其藥學上可接受的鹽。In a second aspect, there is provided a compound having formula (IB): (IB) wherein: R¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy (wherein the cycloalkyl group, alone or as part of a cycloalkoxy group, is substituted with one to three halo groups), halo, haloalkyl, haloalkoxy, alkoxy, aryloxy, or cyano; R² and R^2a are independently hydrogen or deuterium; Hy is cycloalkylene, arylene, heteroarylene, heterocycloene, bicyclic heterocycloene, spiroheterocycloene, bridged heterocycloene, or fused heterocycloene, wherein each of the above rings is substituted with R a , R^b , and R^c , which are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy,^hydroxy , and cyano; The degradation determinant is selected from the following E3 ubiquitin ligase ligands: (a) a group having formula (i): (i); or (b) a group having formula (ii): (ii);^Ya is CH or N;^Za is a bond,_-CH2- , -NH-, -O-, or -NHC(O)-, wherein the NH of -NHC(O)- is attached to^Ya ; Ring A is a group having formula (a) or (b): wherein:^Raa ,^Rbb ,^Rcc , and^Rdd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano;^R4 and^R5 are independently hydrogen or alkyl; or^R4 and^R5 , together with the carbon to which they are attached, form >C=O; M is -O- or^-NR6- ; and^R6 is hydrogen or alkyl; Ring B is phenylene, cycloimino, 5-membered or 6-membered monocyclic heteroaryl, or 9-membered or 10-membered fused bicyclic heteroaryl, wherein each heteroaryl ring contains one to three ring atoms, and the ring atoms are independently selected from nitrogen, oxygen or sulfur heteroatoms, and further, wherein the phenylene, cycloimino and each heteroaryl are independently substituted with R^ee and R^ff independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halogen, halogenated alkyl, halogenated alkoxy and cyano; and Z is -O-, -NR³ - (wherein R³ is hydrogen or alkyl), alkynyl, cycloalkylene, phenylene, monocyclic heteroaryl, unsaturated heterocycloene, heterocycloene, bridged heterocycloene or spiroheterocycloene, and wherein each ring is substituted by R d and R e independently selected from hydrogen, deuterium, alkyl, alkoxy, halogenated, halogenated alkyl, halogenated alkoxy and cyano; alk is C³ to C⁶ alkenyl substituted by R^f selected from hydrogen, fluorine and cyano; C₃ to C₆ alkylene or C₃ to C₆ heteroalkylene, wherein the C₃ to C₆ alkylene and C_{3toC 6heteroalkylene} are substituted by R^g , R^h and Rⁱ , wherein R^g is hydrogen, deuterium or halogenated, R^h is hydrogen, deuterium, cycloalkyl, cycloalkyloxy, bridged cycloalkyl, halogen, halogenated alkoxy, alkoxy, hydroxy, cyano, cyanoalkyl, cyanoalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, phenyl, heteroaryl, heterocyclic, heterocyclicoxy, heterocycliccarbonyl, or bridged heterocyclic (wherein cycloalkyl—itself or R as part of a cycloalkyloxy group, a bridged cycloalkyl group, a phenyl group, a heteroaryl group, a heterocyclo group, itself or as part of a heterocyclooxy group or a heterocyclocarbonyl group, and a bridged heterocyclo group independently selected from hydrogen, deuterium, an alkyl group, an alkoxy group, a halogenated group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, an alkylcarbonyl group, an alkyloxycarbonyl group, an amino group, an alkylamino group, a dialkylamino group, and a cyano group^{or when R g and R hareattached} to the same carbon or adjacent carbon atoms of the linear portion of the C₃ to C₆ alkylene or^C₃ to C₆ heteroalkylene, R^g and R^h may form together with the carbon atoms to which they are attached a cycloalkylene or heterocycloene group (wherein the cycloalkylene and heterocycloene group formed by R^g and R^h are substituted with R 9 and R 10 independently selected from hydrogen, deuterium, alkyl, alkoxy, halogenated, halogenated alkyl, halogenated alkoxy, hydroxy, alkylcarbonyl, alkyloxycarbonyl, amino, alkylamino, dialkylamino, and cyano groups), and Rⁱ is hydrogen or halogenated; and the C₃ to C⁶ alkenylene, C₃ to C₆ alkylene, and C 3 to C₆ heteroalkylene group attached to Ar and Z are substituted with R g and R^h_; wherein the straight chain portion of the_heteroaryl group contains at least three atoms; Ar is a phenylene group, a monocyclic heteroaryl group, a heterocycloene group, an unsaturated^{heterocycloene} group, a bridged heterocycloene group, or a spiroheterocycloene group, wherein each of the above rings is substituted with^Rj ,^Rk , and^Rm independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, halogenated alkyl, halogenated alkoxy, and cyano; or a pharmaceutically acceptable salt thereof.

在第二方面的第一實施方式中，具有式 (IB) 的化合物係具有式 (I) 的化合物：(I) 其中： Ar係伸苯基、單環雜伸芳基、雜亞環基、橋接雜亞環基或螺雜亞環基，其中上述環中之每一個被獨立地選自氫、氘、烷基、烷氧基、鹵代、鹵代烷基、鹵代烷氧基和氰基的R^j、R^k和R^m取代；並且其他基團如式 (IB) 中所定義；或 其藥學上可接受的鹽。In a first embodiment of the second aspect, the compound of formula (IB) is a compound of formula (I): (I) wherein: Ar is a phenylene group, a monocyclic heteroarylene group, a heterocycloene group, a bridged heterocycloene group, or a spiroheterocycloene group, wherein each of the above rings is substituted by^Rj ,^Rk , and^Rm independently selected from hydrogen, deuterium, alkyl, alkoxy, halogenated, halogenated alkyl, halogenated alkoxy, and cyano; and the other groups are as defined in formula (IB); or a pharmaceutically acceptable salt thereof.

具有式 (I) 的化合物係具有式 (IB) 的化合物的子集。Compounds of formula (I) are a subset of compounds of formula (IB).

在第一方面的第一實施方式中，具有式 (IA) 的化合物不是：In a first embodiment of the first aspect, the compound of formula (IA) is not:

在第二方面的第二實施方式及其第一實施方式中，具有式 (IB) 或 (I) 的化合物不是：In a second embodiment of the second aspect and in its first embodiment, the compound of formula (IB) or (I) is not:

在第三方面，提供了一種藥物組成物，其包含具有式 (IA)、(IB) 或式 (I) 的化合物（或本文所述之其任一實施方式）或其藥學上可接受的鹽；以及藥學上可接受的賦形劑。In a third aspect, a pharmaceutical composition is provided, comprising a compound of Formula (IA), (IB), or (I) (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

在第四方面，提供了一種治療患者（較佳的是需要這種治療的患者）的由CDK2和/或CDK4介導的疾病的方法，該方法包括向該患者（較佳的是需要這種治療的患者）投與治療有效量的具有式 (IA)、(IB) 的化合物或具有式 (I) 的化合物（或下文所述之其任一實施方式）或其藥學上可接受的鹽；或本文揭露的其藥物組成物。在第四方面的第一實施方式中，該疾病係癌症。在第四方面的第二子實施方式中，該疾病係選自以下的癌症：肺癌（例如腺癌、小細胞肺癌、非小細胞肺癌、小細胞性癌和非小細胞性癌、支氣管癌、支氣管腺瘤和/或胸膜肺母細胞瘤）、皮膚癌（例如黑色素瘤、鱗狀細胞癌、卡波西肉瘤和/或默克爾細胞皮膚癌）、膀胱癌、乳腺癌、宮頸癌、結直腸癌、小腸癌（如闌尾癌）、結腸癌、直腸癌、肛門癌、子宮內膜癌、胃部癌症、頭頸癌（例如喉癌、下咽癌、鼻咽癌、口咽癌、唇癌和/或口腔癌）、肝癌（例如肝細胞癌和/或膽管細胞癌）、膽管癌、卵巢癌、前列腺癌、睪丸癌、子宮癌、食道癌、膽囊癌、胰臟癌（例如胰臟外分泌癌）、胃癌、甲狀腺癌、甲狀旁腺癌、骨癌、膽道癌、陰道癌、星形細胞瘤、脂肪肉瘤、膠質母細胞瘤、神經母細胞瘤和/或腎癌。在第四方面的第三實施方式中，癌症係那些藉由CDK2介導的機制對CDK4/6抑制劑具有耐藥性的癌症，例如乳腺癌。在第四方面的第四實施方式中，該疾病係自體免疫性疾病或與自體免疫性疾病相關的病症，該方法包括向該患者（較佳的是需要這種治療的患者）投與治療有效量的具有式 (I) 的化合物（或下文所述之其任一實施方式）或其藥學上可接受的鹽。在一些實施方式中，該自體免疫性疾病或與自體免疫性疾病相關的病症選自類風濕性關節炎（RA）、全身性紅斑狼瘡（SLE）、原發性休格倫氏症候群（pSS）、多發性硬化（MS）、克羅恩病（CD）、眼色素層炎、尋常型天疱瘡和敗血症。在第四方面的第五實施方式中，該疾病係痛風。In a fourth aspect, a method for treating a disease mediated by CDK2 and/or CDK4 in a patient (preferably a patient in need of such treatment) is provided, comprising administering to the patient (preferably a patient in need of such treatment) a therapeutically effective amount of a compound of Formula (IA), (IB), or a compound of Formula (I) (or any embodiment thereof described below), or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof disclosed herein. In a first embodiment of the fourth aspect, the disease is cancer. In a second sub-embodiment of the fourth aspect, the disease is selected from the following cancers: lung cancer (e.g., adenocarcinoma, small cell lung cancer, non-small cell lung cancer, small cell carcinoma and non-small cell carcinoma, bronchial carcinoma, bronchial adenoma and/or pleuropulmonary blastoma), skin cancer (e.g., melanoma, squamous cell carcinoma, Kaposi's sarcoma and/or Merkel cell skin cancer), bladder cancer, breast cancer, cervical cancer, colorectal cancer, small intestinal cancer (e.g., coccyx cancer), colon cancer, rectal cancer, anal cancer, uterine cancer, endometrial cancer, gastric cancer, head and neck cancer (e.g., laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip cancer, and/or oral cancer), liver cancer (e.g., hepatocellular carcinoma and/or bile duct cancer), bile duct cancer, ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), gastric cancer, thyroid cancer, parathyroid cancer, bone cancer, gallbladder cancer, vaginal cancer, astrocytoma, liposarcoma, glioblastoma, neuroblastoma, and/or kidney cancer. In a third embodiment of the fourth aspect, the cancer is resistant to CDK4/6 inhibitors through a CDK2-mediated mechanism, such as breast cancer. In a fourth embodiment of the fourth aspect, the disease is an autoimmune disease or a condition associated with an autoimmune disease, and the method comprises administering to the patient (preferably a patient in need of such treatment) a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments described below) or a pharmaceutically acceptable salt thereof. In some embodiments, the autoimmune disease or condition associated with an autoimmune disease is selected from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), multiple sclerosis (MS), Crohn's disease (CD), uveitis, pemphigus vulgaris, and sepsis. In a fifth embodiment of the fourth aspect, the disease is gout.

在第五方面，提供了一種治療噪音誘導的、化療誘導的（順鉑誘導的）、抗生素誘導的或年齡相關的聽力損失的方法，該方法包括向患者（較佳的是需要這種治療的患者）投與治療有效量的具有式 (I) 的化合物（或本文所述之其任一實施方式）或其藥學上可接受的鹽；或其中揭露的其藥物組成物。在一些實施方式中，當與年齡匹配的對照相比時，聽力損失量減少。在一些實施方式中，當與年齡匹配的對照相比時，聽力損失得到預防。In a fifth aspect, a method for treating noise-induced, chemotherapy-induced (cisplatin-induced), antibiotic-induced, or age-related hearing loss is provided, comprising administering to a patient (preferably a patient in need of such treatment) a therapeutically effective amount of a compound of Formula (I) (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof disclosed therein. In some embodiments, the amount of hearing loss is reduced when compared to an age-matched control. In some embodiments, the hearing loss is prevented when compared to an age-matched control.

在第六方面，提供了具有式 (IA)、(IB) 的化合物或具有式 (I) 的化合物（或本文所述之其任一實施方式）或其藥學上可接受的鹽，用於在療法中使用。在第六方面的一個實施方式中，具有式 (IA) 的化合物或具有式 (I) 的化合物（或本文揭露的其任何實施方式）或其藥學上可接受的鹽用於在治療上述第四或第五方面中揭露的一或多種疾病中使用。In a sixth aspect, provided are compounds of Formula (IA), (IB), or (I) (or any embodiment thereof as described herein), or pharmaceutically acceptable salts thereof, for use in therapy. In one embodiment of the sixth aspect, the compound of Formula (IA) or (I) (or any embodiment thereof as disclosed herein), or pharmaceutically acceptable salts thereof, is for use in treating one or more diseases disclosed in the fourth or fifth aspect.

在第七方面，提供了具有式 (IA)、(IB) 的化合物或具有式 (I) 的化合物（或本文所述之其任一實施方式）或其藥學上可接受的鹽在製造用於治療患者的疾病的藥物中之用途，在該疾病中，CDK2和/或CDK4的活性造成該疾病的病理學和/或症狀。在第七方面的一個實施方式中，該疾病係上述第四和/或第五方面中揭露的疾病中之一或多種。In a seventh aspect, provided is the use of a compound of Formula (IA), (IB), or a compound of Formula (I) (or any embodiment thereof described herein), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease in a patient in which CDK2 and/or CDK4 activity contributes to the pathology and/or symptoms of the disease. In one embodiment of the seventh aspect, the disease is one or more of the diseases disclosed in the fourth and/or fifth aspects above.

在第八方面，提供了一種經由泛素蛋白酶體途徑降解細胞中CDK2和/或CDK4的方法，該方法包括使細胞與具有式 (IA)、(IB) 或 (I) 的化合物（或本文揭露的其實施方式）接觸。在第一和第七方面的一個實施方式中，CDK2和/或CDK4在體外降解。在第一和第七方面的另一個實施方式中，CDK2和/或CDK4在體內降解。在第一和第七方面的又一個實施方式中，CDK2和/或CDK4在患者的細胞中降解。In an eighth aspect, a method for degrading CDK2 and/or CDK4 in a cell via the ubiquitin proteasome pathway is provided, the method comprising contacting the cell with a compound of Formula (IA), (IB), or (I) (or an embodiment thereof disclosed herein). In one embodiment of the first and seventh aspects, CDK2 and/or CDK4 is degraded in vitro. In another embodiment of the first and seventh aspects, CDK2 and/or CDK4 is degraded in vivo. In yet another embodiment of the first and seventh aspects, CDK2 and/or CDK4 is degraded in cells of a patient.

令人驚訝的是，發現靶向含有-Z-alk-Ar¹-連接基的CDK的PROTAC選擇性地降解CDK2和CDK4，而不是CDK1和/或CDK6。Surprisingly, we found that PROTACs targeting CDKs containing a -Z-alk-Ar¹ -linker selectively degraded CDK2 and CDK4, but not CDK1 and/or CDK6.

在涉及癌症治療的上述方面，提供了另外的實施方式，包括將第一方面的化合物和具有式 (I) 的化合物或其藥學上可接受的鹽（或本文揭露的其任何實施方式）或第三方面的藥物組成物與至少一種另外的抗癌劑組合投與。當使用組合療法時，可以同時地或依序地投與該等藥劑。In the aforementioned aspects related to cancer treatment, additional embodiments are provided, comprising administering a compound of the first aspect and a compound of Formula (I) or a pharmaceutically acceptable salt thereof (or any embodiment thereof disclosed herein), or a pharmaceutical composition of the third aspect, in combination with at least one additional anticancer agent. When using combination therapy, the agents may be administered simultaneously or sequentially.

相關申請的交叉引用本PCT國際專利申請要求2023年11月27日提交的美國臨時申請案號63/603,095、2023年12月18日提交的美國臨時申請案號63/611,727、以及2024年3月11日提交的美國臨時申請案號63/563,922的權益；將該等申請中之每一個的全部內容藉由引用特此併入。CROSS-REFERENCE TO RELATED APPLICATIONS This PCT international patent application claims the benefit of U.S. Provisional Application No. 63/603,095 filed on November 27, 2023, U.S. Provisional Application No. 63/611,727 filed on December 18, 2023, and U.S. Provisional Application No. 63/563,922 filed on March 11, 2024; the entire contents of each of which are hereby incorporated by reference.

定義： 除非另有說明，否則在本說明書和申請專利範圍中使用的以下術語係出於本申請的目的而被定義並且具有以下含義：Definitions:Unless otherwise indicated, the following terms used in this specification and claims are defined for purposes of this application and have the following meanings:

除非另有說明，否則以「ene」結尾的術語係指相應單價基團的二價基團。例如，伸烷基係烷基的二價基團，伸烯基係烯基的二價基團，雜亞環基係雜環基的二價基團。Unless otherwise specified, terms ending in "ene" refer to the divalent radical of the corresponding monovalent radical. For example, alkylene is a divalent radical of an alkyl group, alkenylene is a divalent radical of an alkenyl group, and heterocycloene is a divalent radical of a heterocyclo group.

「烷基」意指具有一至六個碳原子的直鏈或支鏈飽和單價烴基，例如甲基、乙基、丙基、2-丙基、丁基、戊基等。"Alkyl" refers to a straight or branched chain saturated monovalent hydrocarbon group having one to six carbon atoms, for example, methyl, ethyl, propyl, 2-propyl, butyl, pentyl, etc.

「烯基」意指含有雙鍵的具有二至六個碳原子的直鏈或支鏈單價烴基，例如乙烯基、丙烯基、2-丙烯基、丁烯基、戊烯基等。"Alkenyl" refers to a straight or branched monovalent hydrocarbon group having two to six carbon atoms and containing a double bond, for example, ethenyl, propenyl, 2-propenyl, butenyl, pentenyl, etc.

「炔基」意指含有三鍵的具有二至六個碳原子的直鏈或支鏈單價烴基，例如乙炔基、丙炔基、2-丙炔基、丁炔基等。"Alkynyl" refers to a straight or branched monovalent hydrocarbon group containing three bonds and having two to six carbon atoms, for example, ethynyl, propynyl, 2-propynyl, butynyl, etc.

除非另有說明，否則「伸烷基」意指具有一至六個碳原子的直鏈或支鏈飽和二價烴基。當伸烷基含有三至六個碳原子時，它在本文中也被稱為C3至C6伸烷基。實例包括但不限於亞甲基、伸乙基、亞丙基、1-甲基亞丙基、2-甲基亞丙基、亞丁基、亞戊基等。Unless otherwise specified, "alkylene" refers to a straight or branched saturated divalent hydrocarbon radical having one to six carbon atoms. When an alkylene radical contains three to six carbon atoms, it is also referred to herein as a C3 to C6 alkylene radical. Examples include, but are not limited to, methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, and pentylene.

「伸炔基」意指含有三鍵的具有二至六個碳原子的直鏈或支鏈二價烴基，例如、等。"Alkyne" refers to a straight or branched divalent hydrocarbon radical containing two to six carbon atoms and containing a triple bond, for example 、 wait.

「烷氧基」意指-OR^p基團（其中R^p係如上所定義的烷基），例如甲氧基、乙氧基、丙氧基或2-丙氧基、正丁氧基、異丁氧基或三級丁氧基等。"Alkoxy" refers to a -OR^p group (wherein R^p is an alkyl group as defined above), such as methoxy, ethoxy, propoxy or 2-propoxy, n-butoxy, isobutoxy or tert-butoxy.

「烷氧基羰基」或「烷基氧基羰基」意指-C(O)OR^p基團（其中R^p係如上所定義的烷基），例如甲氧基羰基、乙氧基羰基等。"Alkoxycarbonyl" or "alkyloxycarbonyl" refers to a -C(O)OR^p group (wherein R^p is alkyl as defined above), for example, methoxycarbonyl, ethoxycarbonyl, and the like.

「烷基羰基胺基」意指-NR^p’C(O)R^p基團（其中R^p係烷基，並且R^p’係H或烷基，如上所定義），例如甲基羰基胺基、乙基羰基胺基等。"Alkylcarbonylamino" refers to a^-NRp'C (O)^Rp group (wherein^Rp is alkyl and^Rp ' is H or alkyl, as defined above), for example, methylcarbonylamino, ethylcarbonylamino, and the like.

「烷基羰基」意指-C(O)R^p基團（其中R^p如本文所定義），例如甲基羰基、乙基羰基等。"Alkylcarbonyl" means a -C(O)R^p group (wherein R^p is as defined herein), for example, methylcarbonyl, ethylcarbonyl, and the like.

「胺基」意指-NH₂。"Amine" refers to_-NH2 .

「胺基羰基」意指-C(O)NH₂。"Aminocarbonyl" refers to -C(O)_NH2 .

「烷基胺基羰基」意指-C(O)NHR^p基團（其中R^p係如上所定義的烷基），例如甲基胺基羰基、乙基胺基羰基、丙基胺基羰基等。"Alkylaminocarbonyl" refers to a -C(O)NHR^p group (wherein R^p is alkyl as defined above), for example, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and the like.

「烷基羰基胺基」意指-NHC(O)R^p基團（其中R^p係如上所定義的烷基），例如甲基羰基胺基、乙基羰基胺基、丙基羰基胺基等。"Alkylcarbonylamino" refers to a -NHC(O)^Rp group (wherein^Rp is an alkyl group as defined above), for example, methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, and the like.

「烷基磺醯基」意指-NHS(O)₂R^p基團（其中R^p係如上所定義的烷基），例如甲磺醯基胺基、乙磺醯基胺基等。"Alkylsulfonyl" refers to a -NHS(O)₂ R^p group (wherein R^p is an alkyl group as defined above), for example, methanesulfonylamino, ethylsulfonylamino, and the like.

「二烷基胺基羰基」意指-C(O)NR^p1R^p基團（其中R^p和R^p1獨立地是如上所定義的烷基），例如二甲基胺基羰基、二乙基胺基羰基、二丙基胺基羰基等。"Dialkylaminocarbonyl" refers to a -C(O)NR^p1 R^p group (wherein R^p and R^p1 are independently alkyl as defined above), for example, dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, and the like.

「烷基胺基」意指-NHR^p基團（其中R^p係如上所定義的烷基），例如甲基胺基、乙基胺基、丙基胺基等。"Alkylamino" refers to a^-NHRp group (wherein^Rp is an alkyl group as defined above), for example, methylamino, ethylamino, propylamino, and the like.

「芳基」意指具有6至10個環原子的單價單環或雙環芳香族烴基，例如苯基或萘基。"Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 ring atoms, such as phenyl or naphthyl.

「伸芳基」意指二價芳基（如上所定義），例如伸苯基或伸萘基。"Arylene" means a divalent aromatic radical (as defined above), such as phenylene or naphthylene.

「芳基氧基」意指-O-R^p基團（其中R^p係如上所定義的芳基），例如 苯基氧基（或苯氧基）或萘基氧基。"Aryloxy" means a -OR^p group (wherein R^p is aryl as defined above), for example, phenyloxy (or phenoxy) or naphthyloxy.

除非另有說明，否則「雙環雜亞環基」意指具有8至12個環原子的飽和二價稠合雙環基團，其中一個、兩個或三個環原子係獨立地選自N、NH、O和S(O)_n（其中n係選自0至2的整數）的雜原子，其餘環原子係碳。另外，雙環雜亞環基環的一或兩個環碳原子可以視需要地被-CO-基團替代。更明確地，術語雙環雜亞環基包括但不限於異吲哚啉-二基、十氫-2,6-㖠啶-二基、八氫環戊[c]吡咯-二基、八氫-1H-吡咯并[3,4-c]吡啶-二基、六氫呋喃并[3,2-b]呋喃-3,6-二基等。當雜亞環基環不飽和時，它可以含有一或兩個環雙鍵，前提係該環不是芳香族的。Unless otherwise specified, "bicyclic heterocycloalkylene" refers to a saturated divalent fused bicyclic group having 8 to 12 ring atoms, wherein one, two, or three of the ring atoms are heteroatoms independently selected from N, NH, O, and S(O)_n (wherein n is an integer selected from 0 to 2), and the remaining ring atoms are carbon. In addition, one or two carbon atoms of the bicyclic heterocycloalkylene ring may be optionally replaced by a -CO- group. More specifically, the term bicyclic heterocycloalkylene includes, but is not limited to, isoindoline-diyl, decahydro-2,6-oxidine-diyl, octahydrocyclopenta[c]pyrrol-diyl, octahydro-1H-pyrrolo[3,4-c]pyridine-diyl, hexahydrofuro[3,2-b]furan-3,6-diyl, and the like. When the heterocycloalkylene ring is unsaturated, it may contain one or two cyclodouble bonds, provided that the ring is not aromatic.

「橋接環烷基」意指具有5至8個環碳環原子的飽和單價雙環，其中兩個不相鄰的環原子藉由(CR^pR^p’)_n基團（在本文中也可以被稱為「橋接」基團）連接，其中n係選自1至3的整數並且R^p和R^p’獨立地是H或甲基。實例包括但不限於雙環[1.1.1]戊-1-基、雙環[2.2.1]庚基，較佳的是雙環[2.2.1]庚-2-基等。"Bridged cycloalkyl" refers to a saturated monovalent bicyclic ring having 5 to 8 carbon ring atoms, wherein two non-adjacent ring atoms are linked by a (^CRpRp ')_n group (also referred to herein as a^" bridging" group), where n is an integer selected from 1 to 3 and^Rp and^Rp ' are independently H or methyl. Examples include, but are not limited to, bicyclo[1.1.1]pentan-1-yl, bicyclo[2.2.1]heptyl, preferably bicyclo[2.2.1]hept-2-yl, and the like.

「橋接雜環基」意指具有5至9個環碳環原子的飽和單價雙環，其中兩個不相鄰的環原子藉由(CR^pR^p’)_n基團（在本文中也可以被稱為「橋接」基團）連接，其中n係選自1至3的整數並且R^p和R^p’獨立地是H或甲基，並且進一步地，其中一或兩個環碳原子（包括橋接基團中的原子）被選自N、NH、O和S(O)_n（其中n係選自0至2的整數）的雜原子替代。除非另有說明，否則橋接雜環基視需要地被一或兩個獨立地選自烷基、鹵代、烷氧基、羥基和氰基的取代基取代。實例包括但不限於3,8-二氮雜雙環[3.2.1]辛烷基、7-氧雜雙環[2.2.1]庚烷基、2,5-二氮雜雙環[2.2.1]庚烷基、3,6-二氮雜雙環-[3.1.1]庚烷基、2,5-二氮雜雙環[2.2.2]辛烷基、3,8-二氮雜雙環[3.2.1]辛烷基、6-氮雜雙環[3.1.1]庚烷基、8-氮雜雙環[3.2.1]辛烷基等。"Bridged heterocyclic group" means a saturated monovalent bicyclic ring having 5 to 9 ring carbon atoms, wherein two non-adjacent ring atoms are linked by a (^CRpRp' )_n group (also referred to herein as a "bridging" group), wherein n is an integer selected from 1 to 3 and^Rp and^Rp ' are independently H or methyl, and further wherein one or two ring carbon atoms (including atoms in the bridging group) are replaced by a heteroatom selected from N, NH, O, and S(O)_n (wherein n is an integer selected from 0 to 2). Unless otherwise specified, a bridged heterocyclic group is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano. Examples include, but are not limited to, 3,8-diazabicyclo[3.2.1]octanyl, 7-oxabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 3,6-diazabicyclo-[3.1.1]heptyl, 2,5-diazabicyclo[2.2.2]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 6-azabicyclo[3.1.1]heptyl, 8-azabicyclo[3.2.1]octanyl, and the like.

「橋接雜亞環基」意指具有5至9個環碳環原子的飽和二價雙環，其中兩個不相鄰的環原子藉由(CR^pR^p’)_n基團（在本文中也可以被稱為「橋接」基團）連接，其中n係選自1至3的整數並且R^p和R^p’獨立地是H或甲基，並且進一步地，其中一或兩個環碳原子（包括橋接基團中的原子）被選自N、NH、O和S(O)_n（其中n係選自0至2的整數）的雜原子替代。除非另有說明，否則橋接雜亞環基視需要地被一或兩個獨立地選自烷基、鹵代、烷氧基、羥基和氰基的取代基取代。實例包括但不限於3,8-二氮雜雙環[3.2.1]辛烷-3,8-二基、7-氧雜雙環[2.2.1]庚烷-二基、2,5-二氮雜雙環[2.2.1]庚烷-二基、3,6-二氮雜雙環[3.1.1]庚烷-二基、2,5-二氮雜雙環[2.2.2]辛烷-二基、3,8-二氮雜雙環[3.2.1]辛烷-二基、6-氮雜雙環[3.1.1]庚烷-二基、8-氮雜雙環[3.2.1]辛烷-二基等。"Bridged heterocycloalkylene" means a saturated divalent bicyclic ring having 5 to 9 ring carbon atoms, wherein two non-adjacent ring atoms are linked by a (^CRpRp' )_n group (also referred to herein as a "bridging" group), wherein n is an integer selected from 1 to 3 and^Rp and^Rp ' are independently H or methyl, and further wherein one or two ring carbon atoms (including atoms in the bridging group) are replaced by a heteroatom selected from N, NH, O, and S(O)_n (wherein n is an integer selected from 0 to 2). Unless otherwise specified, the bridged heterocycloalkylene group is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano. Examples include, but are not limited to, 3,8-diazabicyclo[3.2.1]octane-3,8-diyl, 7-oxabicyclo[2.2.1]heptane-diyl, 2,5-diazabicyclo[2.2.1]heptane-diyl, 3,6-diazabicyclo[3.1.1]heptane-diyl, 2,5-diazabicyclo[2.2.2]octane-diyl, 3,8-diazabicyclo[3.2.1]octane-diyl, 6-azabicyclo[3.1.1]heptane-diyl, 8-azabicyclo[3.2.1]octane-diyl, and the like.

「環烷基」意指具有三至十個碳原子的單環飽和單價烴基。實例包括但不限於環丙基、環丁基、環戊基、環己基等。"Cycloalkyl" refers to a monocyclic, saturated, monovalent hydrocarbon radical having three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

「環烷基烷基」意指被如上所定義的環烷基取代的如上所定義的烷基基團。實例包括但不限於環丙基甲基、環丙基乙基、環丁基甲基、環丁基乙基、環戊基甲基、環戊基乙基、環己基甲基、環己基乙基等。"Cycloalkylalkyl" means an alkyl group as defined above substituted with a cycloalkyl group as defined above. Examples include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, and the like.

「環烷基氧基或環烷氧基」意指-OR^p基團（其中R^p係如上所定義的環烷基）。實例包括但不限於環丙基氧基、環丁基氧基、環戊基氧基、環己基氧基等。"Cycloalkyloxy" or "cycloalkoxy" refers to a -OR^p group (wherein R^p is a cycloalkyl group as defined above). Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

「環伸烷基」意指具有三至六個碳原子的二價飽和烴基，另外例如，1,1-環亞丙基、1,1-環亞丁基、1,4-環亞己基等。The term "cycloalkylene" refers to a divalent saturated alkyl group having three to six carbon atoms, and examples thereof include 1,1-cyclopropylene, 1,1-cyclobutylene, and 1,4-cyclohexylene.

「羰基」意指-C(O)-。"Carbonyl" refers to -C(O)-.

「羧基」意指-COOH。"Carboxyl" refers to -COOH.

「環胺基」意指具有4至8個環原子的飽和單價單環，其中一或兩個環原子係氮，其餘環原子係碳。更明確地，術語環胺基包括但不限於吡咯啶基、哌啶基、哌𠯤基等。"Cycloamino" refers to a saturated monovalent monocyclic ring having 4 to 8 ring atoms, one or two of which are nitrogen and the remaining ring atoms are carbon. More specifically, the term cycloamino includes, but is not limited to, pyrrolidinyl, piperidinyl, and piperonyl.

「環亞胺基」意指具有4至8個環原子的飽和二價單環，其中一或兩個環原子係氮，其餘環原子係碳。更明確地，術語環亞胺基包括但不限於亞吡咯啶基、亞哌啶基、高亞哌啶基、亞哌𠯤基等。"Cycloimino" refers to a saturated bivalent monocyclic ring having 4 to 8 ring atoms, one or two of which are nitrogen and the remaining ring atoms are carbon. More specifically, the term cycloimino includes, but is not limited to, pyrrolidinylene, piperidinylene, homopiperidinylene, and piperidineylene.

「氰基烷基」意指被氰基取代的如上所定義的烷基，例如氰基甲基、氰基乙基等。"Cyanoalkyl" refers to an alkyl group as defined above substituted with a cyano group, for example, cyanomethyl, cyanoethyl, and the like.

「氰基烷基氧基」意指-OR^p基團（其中R^p係如上所定義的氰基烷基），例如氰基甲基氧基、氰基乙基氧基等。"Cyanoalkyloxy" refers to a -OR^p group (wherein R^p is cyanoalkyl as defined above), for example, cyanomethyloxy, cyanoethyloxy, and the like.

「氘」意指²H或D。"Deuterium" means^2H or D.

「二烷基胺基」意指-NR^pR^p基團（其中每個R^p係如上所定義的烷基並且被獨立地選擇），例如二甲基胺基、甲基乙基胺基、正丙基甲基胺基、2-丙基甲基胺基、正丁基甲基胺基、異丁基甲基胺基或三級丁基甲基胺基等。"^Dialkylamino " refers to a^-NRpRp group (wherein each^Rp is an alkyl group as defined above and is independently selected), for example, dimethylamino, methylethylamino, n-propylmethylamino, 2-propylmethylamino, n-butylmethylamino, isobutylmethylamino, or tert-butylmethylamino.

除非另有說明，否則「稠合雜環基」意指單價雙環，其中具有4至7個環原子、具有一或兩個獨立地選自N、NH、O和S(O)n（其中n係0、1或2）的雜原子並且其餘環原子係碳的飽和單環的兩個相鄰環原子與苯基或者五員或六員雜芳基（各自如本文所定義）的兩個相鄰環成員稠合。氮原子視需要地被氧化，並且進一步地，其中飽和單環的碳環原子之一視需要地被-C(=O)-基團替代。代表性實例包括但不限於1,2,3,4-四氫喹啉基、3,4-二氫-2H-苯并[b][1,4]㗁𠯤基、3,4-二氫-2H-吡啶并[3,2-b][1,4]㗁𠯤基、4,5,6,7-四氫吡唑并[1,5-a]吡𠯤基等。Unless otherwise indicated, "fused heterocyclic group" means a monovalent bicyclic ring having 4 to 7 ring atoms, one or two heteroatoms independently selected from N, NH, O, and S(O)n (where n is 0, 1, or 2), and wherein the remaining ring atoms are carbon, and two adjacent ring atoms of a saturated monocyclic ring are fused to two adjacent ring members of a phenyl group or a five-membered or six-membered heteroaryl group (each as defined herein). The nitrogen atom is optionally oxidized, and further, one of the carbon ring atoms of the saturated monocyclic ring is optionally replaced by a -C(=O)- group. Representative examples include, but are not limited to, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazolyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrrolidyl, and the like.

除非另有說明，否則「稠合雜亞環基」意指二價雙環，其中具有4至7個環原子、具有一或兩個獨立地選自N、NH、O和S(O)n（其中n係0、1或2）的雜原子並且其餘環原子係碳的飽和單環的兩個相鄰環原子與苯基或者五員或六員雜芳基（各自如本文所定義）的兩個相鄰環成員稠合。氮原子視需要地被氧化，並且進一步地，其中飽和單環的碳環原子之一視需要地被-C(=O)-基團替代。稠合雜亞環基可以附接至環的任何兩個原子上。代表性實例包括但不限於1,2,3,4-四氫喹啉-1,4-二基、3,4-二氫-2H-苯并[b][1,4]㗁𠯤-5,8-二基、3,4-二氫-2H-吡啶并[3,2-b][1,4]㗁𠯤-二基、4,5,6,7-四氫吡唑并[1,5-a]吡𠯤-二基等。Unless otherwise indicated, "fused heterocycloalkylene" refers to a divalent bicyclic ring having 4 to 7 ring atoms, one or two heteroatoms independently selected from N, NH, O, and S(O)n (where n is 0, 1, or 2), and wherein two adjacent ring atoms of a saturated monocyclic ring whose remaining ring atoms are carbon are fused to two adjacent ring members of a phenyl group or a five-membered or six-membered heteroaryl group (each as defined herein). The nitrogen atom is optionally oxidized, and further, one of the carbon ring atoms of the saturated monocyclic ring is optionally replaced by a -C(=O)- group. The fused heterocycloalkylene group may be attached to any two atoms of the ring. Representative examples include, but are not limited to, 1,2,3,4-tetrahydroquinolin-1,4-diyl, 3,4-dihydro-2H-benzo[b][1,4]oxathiol-5,8-diyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxathiol-diyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-diyl, and the like.

「鹵代」意指氟、氯、溴或碘，例如氟或氯。"Halogenated" means fluoro, chloro, bromo or iodo, for example fluoro or chloro.

「鹵代烷基」意指被一或多個鹵素原子（例如一至五個鹵素原子，如氟或氯）取代的如上所定義的烷基基團，包括被不同鹵素取代的那些，例如-CH₂Cl、-CF₃、-CHF₂、-CH₂CF₃、-CF₂CF₃、-CF(CH₃)₂等。當烷基僅被氟取代時，它在本申請中可以被稱為氟烷基。"Haloalkyl" means an alkyl group as defined above substituted with one or more halogen atoms (e.g., one to five halogen atoms, such as fluorine or_chlorine ), including those substituted with different halogens, such as_-CH2Cl ,_-CF3 ,_-CHF2 ,_-CH2CF3 ,_-CF2CF3 , -CF(_CH3 )₂ , etc. When an alkyl_group is substituted only with fluorine, it may be referred to herein as a fluoroalkyl group.

「鹵代烷氧基」意指-OR^p基團（其中R^p係如上所定義的鹵代烷基），例如-OCF₃、-OCHF₂等。當R^p係鹵代烷基（其中烷基僅被氟（在一些實例中，一或多個氟）取代）時，它在本申請中被稱為氟烷氧基。"Haloalkoxy" refers to a^-ORp group (wherein^Rp is a haloalkyl group as defined above), for example,_-OCF3 ,_-OCHF2 , etc. When^Rp is a haloalkyl group (wherein the alkyl group is substituted only with fluorine (in some instances, one or more fluorine groups)), it is referred to herein as a fluoroalkoxy group.

除非另有說明，否則「雜芳基」意指具有5至10個環原子的單價單環或稠合雙環芳香族基團，其中一或多個（在一個實施方式中，一個、兩個或三個）環原子係選自N、NH、O和S的雜原子，其餘環原子係碳。代表性實例包括但不限於吡咯基、噻吩基、噻唑基、咪唑基、呋喃基、吲哚基、異吲哚基、吲唑基、咪唑并[1,2-a]吡啶基、咪唑并[1,2-a]吡𠯤基、㗁唑基、異㗁唑基、㗁二唑基、苯并噻唑基、苯并㗁唑基、喹啉基、異喹啉基、吡啶基、嘧啶基、吡𠯤基、嗒𠯤基、三唑基、四唑基等。如本文所定義，術語「雜芳基」和「芳基」係相互排斥的。當雜芳基環含有5個或6個環原子並且係單環時，它在本文中也被稱為「五員或六員」或「5員或6員」單環雜芳基或者「5員或6員雜芳基」。當雜芳基環含有9個或10個環原子時，它在本文中也被稱為9員或10員稠合雙環雜芳基。Unless otherwise indicated, "heteroaryl" means a monovalent monocyclic or fused bicyclic aromatic group having 5 to 10 ring atoms, wherein one or more (in one embodiment, one, two or three) of the ring atoms are heteroatoms selected from N, NH, O and S, and the remaining ring atoms are carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, indazolyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, triazolyl, tetrazolyl, etc. As defined herein, the terms "heteroaryl" and "aryl" are mutually exclusive. When the heteroaryl ring contains 5 or 6 ring atoms and is monocyclic, it is also referred to herein as a "five- or six-membered" or "five- or six-membered" monocyclic heteroaryl or a "five- or six-membered heteroaryl." When the heteroaryl ring contains 9 or 10 ring atoms, it is also referred to herein as a nine- or ten-membered fused bicyclic heteroaryl.

除非另有說明，否則「5員雜芳基^A」意指具有5個環原子的單環芳香族基團，其中一或兩個環原子係氮，其餘環原子係碳。代表性實例包括但不限於吡咯基、咪唑基、吡唑基等。如本文所定義，術語「雜芳基」和「芳基」係相互排斥的。Unless otherwise indicated, "5-membered heteroaryl^A " refers to a monocyclic aromatic group having five ring atoms, one or two of which are nitrogen and the remaining carbon atoms. Representative examples include, but are not limited to, pyrrolyl, imidazolyl, and pyrazolyl. As defined herein, the terms "heteroaryl" and "aryl" are mutually exclusive.

除非另有說明，否則「雜伸芳基」意指如上所定義的二價雜芳基基團。代表性實例包括但不限於苯并咪唑二基，例如苯并咪唑-1,5-二基等。當雜伸芳基環含有5個或6個環原子並且係單環時，它在本文中也被稱為「單環雜伸芳基」或「5員或6員單環雜伸芳基」，例如吡唑基-二基（吡唑基-1.3-二基、吡唑基-1.4-二基、吡唑基-1.5-二基等）和咪唑-二基（咪唑-1,2-二基、咪唑-1,4-二基、咪唑-1,5-二基）。當雜伸芳基環含有9個或10個環原子並且係稠合雙環時，它在本文中也被稱為9員或10員稠合雙環雜伸芳基。Unless otherwise specified, "heteroaryl" refers to a divalent heteroaryl group as defined above. Representative examples include, but are not limited to, benzimidazole-1,5-diyl. When the heteroaryl ring contains 5 or 6 ring atoms and is monocyclic, it is also referred to herein as a "monocyclic heteroaryl" or "5- or 6-membered monocyclic heteroaryl," such as pyrazolyl-1,3-diyl, pyrazolyl-1,4-diyl, pyrazolyl-1,5-diyl, etc. and imidazole-1,2-diyl, imidazole-1,4-diyl, imidazole-1,5-diyl. When the heteroaryl ring contains 9 or 10 ring atoms and is a fused bicyclic ring, it is also referred to herein as a 9-membered or 10-membered fused bicyclic heteroaryl.

「雜環基^A」意指具有五個或六個環原子的飽和單環，其中一或兩個環原子選自N、NH、O、S(O)_n（其中n係選自0至2的整數），其餘環原子係C。另外，雜環基^A環中之一或兩個環碳原子可以視需要地被-C(=O)-基團替代。代表性實例包括但不限於、、、、、、、、、和。"Heterocyclic group^A " means a saturated monocyclic ring having five or six ring atoms, wherein one or two ring atoms are selected from N, NH, O, S(O)_n (wherein n is an integer selected from 0 to 2), and the remaining ring atoms are C. In addition, one or two ring carbon atoms in the heterocyclic group^A ring may be optionally replaced by a -C(=O)- group. Representative examples include, but are not limited to 、 、 、 、 、 、 、 、 、 and .

除非另有說明，否則「雜環基」意指具有4至8個環原子的飽和單價單環基團，其中一或兩個環原子係獨立地選自N、NH、O和S(O)_n（其中n係選自0至2的整數）的雜原子，其餘環原子係C。另外，雜亞環基環中之一或兩個環碳原子可以視需要地被-C(=O)-基團替代。更明確地，術語雜環基包括但不限於氧環丁烷基、哌啶基、哌𠯤基、吡咯啶基、四氫吖唉基等。Unless otherwise indicated, "heterocyclyl" refers to a saturated monovalent monocyclic group having 4 to 8 ring atoms, wherein one or two ring atoms are independently selected from N, NH, O, and S(O)_n (where n is an integer selected from 0 to 2), and the remaining ring atoms are C. In addition, one or two ring carbon atoms in the heterocyclyl ring may be optionally replaced by a -C(=O)- group. More specifically, the term heterocyclyl includes, but is not limited to, oxetane, piperidinyl, piperonyl, pyrrolidinyl, tetrahydroazolidinyl, and the like.

「雜環基羰基」意指-C(O)R基團（其中R係如本文所定義的雜環基）。更明確地，術語雜環基包括但不限於哌啶基羰基、哌𠯤基羰基、吡咯啶基羰基、四氫吖唉基羰基等。"Heterocyclocarbonyl" means a -C(O)R radical (wherein R is a heterocyclo as defined herein). More specifically, the term heterocyclo includes, but is not limited to, piperidinylcarbonyl, piperonylcarbonyl, pyrrolidinylcarbonyl, tetrahydroazolidinylcarbonyl, and the like.

「雜環基氧基」意指-OR基團（其中R係如本文所定義的雜環基）。更明確地，術語雜環基包括但不限於哌啶基氧基、哌𠯤基氧基、吡咯啶基氧基、四氫吖唉基氧基等。"Heterocyclooxy" refers to an -OR group (wherein R is a heterocyclo as defined herein). More specifically, the term heterocyclo includes, but is not limited to, piperidinyloxy, piperonyloxy, pyrrolidinyloxy, tetrahydroazolyloxy, and the like.

除非另有說明，否則「雜亞環基」意指具有4至8個環原子的飽和二價單環基團，其中一或兩個環原子係獨立地選自N、NH、O和S(O)_n（其中n係選自0至2的整數）的雜原子，其餘環原子係C。另外，雜亞環基環中之一或兩個環碳原子可以視需要地被-C(=O)-基團替代。更明確地，術語雜亞環基包括但不限於、哌啶-1,4-二基、四氫吖唉-1,3-二基等。Unless otherwise specified, "heterocycloalkyl" refers to a saturated bivalent monocyclic group having 4 to 8 ring atoms, wherein one or two ring atoms are heteroatoms independently selected from N, NH, O, and S(O)_n (wherein n is an integer selected from 0 to 2), and the remaining ring atoms are C. In addition, one or two ring carbon atoms in the heterocycloalkyl ring may be optionally replaced by a -C(=O)- group. More specifically, the term heterocycloalkyl includes but is not limited to , piperidine-1,4-diyl, tetrahydroacryl-1,3-diyl, etc.

「C₃至C₆雜伸烷基」意指具有三至六個碳原子的直鏈或支鏈飽和二價烴基，其中 (a) 該二價烴基的直鏈部分的一個碳原子被X^a（其中X^a係-O-、-S-、-SO-、-SO₂-、-CO-或-NR^q-）替代，或 (b) 該二價烴基的直鏈部分的兩個相鄰碳原子被X^a1（其中X^a1係-NR^qCO-、-CONR^q-、-NR^qSO-、-SONR^q-、-NR^qSO₂-或-SO₂NR^q-（其中每個R^q係氫、烷基、烷基羰基或烷基磺醯基））替代，並且此外，上述 (a) 和 (b) 的C₃至C₆雜伸烷基的直鏈部分中不與X^a和X^a1相鄰的另外的碳原子可以被X^y（其中X^y係-O-或-NR^q1-（其中每個R^q1係氫、烷基、烷基羰基或烷基磺醯基））替代，條件係附接Z和Ar的C₃至C₆雜伸烷基的直鏈部分含有至少三個原子。為了清楚起見，如在本定義中使用的，C₃至C₆雜伸烷基的直鏈部分意指連接Z和Ar的C₃至C₆雜伸烷基的連續原子，例如，在結構中，帶有*的原子形成C₅雜伸烷基的直鏈部分。當C₃至C₆雜伸烷基僅含有一或兩個-O-時，它在本文中可以被稱為「側氧基伸烷基」。當C₃至C₆雜伸烷基僅含有一或兩個-NR^q-和/或-NR^q1-時，它在本文中可以被稱為「胺基伸烷基」。當C₃至C₆雜伸烷基僅含有-S-時，它在本文中可以被稱為「氫硫基伸烷基」。當C₃至C₆雜伸烷基僅含有-SO-時，它在本文中可以被稱為「亞磺醯基伸烷基」。當C₃至C₆雜伸烷基僅含有-SO₂-時，它在本文中可以被稱為「磺醯基伸烷基」。C₃至C₆雜伸烷基的代表性實例包括例如等。“C₃ to C₆ heteroaryl” means a straight or branched saturated divalent hydrocarbon group having three to six carbon atoms, wherein (a) one carbon atom of the straight chain portion of the divalent hydrocarbon group is replaced by X^a (wherein X^a is -O-, -S-, -SO-, -SO₂ -, -CO-, or -NR^q -), or (b) two adjacent carbon atoms of the straight chain portion of the divalent hydrocarbon group are replaced by X^a1 (wherein X^a1 is -NR^q CO-, -CONR^q -, -NR^q SO-, -SONR^q -, -NR^q SO₂ -, or -SO₂ NR^q - (wherein each R^q is hydrogen, alkyl, alkylcarbonyl, or alkylsulfonyl)), and further, the C₃ to C 6 heteroaryl groups in the above (a) and (b) are substituted by X a1. Additional carbon atoms in the linear portion of the_{C3 to C6} heteroalkyl group that are not adjacent to^Xa and^Xa1 may be replaced by^Xy (wherein^Xy is -O- or^-NRq1- (wherein each^Rq1 is hydrogen, alkyl, alkylcarbonyl or alkylsulfonyl)), provided that the linear portion of the_C3 to_C6 heteroalkyl group attached to Z and Ar contains at least three atoms. For clarity, as used in this definition, the linear portion of the_C3 to_C6 heteroalkyl group means the consecutive atoms of the_C3 to_C6 heteroalkyl group connecting Z and Ar, for example, in the structure In the examples, the atoms marked with * form the linear portion of the_C5 heteroalkylene group. When the_C3 to_C6 heteroalkylene group contains only one or two -O- groups, it may be referred to herein as a "penoxyalkylene group." When the_C3 to_C6 heteroalkylene group contains only one or two^-NRq- and/or^-NRq1- groups, it may be referred to herein as an "aminoalkylene group." When the_C3 to_C6 heteroalkylene group contains only -S-, it may be referred to herein as a "thiothioalkylene group." When the_C3 to_C6 heteroalkylene group contains only -SO-, it may be referred to herein as a "sulfinylalkylene group." When_theC3 to C6 heteroalkylene group contains only_-SO2- , it may be referred to herein as a "sulfonylalkylene group." Representative examples of_C3 to_C6 heteroaryl groups include, for example wait.

「伸苯基」意指二價苯基。"Phenylene" means a divalent phenyl group.

「部分飽和的9員或10員稠合雙環雜芳基」意指單價雙環，其中含有一或兩個氮環原子的五員或六員雜芳基環的兩個相鄰原子與具有5個或6個環原子的五員或六員環烷基或者五員或六員飽和環的兩個相鄰原子稠合，其中一個、兩個或三個環原子係選自N和O的雜原子，其餘環原子係碳。部分飽和的9員或10員稠合雙環雜芳基經由稠合雙環雜芳基的雜芳基部分附接至式 (IA) 的-NH-。代表性實例包括但不限於5,6,7,8-四氫喹啉基、5,6,7,8-四氫喹唑啉基、5,6,7,8-四氫吡啶并[2,3-d]嘧啶基、7,8-二氫-5H-哌喃并[4,3-d]嘧啶基、3,4-二氫-2H-吡啶并[3,2-b][1,4]㗁𠯤基、4,5,6,7-四氫吡唑并[1,5-a]-吡𠯤基等。"Partially saturated 9- or 10-membered fused bicyclic heteroaryl" refers to a monovalent bicyclic ring in which two adjacent atoms of a 5- or 6-membered heteroaryl ring containing one or two nitrogen ring atoms are fused to two adjacent atoms of a 5- or 6-membered cycloalkyl group having 5 or 6 ring atoms, or a 5- or 6-membered saturated ring, wherein one, two, or three of the ring atoms are heteroatoms selected from N and O, and the remaining ring atoms are carbon. The partially saturated 9- or 10-membered fused bicyclic heteroaryl is attached to -NH- of Formula (IA) via the heteroaryl portion of the fused bicyclic heteroaryl. Representative examples include, but are not limited to, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidinyl, 7,8-dihydro-5H-pyrano[4,3-d]pyrimidinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]pyrimidinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrimidinyl, and the like.

如本文所用的短語「視需要地」或「視需要的」意指隨後描述的事件或情況可能但不必發生，並且該描述包括事件或情況發生的情形和事件或情況不發生的情形。例如，短語「視需要地被鹵代取代的伸烷基」旨在涵蓋未被鹵代取代的伸烷基和被鹵代取代的伸烷基。As used herein, the phrase "optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, the phrase "optionally halogenated alkylene" is intended to encompass both unhalogenated alkylene and halogenated alkylene.

「螺環烷基」意指具有三至十個碳原子的飽和雙環單價烴基，其中該等環僅藉由一個碳原子連接，並且其中該連接原子也稱為螺原子，最通常為四級碳（「螺碳」）。代表性實例包括但不限於螺[2.2]戊烷基、螺[2.5]辛烷基、螺[4.5]癸烷基、螺[5.5]十一烷基等。"Spirocycloalkyl" refers to a saturated bicyclic monovalent hydrocarbon radical having three to ten carbon atoms, wherein the rings are connected by only one carbon atom, and wherein the connecting atom is also called a spiro atom, most commonly a quaternary carbon ("spiro carbon"). Representative examples include, but are not limited to, spiro[2.2]pentanyl, spiro[2.5]octanyl, spiro[4.5]decanyl, spiro[5.5]undecyl, and the like.

「螺雜環基^A」意指具有9至10個環原子的飽和雙環，其中一個、兩個或三個環原子選自N、O、S(O)_n（其中n係選自0至2的整數），其餘環原子係C，並且該等環僅藉由一個原子連接，該連接原子也稱為螺原子，最通常為四級碳（「螺碳」）。另外，螺雜環基環中之一或兩個環碳原子可以視需要地被-C(=O)-基團替代。代表性實例包括但不限於和。"Spiroheterocyclyl^A " means a saturated bicyclic ring having 9 to 10 ring atoms, wherein one, two or three ring atoms are selected from N, O, S(O)_n (where n is an integer selected from 0 to 2), and the remaining ring atoms are C, and the rings are connected by only one atom, which is also called a spiro atom, most commonly a quaternary carbon ("spiro carbon"). In addition, one or two ring carbon atoms in the spiroheterocyclyl ring can be optionally replaced by a -C(=O)- group. Representative examples include, but are not limited to and .

「螺雜環基」意指具有6至10個環原子的飽和單價雙環，其中一個、兩個或三個環原子係選自N、O和S(O)_n（其中n係選自0至2的整數）的雜原子，其餘環原子係C，並且該等環僅藉由一個原子連接，該連接原子也稱為螺原子，最通常為四級碳（「螺碳」）。除非另有說明，否則螺雜亞環基視需要地被一或兩個獨立地選自烷基、鹵代、烷氧基、羥基和氰基的取代基取代。代表性實例包括但不限於2-氮雜螺[3.3]庚烷基、2,6-二氮雜螺[3.3]庚烷基、1,7-二氮雜螺[3.5]壬烷基、2,7-二氮雜螺[3.5]壬烷基、3,9-二氮雜螺[5.5]十一烷基等。"Spiroheterocyclyl" means a saturated monovalent bicyclic ring having 6 to 10 ring atoms, wherein one, two, or three of the ring atoms are heteroatoms selected from N, O, and S(O)_n (where n is an integer selected from 0 to 2), and the remaining ring atoms are C, and the rings are connected by only one atom, which is also called a spiro atom, most commonly a quaternary carbon ("spiro carbon"). Unless otherwise specified, a spiroheterocyclyl group is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano. Representative examples include, but are not limited to, 2-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 3,9-diazaspiro[5.5]undecyl, and the like.

「螺雜亞環基」意指具有6至10個環原子的飽和二價雙環，其中一個、兩個或三個環原子係選自N、O和S(O)_n（其中n係選自0至2的整數）的雜原子，其餘環原子係C，並且該等環僅藉由一個原子連接，該連接原子也稱為螺原子，最通常為四級碳（「螺碳」）。除非另有說明，否則螺雜亞環基視需要地被一或兩個獨立地選自烷基、鹵代、烷氧基、羥基和氰基的取代基取代。代表性實例包括但不限於2-氮雜螺[3.3]庚烷-二基、2,6-二氮雜螺[3.3]庚烷-二基、1,7-二氮雜螺[3.5]壬烷-二基、2,7-二氮雜螺[3.5]壬烷-二基、3,9-二氮雜螺[5.5]十一烷-二基等。"Spiroheterocycloalkylene" means a saturated bivalent ring having 6 to 10 ring atoms, wherein one, two, or three of the ring atoms are heteroatoms selected from N, O, and S(O)_n (where n is an integer selected from 0 to 2), and the remaining ring atoms are C, and the rings are connected by only one atom, which is also called a spiro atom, most commonly a quaternary carbon ("spiro carbon"). Unless otherwise specified, a spiroheterocycloalkylene group is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano. Representative examples include, but are not limited to, 2-diazaspiro[3.3]heptane-diyl, 2,6-diazaspiro[3.3]heptane-diyl, 1,7-diazaspiro[3.5]nonane-diyl, 2,7-diazaspiro[3.5]nonane-diyl, 3,9-diazaspiro[5.5]undecane-diyl, and the like.

除非另有說明，否則「不飽和雜環基^A」意指具有一或兩個雙鍵的、具有6至8個環原子的單環非芳香族基團，並且其中一或兩個環原子係獨立地選自N、O和S(O)_n（其中n係選自0至2的整數）的雜原子，其餘環原子係C。另外，雜環基環中之一或兩個環碳原子可以視需要地被-C(=O)-基團替代。代表性實例包括但不限於和。Unless otherwise specified, "unsaturated heterocyclic group^A " means a monocyclic non-aromatic group having one or two double bonds and 6 to 8 ring atoms, wherein one or two ring atoms are heteroatoms independently selected from N, O and S(O)_n (wherein n is an integer selected from 0 to 2), and the remaining ring atoms are C. In addition, one or two ring carbon atoms in the heterocyclic group may be optionally replaced by a -C(=O)- group. Representative examples include, but are not limited to and .

除非另有說明，否則「不飽和雜亞環基」意指具有一或兩個雙鍵的、具有6至8個環原子的二價單環非芳香族基團，並且其中一或兩個環原子係獨立地選自N、O和S(O)_n（其中n係選自0至2的整數）的雜原子，其餘環原子係C。另外，雜亞環基環中之一或兩個環碳原子可以視需要地被-C(=O)-基團替代。Unless otherwise specified, "unsaturated heterocycloalkylene" refers to a divalent monocyclic non-aromatic group having one or two double bonds and having 6 to 8 ring atoms, wherein one or two ring atoms are heteroatoms independently selected from N, O, and S(O)_n (wherein n is an integer selected from 0 to 2), and the remaining ring atoms are C. In addition, one or two ring carbon atoms in the heterocycloalkylene ring may be optionally replaced by a -C(=O)- group.

除非另有說明，否則「不飽和雜亞環基^X」意指具有一個、兩個或三個雙鍵的、具有5至8個環原子的二價單環非芳香族雜亞環基基團，並且其中一或兩個環原子係獨立地選自N、O和S(O)_n（其中n係選自0至2的整數）的雜原子，其餘環原子係C。另外，雜亞環基環中之一或兩個環碳原子可以視需要地被-C(=O)-基團替代。Unless otherwise specified, "unsaturated heterocycloalkylene^X " means a divalent monocyclic non-aromatic heterocycloalkylene group having 5 to 8 ring atoms and one, two or three double bonds, wherein one or two ring atoms are heteroatoms independently selected from N, O and S(O)_n (wherein n is an integer selected from 0 to 2), and the remaining ring atoms are C. In addition, one or two ring carbon atoms in the heterocycloalkylene ring may be optionally replaced by a -C(=O)- group.

本揭露還包括具有式 (I) 的化合物（或本文揭露的其任何實施方式）或其藥學上可接受的鹽的受保護的衍生物。例如，當具有式 (I) 的化合物含有基團（如羥基、羧基或含有氮原子的任何基團）時，該等基團可以被合適的保護基團保護。合適的保護基團的完整列表可以在以下文獻中找到：T.W.Greene,Protective Groups in Organic Synthesis[有機合成中的保護基團], 第5版, John Wiley & Sons, Inc. [約翰威利父子出版公司] (2014)，其揭露內容藉由引用以其全文併入本文。本揭露化合物的受保護的衍生物可以藉由本領域熟知的方法製備。The present disclosure also includes protected derivatives of compounds of Formula (I) (or any embodiment thereof disclosed herein) or pharmaceutically acceptable salts thereof. For example, when compounds of Formula (I) contain groups (such as hydroxyl groups, carboxyl groups, or any group containing a nitrogen atom), such groups may be protected by suitable protecting groups. A comprehensive list of suitable protecting groups can be found in TW Greene,Protective Groups in Organic Synthesis , 5th ed., John Wiley & Sons, Inc. (2014), the disclosure of which is incorporated herein by reference in its entirety. Protected derivatives of the disclosed compounds can be prepared by methods well known in the art.

本揭露還包括具有式 (I) 的化合物（或本文揭露的其任何實施方式）或其藥學上可接受的鹽的多晶型形式和氘代形式。The present disclosure also includes polymorphic forms and deuterated forms of the compound of Formula (I) (or any embodiment thereof disclosed herein) or a pharmaceutically acceptable salt thereof.

本揭露之某些化合物可以以互變異構物和/或幾何異構物存在。所有可能的互變異構物以及順式和反式異構物（作為單獨的形式及其混合物）都在本揭露之範圍之內。例如，具有羥基取代的吡啶基環的具有式 (IA)、(IB) 或 (I) 的化合物可以作為互變異構物存在，如下所示：Certain compounds disclosed herein may exist as tautomers and/or geometric isomers. All possible tautomers, as well as cis and trans isomers (as individual compounds and as mixtures thereof), are within the scope of this disclosure. For example, compounds of Formula (IA), (IB), or (I) having a hydroxyl-substituted pyridyl ring may exist as tautomers, as shown below:

術語「前驅藥」係指在體內變得更具活性的化合物。具有式 (I) 的某些化合物（以及本文揭露的其任何實施方式，包括特定的化合物）也可以作為前驅藥存在，如以下文獻中所述：Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology[藥物和前驅藥代謝中的水解：化學、生物化學和酶學]（Testa, Bernard和Mayer, Joachim M. Wiley-VHCA [威利-VHCA公司], 瑞士蘇黎世 2003）。本文所述之化合物的前驅藥係在生理條件下容易進行化學變化以提供活性化合物的化合物的結構修飾形式。因為在一些情況下前驅藥比化合物或母體藥物可能更容易投與，所以它們經常是有用的。例如，它們可以藉由口服投與而具有生物可利用性，然而母體藥物卻不行。本領域已知多種前驅藥衍生物，如依賴前驅藥的水解切割或氧化活化的那些。前驅藥的實例（而不限於）將是作為酯（「前驅藥」）投與的化合物，但是然後代謝水解為羧酸（活性實體）。另外的實例包括化合物的肽基衍生物。The term "prodrug" refers to a compound that becomes more active in the body. Certain compounds of Formula (I) (and any embodiments thereof disclosed herein, including specific compounds) may also exist as prodrugs, as described in: Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because, in some cases, they may be easier to administer than the compound or parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug is not. A variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound that is administered as an ester (the "prodrug") but then metabolically hydrolyzes to the carboxylic acid (the active entity). Additional examples include peptidyl derivatives of the compound.

化合物的「藥學上可接受的鹽」意指藥學上可接受的並且具有親體化合物的所希望的藥理學活性的鹽。此類鹽包括： 與無機酸（如鹽酸、氫溴酸、硫酸、硝酸、磷酸等）形成的酸加成鹽；或與有機酸（如甲酸、乙酸、丙酸、己酸、環戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、蘋果酸、順丁烯二酸、反丁烯二酸、酒石酸、檸檬酸、苯甲酸、3-(4-羥基苯甲醯基)苯甲酸、肉桂酸、苦杏仁酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羥基乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟腦磺酸、葡萄庚酸、4,4'-亞甲基雙-(3-羥基-2-烯-1-甲酸)、3-苯基丙酸、三甲基乙酸、三級丁基乙酸、月桂基硫酸、葡糖酸、麩胺酸、羥基萘甲酸、水楊酸、硬脂酸、黏康酸等）形成的酸加成鹽；或者 當親體化合物中存在的酸性質子被金屬離子（例如，鹼金屬離子、鹼土離子或鋁離子）替代；或與有機鹼（如乙醇胺、二乙醇胺、三乙醇胺、三木甲胺、N-甲基葡萄糖胺等）配位形成的鹽。應理解，藥學上可接受的鹽係無毒的。關於合適的藥學上可接受的鹽的另外資訊可以在以下文獻中找到：Remington’s Pharmaceutical Sciences[雷明頓藥物科學], 第17版, Mack Publishing Company [馬克出版公司], 伊斯頓, 賓夕凡尼亞州, 1985，將其藉由引用以其全文併入本文。"Pharmaceutically acceptable salts" of a compound are salts that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. Such salts include: acid addition salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.); or with organic acids (such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthal ... The present invention also provides an acid addition salt formed with 1,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tributylacetic acid, lauryl sulfuric acid, gluconic acid, glutamine, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or when the acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkaline metal ion, an alkaline earth ion, or an aluminum ion); or when coordinated with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, trimethylamine,N -methylglucamine, etc.). It should be understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pennsylvania, 1985, which is incorporated herein by reference in its entirety.

具有式 (IB) 或 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物）可以具有不對稱中心。含有不對稱取代的原子的具有式 (IB) 或 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物）可以以光學活性或外消旋形式分離。化合物的單獨的立體異構物可以藉由從含有手性中心的可商購的起始材料合成製備，或藉由製備鏡像異構物產物的混合物隨後分離（例如轉化成非鏡像異構物的混合物隨後分離或重結晶、層析技術、在手性層析柱上直接分離鏡像異構物或本領域已知的任何其他適當的方法）來製備。除非明確地指出特定的立體化學形式或異構物形式，否則所有的手性形式、非鏡像異構物形式、手性或非鏡像異構物形式的所有混合物、以及外消旋形式都在本揭露之範圍之內。熟悉該項技術者還應理解，當化合物表示為 (R) 立體異構物時，它可以含有對應的 (S) 立體異構物作為雜質，並且反之亦然。Compounds of Formula (IB) or (I) (and any embodiments thereof disclosed herein, including specific compounds) may have asymmetric centers. Compounds of Formula (IB) or (I) (and any embodiments thereof disclosed herein, including specific compounds) containing asymmetrically substituted atoms may be isolated in optically active or racemic forms. Individual stereoisomers of a compound may be prepared synthetically from commercially available starting materials containing a chiral center, or by preparing a mixture of mirror image isomer products followed by separation (e.g., conversion of the mixture to non-mirror image isomers followed by separation or recrystallization, chromatography techniques, direct separation of the mirror image isomers on a chiral chromatography column, or any other suitable method known in the art). Unless a specific stereochemical form or isomeric form is explicitly indicated, all chiral forms, non-mirror isomeric forms, all mixtures of chiral or non-mirror isomeric forms, and racemic forms are within the scope of the present disclosure. It will also be understood by those skilled in the art that when a compound is represented as an (R) stereoisomer, it may contain the corresponding (S) stereoisomer as a contaminant, and vice versa.

具有式 (IB) 或 (I) 的某些化合物（以及本文揭露的其任何實施方式，包括特定的化合物）可以作為互變異構物和/或幾何異構物存在。所有可能的互變異構物以及順式和反式異構物（作為單獨的形式及其混合物）都在本揭露之範圍之內。另外，如本文所用，雖然僅列出了幾個實例，但是術語烷基包括所述烷基基團的所有可能的異構物形式。此外，當該等環狀基團（如芳基）被取代時，雖然僅列出了幾個實例，但是其包括所有位置異構物。此外，具有式 (IB) 或 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物）的所有水合物都在本揭露之範圍之內。Certain compounds of Formula (IB) or (I) (and any embodiments thereof disclosed herein, including specific compounds) may exist as tautomers and/or geometric isomers. All possible tautomers, as well as cis- and trans-isomers (as individual forms and mixtures thereof) are within the scope of this disclosure. Furthermore, as used herein, the term alkyl encompasses all possible isomeric forms of the alkyl group, even though only a few examples are listed. Furthermore, when cyclic groups (e.g., aryl) are substituted, even though only a few examples are listed, all positional isomers are encompassed. Furthermore, all hydrates of compounds of Formula (IB) or (I) (and any embodiments thereof disclosed herein, including specific compounds) are within the scope of this disclosure.

具有式 (IB) 或 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物）還可以在構成此類化合物的一或多個原子上含有非天然量的同位素。非天然量的同位素可以被定義為範圍從自然中發現的量至所討論的原子的100%的量，僅在一或多種同位素增濃原子的存在方面不同。可以併入本揭露化合物（例如具有式 (IB) 或 (I) 的化合物）（以及本文揭露的其任何實施方式，包括特定的化合物）中的示例性同位素包括氫、碳、氮、氧、磷、硫、氟、氯和碘的同位素，分別為例如²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³²P、³³P、³⁵S、¹⁸F、³⁶Cl、¹²³I和¹²⁵1。同位素標記的化合物（例如，用³H和¹⁴C標記的化合物）可以用於化合物或底物組織分布測定中。氚代的（即，³H）和碳-14（即，¹⁴C）同位素因其容易製備和可檢測性而可為有用的。此外，被較重的同位素如氘（即，²H）取代（或同位素增濃）可能會因更高的代謝穩定性（例如，增加的體內半衰期或減少的劑量要求）而提供某些治療優勢。在一些實施方式中，在具有式 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物，包括在下表1中）中，一或多個氫原子被²H或³H替代，或者一或多個碳原子被¹³C-或¹⁴C-增濃的碳替代。正電子發射同位素（如¹⁵O、¹³N、¹¹C和¹⁵F）可用於正電子發射斷層成像（PET）研究，以檢查基質受體的佔有率。通常藉由以下與本文方案或實例中揭露的那些類似的程序，藉由用同位素標記的試劑取代非同位素標記的試劑，可以製備同位素標記的化合物。Compounds of formula (IB) or (I) (and any embodiments thereof disclosed herein, including specific compounds) may also contain unnatural amounts of isotopes at one or more atoms comprising such compounds. Unnatural amounts of isotopes can be defined as amounts ranging from the amount found in nature to 100% of the atom in question, differing only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the present disclosure (e.g., compounds of Formula (IB) or (I)) (and any embodiments thereof disclosed herein, including specific compounds) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as^2H ,^3H ,^11C ,^13C ,^14C ,^13N ,^15N ,^15O ,^17O ,^18O , 32P,^{33P, 35S, 18F,36Cl,123I} , and^125I ,^respectively . Isotopically labeled compounds (e.g., those labeled with^3H and^14C ) can be used in compound or substrate tissue distribution assays. Tritiated (i.e.,^3H ) and carbon-14 (i.e.,^14C ) isotopes can be useful due to their ease of preparation and detectability. In addition, substitution with (or isotopic enrichment of) heavier isotopes such as deuterium (i.e.,^2H ) may provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in a compound of Formula (I) (and any embodiments thereof disclosed herein, including specific compounds, including those listed in Table 1 below), one or more hydrogen atoms are replaced by^2H or^3H , or one or more carbon atoms are replaced by^13C- or^14C -enriched carbon. Positron-emitting isotopes (e.g.,^15O ,^13N ,^11C , and^15F ) can be used in positron emission tomography (PET) studies to examine stromal receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

「藥學上可接受的載劑或賦形劑」意指在製備藥物組成物中有用的載劑或賦形劑，其通常是安全、無毒的並且不是生物學上或其他方面不希望的，並且包括對於獸用連同人類藥用係可接受的載劑或賦形劑。"Pharmaceutically acceptable carrier or excipient" means a carrier or excipient useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes carriers or excipients that are acceptable for veterinary as well as human pharmaceutical use.

如在本說明書和申請專利範圍中使用的「藥學上可接受的載劑/賦形劑」包括一種和多於一種這種賦形劑兩者。如本文所用，術語「約」旨在限定它所修飾的數值，表示這個值為在誤差界限之內的變數。當沒有列舉出特定的誤差範圍（例如，數據圖或表中給出的平均值的標準差）時，術語「約」應理解為表示涵蓋 ± 10%，較佳的是 ± 5%的範圍，包括所列舉的值和範圍。As used in this specification and claims, "pharmaceutically acceptable carrier/formulation" includes both one and more than one such formulation. As used herein, the term "about" is intended to qualify the numerical value it modifies, indicating that the value is variable within the margin of error. When no specific error range is listed (e.g., the standard deviation of the mean value given in a data graph or table), the term "about" should be understood to mean a range of ± 10%, preferably ± 5%, inclusive of the listed value and range.

本文提供的某些結構被繪製為具有一或多個浮動的取代基。除非另外提供或另外從上下文清楚可見，否則在化學上可行且價規則允許的情況下，取代基可以存在於其所附接的環的任何原子上。例如，在結構：中，R^aa取代基以及類似地R^bb取代基可以替代任何CH的氫，CH係尚未被R^bb（在R^aa的情況下）以及類似地被R^aa（在R^bb的情況下）取代的雙環的苯并部分的一部分。Certain structures provided herein are drawn with one or more floating substituents. Unless otherwise provided or otherwise clear from the context, a substituent may be present on any atom of the ring to which it is attached, where chemically feasible and permitted by valence rules. For example, in the structure: In the example, the^Raa substituent, and similarly the^Rbb substituent, may replace any hydrogen of a CH that is part of the bicyclic benzo portion that is not already substituted by^Rbb (in the case of^Raa ) and similarly by^Raa (in the case of^Rbb ).

另外，如在整個申請中（包括在實施方式中）所用的，當基團被引出為二價時，該二價基團的左鍵附接至分子其餘部分中位於其左側的基團，並且該二價基團的右鍵附接至分子其餘部分中位於其右側的基團。例如，在式 (i) 的E3泛素連接酶配位基基團的以下二價基團中，(a) 和 (b) 左側的鍵附接至以下環：， 並且 (a) 和 (b) 右側的附接至式 (I) 結構的Z：。類似地，對於-Z-alk-Ar-，左側的鍵（即Z）附接至其左側的基團，即式 (i) 的環A或式 (ii) 的環B，而右側的鍵（即Ar）附接至-SO₂-（與Hy的原子附接）。例如，當-Z-alk-Ar-係具有下式的基團：， 並且式 (i) 的降解決定子的環A係具有式的基團時，哌啶基的鍵附接至環 (a) 的苯并部分，而苯基的鍵附接至-SO₂-（與Hy附接）。Additionally, as used throughout this application (including in the Examples), when a group is introduced as divalent, the left bond of the divalent group is attached to the group to its left in the rest of the molecule, and the right bond of the divalent group is attached to the group to its right in the rest of the molecule. For example, In the following bivalent groups of the E3 ubiquitin ligase ligand group of formula (i), the left side of (a) and (b) Keys are attached to the following rings: , and (a) and (b) on the right Z attached to the structure of formula (I): Similarly, for -Z-alk-Ar-, the left-hand bond (i.e., Z) is attached to the group to its left, i.e., Ring A of formula (i) or Ring B of formula (ii), while the right-hand bond (i.e., Ar) is attached to -SO₂ - (attached to the Hy atom). For example, when -Z-alk-Ar- is a group having the following formula: , and the ring A of the degradation determinant of formula (i) has the formula When the group is piperidinyl The bond is attached to the benzo portion of ring (a), while the phenyl Bond attached to -SO₂ - (attached to Hy).

如本文所用的術語「疾病」旨在與術語「障礙」、「症候群」和「病症」（如在醫學病症中）大致同義，並可互換使用，其中所有該等都反映了人或動物體的或者損害了其正常功能的部分之一的異常情況，典型表現為差異的體征和症狀，並且使人或動物有減少的壽命期限或生活品質。As used herein, the term "disease" is intended to be generally synonymous with, and used interchangeably with, the terms "disorder," "syndrome," and "condition" (as in medical conditions), all of which reflect an abnormal condition of one of the parts of the human or animal body that impairs its normal function, typically manifests as unusual signs and symptoms, and results in a reduced length of life or quality of life for the human or animal.

術語「組合療法」意指投與兩種或更多種治療劑以治療本揭露中描述的疾病或障礙。這種投與涵蓋以基本上同時的方式共同投與該等治療劑，如以具有固定比率的活性成分的單個膠囊投與或以每種活性成分的多個分開的膠囊投與。此外，這種投與還涵蓋以依序的方式使用每種類型的治療劑。在任一種情況下，治療方案將在治療本文所述之病症或障礙方面提供藥物組合的有益效果。The term "combination therapy" means the administration of two or more therapeutic agents to treat the diseases or disorders described in this disclosure. Such administration encompasses co-administration of the therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple separate capsules of each active ingredient. In addition, such administration also encompasses the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the conditions or disorders described herein.

術語「患者」與術語「受試者」大致同義，並且包括所有哺乳動物，包括人。患者的實例包括人、牲畜（如牛、山羊、綿羊、豬和兔）和伴生動物（如狗、貓、兔和馬）。較佳的是，患者係人。The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, livestock (such as cattle, goats, sheep, pigs, and rabbits), and companion animals (such as dogs, cats, rabbits, and horses). Preferably, the patient is a human.

「治療（treating或treatment）」疾病包括： (1) 預防該疾病，即，使該疾病的臨床症狀在可能暴露於或易患該疾病但尚未經歷或顯示出該疾病的症狀的哺乳動物中不發展； (2) 抑制該疾病，即，延遲、阻滯（穩定）或降低該疾病或其臨床症狀的發展或嚴重程度；或者 (3) 緩解該疾病，即，使該疾病或其臨床症狀消退。“Treating” or “treatment” of a disease includes:(1) preventing the disease, that is, preventing the clinical symptoms of the disease from developing in a mammal that may be exposed to or susceptible to the disease but does not yet experience or display symptoms of the disease;(2) inhibiting the disease, that is, delaying, arresting (stabilizing) or reducing the development or severity of the disease or its clinical symptoms; or(3) relieving the disease, that is, causing the disease or its clinical symptoms to regress.

在一個實施方式中，治療（treating或treatment）疾病包括抑制該疾病，即，延遲、阻滯或降低該疾病或其臨床症狀的發展或嚴重程度；或緩解該疾病，即，使該疾病或其臨床症狀消退。In one embodiment, treating (or treating) a disease includes inhibiting the disease, i.e., delaying, arresting, or reducing the development or severity of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

「治療有效量」意指當向患者投與以用於治療疾病時，足以影響該疾病的這種治療的本揭露化合物和/或其藥學上可接受的鹽的量。「治療有效量」將根據化合物、疾病及其嚴重程度以及所要治療的哺乳動物的年齡、體重等變化。A "therapeutically effective amount" means an amount of a compound of the present disclosure and/or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease, is sufficient to affect such treatment. The therapeutically effective amount will vary depending on the compound, the disease and its severity, and the age and weight of the mammal being treated.

「與自體免疫性疾病相關的病症」意指患有自體免疫性疾病的患者易感的病症（例如敗血症）或由自體免疫性疾病引起的病症（例如眼色素層炎）。"Autoimmune disease-related conditions" refers to conditions to which patients with autoimmune diseases are susceptible (e.g., sepsis) or conditions caused by autoimmune diseases (e.g., uveitis).

具有式 (IB) 或 (I) 的化合物還可以抑制CDK2和CDK4。與CDK2和CDK4相關的術語「抑制」和「降低」或該等術語的任何變體包括分別使CDK2和CDK4的酶活性有任何可測量的降低或得到完全抑制，以實現所希望的結果。例如，減少可為與正常活性相比，CDK2和CDK4活性降低約、至多約或至少約5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、99%或更多，或其中可衍生的任何範圍。在一些實施方式中，與不存在本文揭露的發明內容、實施方式和化合物表1中的本文揭露的化合物的情況下分別包含CDK2或CDK4的等效樣本相比，在存在所述化合物的情況下，CDK2和CDK4活性降低至少40%。具有式 (IB) 或 (I) 的化合物的抑制活性也可以使用生物學實例1來測量，藉由將具有式 (IB) 或 (I) 的化合物轉化為不能被泛素蛋白酶體途徑降解的相應具有式 (IB) 或 (I) 的化合物，例如，藉由甲基化具有式 (IB) 或 (I) 的化合物中存在的連接酶配位基 (i) 或 (ii) 的基團中的氮原子。Compounds of Formula (IB) or (I) may also inhibit CDK2 and CDK4. The terms "inhibit" and "reduce," or any variations thereof, with respect to CDK2 and CDK4 include any measurable decrease or complete inhibition of the enzymatic activity of CDK2 and CDK4, respectively, to achieve the desired result. For example, a decrease can be a decrease in CDK2 and CDK4 activity by about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, compared to normal activity, or any range derivable therein. In some embodiments, the activity of CDK2 and CDK4 is reduced by at least 40% in the presence of a compound as described herein, compared to an equivalent sample comprising CDK2 or CDK4, respectively, in the absence of the compounds disclosed herein. The inhibitory activity of a compound of Formula (IB) or (I) can also be measured using Biological Example 1 by converting a compound of Formula (IB) or (I) into a corresponding compound of Formula (IB) or (I) that cannot be degraded by the ubiquitin proteasome pathway, for example, by methylating a ligase ligand (i) or (ii) present in a compound of Formula (IB) or (I). Nitrogen atoms in the group.

與CDK2、CDK4和CDK1相關的術語「降解（degrading和degrade）」或該等術語的任何變體意指樣本中CDK2、CDK4和CDK1的濃度分別隨時間的可測量的降低。例如，與不存在本文揭露的發明內容、實施方式和化合物表1中的本文揭露的化合物的情況下包含CDK2或CDK4的等效樣本相比，在分別含有CDK2和CDK4以及所述化合物的樣本中，CDK2和CDK4濃度可能降低約5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、99%或更多，或其中可衍生的任何範圍。降解%可以如下文生物學實例2中所述進行測定。在一個實施方式中，CDK2和CDK4濃度的降低 ≥ 20%。在一個實施方式中，CDK2和CDK4濃度的降低 ≥ 40%。在一個實施方式中，CDK2和CDK4濃度的降低 ≥ 50%。在一個實施方式中，CDK2和CDK4濃度的降低 ≥ 60%。在一個實施方式中，CDK2和CDK4濃度的降低 ≥ 70%。在一個實施方式中，CDK2和CDK4濃度的降低 ≥ 80%。The terms "degrading" and "degrade," or any variations thereof, with respect to CDK2, CDK4, and CDK1, refer to a measurable decrease in the concentration of CDK2, CDK4, and CDK1, respectively, in a sample over time. For example, the concentration of CDK2 and CDK4 in a sample containing CDK2 and CDK4, respectively, and a compound as described herein, as compared to an equivalent sample containing CDK2 or CDK4 in the absence of the compounds disclosed herein, embodiments, and Compound Table 1, may be reduced by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein. Percent degradation can be determined as described in Biological Example 2 below. In one embodiment, the reduction in CDK2 and CDK4 concentration is ≥ 20%. In one embodiment, the reduction in CDK2 and CDK4 concentration is ≥ 40%. In one embodiment, the reduction in CDK2 and CDK4 concentration is ≥ 50%. In one embodiment, the reduction in CDK2 and CDK4 concentration is ≥ 60%. In one embodiment, the reduction in CDK2 and CDK4 concentration is ≥ 70%. In one embodiment, the reduction in CDK2 and CDK4 concentration is ≥ 80%.

「E3泛素連接酶」係指與E1泛素活化酶和E2泛素綴合酶聯合起作用、輔助或直接催化泛素與底物蛋白的離胺酸殘基的共價連接的蛋白質家族。E3泛素連接酶直接結合底物蛋白，從而賦予針對泛蛋白化過程的底物特異性。泛蛋白化可以作為底物蛋白的通用訊息標記，該等底物蛋白被靶向以藉由蛋白酶體或其他從易位到轉錄的調節而被降解。小腦蛋白（CRBN）和von Hippel-Lindau（VHL）蛋白係兩種普遍表現且生物學上重要的Cullin RING E3泛素連接酶複合物的底物識別亞基。小腦蛋白與受損的DNA結合蛋白1（DDB1）、Cullin-4A（CUL4A）和cullins 1調節劑（ROC1）形成E3泛素連接酶複合物。VHL係E3連接酶複合物VCB的一部分，VCB還由延伸蛋白B和C、Cul2和Rbx1組成。實施方式："E3 ubiquitin ligase" refers to a family of proteins that work in conjunction with E1 ubiquitin activating enzymes and E2 ubiquitin conjugating enzymes to assist or directly catalyze the covalent attachment of ubiquitin to lysine residues on substrate proteins. E3 ubiquitin ligases directly bind to substrate proteins, conferring substrate specificity for the ubiquitination process. Ubiquitination serves as a universal signaling marker for substrate proteins, targeting them for degradation via the proteasome or other regulatory pathways from translocation to transcription. Cerebellin (CRBN) and von Hippel-Lindau (VHL) proteins are two ubiquitously expressed and biologically important substrate recognition subunits of the Cullin RING E3 ubiquitin ligase complex. Cerebellin forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), andregulator of cullins 1 (ROC1). VHL is part of the E3 ligase complex VCB, which also includes elongins B and C, Cul2, and Rbx1.

實施方式A 在實施方式A1A至A207中，本揭露包括：Implementation AIn implementations A1A to A207, the present disclosure includes:

A1A.      在實施方式A1A中，提供了在發明內容的第二方面或其第二實施方式中描述的具有式 (IB) 的化合物或其藥學上可接受的鹽。A1A. In embodiment A1A, a compound of formula (IB) or a pharmaceutically acceptable salt thereof as described in the second aspect of the invention or the second embodiment thereof is provided.

A1.  在實施方式A1中，提供了在發明內容的第二方面的第一實施方式或其第一實施方式中描述的具有式 (I) 的化合物或其藥學上可接受的鹽。A1. In embodiment A1, a compound having formula (I) or a pharmaceutically acceptable salt thereof described in the first embodiment of the second aspect of the invention or its first embodiment is provided.

A2.  在實施方式A2中，如實施方式A1A或A1所述之化合物或其藥學上可接受的鹽，係其中R¹係鹵代。A2. In embodiment A2, the compound or a pharmaceutically acceptable salt thereof as described in embodiment A1A or A1, wherein R¹ is halogenated.

A3.  在實施方式A3中，如實施方式A1A或A1所述之化合物或其藥學上可接受的鹽，係其中R¹係鹵代烷基或鹵代烷氧基。A3. In embodiment A3, the compound or pharmaceutically acceptable salt thereof as described in embodiment A1A or A1, wherein R¹ is halogenated alkyl or halogenated alkoxy.

A4.  在實施方式A4中，如實施方式A1A、A1或A3所述之化合物或其藥學上可接受的鹽，係其中R¹係鹵代烷基。A4. In embodiment A4, the compound or pharmaceutically acceptable salt thereof as described in embodiment A1A, A1 or A3, wherein R¹ is halogenated alkyl.

A5.  在實施方式A5中，如實施方式A1A、A1或A3所述之化合物或其藥學上可接受的鹽，係其中R¹係鹵代烷氧基。A5. In embodiment A5, the compound or pharmaceutically acceptable salt thereof as described in embodiment A1A, A1 or A3, wherein R¹ is halogenated alkoxy.

A6.  在實施方式A6中，如實施方式A1A至A5中任一項所述之化合物或其藥學上可接受的鹽，係其中R¹係氯、溴、氟、二氟甲基、三氟甲基、二氟乙基、三氟乙基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基，除非另有說明。A6. In embodiment A6, the compound as described in any one of embodiments A1A to A5, or a pharmaceutically acceptable salt thereof, is wherein R¹ is chloro, bromo, fluoro, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy, unless otherwise indicated.

A7.  在實施方式A7中，如實施方式A1A至A6中任一項所述之化合物或其藥學上可接受的鹽，係其中R¹係氯、溴、二氟甲基、三氟甲基、二氟甲氧基或三氟甲氧基，除非另有說明。A7. In Embodiment A7, the compound or pharmaceutically acceptable salt thereof as described in any one of Embodiments A1A to A6, wherein R¹ is chloro, bromo, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, unless otherwise specified.

A8.  在實施方式A8中，如實施方式A1A、A1、A2、A6和A7中任一項所述之化合物或其藥學上可接受的鹽，係其中R¹係氯或溴。A8. In embodiment A8, the compound according to any one of embodiments A1A, A1, A2, A6 and A7, or a pharmaceutically acceptable salt thereof, wherein R¹ is chloro or bromo.

A9.  在實施方式A9中，如實施方式A1A、A1、A3、A4、A6和A7中任一項所述之化合物或其藥學上可接受的鹽，係其中R¹係二氟甲基或三氟甲基。A9. In embodiment A9, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A, A1, A3, A4, A6 and A7, wherein R¹ is difluoromethyl or trifluoromethyl.

A10. 在實施方式A10中，如實施方式A1A、A1、A3、A4、A6、A7和A9中任一項所述之化合物或其藥學上可接受的鹽，係其中R¹係三氟甲基。A10. In embodiment A10, the compound according to any one of embodiments A1A, A1, A3, A4, A6, A7 and A9, or a pharmaceutically acceptable salt thereof, wherein R¹ is trifluoromethyl.

A11. 在實施方式A11中，如實施方式A1A、A1、A3和A5至A7中任一項所述之化合物或其藥學上可接受的鹽，係其中R¹係二氟甲氧基或三氟甲氧基。A11. In embodiment A11, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A, A1, A3 and A5 to A7, wherein R¹ is difluoromethoxy or trifluoromethoxy.

A12. 在實施方式A12中，如實施方式A1A、A1、A3、A5至A7和A11中任一項所述之化合物或其藥學上可接受的鹽，係其中R¹係二氟甲氧基。A12. In embodiment A12, the compound as described in any one of embodiments A1A, A1, A3, A5 to A7 and A11, or a pharmaceutically acceptable salt thereof, wherein R¹ is difluoromethoxy.

A13. 在實施方式A13中，如實施方式A1A或A1所述之化合物或其藥學上可接受的鹽，係其中R¹係烷基、烯基或炔基。A13. In embodiment A13, the compound or pharmaceutically acceptable salt thereof as described in embodiment A1A or A1, wherein R¹ is alkyl, alkenyl or alkynyl.

A14. 在實施方式A14中，如實施方式A1A、A1或A13所述之化合物或其藥學上可接受的鹽，係其中R¹係甲基、乙基、丙基、乙烯基、丙烯基、乙炔基或丙炔基。A14. In embodiment A14, the compound or pharmaceutically acceptable salt thereof as described in embodiment A1A, A1 or A13, wherein R¹ is methyl, ethyl, propyl, vinyl, propenyl, ethynyl or propynyl.

A15. 在實施方式A15中，如實施方式A1A、A1、A13或A14所述之化合物或其藥學上可接受的鹽，係其中R¹係甲基、乙基或丙基。A15. In embodiment A15, the compound or pharmaceutically acceptable salt thereof as described in embodiment A1A, A1, A13 or A14, wherein R¹ is methyl, ethyl or propyl.

A16. 在實施方式A16中，如實施方式A1A、A1、A13或A14所述之化合物或其藥學上可接受的鹽，係其中R¹係乙烯基、丙烯基、乙炔基或丙炔基。A16. In embodiment A16, the compound or pharmaceutically acceptable salt thereof as described in embodiment A1A, A1, A13 or A14, wherein R¹ is ethenyl, propenyl, ethynyl or propynyl.

A17. 在實施方式A17中，如實施方式A1A或A1所述之化合物或其藥學上可接受的鹽，係其中R¹係烷氧基。A17. In embodiment A17, the compound or pharmaceutically acceptable salt thereof as described in embodiment A1A or A1, wherein R¹ is alkoxy.

A18. 在實施方式A18中，如實施方式A1A、A1或A17所述之化合物或其藥學上可接受的鹽，係其中R¹係甲氧基、乙氧基或丙氧基。A18. In embodiment A18, the compound or pharmaceutically acceptable salt thereof as described in embodiment A1A, A1 or A17, wherein R¹ is methoxy, ethoxy or propoxy.

A19. 在實施方式A19中，如實施方式A1A或A1所述之化合物或其藥學上可接受的鹽，係其中R¹係芳基氧基、較佳的是苯氧基。A19. In embodiment A19, the compound or pharmaceutically acceptable salt thereof as described in embodiment A1A or A1 is wherein R¹ is aryloxy, preferably phenoxy.

A20. 在實施方式A20中，如實施方式A1A或A1所述之化合物或其藥學上可接受的鹽，係其中R¹係氰基。A20. In embodiment A20, the compound as described in embodiment A1A or A1, or a pharmaceutically acceptable salt thereof, wherein R¹ is cyano.

A21. 在實施方式A21中，如實施方式A1A或A1所述之化合物或其藥學上可接受的鹽，係其中R¹係環烷基、較佳的是環丙基。A21. In embodiment A21, the compound or pharmaceutically acceptable salt thereof as described in embodiment A1A or A1, wherein R¹ is cycloalkyl, preferably cyclopropyl.

A22. 在實施方式A22中，如實施方式A1A或A1所述之化合物或其藥學上可接受的鹽，係其中R¹係被一至三個鹵代取代的環烷基、較佳的是氟環丙基或二氟環丙基。A22. In embodiment A22, the compound or pharmaceutically acceptable salt thereof as described in embodiment A1A or A1 is a cycloalkyl^group substituted with one to three halogen groups, preferably a fluorocyclopropyl group or a difluorocyclopropyl group.

A22a.     在實施方式A22a中，如實施方式A1A或A1所述之化合物或其藥學上可接受的鹽，係其中R¹係環烷基氧基、較佳的是環丙基氧基。A22a. In embodiment A22a, the compound or a pharmaceutically acceptable salt thereof as described in embodiment A1A or A1, wherein R¹ is cycloalkyloxy, preferably cyclopropyloxy.

A22b.     在實施方式A22b中，如實施方式A1A或A1所述之化合物或其藥學上可接受的鹽，係其中R¹係被一至三個鹵代取代的環烷基氧基、較佳的是氟環丙基氧基或二氟環丙基氧基。A22b. In embodiment A22b, the compound or pharmaceutically acceptable salt thereof as described in embodiment A1A or^A1 is a cycloalkyloxy group substituted with one to three halogen groups, preferably a fluorocyclopropyloxy group or a difluorocyclopropyloxy group.

A23. 在實施方式A23中，如實施方式A1A至A22b中任一項所述之化合物或其藥學上可接受的鹽，係其中R²和R^2a係氫。A23. In embodiment A23, the compound according to any one of embodiments A1A to A22b, or a pharmaceutically acceptable salt thereof, wherein R² and R^2a are hydrogen.

A24. 在實施方式A24中，如實施方式A1A至A22b中任一項所述之化合物或其藥學上可接受的鹽，係其中R²和R^2a中之一個係氘並且R²和R^2a中的另一個係氫，或R²和R^2a都是氘。A24. In embodiment A24, the compound of any one of embodiments A1A to A22b, or a pharmaceutically acceptable salt thereof, wherein one of R² and R^2a is deuterium and the other of R² and R^2a is hydrogen, or both R² and R^2a are deuterium.

A25. 在實施方式A25中，如實施方式A1A至A24中任一項所述之化合物或其藥學上可接受的鹽，係其中Hy係雜亞環基、伸苯基、螺雜亞環基、橋接雜亞環基或環伸烷基，其中上述環中之每一個被R^a、R^b和R^c取代，其中R^a和R^b獨立地選自氫、氘、烷基、鹵代、鹵代烷基、烷氧基、羥基和氰基，並且R^c係氫。A25. In embodiment A25, the compound as described in any one of embodiments A1A to A24, or a pharmaceutically acceptable salt thereof, wherein Hy is a heterocycloalkylene, a phenylene, a spiroheterocycloalkylene, a bridged heterocycloalkylene, or a cycloalkylene, wherein each of the above rings is substituted with^Ra ,^Rb , and^Rc , wherein^Ra and^Rb are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxyl, and cyano, and^Rc is hydrogen.

A26. 在實施方式A26中，如實施方式A1A至A25中任一項所述之化合物或其藥學上可接受的鹽，係其中Hy係被R^a、R^b和R^c取代的雜亞環基，其中R^a和R^b獨立地選自氫、氘、烷基、鹵代、鹵代烷基、烷氧基、羥基和氰基，並且R^c係氫。A26. In embodiment A26, the compound as described in any one of embodiments A1A to A25, or a pharmaceutically acceptable salt thereof, is wherein Hy is a heterocycloalkyl substituted with^Ra ,^Rb , and^Rc , wherein^Ra and^Rb are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxyl, and cyano, and^Rc is hydrogen.

A27. 在實施方式A27中，如實施方式A1A至A26中任一項所述之化合物或其藥學上可接受的鹽，係其中Hy的雜亞環基係吡咯啶-1,3-二基或哌啶-1,4-二基，每個環被R^a、R^b和R^c取代，其中R^a和R^b獨立地是氫、氘、甲基、氟、甲氧基或羥基，R^c係氫，並且-SO₂-附接至Hy的哌啶-1,4-二基或吡咯啶-1,3-二基環的氮原子。A27. In embodiment A27, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A26, wherein the heterocycloalkylene group of Hy is pyrrolidine-1,3-diyl or piperidine-1,4-diyl, each ring is substituted with^Ra ,^Rb , and^Rc , wherein^Ra and^Rb are independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxyl,^Rc is hydrogen, and_-SO2- is attached to the nitrogen atom of the piperidine-1,4-diyl or pyrrolidine-1,3-diyl ring of Hy.

A28. 在實施方式A28中，如實施方式A1A至A27中任一項所述之化合物或其藥學上可接受的鹽，係其中Hy的雜亞環基係：其中吡咯啶-1,3-二基或哌啶-1,4-二基環的N原子附接至-SO₂-A28. In embodiment A28, the compound according to any one of embodiments A1A to A27, or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group of Hy is: wherein the N atom of the pyrrolidine-1,3-diyl or piperidine-1,4-diyl ring is attached to -SO₂ -

A29. 在實施方式A29中，如實施方式A1A至A28中任一項所述之化合物或其藥學上可接受的鹽，係其中Hy的雜亞環基係：其中吡咯啶-1,3-二基或哌啶-1,4-二基環的N原子附接至-SO₂-。A29. In embodiment A29, the compound according to any one of embodiments A1A to A28, or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group of Hy is: wherein the N atom of the pyrrolidine-1,3-diyl or piperidine-1,4-diyl ring is attached to -SO₂ -.

A29a.     在實施方式A29a中，如實施方式A1A至A29中任一項所述之化合物或其藥學上可接受的鹽，係其中Hy的雜亞環基係：其中哌啶-1,4-二基環的N原子附接至-SO₂-。A29a. In embodiment A29a, the compound according to any one of embodiments A1A to A29, or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group of Hy is: wherein the N atom of the piperidine-1,4-diyl ring is attached to -SO₂ -.

A30. 在實施方式A30中，如實施方式A1A至A25中任一項所述之化合物或其藥學上可接受的鹽，係其中Hy係被R^a、R^b和R^c取代的橋接雜亞環基，其中R^c係氫。A30. In embodiment A30, the compound according to any one of embodiments A1A to A25, or a pharmaceutically acceptable salt thereof, wherein Hy is a bridged heterocyclic group substituted with^Ra ,^Rb , and^Rc , wherein^Rc is hydrogen.

A31. 在實施方式A31中，如實施方式A1A至A25和A30中任一項所述之化合物或其藥學上可接受的鹽，係其中Hy的橋接雜亞環基係具有下式的環：其中每個環被R^a、R^b和R^c取代，其中R^c係氫，並且每個環的氮原子附接至-SO₂-。A31. In embodiment A31, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A25 and A30, wherein the bridged heterocyclic group of Hy is a ring having the following formula: wherein each ring is substituted with^Ra ,^Rb , and^Rc , wherein^Rc is hydrogen, and the nitrogen atom of each ring is attached to_-SO2- .

A32. 在實施方式A32中，如實施方式A30或A31所述之化合物或其藥學上可接受的鹽，係其中R^a和R^b獨立地是氫、氘、甲基、氟、甲氧基或羥基。A32. In embodiment A32, the compound according to embodiment A30 or A31, or a pharmaceutically acceptable salt thereof, wherein^Ra and^Rb are independently hydrogen, deuterium, methyl, fluoro, methoxy or hydroxy.

A33. 在實施方式A33中，如實施方式A30、A31或A32所述之化合物或其藥學上可接受的鹽，係其中R^b係氫。A33. In embodiment A33, the compound according to embodiment A30, A31 or A32, or a pharmaceutically acceptable salt thereof, wherein R^b is hydrogen.

A34. 在實施方式A34中，如實施方式A1A至A25中任一項所述之化合物或其藥學上可接受的鹽，係其中Hy係被R^a、R^b和R^c取代的環伸烷基，其中R^a係氘、甲基、氟、甲氧基或羥基，並且R^b和R^c係氫。A34. In embodiment A34, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A25, wherein Hy is a cycloalkylene substituted with^Ra ,^Rb , and^Rc , wherein^Ra is deuterium, methyl, fluoro, methoxy, or hydroxyl, and^Rb and^Rc are hydrogen.

A35. 在實施方式A35中，如實施方式A1A至A25和A34中任一項所述之化合物或其藥學上可接受的鹽，係其中Hy的環伸烷基係環亞己基。A35. In embodiment A35, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A25 and A34, wherein the cycloalkylene group of Hy is cyclohexylene.

A36. 在實施方式A36中，如實施方式A1A至A25、A34和A35中任一項所述之化合物或其藥學上可接受的鹽，係其中Hy的環伸烷基係，其中表示到NH的鍵且表示-SO₂-的鍵。A36. In embodiment A36, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A25, A34 and A35, wherein the cycloalkyl group of Hy is ,in Indicates the key to NH and It represents the bond of -SO₂ -.

A37. 在實施方式A37中，如實施方式A1A至A25中任一項所述之化合物或其藥學上可接受的鹽，係其中Hy係伸芳基，其中該伸芳基係被R^a、R^b和R^c取代的伸苯基，其中R^a和R^b獨立地選自氫、氘、烷基、鹵代、鹵代烷基、烷氧基、羥基和氰基，並且R^c係氫。A37. In embodiment A37, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A25, wherein Hy is arylene, wherein the arylene is phenylene substituted with^Ra ,^Rb , and^Rc , wherein^Ra and^Rb are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxyl, and cyano, and^Rc is hydrogen.

A38. 在實施方式A38中，如實施方式A1A至A25中任一項所述之化合物或其藥學上可接受的鹽，係其中Hy係被R^a、R^b和R^c取代的螺雜亞環基（較佳的是2-氮雜螺[3.3]庚-2-基），其中R^a和R^b獨立地選自氫、氘、烷基、鹵代、鹵代烷基、烷氧基、羥基和氰基，並且R^c係氫。A38. In embodiment A38, the compound as described in any one of embodiments A1A to A25, or a pharmaceutically acceptable salt thereof, is a spiroheterocycloylene group (preferably 2-azaspiro[3.3]hept-2-yl) substituted with^Ra ,^R , and^R , wherein^Ra and^R are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and^R is hydrogen.

A39. 在實施方式A39中，如實施方式A37所述之化合物或其藥學上可接受的鹽，係其中Hy的伸苯基係根據結構的1,4-伸苯基，其中表示到NH的鍵且表示到-SO₂-的鍵，其中R^a係氫、氟、甲基或甲氧基，並且R^b係氫。A39. In embodiment A39, the compound or a pharmaceutically acceptable salt thereof as described in embodiment A37, wherein the phenyl group of Hy is according to the structure 1,4-phenylene, wherein Indicates the key to NH and represents a bond to -SO₂ -, wherein^Ra is hydrogen, fluoro, methyl or methoxy, and^Rb is hydrogen.

A39a.     在實施方式A39a中，如實施方式A1A至A24中任一項所述之化合物或其藥學上可接受的鹽，係其中Hy係被R^a、R^b和R^c取代的稠合雜亞環基，其中R^a和R^b獨立地選自氫、氘、烷基、鹵代、鹵代烷基、烷氧基、羥基和氰基，並且R^c係氫。A39a. In embodiment A39a, the compound as described in any one of embodiments A1A to A24, or a pharmaceutically acceptable salt thereof, is a fused heterocycloalkylene substituted with^Ra ,^Rb , and^Rc , wherein^Ra and^Rb are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxyl, and cyano, and^Rc is hydrogen.

A39b.     在實施方式A39b中，如實施方式A1A至A24中任一項所述之化合物或其藥學上可接受的鹽，係其中Hy係被R^a、R^b和R^c取代的雙環雜亞環基，其中R^a和R^b獨立地選自氫、氘、烷基、鹵代、鹵代烷基、烷氧基、羥基和氰基，並且R^c係氫。A39b. In embodiment A39b, the compound as described in any one of embodiments A1A to A24, or a pharmaceutically acceptable salt thereof, is a bicyclic heterocycloheterocyclic group substituted with^Ra ,^R , and^R , wherein^Ra and^R are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and^R is hydrogen.

A40. 在實施方式A40中，如實施方式A1A至A39b中任一項所述之化合物或其藥學上可接受的鹽，係其中降解決定子係具有式 (i) 的E3泛素連接酶配位基：(i)。A40. In embodiment A40, the compound of any one of embodiments A1A to A39b or a pharmaceutically acceptable salt thereof, wherein the degrader is an E3 ubiquitin ligase ligand having formula (i): (i).

A41. 在實施方式A41中，如實施方式A1A至A40中任一項所述之化合物或其藥學上可接受的鹽，係其中具有式 (i) 的E3泛素連接酶配位基的環A係具有式 (a) 的基團：。A41. In embodiment A41, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A40, wherein Ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (a): .

A42. 在實施方式A42中，如實施方式A1A至A41中任一項所述之化合物或其藥學上可接受的鹽，係其中R⁴和R⁵獨立地是氫或烷基。A42. In embodiment A42, the compound according to any one of embodiments A1A to A41, or a pharmaceutically acceptable salt thereof, wherein R⁴ and R⁵ are independently hydrogen or alkyl.

A43. 在實施方式A43中，如實施方式A1A至A42中任一項所述之化合物或其藥學上可接受的鹽，係其中R⁴和R⁵係氫。A43. In embodiment A43, the compound according to any one of embodiments A1A to A42, or a pharmaceutically acceptable salt thereof, wherein R⁴ and R⁵ are hydrogen.

A44. 在實施方式A44中，如實施方式A1A至42中任一項所述之化合物或其藥學上可接受的鹽，係其中R⁴係氫且R⁵係甲基。A44. In embodiment A44, the compound according to any one of embodiments A1A to A42, or a pharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen and R⁵ is methyl.

A45. 在實施方式A45中，如實施方式A1A至A41中任一項所述之化合物或其藥學上可接受的鹽，係其中R⁴和R⁵與它們所附接的碳一起形成＞C =O。A45. In embodiment A45, the compound as described in any one of embodiments A1A to A41, or a pharmaceutically acceptable salt thereof, wherein R⁴ and R⁵ together with the carbon to which they are attached form >C═O.

A46. 在實施方式A46中，如實施方式A1A至A40中任一項所述之化合物或其藥學上可接受的鹽，係其中具有式 (i) 的E3泛素連接酶配位基的環A係具有式 (b) 的基團：。A46. In embodiment A46, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A40, wherein Ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (b): .

A47. 在實施方式A47中，如實施方式A1A至A40和A46中任一項所述之化合物或其藥學上可接受的鹽，係其中R⁶係氫。A47. In embodiment A47, the compound as described in any one of embodiments A1A to A40 and A46, or a pharmaceutically acceptable salt thereof, wherein R⁶ is hydrogen.

A48. 在實施方式A48中，如實施方式A1A至A40和A46中任一項所述之化合物或其藥學上可接受的鹽，其中R⁶係烷基、較佳的是甲基。A48. In embodiment A48, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A40 and A46, wherein R⁶ is alkyl, preferably methyl.

A49. 在實施方式A49中，如實施方式A1A至A48中任一項所述之化合物或其藥學上可接受的鹽，係其中具有式 (i) 的E3泛素連接酶配位基的環A係：。A49. In embodiment A49, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A48, wherein Ring A of the E3 ubiquitin ligase ligand of formula (i) is: .

A50. 在實施方式A50中，如實施方式A1A至A49中任一項所述之化合物或其藥學上可接受的鹽，係其中具有式 (i) 的E3泛素連接酶配位基的環A係：。A50. In embodiment A50, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A49, wherein Ring A of the E3 ubiquitin ligase ligand of formula (i) is: .

A51. 在實施方式A51中，如實施方式A1A至A50中任一項所述之化合物或其藥學上可接受的鹽，係其中具有式 (i) 的E3泛素連接酶配位基的環A係：。A51. In embodiment A51, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A50, wherein Ring A of the E3 ubiquitin ligase ligand of formula (i) is: .

A52. 在實施方式A52中，如實施方式A1A至A51中任一項所述之化合物或其藥學上可接受的鹽，係其中具有式 (i) 的E3泛素連接酶配位基的環A係：； 即，其中R^bb、R^cc和R^dd係氫。A52. In embodiment A52, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A51, wherein Ring A of the E3 ubiquitin ligase ligand of formula (i) is: ; that is, wherein R^bb , R^cc and R^dd are hydrogen.

A52a.     在實施方式A52a中，如實施方式A1A至A52中任一項所述之化合物或其藥學上可接受的鹽，係其中具有式 (i) 的E3泛素連接酶配位基的環A係：即，其中R^bb係氫。A52a. In embodiment A52a, the compound according to any one of embodiments A1A to A52, or a pharmaceutically acceptable salt thereof, wherein Ring A of the E3 ubiquitin ligase ligand of formula (i) is: That is, wherein R^bb is hydrogen.

A53. 在實施方式A53中，如實施方式A1A至A52中任一項所述之化合物或其藥學上可接受的鹽，係其中具有式 (i) 的E3泛素連接酶配位基的環A係：即，其中R^bb係氫。A53. In embodiment A53, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A52, wherein Ring A of the E3 ubiquitin ligase ligand of formula (i) is: That is, wherein R^bb is hydrogen.

A54. 在實施方式A54中，如實施方式A1A至A52中任一項所述之化合物或其藥學上可接受的鹽，係其中具有式 (i) 的E3泛素連接酶配位基的環A係：即，其中R^bb係氫。A54. In embodiment A54, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A52, wherein Ring A of the E3 ubiquitin ligase ligand of formula (i) is: That is, wherein R^bb is hydrogen.

A55. 在實施方式A55中，如實施方式A1A至A52中任一項所述之化合物或其藥學上可接受的鹽，係其中具有式 (i) 的E3泛素連接酶配位基的環A係：即，其中R^aa和R^bb係氫。A55. In embodiment A55, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A52, wherein Ring A of the E3 ubiquitin ligase ligand of formula (i) is: That is, wherein^Raa and^Rbb are hydrogen.

A56. 在實施方式A56中，如實施方式A1A至A52中任一項所述之化合物或其藥學上可接受的鹽，係其中具有式 (i) 的E3泛素連接酶配位基的環A係：即，其中R^cc和R^dd係氫。A56. In embodiment A56, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A52, wherein Ring A of the E3 ubiquitin ligase ligand of formula (i) is: That is, wherein^Rcc and^Rdd are hydrogen.

A57. 在實施方式A57中，如實施方式A1A至A52中任一項所述之化合物或其藥學上可接受的鹽，係其中具有式 (i) 的E3泛素連接酶配位基的環A係：即，其中R^cc和R^dd係氫。A57. In embodiment A57, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A52, wherein Ring A of the E3 ubiquitin ligase ligand of formula (i) is: That is, wherein^Rcc and^Rdd are hydrogen.

A58. 在實施方式A58中，如實施方式A1A至A54中任一項所述之化合物或其藥學上可接受的鹽，係其中R^aa、R^bb、R^cc和R^dd獨立地選自氫、烷基、烷氧基、鹵代、鹵代烷基和鹵代烷氧基，除非另有說明，即，在實施方式A52至A54中，R^bb、R^cc和R^dd係氫。A58. In embodiment A58, the compound as described in any one of embodiments A1A to A54, or a pharmaceutically acceptable salt thereof, is wherein^Raa ,^Rbb ,^Rcc , and^Rdd are independently selected from hydrogen, alkyl, alkoxy, halogenated, halogenated alkyl, and halogenated alkoxy, unless otherwise indicated, i.e., in embodiments A52 to A54, Rbb^{, Rcc,} and^Rdd are hydrogen.

A59. 在實施方式A59中，如實施方式A1A至A54中任一項所述之化合物或其藥學上可接受的鹽，係其中R^aa、R^bb、R^cc和R^dd獨立地選自氫、烷基、烷氧基、鹵代、鹵代烷基和氰基，除非另有說明。A59. In embodiment A59, the compound as described in any one of embodiments A1A to A54, or a pharmaceutically acceptable salt thereof, is wherein^Raa ,^Rbb ,^Rcc , and^Rdd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and cyano, unless otherwise indicated.

A60. 在實施方式A60中，如實施方式A1A至A54、A58和A59中任一項所述之化合物或其藥學上可接受的鹽，係其中R^aa、R^bb、R^cc和R^dd獨立地選自氫、甲基、甲氧基、乙氧基、氟、三氟甲基、二氟甲基和三氟甲氧基，除非另有說明。A60. In embodiment A60, the compound as described in any one of embodiments A1A to A54, A58 and A59, or a pharmaceutically acceptable salt thereof, is wherein^Raa ,^Rbb ,^Rcc and^Rdd are independently selected from hydrogen, methyl, methoxy, ethoxy, fluoro, trifluoromethyl, difluoromethyl and trifluoromethoxy, unless otherwise indicated.

A61. 在實施方式A61中，如實施方式A1A至A54和A58至A60中任一項所述之化合物或其藥學上可接受的鹽，係其中R^aa、R^bb、R^cc和R^dd獨立地選自氫和甲基，除非另有說明。A61. In embodiment A61, the compound as described in any one of embodiments A1A to A54 and A58 to A60, or a pharmaceutically acceptable salt thereof, wherein^Raa ,^Rbb ,^Rcc and^Rdd are independently selected from hydrogen and methyl, unless otherwise indicated.

A62. 在實施方式A62中，如實施方式A1A至A54和A58至A60中任一項所述之化合物或其藥學上可接受的鹽，係其中R^aa、R^bb、R^cc和R^dd獨立地選自氫和甲氧基，除非另有說明。A62. In embodiment A62, the compound as described in any one of embodiments A1A to A54 and A58 to A60, or a pharmaceutically acceptable salt thereof, wherein^Raa ,^Rbb ,^Rcc and^Rdd are independently selected from hydrogen and methoxy, unless otherwise indicated.

A63. 在實施方式A63中，如實施方式A1A至A54和A58至A60中任一項所述之化合物或其藥學上可接受的鹽，係其中R^aa、R^bb、R^cc和R^dd獨立地選自氫和氟，除非另有說明。A63. In embodiment A63, the compound as described in any one of embodiments A1A to A54 and A58 to A60, or a pharmaceutically acceptable salt thereof, wherein^Raa ,^Rbb ,^Rcc and^Rdd are independently selected from hydrogen and fluorine, unless otherwise indicated.

A64. 在實施方式A64中，如實施方式A1A至A54和A58至A60中任一項所述之化合物或其藥學上可接受的鹽，係其中R^aa、R^bb、R^cc和R^dd獨立地選自氫、三氟甲基和二氟甲基，除非另有說明。A64. In embodiment A64, the compound as described in any one of embodiments A1A to A54 and A58 to A60, or a pharmaceutically acceptable salt thereof, is wherein^Raa ,^Rbb ,^Rcc and^Rdd are independently selected from hydrogen, trifluoromethyl and difluoromethyl, unless otherwise indicated.

A65. 在實施方式A65中，如實施方式A1A至A54、A58和A60中任一項所述之化合物或其藥學上可接受的鹽，係其中R^aa、R^bb、R^cc和R^dd獨立地選自氫和三氟甲氧基，除非另有說明。A65. In embodiment A65, the compound as described in any one of embodiments A1A to A54, A58 and A60, or a pharmaceutically acceptable salt thereof, is wherein^Raa ,^Rbb ,^Rcc and^Rdd are independently selected from hydrogen and trifluoromethoxy, unless otherwise indicated.

A66. 在實施方式A66中，如實施方式A1A至A54和A58至A60中任一項所述之化合物或其藥學上可接受的鹽，係其中R^aa、R^bb、R^cc和R^dd獨立地選自氫、氟和三氟甲基，除非另有說明。A66. In embodiment A66, the compound as described in any one of embodiments A1A to A54 and A58 to A60, or a pharmaceutically acceptable salt thereof, is wherein^Raa ,^Rbb ,^Rcc and^Rdd are independently selected from hydrogen, fluoro and trifluoromethyl, unless otherwise indicated.

A67. 在實施方式A67中，如實施方式A1A至A39b中任一項所述之化合物或其藥學上可接受的鹽，係其中降解決定子係具有式 (ii) 的E3泛素連接酶配位基：(ii)。A67. In embodiment A67, the compound of any one of embodiments A1A to A39b or a pharmaceutically acceptable salt thereof, wherein the degrader is an E3 ubiquitin ligase ligand having formula (ii): (ii).

A68. 在實施方式A68中，如實施方式A1A至A39b和A41至A67中任一項所述之化合物或其藥學上可接受的鹽，係其中Y^a係CH。A68. In embodiment A68, the compound of any one of embodiments A1A to A39b and A41 to A67, or a pharmaceutically acceptable salt thereof, wherein^Ya is CH.

A69. 在實施方式A69中，如實施方式A1A至A39b和A41至A67中任一項所述之化合物或其藥學上可接受的鹽，係其中Y^a係N。A69. In embodiment A69, the compound of any one of embodiments A1A to A39b and A41 to A67, or a pharmaceutically acceptable salt thereof, wherein^Ya is N.

A70. 在實施方式A70中，如實施方式A1A至A39b和A41至A69中任一項所述之化合物或其藥學上可接受的鹽，係其中Z^a係鍵、-NH-、-O-或-NHC(O)-。A70. In embodiment A70, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A39b and A41 to A69, wherein^Za is a bond, -NH-, -O- or -NHC(O)-.

A71. 在實施方式A71中，如實施方式A1A至A39b和A41至A70中任一項所述之化合物或其藥學上可接受的鹽，係其中Z^a係鍵、-NH-或-NHC(O)-。A71. In embodiment A71, the compound as described in any one of embodiments A1A to A39b and A41 to A70, or a pharmaceutically acceptable salt thereof, wherein^Za is a bond, -NH- or -NHC(O)-.

A72. 在實施方式A72中，如實施方式A1A至A39b和A41至A71中任一項所述之化合物或其藥學上可接受的鹽，係其中Z^a係鍵。A72. In embodiment A72, the compound as described in any one of embodiments A1A to A39b and A41 to A71, or a pharmaceutically acceptable salt thereof, wherein^Za is a bond.

A73. 在實施方式A73中，如實施方式A1A至A39b和A41至A71中任一項所述之化合物或其藥學上可接受的鹽，係其中Z^a係-NH-或-NHC(O)-。A73. In embodiment A73, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A39b and A41 to A71, wherein^Za is -NH- or -NHC(O)-.

A74. 在實施方式A74中，如實施方式A1A至A39b、A41至A71和A73中任一項所述之化合物或其藥學上可接受的鹽，係其中Z^a係-NH-。A74. In embodiment A74, the compound as described in any one of embodiments A1A to A39b, A41 to A71 and A73, or a pharmaceutically acceptable salt thereof, wherein^Za is -NH-.

A74a.     在實施方式A74a中，如實施方式A1A至A39b、A41至A71和A73中任一項所述之化合物或其藥學上可接受的鹽，係其中Z^a係-NHC(O)-。A74a. In embodiment A74a, the compound as described in any one of embodiments A1A to A39b, A41 to A71 and A73, or a pharmaceutically acceptable salt thereof, wherein^Za is -NHC(O)-.

A75. 在實施方式A75中，如實施方式A1A至A39b和A41至A74a中任一項所述之化合物或其藥學上可接受的鹽，係其中環B係被R^ee和R^ff取代的伸苯基。A75. In embodiment A75, the compound according to any one of embodiments A1A to A39b and A41 to A74a, or a pharmaceutically acceptable salt thereof, is a phenylene group wherein Ring B is substituted with R^ee and R^ff .

A76. 在實施方式A76中，如實施方式A1A至A39b和A41至A74a中任一項所述之化合物或其藥學上可接受的鹽，係其中環B係被R^ee和R^ff取代的環亞胺基。A76. In embodiment A76, the compound according to any one of embodiments A1A to A39b and A41 to A74a, or a pharmaceutically acceptable salt thereof, wherein Ring B is a cycloimino group substituted with R^ee and R^ff .

A77. 在實施方式A77中，如實施方式A1A至A39b和A41至A74a中任一項所述之化合物或其藥學上可接受的鹽，係其中環B係5員或6員單環雜伸芳基或者9員或10員稠合雙環雜伸芳基，其中每個雜伸芳基環含有一至三個氮環原子，並且每個環被R^ee和R^ff取代。A77. In embodiment A77, the compound as described in any one of embodiments A1A to A39b and A41 to A74a, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5-membered or 6-membered monocyclic heteroaryl group or a 9-membered or 10-membered fused bicyclic heteroaryl group, wherein each heteroaryl ring contains one to three nitrogen ring atoms, and each ring is substituted with R^ee and R^ff .

A78. 在實施方式A78中，如實施方式A1A至A39b、A41至A74a和A77中任一項所述之化合物或其藥學上可接受的鹽，係其中環B係5員或6員單環雜伸芳基，其含有一或兩個氮環原子，被R^ee和R^ff取代。A78. In embodiment A78, the compound as described in any one of embodiments A1A to A39b, A41 to A74a and A77, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5- or 6-membered monocyclic heteroaryl group containing one or two nitrogen ring atoms, substituted by R^ee and R^ff .

A79. 在實施方式A79中，如實施方式A1A至A39b、A41至A74a和A77中任一項所述之化合物或其藥學上可接受的鹽，係其中環B係9員或10員稠合雙環雜伸芳基，其含有一至三個氮環原子且被R^ee和R^ff取代。A79. In embodiment A79, the compound as described in any one of embodiments A1A to A39b, A41 to A74a and A77, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 9- or 10-membered fused bicyclic heteroaryl group containing one to three nitrogen ring atoms and substituted with R^ee and R^ff .

A80. 在實施方式A80中，如實施方式A1A至A39b、A41至A74a、A77和A79中任一項所述之化合物或其藥學上可接受的鹽，係其中環B係9員或10員稠合雙環雜伸芳基，其含有一或兩個氮環原子且被R^ee和R^ff取代。A80. In embodiment A80, the compound as described in any one of embodiments A1A to A39b, A41 to A74a, A77 and A79, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 9- or 10-membered fused bicyclic heteroaryl group containing one or two nitrogen ring atoms and substituted with R^ee and R^ff .

A81. 在實施方式A81中，如實施方式A1A至A39b和A41至A80中任一項所述之化合物或其藥學上可接受的鹽，係其中具有式 (ii) 的E3泛素連接酶配位基係：、、或。A81. In embodiment A81, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A39b and A41 to A80, wherein the E3 ubiquitin ligase ligand of formula (ii) is: 、 、 or .

A82-1.    在實施方式A82-1中，如實施方式A1A至A39b和A41至A81中任一項所述之化合物或其藥學上可接受的鹽，係其中具有式 (ii) 的E3泛素連接酶配位基係：、、、、、、、、、、、、、或其中環B係環亞胺基，為了清楚起見，應當理解，當R^ee和/或R^ff未在結構中拉出（drawn out）時，它們就是氫。A82-1. In embodiment A82-1, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A39b and A41 to A81, wherein the E3 ubiquitin ligase ligand of formula (ii) is: 、 、 、 、 、 、 、 、 、 、 、 、 、 or Wherein Ring B is a cycloimide group, for the sake of clarity, it should be understood that when R^ee and/or R^ff are not drawn out in the structure, they are hydrogen.

A82. 在實施方式A82中，如實施方式A1A至A39b和A41至A82-1中任一項所述之化合物或其藥學上可接受的鹽，係其中具有式 (ii) 的E3泛素連接酶配位基係：、、、、、、、、、、或其中環B係環亞胺基。A82. In embodiment A82, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A39b and A41 to A82-1, wherein the E3 ubiquitin ligase ligand of formula (ii) is: 、 、 、 、 、 、 、 、 、 、 or Ring B is a cycloimino group.

A82A.    在實施方式A82A中，如實施方式A1A至A39b和A41至A82中任一項所述之化合物或其藥學上可接受的鹽，係其中具有式 (ii) 的E3泛素連接酶配位基係。A82A. In embodiment A82A, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A39b and A41 to A82, wherein the E3 ubiquitin ligase ligand of formula (ii) is .

A83. 在實施方式A83中，如實施方式A1A至A39b和A41至A82中任一項所述之化合物或其藥學上可接受的鹽，係其中具有式 (ii) 的E3泛素連接酶配位基係：、、、、、、、、、、或。A83. In embodiment A83, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A39b and A41 to A82, wherein the E3 ubiquitin ligase ligand of formula (ii) is: 、 、 、 、 、 、 、 、 、 、 or .

A83A.    在實施方式A83A中，如實施方式A1A至A39b和A41至A82和A83中任一項所述之化合物或其藥學上可接受的鹽，係其中具有式 (ii) 的E3泛素連接酶配位基係或。A83A. In embodiment A83A, the compound of any one of embodiments A1A to A39b and A41 to A82 and A83, or a pharmaceutically acceptable salt thereof, wherein the E3 ubiquitin ligase ligand of formula (ii) is or .

A84. 在實施方式A84中，如實施方式A1A至A39b和A41至A83A中任一項所述之化合物或其藥學上可接受的鹽，係其中每個R^ee和R^ff獨立地選自氫、烷基、烷氧基、鹵代、氰基、鹵代烷基和鹵代烷氧基，除非另有說明。A84. In embodiment A84, the compound as described in any one of embodiments A1A to A39b and A41 to A83A, or a pharmaceutically acceptable salt thereof, is wherein each R^ee and R^ff is independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, and haloalkoxy, unless otherwise indicated.

A85. 在實施方式A85中，如實施方式A1A至A39b和A41至A84中任一項所述之化合物或其藥學上可接受的鹽，係其中R^ee和R^ff獨立地選自氫、烷基、環烷基、烷氧基、鹵代、鹵代烷基和氰基，除非另有說明。A85. In embodiment A85, the compound as described in any one of embodiments A1A to A39b and A41 to A84, or a pharmaceutically acceptable salt thereof, is wherein R^ee and R^ff are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and cyano, unless otherwise indicated.

A86. 在實施方式A86中，如實施方式A1A至A39b和A41至A85中任一項所述之化合物或其藥學上可接受的鹽，係其中R^ee和R^ff獨立地選自氫、甲基、乙基、異丙基、環丙基、甲氧基、乙氧基、氟、氯、三氟甲基、2,2,2-三氟乙基、二氟甲基、二氟甲氧基、三氟甲氧基和氰基，除非另有說明。A86. In embodiment A86, the compound as described in any one of embodiments A1A to A39b and A41 to A85, or a pharmaceutically acceptable salt thereof, is wherein R^ee and R^ff are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, and cyano, unless otherwise indicated.

A87. 在實施方式A87中，如實施方式A1A至A39b和A41至A86中任一項所述之化合物或其藥學上可接受的鹽，係其中R^ee和R^ff獨立地選自氫、甲基、乙基和異丙基，除非另有說明。A87. In embodiment A87, the compound as described in any one of embodiments A1A to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein R^ee and R^ff are independently selected from hydrogen, methyl, ethyl and isopropyl, unless otherwise indicated.

A88. 在實施方式A88中，如實施方式A1A至A39b和A41至A86中任一項所述之化合物或其藥學上可接受的鹽，係其中R^ee和R^ff獨立地選自氫和甲氧基，除非另有說明。A88. In embodiment A88, the compound as described in any one of embodiments A1A to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein R^ee and R^ff are independently selected from hydrogen and methoxy, unless otherwise indicated.

A89. 在實施方式A89中，如實施方式A1A至A39b和A41至A86中任一項所述之化合物或其藥學上可接受的鹽，係其中R^ee和R^ff獨立地選自氫、甲基、乙基、異丙基、氯和氟，除非另有說明。A89. In embodiment A89, the compound as described in any one of embodiments A1A to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein R^ee and R^ff are independently selected from hydrogen, methyl, ethyl, isopropyl, chloro and fluoro, unless otherwise indicated.

A90. 在實施方式A90中，如實施方式A1A至A39b、A41至A86中任一項所述之化合物或其藥學上可接受的鹽，係其中R^ee和R^ff中之一個係氫或氟並且R^ee和R^ff中的另一個選自氫、三氟甲基、2,2,2-三氟乙基和二氟甲基，除非另有說明。A90. In embodiment A90, the compound as described in any one of embodiments A1A to A39b, A41 to A86, or a pharmaceutically acceptable salt thereof, wherein one of R^ee and R^ff is hydrogen or fluorine and the other of R^ee and R^ff is selected from hydrogen, trifluoromethyl, 2,2,2-trifluoroethyl and difluoromethyl, unless otherwise specified.

A91. 在實施方式A91中，如實施方式A1A至A39b和A41至A86中任一項所述之化合物或其藥學上可接受的鹽，係其中R^ee和R^ff獨立地選自氫、二氟甲氧基和三氟甲氧基，除非另有說明。A91. In embodiment A91, the compound as described in any one of embodiments A1A to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein R^ee and R^ff are independently selected from hydrogen, difluoromethoxy, and trifluoromethoxy, unless otherwise indicated.

A92. 在實施方式A92中，如實施方式A1A至A39b和A41至A86中任一項所述之化合物或其藥學上可接受的鹽，係其中R^ee和R^ff獨立地選自氫、氯、氟和三氟甲基，除非另有說明。A92. In embodiment A92, the compound as described in any one of embodiments A1A to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein R^ee and R^ff are independently selected from hydrogen, chloro, fluoro, and trifluoromethyl, unless otherwise indicated.

A93. 在實施方式A93中，如實施方式A1A至A39b和A41至A86中任一項所述之化合物或其藥學上可接受的鹽，係其中R^ee和R^ff係氫。A93. In embodiment A93, the compound of any one of embodiments A1A to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, wherein R^ee and R^ff are hydrogen.

A94. 在實施方式A94中，如實施方式A1A至A39b和A41至A86中任一項所述之化合物或其藥學上可接受的鹽，係其中R^ee和R^ff係氯，除非另有說明。A94. In embodiment A94, the compound as described in any one of embodiments A1A to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein R^ee and R^ff are chloro, unless otherwise indicated.

A95. 在實施方式A95中，如實施方式A1A至A39b和A41至A86中任一項所述之化合物或其藥學上可接受的鹽，係其中R^ee和R^ff係氟，除非另有說明。A95. In embodiment A95, the compound as described in any one of embodiments A1A to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein R^ee and R^ff are fluoro, unless otherwise indicated.

A96. 在實施方式A96中，如實施方式A1A至A39b和A41至A86中任一項所述之化合物或其藥學上可接受的鹽，係其中R^ee和R^ff獨立地是三氟甲基或2,2,2-三氟乙基，除非另有說明。A96. In embodiment A96, the compound as described in any one of embodiments A1A to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein R^ee and R^ff are independently trifluoromethyl or 2,2,2-trifluoroethyl, unless otherwise indicated.

A97a.     在實施方式A97a中，如實施方式A1A和A2至A96中任一項所述之化合物或其藥學上可接受的鹽，係其中Ar係伸苯基、單環雜伸芳基、橋接雜亞環基、雜亞環基或不飽和雜亞環基^X，其中每個環被R^j、R^k和R^m取代，其中R^m係氫。A97a. In embodiment A97a, the compound as described in any one of embodiments A1A and A2 to A96, or a pharmaceutically acceptable salt thereof, wherein Ar is a phenylene group, a monocyclic heteroarylene group, a bridged heterocycloalkylene group, a heterocycloalkylene group, or an unsaturated heterocycloalkylene group^X , wherein each ring is substituted with^Rj ,^Rk , and^Rm , wherein^Rm is hydrogen.

A97. 在實施方式A97中，如實施方式A1A至A97a中任一項所述之化合物或其藥學上可接受的鹽，係其中Ar係伸苯基、單環雜伸芳基、橋接雜亞環基或雜亞環基，其中每個環被R^j、R^k和R^m取代，其中R^m係氫。A97. In embodiment A97, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A97a, wherein Ar is phenylene, monocyclic heteroarylene, bridged heterocycloalkylene, or heterocycloalkylene, wherein each ring is substituted with^Rj ,^Rk , and^Rm , wherein^Rm is hydrogen.

A98. 在實施方式A98中，如實施方式A1A至A97中任一項所述之化合物或其藥學上可接受的鹽，係其中-Ar-係被R^j、R^k和R^m取代的具有式或的伸苯基（即，Ar，係其中alk和SO₂附接在伸苯基環的間位或對位的伸苯基），其中R^j和R^k獨立地選自氫、烷基、烷氧基、鹵代、氰基、鹵代烷基和鹵代烷氧基，並且R^m係氫。A98. In embodiment A98, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A97 is wherein -Ar- is substituted by R^j , R^k and R^m and has the formula or phenylene (i.e., Ar is a phenylene group in which alk and SO₂ are attached at the meta or para position of the phenylene ring), wherein R^j and R^k are independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl and haloalkoxy, and R^m is hydrogen.

A99. 在實施方式A99中，如實施方式A1A至A98中任一項所述之化合物或其藥學上可接受的鹽，係其中-Ar-的伸苯基係被R^j、R^k和R^m取代的或，其中R^j和R^k獨立地選自氫、氘、甲基、甲氧基、氟、氯、氰基、二氟甲基、三氟甲基、二氟甲氧基和三氟甲氧基，並且R^m係氫。A99. In embodiment A99, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A98, wherein the phenyl group of -Ar- is substituted by^Rj ,^Rk and Rm^. or , wherein R^j and R^k are independently selected from hydrogen, deuterium, methyl, methoxy, fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy, and R^m is hydrogen.

A100.     在實施方式A100中，如實施方式A1A至A99中任一項所述之化合物或其藥學上可接受的鹽，係其中-Ar-的伸苯基係被R^j、R^k和R^m取代的或，其中R^j和R^k獨立地選自氫、氟、氰基或三氟甲基，並且R^m係氫。A100. In embodiment A100, the compound or a pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A99, wherein the phenyl group of -Ar- is substituted by R^j , R^k and R^m or , wherein^Rj and^Rk are independently selected from hydrogen, fluorine, cyano or trifluoromethyl, and^Rm is hydrogen.

A101-1.  在實施方式A101-1中，如實施方式A1A至A100中任一項所述之化合物或其藥學上可接受的鹽，係其中-Ar-的伸苯基係。A101-1. In embodiment A101-1, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A100, wherein -Ar- is a phenyl group. .

A101.     在實施方式A101中，如實施方式A1A至A100中任一項所述之化合物或其藥學上可接受的鹽，係其中-Ar-的伸苯基係。A101. In embodiment A101, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A100, wherein -Ar- is a phenyl group. .

A102.     在實施方式A102中，如實施方式A1A至A97中任一項所述之化合物或其藥學上可接受的鹽，係其中-Ar-係被R^j、R^k和R^m取代的單環雜伸芳基（如咪唑-1,5-二基、吡啶-2,4-二基、吡啶-2,6-二基、吡啶-2,5-二基或吡啶-3,5-二基），其中R^j和R^k獨立地選自氫、烷基、烷氧基、鹵代、鹵代烷基、氰基和鹵代烷氧基，並且R^m係氫。A102. In embodiment A102, the compound as described in any one of embodiments A1A to A97, or a pharmaceutically acceptable salt thereof, is wherein -Ar- is a monocyclic heteroaryl group substituted with^Rj ,^Rk , and^Rm (such as imidazole-1,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl, pyridine-2,5-diyl, or pyridine-3,5-diyl), wherein^Rj and^Rk are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, cyano, and haloalkoxy, and^Rm is hydrogen.

A103.     在實施方式A103中，如實施方式A1A至A97和A99至A102中任一項所述之化合物或其藥學上可接受的鹽，係其中-Ar-的單環雜伸芳基係咪唑-2,5-二基、吡啶-2,4-二基、吡啶-2,6-二基、吡啶-2,5-二基或吡啶-3,5-二基，每個環被R^j、R^k和R^m取代，其中R^j和R^k獨立地選自氫、甲基、甲氧基、氟、氯、二氟甲基、三氟甲基、2,2,2-三氟乙基、二氟甲氧基和三氟甲氧基，並且R^m係氫。A103. In embodiment A103, the compound as described in any one of embodiments A1A to A97 and A99 to A102, or a pharmaceutically acceptable salt thereof, is wherein the monocyclic heteroaryl of -Ar- is imidazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl, pyridine-2,5-diyl or pyridine-3,5-diyl, each ring is substituted by R^j , R^k and R^m , wherein R^j and R^k are independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy and trifluoromethoxy, and R^m is hydrogen.

A104.     在實施方式A104中，如實施方式A1A至A97和A99至A103中任一項所述之化合物或其藥學上可接受的鹽，係其中-Ar-的單環雜伸芳基係咪唑-2,5-二基、吡啶-2,4-二基、吡啶-2,6-二基或吡啶-3,5-二基，每個環被R^j、R^k和R^m取代，其中R^j和R^k獨立地選自氫、甲基、甲氧基、氟、氯、二氟甲基、三氟甲基、二氟甲氧基和三氟甲氧基，並且R^m係氫。A104. In embodiment A104, the compound as described in any one of embodiments A1A to A97 and A99 to A103, or a pharmaceutically acceptable salt thereof, is wherein the monocyclic heteroaryl of -Ar- is imidazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl, or pyridine-3,5-diyl, each ring being substituted by R^j , R^k and R^m , wherein R^j and R^k are independently selected from hydrogen, methyl, methoxy, fluorine, chlorine, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy, and R^m is hydrogen.

A105.     在實施方式A105中，如實施方式A1A至A97中任一項所述之化合物或其藥學上可接受的鹽，係其中-Ar-係被R^j、R^k和R^m取代的雜亞環基，其中R^j和R^k獨立地選自氫、甲基、甲氧基、氟、氯、二氟甲基、三氟甲基、2,2,2-三氟乙基、二氟甲氧基和三氟甲氧基，並且R^m係氫。A105. In embodiment A105, the compound as described in any one of embodiments A1A to A97, or a pharmaceutically acceptable salt thereof, is wherein -Ar- is a heterocycloalkyl substituted with R^j , R^k and R^m , wherein R^j and R^k are independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy and trifluoromethoxy, and R^m is hydrogen.

A106.     在實施方式A106中，如實施方式A1A至A97、A99至A101和A103至A105中任一項所述之化合物或其藥學上可接受的鹽，係其中-Ar-的雜亞環基係二價四氫吖唉基、吡咯啶基、哌𠯤基或哌啶基。A107.  在實施方式A107中，如實施方式A1A至A97中任一項所述之化合物或其藥學上可接受的鹽，係其中-Ar-係橋接雜亞環基。A106. In embodiment A106, the compound as described in any one of embodiments A1A to A97, A99 to A101 and A103 to A105, or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group of -Ar- is a divalent tetrahydroazide, pyrrolidinyl, piperidine or piperidinyl. A107. In embodiment A107, the compound as described in any one of embodiments A1A to A97, or a pharmaceutically acceptable salt thereof, wherein -Ar- is a bridged heterocyclic group.

A108a.   在實施方式A108a中，如實施方式A1A和A2至A97a中任一項所述之化合物或其藥學上可接受的鹽，係其中Ar係被R^j、R^k和R^m取代的不飽和雜亞環基^X，其中R^m係氫。A108a. In embodiment A108a, the compound as described in any one of embodiments A1A and A2 to A97a, or a pharmaceutically acceptable salt thereof, is wherein Ar is an unsaturated heterocycloalkylene group^X substituted with R^j , R^k and R^m , wherein R^m is hydrogen.

A108b.   在實施方式A108b中，如實施方式A1A和A2至A97a、A99至A101、A103、A104、A106和108a中任一項所述之化合物或其藥學上可接受的鹽，係其中不飽和雜亞環基^X係、或。A108b. In embodiment A108b, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A and A2 to A97a, A99 to A101, A103, A104, A106 and 108a, wherein the unsaturated heterocyclic group^X is 、 or .

A108.     在實施方式A108中，如實施方式A1A至A97、A99至A101、A103、A104、A106和A107中任一項所述之化合物或其藥學上可接受的鹽，係其中-Ar-的橋接雜亞環基選自：A108. In embodiment A108, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A97, A99 to A101, A103, A104, A106 and A107, wherein the bridged heterocyclic group of -Ar- is selected from:

A109.     在實施方式A109中，如實施方式A1A至A108中任一項所述之化合物或其藥學上可接受的鹽，係其中Z係環伸烷基，其選自環亞丙基、環亞丁基、環亞戊基和環亞己基並且如其中所定義的被取代。A109. In embodiment A109, the compound as described in any one of embodiments A1A to A108, or a pharmaceutically acceptable salt thereof, is wherein Z is a cycloalkylene group selected from cyclopropylene, cyclobutylene, cyclopentylene and cyclohexylene and is substituted as defined therein.

A110.     在實施方式A110中，如實施方式A1A至A109中任一項所述之化合物或其藥學上可接受的鹽，係其中Z的環伸烷基獨立地選自1,3-環亞戊基、1,3-環亞己基和1,4-環亞己基。A110. In embodiment A110, the compound as described in any one of embodiments A1A to A109 or a pharmaceutically acceptable salt thereof, wherein the cycloalkylene group of Z is independently selected from 1,3-cyclopentylene, 1,3-cyclohexylene and 1,4-cyclohexylene.

A111.     在實施方式A111中，如實施方式A1A至A108和A110中任一項所述之化合物或其藥學上可接受的鹽，係其中Z係伸苯基或單環雜伸芳基（如咪唑二基、吡啶二基和嘧啶二基）並且被如其中所定義的R^d和R^e取代。A111. In embodiment A111, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A108 and A110, wherein Z is phenyl or monocyclic heteroaryl (such as imidazolediyl, pyridinediyl and pyrimidinediyl) and is substituted by R^d and^Re as defined therein.

A112.     在實施方式A112中，如實施方式A1A至A108和A111中任一項所述之化合物或其藥學上可接受的鹽，係其中Z係單環雜伸芳基，其選自咪唑-2,5-二基、吡啶-2,4-二基、吡啶-2,6-二基和吡啶-3,5-二基。A112. In embodiment A112, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A108 and A111 is wherein Z is a monocyclic heteroaryl group selected from imidazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl and pyridine-3,5-diyl.

A113.     在實施方式A113中，如實施方式A1A至A108和A111中任一項所述之化合物或其藥學上可接受的鹽，係其中Z係1,3-伸苯基或1,4-伸苯基。A113. In embodiment A113, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A108 and A111, wherein Z is 1,3-phenylene or 1,4-phenylene.

A114.     在實施方式A114中，如實施方式A1A至A108中任一項所述之化合物或其藥學上可接受的鹽，係其中Z係雜亞環基、橋接雜亞環基或螺雜亞環基，每個環被如其中所定義的R^d和R^e取代。A114. In embodiment A114, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A108, wherein Z is a heterocycloalkylene, a bridged heterocycloalkylene, or a spiroheterocycloalkylene, each ring being substituted with R^d and^Re as defined therein.

A115.     在實施方式A115中，如實施方式A1A至A108和A114中任一項所述之化合物或其藥學上可接受的鹽，係其中Z的雜亞環基、橋接雜亞環基和螺雜亞環基選自：其中每個環被獨立地選自氫、氘、烷基和鹵代的R^d和R^e取代。A115. In embodiment A115, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A108 and A114, wherein the heterocyclic group, bridged heterocyclic group, and spiroheterocyclic group of Z is selected from: wherein each ring is substituted with R^d and^Re independently selected from hydrogen, deuterium, alkyl, and halogen.

A116.     在實施方式A116中，如實施方式A1A至A108、A114和A115中任一項所述之化合物或其藥學上可接受的鹽，係其中Z的雜亞環基、橋接雜亞環基和螺雜亞環基分別獨立地選自：。A116. In embodiment A116, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A108, A114 and A115, wherein the heterocyclic group, bridged heterocyclic group and spiroheterocyclic group of Z are independently selected from: .

A117.     在實施方式A117中，如實施方式A1A至A108和A114至A116中任一項所述之化合物或其藥學上可接受的鹽，係其中Z係選自以下的雜亞環基：A117. In embodiment A117, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A108 and A114 to A116, wherein Z is a heterocyclic group selected from the following:

A118.     在實施方式A118中，如實施方式A1A至A108和A114至A117中任一項所述之化合物或其藥學上可接受的鹽，係其中Z係雜亞環基、。A118. In embodiment A118, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A108 and A114 to A117, wherein Z is a heterocyclic group, .

A119.     在實施方式A119中，如實施方式A1A至A108中任一項所述之化合物或其藥學上可接受的鹽，係其中Z係-O-、-NH-或-NCH₃-。A119. In embodiment A119, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A108, wherein Z is -O-, -NH-, or -NCH₃ -.

A120.     在實施方式A120中，如實施方式A1A至A98和A114中任一項所述之化合物或其藥學上可接受的鹽，係其中-Z-alk-Ar-SO₂-係：其中每個R^d、R^e和R^k獨立地選自氫、烷基、鹵代、鹵代烷基、鹵代烷氧基、烷氧基和氰基，並且R^j係氫。A120. In embodiment A120, the compound as described in any one of embodiments A1A to A98 and A114, or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SO₂ - is: wherein each of R^d ,^Re and R^k is independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy and cyano, and R^j is hydrogen.

A121.     在實施方式A121中，如實施方式A1A至A98、A114和A120中任一項所述之化合物或其藥學上可接受的鹽，係其中-Z-alk-Ar-SO₂-係：其中每個R^d、R^e和R^k獨立地選自氫、烷基、鹵代、鹵代烷基、鹵代烷氧基、烷氧基和氰基，並且R^j係氫。A121. In embodiment A121, the compound as described in any one of embodiments A1A to A98, A114 and A120, or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SO₂ - is: wherein each of R^d ,^Re and R^k is independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy and cyano, and R^j is hydrogen.

A122.     在實施方式A122中，如實施方式A1A至A98、A114和A120中任一項所述之化合物或其藥學上可接受的鹽，係其中-Z-alk-Ar-SO₂-係：其中每個R^d、R^e和R^k獨立地選自氫、烷基、鹵代、鹵代烷基、鹵代烷氧基、烷氧基和氰基，並且R^j係氫。A122. In embodiment A122, the compound as described in any one of embodiments A1A to A98, A114 and A120, or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SO₂ - is: wherein each of R^d ,^Re and R^k is independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy and cyano, and R^j is hydrogen.

A123.     在實施方式A123中，如實施方式A1A至A98、A114、A120和A121中任一項所述之化合物或其藥學上可接受的鹽，係其中-Z-alk-Ar-SO₂-係：其中R^d、R^e和R^k係如其中所定義的。A123. In embodiment A123, the compound as described in any one of embodiments A1A to A98, A114, A120 and A121, or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SO₂ - is: wherein R^d ,^Re and R^k are as defined herein.

A124.     在實施方式A124中，如實施方式A1A至A98、A114、A120和A121中任一項所述之化合物或其藥學上可接受的鹽，係其中-Z-alk-Ar-SO₂-係：其中R^d、R^e和R^k係如其中所定義的。A124. In embodiment A124, the compound as described in any one of embodiments A1A to A98, A114, A120 and A121, or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SO₂ - is: wherein R^d ,^Re and R^k are as defined herein.

A125.     在實施方式A125中，如實施方式A1A至A98、A114、A120和A121中任一項所述之化合物或其藥學上可接受的鹽，係其中-Z-alk-Ar-SO₂-係：其中R^d、R^e和R^k係如其中所定義的。A125. In embodiment A125, the compound as described in any one of embodiments A1A to A98, A114, A120 and A121, or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SO₂ - is: wherein R^d ,^Re and R^k are as defined herein.

A126.     在實施方式A126中，如實施方式A1A至A98、A114、A120和A121中任一項所述之化合物或其藥學上可接受的鹽，係其中-Z-alk-Ar-SO₂-係：其中R^d、R^e和R^k係如其中所定義的。A126. In embodiment A126, the compound as described in any one of embodiments A1A to A98, A114, A120 and A121, or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SO₂ - is: wherein R^d ,^Re and R^k are as defined herein.

A127.     在實施方式A127中，如實施方式A1A至A98、A114、A120和A121中任一項所述之化合物或其藥學上可接受的鹽，係其中-Z-alk-Ar-SO₂-係：其中R^d、R^e和R^k係如其中所定義的。A127. In embodiment A127, the compound as described in any one of embodiments A1A to A98, A114, A120 and A121, or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SO₂ - is: wherein R^d ,^Re and R^k are as defined herein.

A128.     在實施方式A128中，如實施方式A1A至A98、A114、A120和A122中任一項所述之化合物或其藥學上可接受的鹽，係其中-Z-alk-Ar-SO₂-係：其中R^d、R^e和R^k係如其中所定義的。A128. In embodiment A128, the compound as described in any one of embodiments A1A to A98, A114, A120 and A122, or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SO₂ - is: wherein R^d ,^Re and R^k are as defined herein.

A129.     在實施方式A129中，如實施方式A1A至A98、A114、A120和A122中任一項所述之化合物或其藥學上可接受的鹽，係其中-Z-alk-Ar-SO₂-係：其中R^d、R^e和R^k係如其中所定義的。A129. In embodiment A129, the compound as described in any one of embodiments A1A to A98, A114, A120 and A122, or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SO₂ - is: wherein R^d ,^Re and R^k are as defined herein.

A130.     在實施方式A130中，如實施方式A1A至A98、A114、A120和A122中任一項所述之化合物或其藥學上可接受的鹽，係其中-Z-alk-Ar-SO₂-係：其中R^d、R^e和R^k係如其中所定義的。A130. In embodiment A130, the compound as described in any one of embodiments A1A to A98, A114, A120 and A122, or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SO₂ - is: wherein R^d ,^Re and R^k are as defined herein.

A131.     在實施方式A131中，如實施方式A1A至A98、A114、A120和A122中任一項所述之化合物或其藥學上可接受的鹽，係其中-Z-alk-Ar-SO₂-係：其中R^d、R^e和R^k係如其中所定義的。A131. In embodiment A131, the compound as described in any one of embodiments A1A to A98, A114, A120 and A122, or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SO₂ - is: wherein R^d ,^Re and R^k are as defined herein.

A132.     在實施方式A132中，如實施方式A1A至A98、A114、A120和A122中任一項所述之化合物或其藥學上可接受的鹽，係其中-Z-alk-Ar-SO₂-係：其中R^d、R^e和R^k係如其中所定義的。A132. In embodiment A132, the compound as described in any one of embodiments A1A to A98, A114, A120 and A122, or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SO₂ - is: wherein R^d ,^Re and R^k are as defined herein.

A133.     在實施方式A133中，如實施方式A1A至A98、A114、A120、A121和A123至A127中任一項所述之化合物或其藥學上可接受的鹽，係其中（即，Ar）係：。A133. In embodiment A133, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A98, A114, A120, A121 and A123 to A127 is (i.e., Ar) is: .

A134.     在實施方式A134中，如實施方式A1A至A98、A114、A120、A121、A123至A127和A133中任一項所述之化合物或其藥學上可接受的鹽，係其中係、或（即，Ar）。A134. In embodiment A134, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A98, A114, A120, A121, A123 to A127 and A133 is wherein Department 、 or (i.e., Ar).

A135.     在實施方式A135中，如實施方式A1A至A134中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係被R^f取代的C₃至C₆伸烯基，其中R^f係氫。A135. In embodiment A135, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A134, wherein alk is C₃ to C₆ alkenyl substituted with R^f , wherein R^f is hydrogen.

A136.     在實施方式A136中，如實施方式A1A至A134中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係被R^f取代的C₃至C₆伸烯基，其中R^f係氟或氰基。A136. In embodiment A136, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A134, wherein alk is C₃ to C₆ alkenyl substituted with R^f , wherein R^f is fluoro or cyano.

A137.     在實施方式A137中，如實施方式A1A至A134中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，其中R^g、R^h和Rⁱ係氫。A137. In embodiment A137, the compound as described in any one of embodiments A1A to A134, or a pharmaceutically acceptable salt thereof, wherein alk is C₃ to C₆ alkylene substituted with R^g , R^h and Rⁱ , wherein R^g , R^h and Rⁱ are hydrogen.

A138.     在實施方式A138中，如實施方式A1A至A134中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，其中R^g、R^h和Rⁱ係氫或鹵代，條件係R^g、R^h和Rⁱ中之至少一個係鹵代。A138. In embodiment A138, the compound as described in any one of embodiments A1A to A134, or a pharmaceutically acceptable salt thereof, is wherein alk is a C₃ to C₆ alkylene substituted with R^g , R^h and Rⁱ , wherein R^g , R^h and Rⁱ are hydrogen or halogenated, with the proviso that at least one of R^g , R^h and Rⁱ is halogenated.

A139.     在實施方式A139中，如實施方式A138所述之化合物或其藥學上可接受的鹽，係其中R^g、R^h和Rⁱ中之至少一個的鹵代係氟。A139. In embodiment A139, the compound according to embodiment A138 or a pharmaceutically acceptable salt thereof, wherein at least one of R^g , R^h and Rⁱ is halogenated and is fluoro.

A140.     在實施方式A140中，如實施方式A1A至A134中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，其中R^h不是氫並且Rⁱ係氫，或者當R^g和R^h附接至該C₃至C₆伸烷基的直鏈部分的相同碳或相鄰碳原子時，R^g和R^h可與它們所附接的碳原子一起形成環伸烷基或雜亞環基，其中由R^g和R^h形成的該環伸烷基和雜亞環基被R⁹和R¹⁰取代。A140. In embodiment A140, the compound as described in any one of embodiments A1A to A134, or a pharmaceutically acceptable salt thereof, is a C₃ to C₆ alkylene group substituted with R^g , R^h , and Rⁱ , wherein R^h is not hydrogen and Rⁱ is hydrogen, or when R^g and R^h are attached to the same carbon or adjacent carbon atoms of the straight chain portion of the C₃ to C₆ alkylene group, R^g and R^h may be taken together with the carbon atoms to which they are attached to form a cycloalkylene group or a heterocycloalkylene group, wherein the cycloalkylene group and heterocycloalkylene group formed by R^g and R^h are substituted with R⁹ and R¹⁰ .

A141.     在實施方式A141中，如實施方式A140中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，其中R^h不是氫並且Rⁱ係氫。A141. In embodiment A141, the compound as described in any one of embodiments A140, or a pharmaceutically acceptable salt thereof, is wherein alk is C₃ to C₆ alkylene substituted with R^g , R^h and Rⁱ , wherein R^h is not hydrogen and Rⁱ is hydrogen.

A142.     在實施方式A142中，如實施方式A1A至141中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的C₃至C₆伸烯基和C₃至C₆伸烷基分別是直鏈伸烯基和伸烷基並且如其中所定義的被取代。A142. In embodiment A142, the compound as described in any one of embodiments A1A to 141, or a pharmaceutically acceptable salt thereof, wherein the C₃ to C₆ alkenylene and C₃ to C₆ alkylene of alk are linear alkenylene and alkylene, respectively, and are substituted as defined therein.

A143.     在實施方式A143中，如實施方式A1A至A136和A140至A142中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的該直鏈C₃至C₆伸烯基係-CH=C(R^f)CH₂-，並且alk的C₃至C₆伸烷基的直鏈伸烷基係-CH₂CH(R^h)CH₂-、-CH₂CH₂CH(R^h)-、-CH₂C(R^g)(R^h)CH₂-、-CH₂CH₂C(R^g)(R^h)-，其中R^h不是氫並且Rⁱ係氫。A143. In embodiment A143, the compound as described in any one of embodiments A1A to A136 and A140 to A142, or a pharmaceutically acceptable salt thereof, is wherein the linear C₃ to C₆ alkenylene of alk is -CH═C(R^f )CH₂ -, and the linear alkylene of the C₃ to C₆ alkylene of alk is -CH₂ CH(R^h )CH₂ -, -CH₂ CH₂ CH(R^h )-, -CH₂ C(R^g )(R^h )CH₂ -, -CH₂ CH₂ C(R^g )(R^h )-, wherein R^h is not hydrogen and Rⁱ is hydrogen.

A144.     在實施方式A144中，如實施方式A1A至A134和A140至A143中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的該直鏈C₃至C₆伸烷基係-CH₂CH(R^h)CH₂-，其中R^h不是氫並且Rⁱ係氫。A144. In embodiment A144, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A134 and A140 to A143, wherein the linear C₃ to C₆ alkylene group of alk is -CH₂ CH(R^h )CH₂ -, wherein R^h is not hydrogen and Rⁱ is hydrogen.

A145.     在實施方式A145中，如實施方式A1A至A134和A140至A144中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的直鏈C₃至C₆伸烷基的R^g係氫、氘或鹵代，並且alk的直鏈C₃至C₆伸烷基的R^h係鹵代、鹵代烷氧基、環烷基、環烷基氧基、烷氧基、羥基、胺基羰基、烷基胺基羰基、二烷基胺基羰基、烷基羰基胺基、氰基、氰基烷基氧基、苯基、雜芳基、雜環基或橋接雜環基，每個環如其中所定義的被取代，除非另有說明。A145. In embodiment A145, the compound as described in any one of embodiments A1A to A134 and A140 to A144, or a pharmaceutically acceptable salt thereof, is wherein^Rg of the linear_C3 to_C6 alkylene group of alk is hydrogen, deuterium or halogenated, and^Rh of the linear_C3 to_C6 alkylene group of alk is halogenated, halogenated alkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclic or bridged heterocyclic, each ring being substituted as defined herein unless otherwise specified.

A146.     在實施方式A146中，如實施方式A1A至A134和A140至A145中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的直鏈C₃至C₆伸烷基的R^g係氫，並且alk的直鏈C₃至C₆伸烷基的R^h係鹵代、鹵代烷氧基、環烷基、環烷基氧基、烷氧基、羥基、二烷基胺基羰基、烷基羰基胺基、氰基、苯基、雜芳基、雜環基或橋接雜環基，每個環如其中所定義的被取代。A146. In embodiment A146, the compound as described in any one of embodiments A1A to A134 and A140 to A145, or a pharmaceutically acceptable salt thereof, is wherein^Rg of the linear_C3 to_C6 alkylene group of alk is hydrogen, and^Rh of the linear_C3 to_C6 alkylene group of alk is halogenated, halogenated alkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclic or bridged heterocyclic, each ring being substituted as defined therein.

A147.     在實施方式A147中，如實施方式A1A至A134和A140至A146中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的直鏈C₃至C₆伸烷基的R^g係氫，並且alk的直鏈C₃至C₆伸烷基的R^h係鹵代、鹵代烷氧基、烷氧基、羥基、二烷基胺基羰基、氰基、雜環基或雜芳基，每個環如其中所定義的被取代。A147. In embodiment A147, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A134 and A140 to A146, wherein^Rg of the linear_C3 to_C6 alkylene group of alk is hydrogen, and^Rh of the linear_C3 to_C6 alkylene group of alk is halogenated, halogenated alkoxy, alkoxy, hydroxyl, dialkylaminocarbonyl, cyano, heterocyclic or heteroaryl, each ring being substituted as defined therein.

A148.     在實施方式A148中，如實施方式A1A至A134和A140至A147中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的直鏈C₃至C₆伸烷基的R^h的雜芳基、雜環基和橋接雜環基，當存在時，係五員或六員環，並且每個環如其中所定義的被取代。A148. In embodiment A148, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A134 and A140 to A147 is wherein the heteroaryl, heterocyclic and bridged heterocyclic groups of^Rh of the linear_C3 to_C6 alkylene group of alk, when present, are five-membered or six-membered rings, and each ring is substituted as defined therein.

A149.     在實施方式A149中，如實施方式A1A至A134和A140至A148中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的直鏈C₃至C₆伸烷基的R^g係氫、氘或氟，除非另有說明，並且alk的直鏈C₃至C₆伸烷基的R^h係氟、環丙基、環丁基、環丙基氧基、環丁基氧基、二氟甲氧基、三氟甲氧基、甲氧基、乙氧基、羥基、氰基、胺基羰基、甲基胺基羰基、二甲基胺基羰基、二乙基胺基羰基、甲基羰基胺基、乙基羰基胺基、苯基、吡唑基、呋喃基、噻唑基、吡啶基、吡咯啶基、2-側氧基吡咯啶基、哌啶基、哌𠯤基或四氫呋喃基，其中R^h的每個環被獨立地選自氫、氘、甲基、甲氧基、氟、二氟甲基、三氟甲基、二氟甲氧基、三氟甲基、羥基、胺基、甲基胺基、二甲基胺基和氰基的R⁷和R⁸取代，除非另有說明。A149. In embodiment A149, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A134 and A140 to A148, wherein^Rg of the linear_C3 to_C6 alkylene group of alk is hydrogen, deuterium or fluorine, unless otherwise specified, and Rg of the linear_C3 to_C6 alkylene group of alk is^R is fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, furanyl, thiazolyl, pyridyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, piperonyl or tetrahydrofuranyl, wherein each ring of R is substituted with R^{and R} independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino,^methylamino , dimethylamino and^cyano , unless otherwise specified.

A149A.  在實施方式A149A中，如實施方式A1A至A134和A140至A149中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的直鏈C₃至C₆伸烷基的R^g係氫、氘或氟，除非另有說明，並且alk的直鏈C₃至C₆伸烷基的R^h係氟、環丙基、環丙基氧基、二氟甲氧基、三氟甲氧基、甲氧基、乙氧基、羥基、氰基、甲基胺基羰基、二甲基胺基羰基、甲基羰基胺基、苯基、吡唑-1-基、吡唑-4-基、吡啶-4-基、吡咯啶-1-基、2-側氧基吡咯啶-1-基，其中R^h的每個環被獨立地選自氫、氘、甲基或氟的R⁷和R⁸取代，除非另有說明。A149A. In embodiment A149A, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A134 and A140 to A149 is wherein^Rg of the linear_C3 to_C6 alkylene group of alk is hydrogen, deuterium or fluorine, unless otherwise specified, and^Rh of the linear_C3 to_C6 alkylene group of alk is fluorine, cyclopropyl, cyclopropyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxyl, cyano, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonylamino, phenyl, pyrazol-1-yl, pyrazol-4-yl, pyridin-4-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, wherein each ring of^Rh is independently selected from^R7 and R7 of hydrogen, deuterium, methyl or fluorine.⁸ substituted unless otherwise stated.

A150.     在實施方式A150中，如實施方式A1A至A134中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係被如其中所定義的R^g、R^h和Rⁱ取代的支鏈C₄至C₆伸烷基。A150. In embodiment A150, the compound according to any one of embodiments A1A to A134, or a pharmaceutically acceptable salt thereof, wherein alk is a branched C₄ -C₆ alkylene substituted with R^g , R^h and Rⁱ as defined therein.

A151.     在實施方式A151中，如實施方式A1A至A138和A150中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的C₃至C₆伸烯基和C₃至C₆伸烷基分別是支鏈C₄至C₆伸烯基和C₄至C₆伸烷基，其中該C₄至C₆伸烷基被如其中所定義的R^g、R^h和Rⁱ取代。A151. In embodiment A151, the compound as described in any one of embodiments A1A to A138 and A150, or a pharmaceutically acceptable salt thereof, wherein the_C3 to_C6 alkenyl and_C3 to_C6 alkylene of alk are branched_C4 to_C6 alkenyl and_C4 to_C6 alkylene, respectively, wherein the_C4 to_C6 alkylene is substituted with^Rg ,^Rh and^Ri as defined therein.

A152.     在實施方式A152中，如實施方式A1A至A138、A150和A151中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的該支鏈C₄至C₆伸烯基係-CH₂CH₂C(CH₃)=C(R^f)-、-CH₂C(CH₃)=C(R^f)-或-CH₂C(=CH₂)CH₂-，並且alk的該支鏈C₄至C₆伸烷基係-CH₂C(CH₃)(R^h)CH₂-、-CH₂C(C₂H₅)(R^h)CH₂-、-CH₂CH(CH₂R^h)CH₂-、-CH₂CH(CH₂CH₂R^h)CH₂-、-CH₂C(CH₃)(CH₂R^h)CH₂-、-CH₂C(C₂H₅)(CH₂R^h)CH₂-、-CH₂C(CH₃)(CH₂CH₂R^h)CH₂-、-CH₂CH(CH₃)CH(CH₂R^h)-、-CH₂CH₂C(CH₃)(CH₂R^h)-、-CH₂CH(CH₃)C(R^g)(R^h)-、-CH₂CH(C₂H₅)C(R^g)(R^h)-、-CH₂CH(C(R^g)(R^h)(Rⁱ))CH(CH₃)-、-CH₂C(CH₃)(C(R^g)(R^h)(Rⁱ))CH(CH₃)-、-CH₂CH(C(R^g)(R^h)(Rⁱ))CH₂-、-CH₂CH₂CH(C(R^g)(R^h)(Rⁱ))-、-CH₂CH₂CH(C(R^g)(R^h)(Rⁱ))CH₂-或-CH₂CH₂CH₂CH(C(R^g)(R^h)(Rⁱ))-，其中R^g、R^h和Rⁱ係如其中所定義的。A152. In embodiment A152, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A138, A150 and A151, wherein the side-chain C₄ to C₆ alkenylene group of alk is -CH₂ CH₂ C(CH₃ )═C(R^f )-, -CH₂ C(CH₃ )═C(R^f )-, or -CH₂ C(═CH₂ )CH₂ -, and the side-chain C₄ to C₆ alkylene group of alk is -CH₂ C(CH₃ )(R^h )CH₂ -, -CH₂ C(C₂ H₅ )(R^h )CH₂ -, -CH₂ CH(CH₂ R^h )CH₂ -, -CH₂ CH(CH₂ CH₂ R^h )CH₂ -, -CH₂ C(CH₃ )(CH₂ R^h )CH₂ -, -CH₂ C(C₂ H₅ )(CH₂ R^h )CH₂ -, -CH₂ C(CH₃ )(CH₂ CH₂ R^h )CH₂ -, -CH₂ CH(CH₃ )CH(CH₂ R^h )-, -CH₂ CH₂ C(CH₃ )(CH₂ R^h )-, -CH₂ CH(CH₃ )C(R^g )(R^h )-, -CH₂ CH(C₂ H₅ )C(R^g )(R^h )-, -CH₂ CH(C(R^g )(R^h )(Rⁱ ))CH(CH₃ )-, -CH₂ C(CH₃ )(C(R^g )(R^h )(Rⁱ ))CH(CH₃ )-, -CH₂ CH(C(R^g )(R^h )(Rⁱ ))CH₂ -,_-CH2CH2CH( C(^Rg )(^Rh )(^Ri ))-,_-CH2CH2CH( C(^Rg )(^Rh )(^Ri ))_CH2- ,_{or-CH2CH2CH2CH} (C(_Rg )(^Rh )(^Ri) )-, wherein^Rg ,^Rh and^Ri are as defined herein.

A153.     在實施方式A153中，如實施方式A1A至A138和A150至152中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的該支鏈C₄至C₆伸烯基係-CH₂C(CH₃)=C(R^f)-或-CH₂C(=)CH₂-，並且alk的該支鏈C₄至C₆伸烷基係-CH₂C(CH₃)(R^h)CH₂-、-CH₂CH(CH₂R^h)CH₂-、-CH₂CH(CH₂CH₂R^h)CH₂-、-CH₂CH(C(R^g)(R^h)(Rⁱ))CH₂-、-CH₂CH₂CH(C(R^g)(R^h)(Rⁱ))CH₂-或-CH₂CH₂CH₂CH(C(R^g)(R^h)(Rⁱ))-，其中R^g、R^h和Rⁱ係如其中所定義的。A153. In embodiment A153, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A138 and A150 to 152, wherein the side-chain C₄ to C₆ alkenylene group of alk is -CH₂ C(CH₃ )═C(R^f )- or -CH₂ C(═)CH₂ -, and the side-chain C₄ to C₆ alkylene group of alk is -CH₂ C(CH₃ )(R^h )CH₂ -, -CH₂ CH(CH₂ R^h )CH₂ -, -CH₂ CH(CH₂ CH₂ R^h )CH₂ -, -CH₂ CH(C(R^g )(R^h )(Rⁱ ))CH₂ -, -CH₂ CH₂ CH(C(R^g )(R^h )(Rⁱ ))CH₂ -, or -CH₂ CH₂ CH₂ CH(C(R^g )(R^h )(Rⁱ ))-, wherein R^g , R^h and Rⁱ are as defined herein.

A154.     在實施方式A154中，如實施方式A1A至A138和A150至A153中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的支鏈C₄至C₆伸烷基的R^g和Rⁱ獨立地是氫或鹵代（除非另有說明），並且alk的支鏈C₄至C₆伸烷基的R^h係氫、鹵代、鹵代烷氧基、環烷基、環烷基氧基、烷氧基、羥基、胺基羰基、烷基胺基羰基、二烷基胺基羰基、烷基羰基胺基、氰基、氰基烷基氧基、苯基、雜芳基、雜環基、雜環基氧基、雜環基羰基或橋接雜環基（除非另有說明），R^h的每個環如其中所定義的被取代。A154. In embodiment A154, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A138 and A150 to A153, wherein^Rg and^Ri of the branched_C4 to_C6 alkylene group of alk are independently hydrogen or halogenated (unless otherwise specified), and^Rh of the branched_C4 to_C6 alkylene group of alk is hydrogen, halogenated, halogenated alkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclic, heterocyclicoxy, heterocycliccarbonyl or bridged heterocyclic (unless otherwise specified), and R Each ring of^h is substituted as defined therein.

A155.     在實施方式A155中，如實施方式A1A至A138和A150至A154中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的支鏈C₄至C₆伸烷基的R^g和Rⁱ係氫或氟（除非另有說明），並且alk的支鏈C₄至C₆伸烷基的R^h係氫、鹵代、環烷基、環烷基氧基、烷氧基、羥基、烷基胺基羰基、二烷基胺基羰基、烷基羰基胺基、氰基、苯基、雜芳基、雜環基、雜環基氧基、雜環基羰基或橋接雜環基（除非另有說明），R^h的每個環如其中所定義的被取代。A155. In embodiment A155, the compound as described in any one of embodiments A1A to A138 and A150 to A154, or a pharmaceutically acceptable salt thereof, is wherein^Rg and^R1 of the branched_C4 to_C6 alkylene group of alk are hydrogen or fluorine (unless otherwise specified), and^Rh of the branched_C4 to_C6 alkylene group of alk is hydrogen, halogen, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclo, heterocyclooxy, heterocyclocarbonyl, or bridged heterocyclo (unless otherwise specified), and each ring of^Rh is substituted as defined herein.

A156.     在實施方式A156中，如實施方式A1A至A138和A150至A155中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的支鏈C₄至C₆伸烷基的R^g和Rⁱ係氫或氟（除非另有說明），並且alk的支鏈C₄至C₆伸烷基的R^h係氫、鹵代、烷氧基、羥基、二烷基胺基羰基、氰基或雜芳基，如其中所定義的被取代。A156. In embodiment A156, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A138 and A150 to A155 is wherein^Rg and^Ri of the branched_C4 to_C6 alkylene group of alk are hydrogen or fluorine (unless otherwise indicated), and^Rh of the branched_C4 to_C6 alkylene group of alk is hydrogen, halogen, alkoxy, hydroxy, dialkylaminocarbonyl, cyano or heteroaryl, substituted as defined therein.

A157.     在實施方式A157中，如實施方式A1A至A138和A150至A155中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係如其中所定義的被取代的支鏈C₄至C₆伸烷基，並且alk的支鏈C₄至C₆伸烷基的雜芳基、雜環基——本身或作為雜環基氧基、雜環基羰基的一部分、和橋接雜環基，當存在時，係五員或六員環，並且R^h的每個環如其中所定義的被取代。A157. In embodiment A157, the compound as described in any one of embodiments A1A to A138 and A150 to A155, or a pharmaceutically acceptable salt thereof, is wherein alk is a substituted branched_C4 to_C6 alkylene group as defined herein, and the heteroaryl, heterocycloalkyl group - itself or as part of a heterocyclooxy group, heterocyclocarbonyl group, and bridged heterocycloalkyl group of the branched_C4 to_C6 alkylene group of alk, when present, is a five-membered or six-membered ring, and each ring of^Rh is substituted as defined herein.

A158.     在實施方式A158中，如實施方式A1A至A138和A150至A157中任一項所述之化合物或其藥學上可接受的鹽係alk的支鏈C₄至C₆伸烷基的R^g和Rⁱ獨立地是氫、氘或氟（除非另有說明），並且alk的支鏈C₄至C₆伸烷基的R^h，當存在時且除非另有說明，係氫、氘、氟、環丙基、環丁基、環丙基氧基、環丁基氧基、二氟甲氧基、三氟甲氧基、甲氧基、乙氧基、羥基、氰基、胺基羰基、甲基胺基羰基、二甲基胺基羰基、二乙基胺基羰基、甲基羰基胺基、乙基羰基胺基、苯基、吡唑基、噻唑基、呋喃基、吡啶基、吡咯啶基、2-側氧基吡咯啶基、哌啶基、哌𠯤基或四氫呋喃基，其中R^h的每個環被獨立地選自氫、氘、甲基、甲氧基、氟、二氟甲基、三氟甲基、二氟甲氧基、三氟甲基、羥基、胺基、甲基胺基、二甲基胺基和氰基的R⁷和R⁸取代，除非另有說明。A158. In embodiment A158, the compound of any one of embodiments A1A to A138 and A150 to A157, or a pharmaceutically acceptable salt thereof, wherein^Rg and^Ri of the branched_C4 to_C6 alkylene group of alk are independently hydrogen, deuterium or fluorine (unless otherwise specified), and^Rh of the branched_C4 to_C6 alkylene group of alk is , when present and unless otherwise indicated, is hydrogen, deuterium, fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, thiazolyl, furanyl, pyridinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, piperonyl, or tetrahydrofuranyl, wherein each ring of^R is substituted with R and R independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino,^{dimethylamino} , and^cyano , unless otherwise indicated.

A158A.  在實施方式A158A中，如實施方式A1A至A138和A150至A158中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的支鏈C₄至C₆伸烷基的R^g和Rⁱ，當存在時且除非另有說明，係氫或氟，並且alk的支鏈C₄至C₆伸烷基的R^h，當存在時且除非另有說明，係氫、氟、羥基、甲氧基、氰基、吡唑基-1-基或甲基胺基羰基。A158A. In embodiment A158A, the compound as described in any one of embodiments A1A to A138 and A150 to A158, or a pharmaceutically acceptable salt thereof, is wherein^Rg and^R1 of the branched_C4 to_C6 alkylene group of alk, when present and unless otherwise stated, are hydrogen or fluoro, and^Rh of the branched_C4 to_C6 alkylene group of alk, when present and unless otherwise stated, is hydrogen, fluoro, hydroxy, methoxy, cyano, pyrazol-1-yl, or methylaminocarbonyl.

A159.     在實施方式A159中，如實施方式A1A至A134和A140中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，其中R^g和R^h附接至該C₃至C₆伸烷基的直鏈部分的相同碳或相鄰碳原子，並且R^g和R^h可與它們所附接的碳原子一起形成環伸烷基或雜亞環基，其中由R^g和R^h形成的該環伸烷基和雜亞環基被R⁹和R¹⁰取代。A159. In embodiment A159, the compound as described in any one of embodiments A1A to A134 and A140, or a pharmaceutically acceptable salt thereof, is a C₃ to C₆ alkylene group substituted with R^g , R^h , and Rⁱ , wherein R^g and R^h are attached to the same carbon or adjacent carbon atoms of the straight chain portion of the C₃ to C₆ alkylene group, and R^g and R^h may form a cycloalkylene group or a heterocycloalkylene group together with the carbon atoms to which they are attached, wherein the cycloalkylene group and the heterocycloalkylene group formed by R^g and R^h are substituted with R⁹ and R¹⁰ .

A160.     在實施方式A160中，如實施方式A1A至A134、A140和A159中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，其中R^g和R^h附接至該C₃至C₆伸烷基的直鏈部分的相同碳原子並且可與它們所附接的碳原子一起形成被R⁹和R¹⁰取代的環伸烷基。A160. In embodiment A160, the compound as described in any one of embodiments A1A to A134, A140 and A159, or a pharmaceutically acceptable salt thereof, is a C₃ to C₆ alkylene group substituted with R^g , R^h and Rⁱ , wherein R^g and R^h are attached to the same carbon atom of the straight chain portion of the C₃ to C₆ alkylene group and can form a cycloalkylene group substituted with R⁹ and R¹⁰ together with the carbon atom to which they are attached.

A161.     在實施方式A161中，如實施方式A1A至A134、A140和A159中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，其中R^g和R^h附接至該C₃至C₆伸烷基的直鏈部分的相同碳原子並且可與它們所附接的碳原子一起形成被R⁹和R¹⁰取代的雜亞環基。A161. In embodiment A161, the compound as described in any one of embodiments A1A to A134, A140 and A159, or a pharmaceutically acceptable salt thereof, is a C₃ to C₆ alkylene group substituted with R^g , R^h and Rⁱ , wherein R^g and R^h are attached to the same carbon atom of the linear portion of the C₃ to C₆ alkylene group and may form, together with the carbon atom to which they are attached, a heterocycloalkylene group substituted with R⁹ and R¹⁰ .

A162.     在實施方式A162中，如實施方式A1A至A134、A140和A159中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，其中R^g和R^h附接至該C₃至C₆伸烷基的直鏈部分的相鄰碳原子並且可與它們所附接的碳原子一起形成被R⁹和R¹⁰取代的環伸烷基。A162. In embodiment A162, the compound as described in any one of embodiments A1A to A134, A140 and A159, or a pharmaceutically acceptable salt thereof, is a C₃ to C₆ alkylene group substituted with R^g , R^h and Rⁱ , wherein R^g and R^h are attached to adjacent carbon atoms of the straight chain portion of the C₃ to C₆ alkylene group and can form a cycloalkylene group substituted with R⁹ and R¹⁰ together with the carbon atoms to which they are attached.

A163.     在實施方式A163中，如實施方式A1A至A134、A140和A159中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，其中R^g和R^h附接至該C₃至C₆伸烷基的直鏈部分的相鄰的相同碳原子並且可與它們所附接的碳原子一起形成被R⁹和R¹⁰取代的雜亞環基。A163. In embodiment A163, the compound as described in any one of embodiments A1A to A134, A140 and A159, or a pharmaceutically acceptable salt thereof, is a C₃ to C₆ alkylene group substituted with R^g , R^h and Rⁱ , wherein R^g and R^h are attached to adjacent identical carbon atoms of the linear portion of the C₃ to C₆ alkylene group and may form, together with the carbon atoms to which they are attached, a heterocycloalkylene group substituted with R⁹ and R¹⁰ .

A164.     在實施方式A164中，如實施方式A1A至A134、A140和A159至A161中任一項所述之化合物或其藥學上可接受的鹽，係其中R^g和R^h附接至該C₃至C₆伸烷基的直鏈部分的相同碳原子並且可與它們所附接的碳原子一起形成具有下式的環伸烷基：或具有下式的雜亞環基：其中每個環被R⁹和R¹⁰取代，較佳的是R⁹係氫、鹵代、甲基或乙基，並且R¹⁰係氫。A164. In embodiment A164, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A134, A140, and A159 to A161, wherein R^g and R^h are attached to the same carbon atom of the linear portion of the C₃ to C₆ alkylene group and can form, together with the carbon atom to which they are attached, a cycloalkylene group having the formula: or a heterocyclic group having the formula: Wherein each ring is substituted by R⁹ and R¹⁰ , preferably R⁹ is hydrogen, halogen, methyl or ethyl, and R¹⁰ is hydrogen.

A165.     在實施方式A165中，如實施方式A1A至A134、A140、A159、A162和A163中任一項所述之化合物或其藥學上可接受的鹽，係其中R^g和R^h附接至該C₃至C₆伸烷基的直鏈部分的相鄰碳原子並且可與它們所附接的碳原子一起形成具有下式的環伸烷基：或具有下式的雜亞環基：其中每個環被R⁹和R¹⁰取代，較佳的是R⁹係氫、鹵代、甲基或乙基，並且R¹⁰係氫。A165. In embodiment A165, the compound as described in any one of embodiments A1A to A134, A140, A159, A162 and A163, or a pharmaceutically acceptable salt thereof, is wherein R^g and R^h are attached to adjacent carbon atoms of the linear portion of the C₃ to C₆ alkylene group and can form, together with the carbon atoms to which they are attached, a cycloalkylene group having the formula: or a heterocyclic group having the formula: Wherein each ring is substituted by R⁹ and R¹⁰ , preferably R⁹ is hydrogen, halogen, methyl or ethyl, and R¹⁰ is hydrogen.

A166.     在實施方式A166中，如實施方式A1A至A134中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆雜伸烷基。A166. In embodiment A166, the compound according to any one of embodiments A1A to A134, or a pharmaceutically acceptable salt thereof, wherein alk is a C₃ -C₆ heteroalkyl substituted with R^g , R^h and Rⁱ .

A167.     在實施方式A167中，如實施方式A1A至A134和A166中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆雜伸烷基，其中R^g、R^h和Rⁱ係氫。A167. In embodiment A167, the compound as described in any one of embodiments A1A to A134 and A166, or a pharmaceutically acceptable salt thereof, wherein alk is a C₃ to C₆ heteroaryl alkyl substituted with R^g , R^h and Rⁱ , wherein R^g , R^h and Rⁱ are hydrogen.

A168.     在實施方式A168中，如實施方式A1A至A134和A166中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆雜伸烷基，其中R^g、R^h和Rⁱ係氫或鹵代，條件係R^g、R^h和Rⁱ中之至少一個係鹵代。A168. In embodiment A168, the compound as described in any one of embodiments A1A to A134 and A166, or a pharmaceutically acceptable salt thereof, is wherein alk is a C₃ to C₆ heteroalkyl substituted with R^g , R^h and Rⁱ , wherein R^g , R^h and Rⁱ are hydrogen or halogenated, with the proviso that at least one of R^g , R^h and Rⁱ is halogenated.

A169.     在實施方式A169中，如實施方式A1A至A134和A166中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆雜伸烷基，其中R^h不是氫並且Rⁱ係氫，或者當R^g和R^h附接至該C₃至C₆雜伸烷基的直鏈部分的相同碳或相鄰碳原子時，R^g和R^h可與它們所附接的碳原子一起形成環伸烷基或雜亞環基，其中該環伸烷基和雜亞環基被R⁹和R¹⁰取代。A169. In embodiment A169, the compound as described in any one of embodiments A1A to A134 and A166, or a pharmaceutically acceptable salt thereof, is a_C3 to_C6 heteroalkylene substituted with^Rg ,^Rh , and^R , wherein^Rh is not hydrogen and^Ri is hydrogen, or when^Rg and^Rh are attached to the same carbon or adjacent carbon atoms of the straight chain portion of the_C3 to_C6 heteroalkylene,^Rg and^Rh can be taken together with the carbon atoms to which they are attached to form a cycloalkylene or heterocycloalkylene, wherein the cycloalkylene and heterocycloalkylene are substituted with^R9 and^R10 .

A169a.   在實施方式A169a中，如實施方式A1A至A134和A169中任一項所述之化合物或其藥學上可接受的鹽，係其中R^g和R^h附接至該C₃至C₆雜伸烷基的直鏈部分的相同碳原子並且可與它們所附接的碳原子一起形成具有下式的環伸烷基：或具有下式的雜亞環基：其中每個環被R⁹和R¹⁰取代，較佳的是R⁹係氫、鹵代、甲基或乙基，並且R¹⁰係氫。A169a. In embodiment A169a, the compound as described in any one of embodiments A1A to A134 and A169, or a pharmaceutically acceptable salt thereof, is wherein R^g and R^h are attached to the same carbon atom of the linear portion of the C₃ to C₆ heteroaryl alkyl group and can form, together with the carbon atom to which they are attached, a cycloalkyl group having the formula: or a heterocyclic group having the formula: Wherein each ring is substituted by R⁹ and R¹⁰ , preferably R⁹ is hydrogen, halogen, methyl or ethyl, and R¹⁰ is hydrogen.

A169b.   在實施方式A169b中，如實施方式A1A至A134和A169中任一項所述之化合物或其藥學上可接受的鹽，係其中R^g和R^h附接至該C₃至C₆雜伸烷基的直鏈部分的相鄰碳原子並且可與它們所附接的碳原子一起形成具有下式的環伸烷基：或具有下式的雜亞環基：其中每個環被R⁹和R¹⁰取代，較佳的是R⁹係氫、鹵代、甲基或乙基，並且R¹⁰係氫。A169b. In embodiment A169b, the compound as described in any one of embodiments A1A to A134 and A169, or a pharmaceutically acceptable salt thereof, is wherein R^g and R^h are attached to adjacent carbon atoms of the linear portion of the C₃ to C₆ heteroaryl alkyl group and can form, together with the carbon atoms to which they are attached, a cycloalkyl group having the formula: or a heterocyclic group having the formula: Wherein each ring is substituted by R⁹ and R¹⁰ , preferably R⁹ is hydrogen, halogen, methyl or ethyl, and R¹⁰ is hydrogen.

A170.     在實施方式A170中，如實施方式A1A至A134、A166和A169中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆雜伸烷基，其中R^h不是氫並且Rⁱ係氫。A170. In embodiment A170, the compound as described in any one of embodiments A1A to A134, A166 and A169, or a pharmaceutically acceptable salt thereof, is wherein alk is a C₃ to C₆ heteroalkyl substituted with R^g , R^h and Rⁱ , wherein R^h is not hydrogen and Rⁱ is hydrogen.

A171.     在實施方式A171中，如實施方式A1A至134、A142至A149A、A151至A156、A158、A158A和A166至A170中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的該C₃至C₆雜伸烷基係直鏈C₃至C₆雜伸烷基，並且為了清楚起見，由於該實施方式僅表徵alk的該C₃至C₆雜伸烷基在本質上係直鏈的，因此應理解為該直鏈C₃至C₆雜伸烷基被R^g、R^h和Rⁱ取代，如參考的實施方式所提供的。A171. In embodiment A171, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to 134, A142 to A149A, A151 to A156, A158, A158A and A166 to A170, wherein the_C3 to_C6 heteroalkyl group of alk is a linear_C3 to_C6 heteroalkyl group, and for the sake of clarity, since this embodiment only represents that the_C3 to_C6 heteroalkyl group of alk is linear in nature, it should be understood that the linear_C3 to_C6 heteroalkyl group is substituted by^Rg ,^Rh and^Ri , as provided in the reference embodiment.

A172.     在實施方式A172中，如實施方式A1A至A134、A142至A149A、A152至A156、A158、A158A、和A166至A169、A170和A171中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的該直鏈C₃至C₆雜伸烷基係-CH₂CH₂X^aCH₂-、-CH₂X^aCH₂CH₂-、-CH₂CH₂CH₂X^a-、-X^aCH₂CH₂CH₂-、-X^yCH₂CH₂X^a-、-X^yCH₂CH₂X^aCH₂-、-CH₂CH₂CH₂X^aCH₂-、-CH₂X^aCH₂-、-X^aCH₂CH₂-、-CH₂CH₂X^a-、-CH₂CONR^qCH₂-、-CH₂SO₂NR^qCH₂-、-CH₂NR^qCOCH₂-、-CH₂NR^qSO₂CH₂-、-CH₂CH₂CH₂NR^qCO-、-CH₂CONR^q-、-CH₂SO₂NR^q-、-CH₂NR^qCO-、-CH₂NR^qSO₂-、-CONR^qCH₂-、-SO₂NR^qCH₂-、-NR^qCOCH₂-或-NR^qSO₂CH₂-，其被如其中所定義的R^g、R^h和Rⁱ取代，並且X^a係-NR^q-、-O-、-S-、-SO-、-SO₂-或-CO-。A172. In embodiment A172, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A134, A142 to A149A, A152 to A156, A158, A158A, and A166 to A169, A170 and A171, wherein the linear C₃ to C₆ heteroalkyl group of alk is -CH₂ CH₂ X^a CH₂ -, -CH₂ X^a CH₂ CH₂ -, -CH₂ CH₂ CH₂ X^a -, -X^a CH₂ CH₂ CH₂ -, -X^y CH₂ CH₂ X^a -, -X^y CH₂ CH₂ X^a CH₂ -, -CH₂ CH₂ CH₂ X^a CH₂ -, -CH₂ X^a CH₂ -, -X^a CH₂ CH₂ -, -CH_-2CH2Xa-,^{-CH2CONRqCH2-,-CH2SO2NRqCH2-}_,^{-CH2NRqCOCH2-}_, -CH2NRqSO2CH2-_,^{-CH2CH2CH2NRqCO-,}_{-CH2CONRq-,-CH2SO2NRq-,-CH2NRqCO-,}^-CH2NRqSO2-_, -CONRqCH2-^,_{-SO2NRqCH2-,-NRqCOCH2-} ,_{or-NRqSO2CH2-} ,_which is substituted_byRg^,RhandRi as defined herein^,_and^Xa is_-NRq-^,_-O-,^-S- ,_-SO-^,_-SO2-,or^-CO-.

A173.     在實施方式A173中，如實施方式A1A至A134、A142至A149A、A151至A156、A158、A158A和A166至A172中任一項所述之化合物或其藥學上可接受的鹽，係其中R^q係氫、甲基、乙基、甲基羰基或甲磺醯基。A173. In embodiment A173, the compound as described in any one of embodiments A1A to A134, A142 to A149A, A151 to A156, A158, A158A and A166 to A172, or a pharmaceutically acceptable salt thereof, wherein R^q is hydrogen, methyl, ethyl, methylcarbonyl or methanesulfonyl.

A174.     在實施方式A174中，如實施方式A1A至A134、A142至A149A、A151至A156、A158、A158A、A166至A169和A170至A173中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的該直鏈C₃至C₆雜伸烷基係-CH₂X^aCH₂-、-X^aCH₂CH₂-、-CH₂CH₂X^a-、-CH₂CH(R^h)X^a-、-X^aCH(R^h)CH₂-、-CH₂CONR^q-、-CH₂SO₂NR^q-、-CH₂NR^qCO-、-CH₂NR^qSO₂-、-CONR^qCH₂-、-SO₂NR^qCH₂-、-NR^qCOCH₂-、或-NR^qSO₂CH₂-，其中X^a係-S-、-SO₂-、-O-或-NR^q-。A174. In embodiment A174, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169 and A170 to A173, wherein the linear C₃ to C₆ heteroalkyl group of alk is -CH₂ X^a CH₂ -, -X^a CH₂ CH₂ -, -CH₂ CH₂ X^a -, -CH₂ CH(R^h )X a -,^{-X aCH} (R^h )CH₂ -, -CH₂ CONR^q -, -CH₂ SO₂ NR^q -, -CH₂ NR^q CO-, -CH₂ NR^q SO₂ -, -CONR^q CH₂ -, -SO₂ NR^q CH₂ -, -NR^q COCH₂ -, or -NR^q SO₂ CH₂ -, wherein X^a is -S-, -SO₂ -, -O-, or -NR^q -.

A175.     在實施方式A175中，如實施方式A1A至A134、A142至A149A、A151至A156、A158、A158A、A166至A169和A170至A174中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的該直鏈C₃至C₆雜伸烷基係-CH₂CH₂CH₂X^a-或-CH₂CH₂X^a。A175. In embodiment A175, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169 and A170 to A174, wherein the linear C₃ to C₆ heteroalkyl group of alk is -CH₂ CH₂ CH₂ X^a - or -CH₂ CH₂ X^a .

A176.     在實施方式A176中，如實施方式A1A至A134、A142至A149A、A151至A156、A158、A158A、A166至A169和A170至A175中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的直鏈C₃至C₆雜伸烷基的R^g係氫或鹵代（除非另有說明），並且alk的直鏈C₃至C₆雜伸烷基的R^h係（除非另有說明）氫、鹵代、鹵代烷氧基、環烷基、環烷基氧基、烷氧基、羥基、胺基羰基、烷基胺基羰基、二烷基胺基羰基、烷基羰基胺基、氰基、氰基烷基氧基、苯基、雜芳基、雜環基或橋接雜環基，每個環如其中所定義的被取代並且Rⁱ係氫。A176. In embodiment A176, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169 and A170 to A175, wherein^Rg of the linear_C3 to_C6 heteroaryl group of alk is hydrogen or halogen (unless otherwise specified), and Rg of the linear_C3 to_C6 heteroaryl group of alk is^R is (unless otherwise indicated) hydrogen, halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclic or bridged heterocyclic, each ring being substituted as defined therein and^R is hydrogen.

A177.     在實施方式A177中，如實施方式A1A至A134、A142至A149A、A151至A156、A158、A158A、A166至A169和A170至A176中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的直鏈C₃至C₆雜伸烷基的R^g係氫或氟（除非另有說明），並且alk的直鏈C₃至C₆雜伸烷基的R^h（除非另有說明）係氫、鹵代、鹵代烷氧基、烷氧基、羥基、二烷基胺基羰基、氰基或雜芳基，如其中所定義的被取代。A177. In embodiment A177, the compound as described in any one of embodiments A1A to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169 and A170 to A176, or a pharmaceutically acceptable salt thereof, is wherein^Rg of the linear_C3 to_C6 heteroalkyl group of alk is hydrogen or fluorine (unless otherwise stated), and^Rh of the linear_C3 to_C6 heteroalkyl group of alk (unless otherwise stated) is hydrogen, halo, haloalkoxy, alkoxy, hydroxy, dialkylaminocarbonyl, cyano or heteroaryl, substituted as defined therein.

A178.     在實施方式A178中，如實施方式A1A至A134、A142至A149A、A151至A156、A158、A158A、A166至A169和A170至A177中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的直鏈C₃至C₆雜伸烷基的R^h的雜芳基、雜環基和橋接雜環基，當存在時，係五員或六員環，並且每個環如其中所定義的被取代。A178. In embodiment A178, the compound as described in any one of embodiments A1A to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169 and A170 to A177, or a pharmaceutically acceptable salt thereof, is wherein the heteroaryl, heterocyclic and bridged heterocyclic groups of^Rh of the linear_C3 to_C6 heteroalkylene group of alk, when present, are five-membered or six-membered rings, and each ring is substituted as defined therein.

A179.     在實施方式A179中，如實施方式A1A至A134、A142至A149A、A151至A156、A158、A158A、A166至A169和A170至A178中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的直鏈C₃至C₆雜伸烷基的R^g，當存在時且除非另有說明，係氫、氘或氟，並且alk的直鏈C₃至C₆雜伸烷基的R^h，當存在時且除非另有說明，係氫、氘、氟、環丙基、環丁基、環丙基氧基、環丁基氧基、二氟甲氧基、三氟甲氧基、甲氧基、乙氧基、羥基、氰基、胺基羰基、甲基胺基羰基、二甲基胺基羰基、二乙基胺基羰基、甲基羰基胺基、乙基羰基胺基、苯基、吡唑基、噻唑基、呋喃基、吡啶基、吡咯啶基、2-側氧基吡咯啶基、哌啶基、哌𠯤基、四氫呋喃基，每個環被獨立地選自氫、氘、甲基、甲氧基、氟、二氟甲基、三氟甲基、二氟甲氧基、三氟甲基、羥基、胺基、甲基胺基、二甲基胺基和氰基的R⁷和R⁸取代。A179. In embodiment A179, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169 and A170 to A178, wherein^Rg of the linear_C3 to_C6 heteroaryl group of alk, when present and unless otherwise specified, is hydrogen, deuterium or fluorine, and^Rh of the linear_C3 to_C6 heteroaryl group of alk , when present and unless otherwise indicated, is hydrogen, deuterium, fluorine, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, thiazolyl, furanyl, pyridinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, piperonyl, tetrahydrofuranyl, each ring being substituted with R and R independently selected from hydrogen, deuterium, methyl, methoxy, fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino,^{dimethylamino} , and^cyano .

A180.     在實施方式A180中，如實施方式A1A至A134、A142至A149A、A151至A156、A158、A158A、A166至A169和A170至A179中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的直鏈C₃至C₆雜伸烷基的R^g係氫，並且alk的直鏈C₃至C₆雜伸烷基的R^h係氟、環丙基、環丙基氧基、二氟甲氧基、三氟甲氧基、甲氧基、乙氧基、羥基、氰基、甲基胺基羰基、二甲基胺基羰基、甲基羰基胺基、苯基、吡唑-1-基、吡唑-4-基、吡啶-4-基、吡咯啶-1-基、2-側氧基吡咯啶-1-基，每個環被獨立地選自氫、氘、甲基或氟的R⁷和R⁸取代。A180. In embodiment A180, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A179, wherein^Rg of the linear_C3 to_C6 heteroaryl group of alk is hydrogen, and Rg of the linear_C3 to_C6 heteroaryl group of alk is^R is fluoro, cyclopropyl, cyclopropyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonylamino, phenyl, pyrazol-1-yl, pyrazol-4-yl, pyridin-4-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, and each ring is substituted by^R and^R independently selected from hydrogen, deuterium, methyl or fluoro.

A181.     在實施方式A181中，如實施方式A172至A180中任一項所述之化合物或其藥學上可接受的鹽，係其中X^a係-NR^q-、-O-、-S-或-SO₂-，較佳的是-NR^q-、-O-或-S-。A181. In embodiment A181, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A172 to A180, wherein X^a is -NR^q -, -O-, -S-, or -SO₂ -, preferably -NR^q -, -O-, or -S-.

A182.     在實施方式A182中，如實施方式A172至A181中任一項所述之化合物或其藥學上可接受的鹽，係其中X^a係-NR^q-，其中R^q係氫或甲基。A182. In embodiment A182, the compound according to any one of embodiments A172 to A181, or a pharmaceutically acceptable salt thereof, wherein X^a is -NR^q -, wherein R^q is hydrogen or methyl.

A183.     在實施方式A183中，如實施方式A172至A181中任一項所述之化合物或其藥學上可接受的鹽，係其中X^a係-O-。A183. In embodiment A183, the compound according to any one of embodiments A172 to A181 or a pharmaceutically acceptable salt thereof, wherein X^a is -O-.

A184.     在實施方式A184中，如實施方式A172至A181中任一項所述之化合物或其藥學上可接受的鹽，係其中X^a係-S-。A184. In embodiment A184, the compound according to any one of embodiments A172 to A181 or a pharmaceutically acceptable salt thereof, wherein X^a is -S-.

A185.     在實施方式A185中，如實施方式A172至A184中任一項所述之化合物或其藥學上可接受的鹽，係其中X^y係-O-。A185. In embodiment A185, the compound according to any one of embodiments A172 to A184 or a pharmaceutically acceptable salt thereof, wherein^Xy is -O-.

A186.     在實施方式A186中，如實施方式A172至A184中任一項所述之化合物或其藥學上可接受的鹽，係其中X^y係-NH-或-NCH₃-。A186. In embodiment A186, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A172 to A184, wherein X^y is -NH- or -NCH₃ -.

A187.     在實施方式A187中，如實施方式A1A至134、A166至A169和A170中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的該C₃至C₆雜伸烷基係支鏈C₄至C₆雜伸烷基，並且為了清楚起見，由於該實施方式僅表徵alk的該C₄至C₆雜伸烷基在本質上係支鏈的，因此應理解為該支鏈C₄至C₆雜伸烷基被R^g、R^h和Rⁱ取代，如參考的實施方式所提供的。A187. In embodiment A187, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to 134, A166 to A169 and A170, wherein the_C3 to_C6 heteroalkylene group of alk is a branched_C4 to_C6 heteroalkylene group, and for the sake of clarity, since this embodiment only represents that the_C4 to_C6 heteroalkylene group of alk is branched in nature, it should be understood that the branched_C4 to C6_{heteroalkylene} group is substituted with^Rg ,^Rh and^Ri , as provided in the reference embodiment.

A188.     在實施方式A188中，如實施方式A1A至A134、A166至A169、A170和A187中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的該支鏈C₄至C₆雜伸烷基係-CH₂X^aCH(CH₃)CH₂-、-CH₂X^yCH₂CH(CH₃)X^a-、-CH₂CH₂CH(CH₃)X^a-、-X^aCH(CH₃)CH₂CH₂-、-X^yCH₂CH(CH₃)X^a-、-X^yCH(CH₃)CH₂X^a-、-CH₂CH₂CH₂CH(CH₃)X^a-、-X^aCH(CH₂R^h)CH₂-、-CH₂CH(CH₂R^h)X^a-、-X^aCH(CH₂CH₂R^h)CH₂-、-CH₂CH(CH₂CH₂R^h)X^a-、-CH₂C(CH₃)(CH₃)X^a-、-X^aC(CH₃)(CH₃)CH₂-、-CH(CH₃)CH(CH₃)X^a-、-CONR^qCH₂CH(CH₃)X^a-、-CH₂NR^qCOCH(CH₃)CH₂-、或-NR^qCOCH(CH₃)CH₂-，其中X^a係-NR^q-、-O-、-S-、-SO-、-SO₂-或-CO-。A188. In embodiment A188, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A134, A166 to A169, A170 and A187, wherein the branched C₄ to C₆ heteroalkyl group of alk is -CH₂ X^a CH(CH₃ )CH₂ -, -CH₂ X^y CH₂ CH(CH₃ )X^a -, -CH₂ CH₂ CH(CH₃ )X^a -, -X^a CH(CH₃ )CH₂ CH₂ -, -X^y CH₂ CH(CH₃ )X^a -_, -X y CH(^CH₃ )CH₂ X^a -, -CH₂ CH₂ CH(CH₃ )X a -,^-Xa CH(CH₂ R^h )CH₂ -, -CH₂ CH(CH₂ R^h )X^a -, -X^a CH(CH₂ CH₂ R^h )CH₂ -, -CH₂ CH(CH₂ CH₂ R^h )X^a -, -CH₂ C(CH₃ )(CH₃ )^{X a} -, -X^a C(CH₃ )(CH₃ )CH₂ -, -CH(CH₃ )CH(CH₃ )X^a -, -CONR^q CH₂ CH(CH₃ )X^a -, -CH₂ NR^q COCH(CH₃ )CH₂ -, or -NR^q COCH(CH₃ )CH₂ -, where X^a is -NR^q -, -O-, -S-, -SO-, -SO₂ - or -CO-.

A189.     在實施方式A189中，如實施方式A1A至134、A166至A169、A170、A187和A188中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的該支鏈C₄至C₆雜伸烷基係-CH₂C(CH₃)(CH₃)X^a-、-CH(CH₃)(CHCH₃)X^a-、-X^aCH(CH₂CH₂R^h)CH₂-、-CH₂CH(CH₂CH₂R^h)X^a-、-X^aCH(CH₂R^h)CH₂-、或-CH₂CH(CH₂R^h)X^a-。A189. In embodiment A189, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to 134, A166 to A169, A170, A187_and A188, wherein the^branched_C4 to_C6 heteroalkyl group of alk is_-CH2C (_CH3 )(_CH3^)Xa-_,^-CH_(CH3 )(_CHCH3 )_Xa-^,-XaCH (^CH2CH2Rh )_CH2- , -CH2CH(_CH2CH2Rh⁾ Xa-,_-XaCH (CH2Rh)_CH2-, or -CH2CH⁽_CH2Rh )^Xa- .

A190.     在實施方式A190中，如實施方式A1A至134、A166至A166、A170、A173和A187至A189中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的支鏈C₄至C₆雜伸烷基的R^g和Rⁱ係氫或鹵代（除非另有說明），並且alk的支鏈C₄至C₆雜伸烷基的R^h係氫、鹵代、鹵代烷氧基、環烷基、環烷基氧基、烷氧基、羥基、胺基羰基、烷基胺基羰基、二烷基胺基羰基、烷基羰基胺基、氰基、氰基烷基氧基、苯基、雜芳基、雜環基、雜環基氧基、雜環基羰基或橋接雜環基，如其中所定義的被取代。A190. In embodiment A190, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A to 134, A166 to A166, A170, A173 and A187 to A189, wherein^Rg and^Ri of the branched_C4 to_C6 heteroalkyl group of alk are hydrogen or halogenated (unless otherwise specified), and Rg of the branched_C4 to C6_heteroalkyl group of alk is hydrogen or halogenated.^H is hydrogen, halogen, halogenated alkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclic, heterocyclicoxy, heterocycliccarbonyl, or bridged heterocyclic, substituted as defined therein.

A191.     在實施方式A191中，如實施方式A1A至134、A166至A169、A170、A173和A187至A190中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的支鏈C₄至C₆雜伸烷基的R^g和Rⁱ係氫或氟（除非另有說明），並且R^h（除非另有說明）係氫、鹵代、環烷基、環烷基氧基、烷氧基、羥基、烷基胺基羰基、二烷基胺基羰基、烷基羰基胺基、氰基、苯基、雜芳基、雜環基、雜環基氧基、雜環基羰基或橋接雜環基，如其中所定義的被取代。A191. In embodiment A191, the compound as described in any one of embodiments A1A to 134, A166 to A169, A170, A173 and A187 to A190, or a pharmaceutically acceptable salt thereof, is wherein^Rg and^R1 of the branched_C4 to_C6 heteroalkylene group of alk are hydrogen or fluoro (unless otherwise indicated), and^Rh (unless otherwise indicated) is hydrogen, halo, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclo, heterocyclooxy, heterocyclocarbonyl or bridged heterocyclo, substituted as defined therein.

A192.     在實施方式A192中，如實施方式A1A至134、A166至A169、A170、A173和A187至A191中任一項所述之化合物或其藥學上可接受的鹽，係其中R^g和Rⁱ係氫，並且R^h係氫、雜芳基、烷基胺基羰基或氰基。A192. In embodiment A192, the compound as described in any one of embodiments A1A to 134, A166 to A169, A170, A173 and A187 to A191, or a pharmaceutically acceptable salt thereof, wherein R^g and Rⁱ are hydrogen, and R^h is hydrogen, heteroaryl, alkylaminocarbonyl or cyano.

A193.     在實施方式A193中，如實施方式A1A至134、A166至A169、A170、A173和A187至A192中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的支鏈C₄至C₆雜伸烷基的雜芳基、雜環基——本身或作為雜環基氧基、雜環基羰基的一部分、和橋接雜環基，當存在時，係五員或六員環，並且每個環如其中所定義的被取代。A193. In embodiment A193, the compound as described in any one of embodiments A1A to 134, A166 to A169, A170, A173 and A187 to A192, or a pharmaceutically acceptable salt thereof, is wherein the branched_C4 to_C6 heteroalkylene, heteroaryl, heterocycloalkyl - itself or as part of a heterocyclooxy, heterocyclocarbonyl, and bridged heterocycloalkyl of alk, when present, is a five-membered or six-membered ring, and each ring is substituted as defined therein.

A194.     在實施方式A194中，如實施方式A1A至134、A166至A169、A170、A173和A187至A193中任一項所述之化合物或其藥學上可接受的鹽，係其中alk的支鏈C₄至C₆雜伸烷基的R^h，當存在時且除非另有說明，係氫、氘、氟、環丙基、環丁基、環丙基氧基、環丁基氧基、二氟甲氧基、三氟甲氧基、甲氧基、乙氧基、羥基、氰基、胺基羰基、甲基胺基羰基、二甲基胺基羰基、二乙基胺基羰基、甲基羰基胺基、乙基羰基胺基、苯基、吡唑基、噻唑基、呋喃基、吡咯啶基、吡啶基、哌啶基、哌𠯤基、四氫呋喃基，每個環被獨立地選自氫、氘、甲基、甲氧基、氟、二氟甲基、三氟甲基、二氟甲氧基、三氟甲基、羥基、胺基、甲基胺基、二甲基胺基和氰基的R⁷和R⁸取代。A194. In embodiment A194, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to 134, A166 to A169, A170, A173 and A187 to A193, wherein R^h of the branched C₄ to C₆ heteroaryl group of alk is , when present and unless otherwise indicated, is hydrogen, deuterium, fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, thiazolyl, furanyl, pyrrolidinyl, pyridyl, piperidinyl, piperidine, tetrahydrofuranyl, each ring being substituted with R and R independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino,^{dimethylamino} , and^cyano .

A195.     在實施方式A195中，如實施方式A188至A194中任一項所述之化合物或其藥學上可接受的鹽，係其中X^a係-NR^q-、-O-、-S-或-SO₂-，較佳的是-NR^q-或-O-。A195. In embodiment A195, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A188 to A194, wherein X^a is -NR^q -, -O-, -S-, or -SO₂ -, preferably -NR^q - or -O-.

A196.     在實施方式A196中，如實施方式A188至A195中任一項所述之化合物或其藥學上可接受的鹽，係其中X^a係-NR^q-，其中R^q係氫或甲基。A196. In embodiment A196, the compound according to any one of embodiments A188 to A195, or a pharmaceutically acceptable salt thereof, wherein X^a is -NR^q -, wherein R^q is hydrogen or methyl.

A197.     在實施方式A197中，如實施方式A188至A195中任一項所述之化合物或其藥學上可接受的鹽，係其中X^a係-O-。A197. In embodiment A197, the compound according to any one of embodiments A188 to A195 or a pharmaceutically acceptable salt thereof, wherein X^a is -O-.

A198.     在實施方式A198中，如實施方式A188至A195中任一項所述之化合物或其藥學上可接受的鹽，係其中X^a係-S-。A198. In embodiment A198, the compound according to any one of embodiments A188 to A195 or a pharmaceutically acceptable salt thereof, wherein X^a is -S-.

A199.     在實施方式A199中，如實施方式A188至A198中任一項所述之化合物或其藥學上可接受的鹽，係其中X^y係-O-。A199. In embodiment A199, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A188 to A198, wherein^Xy is -O-.

A200.     在實施方式A200中，如實施方式A188至A198中任一項所述之化合物或其藥學上可接受的鹽，係其中X^y係-NH-或-NCH₃-。A200. In embodiment A200, the compound according to any one of embodiments A188 to A198 or a pharmaceutically acceptable salt thereof, wherein X^y is -NH- or -NCH₃ -.

A201a.   在實施方式A201a中，如實施方式A1A至A200中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係：。A201a. In embodiment A201a, the compound according to any one of embodiments A1A to A200, or a pharmaceutically acceptable salt thereof, wherein alk is: .

A201.     在實施方式A201中，如實施方式A1A至A200a中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係：A201. In embodiment A201, the compound according to any one of embodiments A1A to A200a, or a pharmaceutically acceptable salt thereof, wherein alk is:

A202.     在實施方式A202中，如實施方式A1A至A201中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係：A202. In embodiment A202, the compound according to any one of embodiments A1A to A201, or a pharmaceutically acceptable salt thereof, wherein alk is:

A203a.   在實施方式A203a中，如實施方式A1A至A202中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係：A203a. In embodiment A203a, the compound according to any one of embodiments A1A to A202, or a pharmaceutically acceptable salt thereof, wherein alk is:

A203b. 在實施方式A203b中，如實施方式A1A至203a中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係：A203b. In embodiment A203b, the compound according to any one of embodiments A1A to 203a, or a pharmaceutically acceptable salt thereof, wherein alk is:

A203.     在實施方式A203中，如實施方式A1A至A202中任一項所述之化合物或其藥學上可接受的鹽，係其中alk係：A203. In embodiment A203, the compound according to any one of embodiments A1A to A202, or a pharmaceutically acceptable salt thereof, wherein alk is:

A204.     在實施方式A204中，如實施方式A1A至A203中任一項所述之化合物或其藥學上可接受的鹽，係其中降解決定子係選自以下的E3泛素連接酶配位基：、、、、、、、、、、、和； 其中R^ee係氫、甲基、乙基、環丙基或2,2,2-三氟乙基，並且R^ff係氫、甲基、環丙基、氟、氰基、甲氧基、二氟甲氧基、三氟甲氧基或三氟甲基。A204. In embodiment A204, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A203, wherein the degradation determinant is selected from the following E3 ubiquitin ligase ligands: 、 、 、 、 、 、 、 、 、 、 、 and wherein R^ee is hydrogen, methyl, ethyl, cyclopropyl or 2,2,2-trifluoroethyl, and R^ff is hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.

A205.     在實施方式A205中，如實施方式A1A至A204中任一項所述之化合物或其藥學上可接受的鹽，係其中降解決定子係選自以下的E3泛素連接酶配位基：、、、、、、、、、和； 其中R^ee係氫、甲基、乙基、環丙基或2,2,2-三氟乙基，並且R^ff係氫、甲基、環丙基、氟、氰基、甲氧基、二氟甲氧基、三氟甲氧基或三氟甲基。A205. In embodiment A205, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments A1A to A204, wherein the degradation determinant is selected from the following E3 ubiquitin ligase ligands: 、 、 、 、 、 、 、 、 、 and wherein R^ee is hydrogen, methyl, ethyl, cyclopropyl or 2,2,2-trifluoroethyl, and R^ff is hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.

A206.     在實施方式A206中，如實施方式A1A至A205中任一項所述之化合物或其藥學上可接受的鹽，係其中降解決定子係選自以下的E3連接酶配位基：A206. In embodiment A206, the compound of any one of embodiments A1A to A205 or a pharmaceutically acceptable salt thereof, wherein the degradation determinant is selected from the following E3 ligase ligands:

A207.     在實施方式A207中，如實施方式A1A、A39b、A67、A69至A72、A77、A79至A93、A97a至A205中任一項所述之化合物或其藥學上可接受的鹽，係其中降解決定子係E3泛素連接酶配位基，其中每個R^ee係氫、甲基、乙基、環丙基或2,2,2-三氟乙基，較佳的是甲基，並且R^ff係氫、甲基、環丙基、氟、氰基、甲氧基、二氟甲氧基、三氟甲氧基或三氟甲基。A207. In embodiment A207, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1A, A39b, A67, A69 to A72, A77, A79 to A93, A97a to A205, wherein the degradation determinant is an E3 ubiquitin ligase ligand. , wherein each R^ee is hydrogen, methyl, ethyl, cyclopropyl or 2,2,2-trifluoroethyl, preferably methyl, and R^ff is hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.

實施方式中使用的「除非另有說明」意指當實施方式涉及不同範圍的多於一個前述實施方式時，僅落入前述實施方式中列舉的基團的範圍內的那些基團應當選自與其相關的實施方式。例如，在實施方式A6中列舉的基團中，雖然對於實施方式A1應選擇A6中列舉的所有基團，但是對於實施方式A2應僅選擇氟、氯和溴，因為A2的範圍限於鹵代；並且對於實施方式A4應僅選擇二氟甲基、三氟甲基、二氟乙基和三氟乙基，因為A4的範圍限於鹵代烷基。The phrase "unless otherwise indicated" used in the embodiments means that when an embodiment relates to more than one preceding embodiment of different scope, only those groups that fall within the scope of the groups listed in the preceding embodiment should be selected from the embodiment to which it relates. For example, among the groups listed in Embodiment A6, although all the groups listed in A6 should be selected for Embodiment A1, only fluorine, chlorine, and bromine should be selected for Embodiment A2 because the scope of A2 is limited to halogenated groups; and only difluoromethyl, trifluoromethyl, difluoroethyl, and trifluoroethyl should be selected for Embodiment A4 because the scope of A4 is limited to halogenated alkyl groups.

實施方式B： B1.      在實施方式B1中，提供了在發明內容的第一方面和/或其第一實施方式中描述的具有式 (IA) 的化合物或其藥學上可接受的鹽。Embodiment B:B1. In embodiment B1, a compound having formula (IA) or a pharmaceutically acceptable salt thereof as described in the first aspect of the present invention and/or the first embodiment thereof is provided.

B2.   在實施方式B2中，提供了具有式 (IA) 的化合物或其藥學上可接受的鹽，其中式 (IA) 中的HET係：其中上述環中之每一個被R^x、R^y和R^z取代。B2. In embodiment B2, a compound of formula (IA) or a pharmaceutically acceptable salt thereof is provided, wherein HET in formula (IA) is: wherein each of the above rings is substituted by R^x , R^y and R^z .

B3.   在實施方式B3中，提供了如實施方式B1或B2所述之化合物或其藥學上可接受的鹽，其中Q係CH。B3. In embodiment B3, a compound as described in embodiment B1 or B2 or a pharmaceutically acceptable salt thereof is provided, wherein Q is CH.

B4.   在實施方式B4中，提供了如實施方式B1或B2所述之化合物或其藥學上可接受的鹽，其中Q係N。B4. In embodiment B4, a compound as described in embodiment B1 or B2 or a pharmaceutically acceptable salt thereof is provided, wherein Q is N.

B5.   在實施方式B5中，提供了如實施方式B1至B4中任一項所述之化合物或其藥學上可接受的鹽，其中R^1a係氫。B5. In embodiment B5, provided is a compound as described in any one of embodiments B1 to B4 or a pharmaceutically acceptable salt thereof, wherein R^1a is hydrogen.

B6.   在實施方式B6中，提供了如實施方式B1至B4中任一項所述之化合物或其藥學上可接受的鹽，其中R^1a係氘。B6. In embodiment B6, provided is a compound as described in any one of embodiments B1 to B4 or a pharmaceutically acceptable salt thereof, wherein R^1a is deuterium.

B7.   在實施方式B7中，提供了如實施方式B1至B4中任一項所述之化合物或其藥學上可接受的鹽，其中R^1a係烷基，較佳的是甲基或乙基。B7. In embodiment B7, provided is a compound according to any one of embodiments B1 to B4 or a pharmaceutically acceptable salt thereof, wherein R^1a is alkyl, preferably methyl or ethyl.

B8.   在實施方式B8中，提供了如實施方式B1至B4中任一項所述之化合物或其藥學上可接受的鹽，其中R^1a係鹵代，較佳的是氟。B8. In embodiment B8, provided is a compound according to any one of embodiments B1 to B4 or a pharmaceutically acceptable salt thereof, wherein R^1a is halogen, preferably fluorine.

B9.   在實施方式B9中，提供了如實施方式B1至B4中任一項所述之化合物或其藥學上可接受的鹽，其中R^1a係鹵代烷基，較佳的是三氟甲基。B9. In embodiment B9, provided is a compound as described in any one of embodiments B1 to B4 or a pharmaceutically acceptable salt thereof, wherein R^1a is halogenated alkyl, preferably trifluoromethyl.

B10. 在實施方式B10中，提供了如實施方式B1至B4中任一項所述之化合物或其藥學上可接受的鹽，其中R^1a係烷氧基，較佳的是甲氧基。B10. In embodiment B10, provided is a compound according to any one of embodiments B1 to B4 or a pharmaceutically acceptable salt thereof, wherein R^1a is alkoxy, preferably methoxy.

B11. 在實施方式B11中，提供了如實施方式B1至B4中任一項所述之化合物或其藥學上可接受的鹽，其中R^1a係羥基。B11. In embodiment B11, provided is a compound according to any one of embodiments B1 to B4 or a pharmaceutically acceptable salt thereof, wherein R^1a is hydroxyl.

B12. 在實施方式B12中，提供了如實施方式B1至B4中任一項所述之化合物或其藥學上可接受的鹽，其中R^1a係氰基。B12. In embodiment B12, provided is a compound according to any one of embodiments B1 to B4 or a pharmaceutically acceptable salt thereof, wherein R^1a is cyano.

B13至B73.    在實施方式B13至B73中，提供了如實施方式B1至B12中任一項所述之化合物或其藥學上可接受的鹽，其中降解決定子係如實施方式A40至A96和A204至A207中任一項所提供的。B13 to B73. In embodiments B13 to B73, a compound as described in any one of embodiments B1 to B12 or a pharmaceutically acceptable salt thereof is provided, wherein the degradation determinant is provided in any one of embodiments A40 to A96 and A204 to A207.

B74至B84.    在實施方式B74至B84中，提供了如實施方式B1至B73中任一項所述之化合物或其藥學上可接受的鹽，其中Z係如實施方式A109至A119中任一項所提供的。B74 to B84. In embodiments B74 to B84, a compound as described in any one of embodiments B1 to B73 or a pharmaceutically acceptable salt thereof is provided, wherein Z is provided in any one of embodiments A109 to A119.

B85至B97.在實施方式B85至B97中，提供了如實施方式B1至B84中任一項所述之化合物或其藥學上可接受的鹽，其中-Z-alk-Ar-SO₂-係如實施方式A120至A132中任一項所提供的。B85 to B97. In embodiments B85 to B97, provided is a compound as described in any one of embodiments B1 to B84 or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SO₂ - is provided in any one of embodiments A120 to A132.

B98至B166.  在實施方式B98至B166中，提供了如實施方式B1至B97中任一項所述之化合物或其藥學上可接受的鹽，其中alk係如實施方式A135至A203中任一項所提供的。B98 to B166. In embodiments B98 to B166, a compound as described in any one of embodiments B1 to B97 or a pharmaceutically acceptable salt thereof is provided, wherein alk is provided in any one of embodiments A135 to A203.

B167至B190.      在實施方式B167至B190中，提供了如實施方式B1至B166中任一項所述之化合物或其藥學上可接受的鹽，其中Ar係如實施方式A97至A108和A133至A134中任一項所提供的。B167 to B190. In embodiments B167 to B190, a compound as described in any one of embodiments B1 to B166 or a pharmaceutically acceptable salt thereof is provided, wherein Ar is provided in any one of embodiments A97 to A108 and A133 to A134.

實施方式C： C1.      在實施方式C1中，提供了如發明內容中所定義的具有式 (I) 的化合物或藥學上可接受的鹽；或其藥學上可接受的鹽。Embodiment C: C1. In embodiment C1, a compound having formula (I) or a pharmaceutically acceptable salt thereof as defined in the present invention is provided; or a pharmaceutically acceptable salt thereof.

C2.   在實施方式C2中，如實施方式C1所述之化合物或其藥學上可接受的鹽，其中R¹係鹵代。C2. In embodiment C2, the compound or a pharmaceutically acceptable salt thereof as described in embodiment C1, wherein R¹ is halogenated.

C3.   在實施方式C3中，如實施方式C1所述之化合物或其藥學上可接受的鹽，其中R¹係鹵代烷基或鹵代烷氧基。C3. In embodiment C3, the compound or a pharmaceutically acceptable salt thereof as described in embodiment C1, wherein R¹ is halogenated alkyl or halogenated alkoxy.

C4.   在實施方式C4中，如實施方式C1和C3所述之化合物或其藥學上可接受的鹽，其中R¹係鹵代烷基。C4. In embodiment C4, the compound or pharmaceutically acceptable salt thereof as described in embodiments C1 and C3, wherein R¹ is halogenated alkyl.

C5.   在實施方式C5中，如實施方式C1和C3所述之化合物或其藥學上可接受的鹽，其中R¹係鹵代烷氧基。C5. In embodiment C5, the compound or pharmaceutically acceptable salt thereof as described in embodiments C1 and C3, wherein R¹ is halogenated alkoxy.

C6.   在實施方式C6中，如實施方式C1或C2所述之化合物或其藥學上可接受的鹽，其中R¹係氯或溴。C6. In embodiment C6, the compound or pharmaceutically acceptable salt thereof as described in embodiment C1 or C2, wherein R¹ is chlorine or bromine.

C7.   在實施方式C7中，如實施方式C1、C3或C4所述之化合物或其藥學上可接受的鹽，其中R¹係二氟甲基或三氟甲基。C7. In embodiment C7, the compound or pharmaceutically acceptable salt thereof as described in embodiment C1, C3 or C4, wherein R¹ is difluoromethyl or trifluoromethyl.

C8.   在實施方式C8中，如實施方式C1、C3和C5中任一項所述之化合物或其藥學上可接受的鹽，其中R¹係二氟甲氧基或三氟甲氧基。C8. In embodiment C8, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1, C3 and C5, wherein R¹ is difluoromethoxy or trifluoromethoxy.

C9.   在實施方式C9中，如實施方式C1所述之化合物或其藥學上可接受的鹽，其中R¹係甲基、乙基、丙基、乙烯基、丙烯基、乙炔基或丙炔基。C9. In embodiment C9, the compound or a pharmaceutically acceptable salt thereof as described in embodiment C1, wherein R¹ is methyl, ethyl, propyl, vinyl, propenyl, ethynyl or propynyl.

C10. 在實施方式C10中，如實施方式C1至C9中任一項所述之化合物或其藥學上可接受的鹽，其中R²和R^2a係氫。C10. In embodiment C10, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C9, wherein R² and R^2a are hydrogen.

C11. 在實施方式C11中，如實施方式C1至C9中任一項所述之化合物或其藥學上可接受的鹽，其中R²和R^2a中之一個係氘並且R²和R^2a中的另一個係氫，或R²和R^2a都是氘。C11. In embodiment C11, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C9, wherein one of R² and R^2a is deuterium and the other of R² and R^2a is hydrogen, or both R² and R^2a are deuterium.

C12. 在實施方式C12中，如實施方式C1至C11中任一項所述之化合物或其藥學上可接受的鹽，其中Hy係被R^a、R^b和R^c取代的雜亞環基，其中R^a和R^b獨立地選自氫、氘、烷基、鹵代、鹵代烷基、烷氧基、羥基和氰基，並且R^c係氫。C12. In embodiment C12, the compound as described in any one of embodiments C1 to C11, or a pharmaceutically acceptable salt thereof, wherein Hy is a heterocycloalkylene substituted with^Ra ,^Rb , and^Rc , wherein Ra and^Rb are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxyl,^and cyano, and^Rc is hydrogen.

C13. 在實施方式C13中，如實施方式C1至C12中任一項所述之化合物或其藥學上可接受的鹽，其中Hy的雜亞環基係：其中吡咯啶-1,3-二基或哌啶-1,4-二基環的N原子附接至-SO₂-。C13. In embodiment C13, the compound according to any one of embodiments C1 to C12, or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group of Hy is: wherein the N atom of the pyrrolidine-1,3-diyl or piperidine-1,4-diyl ring is attached to -SO₂ -.

C14. 在實施方式C14中，如實施方式C1至C13中任一項所述之化合物或其藥學上可接受的鹽，其中Hy的雜亞環基係：其中哌啶-1,4-二基環的N原子附接至-SO₂-。C14. In embodiment C14, the compound according to any one of embodiments C1 to C13, or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group of Hy is: wherein the N atom of the piperidine-1,4-diyl ring is attached to -SO₂ -.

C15. 在實施方式C15中，如實施方式C1至C11中任一項所述之化合物或其藥學上可接受的鹽，其中Hy的伸苯基係根據結構的1,4-伸苯基，其中表示到NH的鍵且表示到-SO₂-的鍵，並且R^a係氫、氟、甲基或甲氧基，並且R^b係氫。C15. In embodiment C15, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments C1 to C11, wherein the phenyl group of Hy is according to the structure 1,4-phenylene, wherein Indicates the key to NH and represents a bond to -SO₂ -, and^Ra is hydrogen, fluorine, methyl or methoxy, and^Rb is hydrogen.

C16. 在實施方式C16中，如實施方式C1至C15中任一項所述之化合物或其藥學上可接受的鹽，其中降解決定子係具有式 (i) 的E3泛素連接酶配位基：(i)。C16. In embodiment C16, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments C1 to C15, wherein the degron is an E3 ubiquitin ligase ligand having formula (i): (i).

C17. 在實施方式C17中，如實施方式C1至C16中任一項所述之化合物或其藥學上可接受的鹽，其中具有式 (i) 的E3泛素連接酶配位基的環A係具有式 (a) 的基團：。C17. In embodiment C17, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments C1 to C16, wherein Ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (a): .

C18. 在實施方式C18中，如實施方式C1至C16中任一項所述之化合物或其藥學上可接受的鹽，其中具有式 (i) 的E3泛素連接酶配位基的環A係具有式 (b) 的基團：。C18. In embodiment C18, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments C1 to C16, wherein Ring A of the E3 ubiquitin ligase ligand of formula (i) has a group of formula (b): .

C19. 在實施方式C19中，如實施方式C1至C18中任一項所述之化合物或其藥學上可接受的鹽，其中具有式 (i) 的E3泛素連接酶配位基的環A係：。C19. In embodiment C19, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments C1 to C18, wherein Ring A of the E3 ubiquitin ligase ligand of formula (i) is: .

C20. 在實施方式C20中，如實施方式C1至C19中任一項所述之化合物或其藥學上可接受的鹽，其中R^aa和R^bb、R^cc和R^dd獨立地選自氫、甲基、甲氧基、乙氧基、氟、三氟甲基、二氟甲基和三氟甲氧基。C20. In embodiment C20, the compound as described in any one of embodiments C1 to C19, or a pharmaceutically acceptable salt thereof, wherein^Raa and^Rbb ,^Rcc and^Rdd are independently selected from hydrogen, methyl, methoxy, ethoxy, fluoro, trifluoromethyl, difluoromethyl and trifluoromethoxy.

C21. 在實施方式C21中，如實施方式C1至C15中任一項所述之化合物或其藥學上可接受的鹽，其中降解決定子係具有式 (ii) 的E3泛素連接酶配位基：(ii)。C21. In embodiment C21, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments C1 to C15, wherein the degron is an E3 ubiquitin ligase ligand having formula (ii): (ii).

C22. 在實施方式C22中，如實施方式C1至C15和17至21中任一項所述之化合物或其藥學上可接受的鹽，其中Y^a係CH。C22. In embodiment C22, the compound as described in any one of embodiments C1 to C15 and 17 to 21, or a pharmaceutically acceptable salt thereof, wherein^Ya is CH.

C23. 在實施方式C23中，如實施方式C1至C15和C17至C21中任一項所述之化合物或其藥學上可接受的鹽，其中Y^a係N。C23. In embodiment C23, the compound as described in any one of embodiments C1 to C15 and C17 to C21, or a pharmaceutically acceptable salt thereof, wherein^Ya is N.

C24. 在實施方式C24中，如實施方式C1至C15和C17至C23中任一項所述之化合物或其藥學上可接受的鹽，其中Z^a係鍵、-NH-、-O-或-NHC(O)-。C24. In embodiment C24, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C15 and C17 to C23, wherein^Za is a bond, -NH-, -O- or -NHC(O)-.

C25. 在實施方式C25中，如實施方式C1至C15和C17至C24中任一項所述之化合物或其藥學上可接受的鹽，其中環B係5員或6員單環雜伸芳基或者9員或10員稠合雙環雜伸芳基，其中每個雜伸芳基環含有一至三個氮環原子，並且環B的每個環被R^ee和R^ff取代。C25. In embodiment C25, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C15 and C17 to C24, wherein ring B is a 5-membered or 6-membered monocyclic heteroaryl group or a 9-membered or 10-membered fused bicyclic heteroaryl group, wherein each heteroaryl ring contains one to three nitrogen ring atoms, and each ring of ring B is substituted with R^ee and R^ff .

C26. 在實施方式C26中，如實施方式C1至C15和C17至C25中任一項所述之化合物或其藥學上可接受的鹽，其中具有式 (ii) 的E3泛素連接酶配位基係：、、、、、、、、、、、、、或其中環B係環亞胺基。C26. In embodiment C26, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments C1 to C15 and C17 to C25, wherein the E3 ubiquitin ligase ligand of formula (ii) is: 、 、 、 、 、 、 、 、 、 、 、 、 、 or Ring B is a cycloimino group.

C27. 在實施方式C27中，如實施方式C1至C15和C17至C26中任一項所述之化合物或其藥學上可接受的鹽，其中具有式 (ii) 的E3泛素連接酶配位基係。C27. In embodiment C27, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C15 and C17 to C26, wherein the E3 ubiquitin ligase ligand of formula (ii) is .

C28. 在實施方式C28中，如實施方式C1至C15和C17至C27中任一項所述之化合物或其藥學上可接受的鹽，其中具有式 (ii) 的E3泛素連接酶配位基係或。C28. In embodiment C28, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C15 and C17 to C27, wherein the E3 ubiquitin ligase ligand of formula (ii) is or .

C29. 在實施方式C29中，如實施方式C1至C15和C17至C28中任一項所述之化合物或其藥學上可接受的鹽，其中R^ee和R^ff獨立地選自氫、甲基、乙基、異丙基、環丙基、甲氧基、乙氧基、氟、氯、三氟甲基、2,2,2-三氟乙基、二氟甲基、二氟甲氧基、三氟甲氧基和氰基。C29. In embodiment C29, the compound as described in any one of embodiments C1 to C15 and C17 to C28, or a pharmaceutically acceptable salt thereof, wherein R^ee and R^ff are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy and cyano.

C30. 在實施方式C30中，如實施方式C1至C29中任一項所述之化合物或其藥學上可接受的鹽，其中Ar係伸苯基、單環雜伸芳基、橋接雜亞環基或雜亞環基，其中Ar的每個環被R^j、R^k和R^m取代，其中R^m係氫。C30. In embodiment C30, the compound as described in any one of embodiments C1 to C29, or a pharmaceutically acceptable salt thereof, wherein Ar is a phenylene group, a monocyclic heteroarylene group, a bridged heterocycloalkylene group, or a heterocycloalkylene group, wherein each ring of Ar is substituted with^Rj ,^Rk , and^Rm , wherein^Rm is hydrogen.

C31. 在實施方式C31中，如實施方式C1至C30中任一項所述之化合物或其藥學上可接受的鹽，其中Ar係被R^j、R^k和R^m取代的具有式或的伸苯基，其中R^j和R^k獨立地選自氫、烷基、烷氧基、鹵代、氰基、鹵代烷基和鹵代烷氧基，並且R^m係氫。C31. In embodiment C31, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments C1 to C30, wherein Ar is substituted with R^j , R^k and R^m and has the formula or phenylene, wherein^Rj and^Rk are independently selected from hydrogen, alkyl, alkoxy, halogen, cyano, halogenated alkyl and halogenated alkoxy, and^Rm is hydrogen.

C32. 在實施方式C32中，如實施方式C1至C31中任一項所述之化合物或其藥學上可接受的鹽，其中-Ar-的伸苯基係。C32. In embodiment C32, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments C1 to C31, wherein the phenyl group of -Ar- is .

C33. 在實施方式C33中，如實施方式C1至C31中任一項所述之化合物或其藥學上可接受的鹽，其中-Ar-的伸苯基係。C33. In embodiment C33, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments C1 to C31, wherein the phenyl group of -Ar- is .

C34. 在實施方式C34中，如實施方式C1至C30中任一項所述之化合物或其藥學上可接受的鹽，其中-Ar-係被R^j、R^k和R^m取代的單環雜伸芳基（如咪唑-1,5-二基、吡啶-2,4-二基、吡啶-2,6-二基、吡啶-2,5-二基或吡啶-3,5-二基），其中R^j和R^k獨立地選自氫、烷基、烷氧基、鹵代、鹵代烷基、氰基和鹵代烷氧基，並且R^m係氫。C34. In embodiment C34, the compound as described in any one of embodiments C1 to C30, or a pharmaceutically acceptable salt thereof, wherein -Ar- is a monocyclic heteroaryl group substituted by^Rj ,^Rk and^Rm (such as imidazole-1,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl, pyridine-2,5-diyl or pyridine-3,5-diyl), wherein^Rj and^Rk are independently selected from hydrogen, alkyl, alkoxy, halogenated, halogenated alkyl, cyano and halogenated alkoxy, and^Rm is hydrogen.

C35. 在實施方式C35中，如實施方式C1至C30中任一項所述之化合物或其藥學上可接受的鹽，其中-Ar-係被R^j、R^k和R^m取代的雜亞環基，其中R^j和R^k獨立地選自氫、甲基、甲氧基、氟、氯、二氟甲基、三氟甲基、2,2,2-三氟乙基、二氟甲氧基和三氟甲氧基，並且R^m係氫。C35. In embodiment C35, the compound as described in any one of embodiments C1 to C30, or a pharmaceutically acceptable salt thereof, wherein -Ar- is a heterocyclic group substituted with^Rj ,^Rk , and^Rm , wherein^Rj and^Rk are independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy, and trifluoromethoxy, and^Rm is hydrogen.

C36. 在實施方式C36中，如實施方式C1至C35中任一項所述之化合物或其藥學上可接受的鹽，其中Z係雜亞環基、橋接雜亞環基或螺雜亞環基，其中Z的每個環被R^d和R^e取代。C36. In embodiment C36, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C35, wherein Z is a heterocycloalkylene, a bridged heterocycloalkylene, or a spiroheterocycloalkylene, wherein each ring of Z is substituted by R^d and^Re .

C37. 在實施方式C37中，如實施方式C1至C36中任一項所述之化合物或其藥學上可接受的鹽，其中Z的雜亞環基、橋接雜亞環基和螺雜亞環基分別選自：，並且其中上述環中之每一個被獨立地選自氫、氘、烷基和鹵代的R^d和R^e取代。C37. In embodiment C37, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments C1 to C36, wherein the heterocyclic group, bridged heterocyclic group and spiroheterocyclic group of Z are selected from: , and wherein each of the above rings is substituted with R^d and^Re independently selected from hydrogen, deuterium, alkyl and halogen.

C38. 在實施方式C38中，如實施方式C1至C37中任一項所述之化合物或其藥學上可接受的鹽，其中Z的雜亞環基、橋接雜亞環基和螺雜亞環基分別獨立地選自：。C38. In embodiment C38, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments C1 to C37, wherein the heterocyclic group, bridged heterocyclic group, and spiroheterocyclic group of Z are independently selected from: .

C39. 在實施方式C39中，如實施方式C1至C31和C36至C38中任一項所述之化合物或其藥學上可接受的鹽，其中-Z-alk-Ar-SO₂-係：其中每個R^d、R^e和R^k獨立地選自氫、烷基、鹵代、鹵代烷基、鹵代烷氧基、烷氧基和氰基，並且R^j係氫。C39. In embodiment C39, the compound according to any one of embodiments C1 to C31 and C36 to C38, or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SO₂ - is: wherein each of R^d ,^Re and R^k is independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy and cyano, and R^j is hydrogen.

C40. 在實施方式C40中，如實施方式C1至C31和C36至C39中任一項所述之化合物或其藥學上可接受的鹽，其中-Z-alk-Ar-SO₂-係：其中每個R^d、R^e和R^k獨立地選自氫、烷基、鹵代、鹵代烷基、鹵代烷氧基、烷氧基和氰基，並且R^j係氫。C40. In embodiment C40, the compound according to any one of embodiments C1 to C31 and C36 to C39, or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SO₂ - is: wherein each of R^d ,^Re and R^k is independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy and cyano, and R^j is hydrogen.

C41. 在實施方式C41中，如實施方式C1至C31和C36至C40中任一項所述之化合物或其藥學上可接受的鹽，其中-Z-alk-Ar-SO₂-係：。C41. In embodiment C41, the compound according to any one of embodiments C1 to C31 and C36 to C40, or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SO₂ - is: .

C42. 在實施方式C42中，如實施方式C1至C31和C36至C39中任一項所述之化合物或其藥學上可接受的鹽，其中-Z-alk-Ar-SO₂-係：。C42. In embodiment C42, the compound according to any one of embodiments C1 to C31 and C36 to C39, or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SO₂ - is: .

C43. 在實施方式C43中，如實施方式C39、C40和C41中任一項所述之化合物或其藥學上可接受的鹽，其中係：。C43. In embodiment C43, the compound as described in any one of embodiments C39, C40 and C41, or a pharmaceutically acceptable salt thereof, wherein Department: .

C44. 在實施方式C44中，如實施方式C39、C40、C41和C43中任一項所述之化合物或其藥學上可接受的鹽，其中係、或。C44. In embodiment C44, the compound as described in any one of embodiments C39, C40, C41 and C43, or a pharmaceutically acceptable salt thereof, wherein Department 、 or .

C45. 在實施方式C45中，如實施方式C1至C44中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^f取代的C₃至C₆伸烯基，其中R^f係氫。C45. In embodiment C45, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C44, wherein alk is C₃ to C₆ alkenyl substituted with R^f , wherein R^f is hydrogen.

C46. 在實施方式C46中，如實施方式C1至C44中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^f取代的C₃至C₆伸烯基，其中R^f係氟或氰基。C46. In embodiment C46, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C44, wherein alk is C₃ to C₆ alkenyl substituted with R^f , wherein R^f is fluoro or cyano.

C47. 在實施方式C47中，如實施方式C1至C44中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，其中R^g、R^h和Rⁱ係氫。C47. In embodiment C47, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C44, wherein alk is C₃ to C₆ alkylene substituted with R^g , R^h and Rⁱ , wherein R^g , R^h and Rⁱ are hydrogen.

C48. 在實施方式C48中，如實施方式C1至4C4中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，其中R^g、R^h和Rⁱ係氫或鹵代，條件係R^g、R^h和Rⁱ中之至少一個係鹵代。C48. In embodiment C48, the compound as described in any one of embodiments C1 to 4C4, or a pharmaceutically acceptable salt thereof, wherein alk is a C₃ to C₆ alkylene substituted with R^g , R^h and Rⁱ , wherein R^g , R^h and Rⁱ are hydrogen or halogenated, with the proviso that at least one of R^g , R^h and Rⁱ is halogenated.

C49. 在實施方式C49中，如實施方式C1至C44中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，其中R^h不是氫並且Rⁱ係氫，或者當R^g和R^h附接至該C₃至C₆伸烷基的直鏈部分的相同碳或相鄰碳原子時，R^g和R^h可與它們所附接的碳原子一起形成環伸烷基或雜亞環基，其中由R^g和R^h形成的該環伸烷基和雜亞環基被R⁹和R¹⁰取代。C49. In embodiment C49, the compound as described in any one of embodiments C1 to C44, or a pharmaceutically acceptable salt thereof, wherein alk is a C₃ to C₆ alkylene substituted with R^g , R^h and Rⁱ , wherein R^h is not hydrogen and Rⁱ is hydrogen, or when R^g and R^h are attached to the same carbon or adjacent carbon atoms of the straight chain portion of the C₃ to C₆ alkylene, R^g and R^h can be taken together with the carbon atoms to which they are attached to form a cycloalkylene or heterocycloalkylene, wherein the cycloalkylene and heterocycloalkylene formed by R^g and R^h are substituted with R⁹ and R¹⁰ .

C50. 在實施方式C50中，如實施方式C1至C44和C49中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，其中R^h不是氫並且Rⁱ係氫。在實施方式中，如實施方式C49所述之化合物或其藥學上可接受的鹽，係其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，其中R^h不是氫並且Rⁱ係氫。C50. In Embodiment C50, the compound or pharmaceutically acceptable salt thereof as described in any one of Embodiments C1 to C44 and C49, wherein alk is C₃ to C₆ alkylene substituted with R^g , R^h , and Rⁱ , wherein R^h is not hydrogen and Rⁱ is hydrogen. In an embodiment, the compound or pharmaceutically acceptable salt thereof as described in Embodiment C49, wherein alk is C₃ to C₆ alkylene substituted with R^g , R^h , and Rⁱ , wherein R^h is not hydrogen and Rⁱ is hydrogen.

C51. 在實施方式C51中，如實施方式C1至C50中任一項所述之化合物或其藥學上可接受的鹽，其中alk的C₃至C₆伸烯基和C₃至C₆伸烷基分別是直鏈C₃至C₆伸烯基和直鏈C₃至C₆伸烷基，其中alk被R^g、R^h和Rⁱ取代。C51. In embodiment C51, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C50, wherein the C₃ to C₆ alkenyl and C₃ to C₆ alkylene of alk are linear C₃ to C₆ alkenyl and linear C₃ to C₆ alkylene, respectively, wherein alk is substituted with R^g , R^h and Rⁱ .

C52. 在實施方式C52中，如實施方式C1至C46和49至51中任一項所述之化合物或其藥學上可接受的鹽，其中alk的該直鏈C₃至C₆伸烯基係-CH=C(R^f)CH₂-，並且alk的C₃至C₆伸烷基的直鏈伸烷基係-CH₂CH(R^h)CH₂-、-CH₂CH₂CH(R^h)-、-CH₂C(R^g)(R^h)CH₂-、-CH₂CH₂C(R^g)(R^h)-，其中R^h不是氫並且Rⁱ係氫。C52. In embodiment C52, the compound as described in any one of embodiments C1 to C46 and 49 to 51, or a pharmaceutically acceptable salt thereof, wherein the linear C₃ to C₆ alkenylene of alk is -CH═C(R^f )CH₂ -, and the linear alkylene of the C₃ to C₆ alkylene of alk is -CH₂ CH(R^h )CH₂ -, -CH₂ CH₂ CH(R^h )-, -CH₂ C(R^g )(R^h )CH₂ -, -CH₂ CH₂ C(R^g )(R^h )-, wherein R^h is not hydrogen and Rⁱ is hydrogen.

C53. 在實施方式C53中，如實施方式C1至C44和C49至C52中任一項所述之化合物或其藥學上可接受的鹽，其中alk的該直鏈C₃至C₆伸烷基係-CH₂CH(R^h)CH₂-，其中R^h不是氫並且Rⁱ係氫。C53. In embodiment C53, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C44 and C49 to C52, wherein the linear C₃ to C₆ alkylene group of alk is -CH₂ CH(R^h )CH₂ -, wherein R^h is not hydrogen and Rⁱ is hydrogen.

C54. 在實施方式C54中，如實施方式C1至C44和C49至C53中任一項所述之化合物或其藥學上可接受的鹽，其中alk的直鏈C₃至C₆伸烷基的R^g係氫、氘或鹵代，並且alk的直鏈C₃至C₆伸烷基的R^h係鹵代、鹵代烷氧基、環烷基、環烷基氧基、烷氧基、羥基、胺基羰基、烷基胺基羰基、二烷基胺基羰基、烷基羰基胺基、氰基、氰基烷基氧基、苯基、雜芳基、雜環基或橋接雜環基，R^h的每個環被R⁷和R⁸取代。C54. In embodiment C54, the compound as described in any one of embodiments C1 to C44 and C49 to C53, or a pharmaceutically acceptable salt thereof, wherein^Rg of the straight-chain_C3 to_C6 alkylene group of alk is hydrogen, deuterium or halogenated, and^Rh of the straight-chain_C3 to_C6 alkylene group of alk is halogenated, halogenated alkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclic group or bridged heterocyclic group, and each ring of^Rh is substituted with^R7 and^R8 .

C55. 在實施方式C55中，如實施方式C1至C44和C49至C54中任一項所述之化合物或其藥學上可接受的鹽，其中alk的直鏈C₃至C₆伸烷基的R^g係氫，並且alk的直鏈C₃至C₆伸烷基的R^h係鹵代、鹵代烷氧基、環烷基、環烷基氧基、烷氧基、羥基、二烷基胺基羰基、烷基羰基胺基、氰基、苯基、雜芳基、雜環基或橋接雜環基，R^h的每個環被R⁷和R⁸取代。C55. In embodiment C55, the compound as described in any one of embodiments C1 to C44 and C49 to C54, or a pharmaceutically acceptable salt thereof, wherein^Rg of the straight-chain_C3 to_C6 alkylene group of alk is hydrogen, and^Rh of the straight-chain_C3 to_C6 alkylene group of alk is halogenated, halogenated alkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclic group or bridged heterocyclic group, and each ring of^Rh is substituted with^R7 and^R8 .

C56. 在實施方式C56中，如實施方式C1至C44和C49至C55中任一項所述之化合物或其藥學上可接受的鹽，其中alk的直鏈C₃至C₆伸烷基的R^g係氫，並且alk的直鏈C₃至C₆伸烷基的R^h係鹵代、鹵代烷氧基、烷氧基、羥基、二烷基胺基羰基、氰基、雜環基或雜芳基，R^h的每個環被R⁷和R⁸取代。C56. In embodiment C56, the compound as described in any one of embodiments C1 to C44 and C49 to C55, or a pharmaceutically acceptable salt thereof, wherein^Rg of the linear_C3 to_C6 alkylene group of alk is hydrogen, and^Rh of the linear_C3 to_C6 alkylene group of alk is halogenated, halogenated alkoxy, alkoxy, hydroxyl, dialkylaminocarbonyl, cyano, heterocyclic or heteroaryl, and each ring of^Rh is substituted with^R7 and^R8 .

C57. 在實施方式C57中，如實施方式C1至C44和C49至C56中任一項所述之化合物或其藥學上可接受的鹽，其中alk的直鏈C₃至C₆伸烷基的R^h的雜芳基、雜環基和橋接雜環基，當存在時，係五員或六員環，並且R^h的每個環被R⁷和R⁸取代。C57. In embodiment C57, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C44 and C49 to C56, wherein the heteroaryl, heterocyclic and bridged heterocyclic groups of^Rh of the linear_C3 to_C6 alkylene group of alk, when present, are five-membered or six-membered rings, and each ring of^Rh is substituted by^R7 and^R8 .

C58. 在實施方式C58中，如實施方式C1至C44和C49至C57中任一項所述之化合物或其藥學上可接受的鹽，其中alk的直鏈C₃至C₆伸烷基的R^g係氫、氘或氟（除非另有說明，例如其中R^g係如實施方式C55和C56中所述之氫），並且alk的直鏈C₃至C₆伸烷基的R^h係氟、環丙基、環丁基、環丙基氧基、環丁基氧基、二氟甲氧基、三氟甲氧基、甲氧基、乙氧基、羥基、氰基、胺基羰基、甲基胺基羰基、二甲基胺基羰基、二乙基胺基羰基、甲基羰基胺基、乙基羰基胺基、苯基、吡唑基、呋喃基、噻唑基、吡啶基、吡咯啶基、2-側氧基吡咯啶基、哌啶基、哌𠯤基或四氫呋喃基，R^h的每個環被獨立地選自氫、氘、甲基、甲氧基、氟、二氟甲基、三氟甲基、二氟甲氧基、三氟甲基、羥基、胺基、甲基胺基、二甲基胺基和氰基的R⁷和R⁸取代，除非另有說明。C58. In embodiment C58, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C44 and C49 to C57, wherein^Rg of the linear_C3 to_C6 alkylene group of alk is hydrogen, deuterium or fluorine (unless otherwise specified, for example, wherein^Rg is hydrogen as described in embodiments C55 and C56), and Rg of the linear_C3 to_C6 alkylene group of alk is hydrogen, deuterium or fluorine.^R is fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, furanyl, thiazolyl, pyridyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, piperonyl or tetrahydrofuranyl, and each ring of R is substituted by R^{and R} independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino,^methylamino , dimethylamino and^cyano , unless otherwise specified.

C59. 在實施方式C59中，如實施方式C1至C44和C49至C58中任一項所述之化合物或其藥學上可接受的鹽，其中alk的直鏈C₃至C₆伸烷基的R^g係氫，並且alk的直鏈C₃至C₆伸烷基的R^h係氟、環丙基、環丙基氧基、二氟甲氧基、三氟甲氧基、甲氧基、乙氧基、羥基、氰基、甲基胺基羰基、二甲基胺基羰基、甲基羰基胺基、苯基、吡唑-1-基、吡唑-4-基、吡啶-4-基、吡咯啶-1-基或2-側氧基吡咯啶-1-基，R^h的每個環被獨立地選自氫、氘、甲基和氟的R⁷和R⁸取代，除非另有說明。C59. In embodiment C59, the compound as described in any one of embodiments C1 to C44 and C49 to C58, or a pharmaceutically acceptable salt thereof, wherein^Rg of the linear_C3 to_C6 alkylene group of alk is hydrogen, and^Rh of the linear_C3 to_C6 alkylene group of alk is fluoro, cyclopropyl, cyclopropyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonylamino, phenyl, pyrazol-1-yl, pyrazol-4-yl, pyridin-4-yl, pyrrolidin-1-yl or 2-oxopyrrolidin-1-yl, unless otherwise specified, each ring of^Rh is substituted with^R7 and^R8 independently selected from hydrogen, deuterium, methyl and fluoro.

C60. 在實施方式C60中，如實施方式C1至C44中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^g、R^h和Rⁱ取代的支鏈C₄至C₆伸烷基。C60. In embodiment C60, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C44, wherein alk is a branched C₄ to C₆ alkylene substituted with R^g , R^h and Rⁱ .

C61. 在實施方式C61中，如實施方式C1至C46和C60中任一項所述之化合物或其藥學上可接受的鹽，其中alk的C₃至C₆伸烯基和C₃至C₆伸烷基分別是支鏈C₄至C₆伸烯基和C₄至C₆伸烷基。C61. In embodiment C61, the compound as described in any one of embodiments C1 to C46 and C60, or a pharmaceutically acceptable salt thereof, wherein the C₃ to C₆ alkenyl group and C₃ to C₆ alkylene group of alk are branched C₄ to C₆ alkenyl group and C₄ to C₆ alkylene group, respectively.

C62. 在實施方式C62中，如實施方式C1至C46、C60和C61中任一項所述之化合物或其藥學上可接受的鹽，其中alk的該支鏈C₄至C₆伸烯基係-CH₂CH₂C(CH₃)=C(R^f)-、-CH₂C(CH₃)=C(R^f)-或-CH₂C(=CH₂)CH₂-，並且alk的該支鏈C₄至C₆伸烷基係-CH₂C(CH₃)(R^h)CH₂-、-CH₂C(C₂H₅)(R^h)CH₂-、-CH₂CH(CH₂R^h)CH₂-、-CH₂CH(CH₂CH₂R^h)CH₂-、-CH₂C(CH₃)(CH₂R^h)CH₂-、-CH₂C(C₂H₅)(CH₂R^h)CH₂-、-CH₂C(CH₃)(CH₂CH₂R^h)CH₂-、-CH₂CH(CH₃)CH(CH₂R^h)-、-CH₂CH₂C(CH₃)(CH₂R^h)-、-CH₂CH(CH₃)C(R^g)(R^h)-、-CH₂CH(C₂H₅)C(R^g)(R^h)-、-CH₂CH(C(R^g)(R^h)(Rⁱ))CH(CH₃)-、-CH₂C(CH₃)(C(R^g)(R^h)(Rⁱ))CH(CH₃)-、-CH₂CH(C(R^g)(R^h)(Rⁱ))CH₂-、-CH₂CH₂CH(C(R^g)(R^h)(Rⁱ))-、-CH₂CH₂CH(C(R^g)(R^h)(Rⁱ))CH₂-、或-CH₂CH₂CH₂CH(C(R^g)(R^h)(Rⁱ))-。C62. In embodiment C62, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C46, C60 and C61, wherein the side-chain C₄ to C₆ alkenylene group of alk is -CH₂ CH₂ C(CH₃ )═C(R^f )-, -CH₂ C(CH₃ )═C(R^f )-, or -CH₂ C(═CH₂ )CH₂ -, and the side-chain C₄ to C₆ alkylene group of alk is -CH₂ C(CH₃ )(R^h )CH₂ -, -CH₂ C(C₂ H₅ )(R^h )CH₂ -, -CH₂ CH(CH₂ R^h )CH₂ -, -CH₂ CH(CH₂ CH₂ R^h )CH₂ -, -CH₂ C(CH₃ )(CH₂ R^h )CH₂ -, -CH₂ C(C₂ H₅ )(CH₂ R^h )CH₂ -, -CH₂ C(CH₃ )(CH₂ CH₂ R^h )CH₂ -, -CH₂ CH(CH₃ )CH(CH₂ R^h )-, -CH₂ CH₂ C(CH₃ )(CH₂ R^h )-, -CH₂ CH(CH₃ )C(R^g )(R^h )-, -CH₂ CH(C₂ H₅ )C(R^g )(R^h )-, -CH₂ CH(C(R^g )(R^h )(Rⁱ ))CH(CH₃ )-, -CH₂ C(CH₃ )(C(R^g )(R^h )(Rⁱ ))CH(CH₃ )-, -CH₂ CH(C(R^g )(R^h )(Rⁱ ))CH₂ -, -CH₂ CH₂ CH(C(R^g )(R^h )(Rⁱ ))-, -CH₂ CH₂ CH(C(R^g )(R^h )(Rⁱ ))CH₂ -, or -CH₂ CH₂ CH₂ CH(C(R^g )(R^h )(Rⁱ ))-.

C63. 在實施方式C63中，如實施方式C1至C46和C60至C62中任一項所述之化合物或其藥學上可接受的鹽，其中alk的該支鏈C₄至C₆伸烯基係-CH₂C(CH₃)=C(R^f)-或-CH₂C(=)CH₂-，並且alk的該支鏈C₄至C₆伸烷基係-CH₂C(CH₃)(R^h)CH₂-、-CH₂CH(CH₂R^h)CH₂-、-CH₂CH(CH₂CH₂R^h)CH₂-、-CH₂CH(C(R^g)(R^h)(Rⁱ))CH₂-、-CH₂CH₂CH(C(R^g)(R^h)(Rⁱ))CH₂-、或-CH₂CH₂CH₂CH(C(R^g)(R^h)(Rⁱ))-。C63. In embodiment C63, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C46 and C60 to C62, wherein the side-chain C₄ to C₆ alkenylene group of alk is -CH₂ C(CH₃ )═C(R^f )- or -CH₂ C(═)CH₂ -, and the side-chain C₄ to C₆ alkylene group of alk is -CH₂ C(CH₃ )(R^h )CH₂ -, -CH₂ CH(CH₂ R^h )CH₂ -, -CH₂ CH(CH₂ CH₂ R^h )CH₂ -, -CH₂ CH(C(R^g )(R^h )(Rⁱ ))CH₂ -, -CH₂ CH₂ CH(C(R^g )(R^h )(Rⁱ ))CH₂ -, or -CH₂ CH₂ CH₂ CH(C(R^g )(R^h )(Rⁱ ))-.

C64. 在實施方式C64中，如實施方式C1至C44和C60至C63中任一項所述之化合物或其藥學上可接受的鹽，其中alk的支鏈C₄至C₆伸烷基的R^g和Rⁱ獨立地是氫或鹵代（除非另有說明），並且alk的支鏈C₄至C₆伸烷基的R^h係氫、鹵代、鹵代烷氧基、環烷基、環烷基氧基、烷氧基、羥基、胺基羰基、烷基胺基羰基、二烷基胺基羰基、烷基羰基胺基、氰基、氰基烷基氧基、苯基、雜芳基、雜環基、雜環基氧基、雜環基羰基或橋接雜環基，R^h的每個環被R⁷和R⁸取代。C64. In embodiment C64, the compound as described in any one of embodiments C1 to C44 and_C60 to C63, or a pharmaceutically acceptable salt thereof, wherein^Rg and^R1 of the branched C4 to_C6 alkylene group of alk are independently hydrogen or halogenated (unless otherwise specified), and^Rh of the branched_C4 to_C6 alkylene group of alk is hydrogen, halogenated, halogenated alkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclo, heterocyclooxy, heterocyclocarbonyl, or bridged heterocyclo, and each ring of^Rh is substituted with^R7 and^R8 .

C65. 在實施方式C65中，如實施方式C1至C44和C60至C64中任一項所述之化合物或其藥學上可接受的鹽，其中alk的支鏈C₄至C₆伸烷基的R^g和Rⁱ係氫或氟（除非另有說明），並且alk的支鏈C₄至C₆伸烷基的R^h係氫、鹵代、環烷基、環烷基氧基、烷氧基、羥基、烷基胺基羰基、二烷基胺基羰基、烷基羰基胺基、氰基、苯基、雜芳基、雜環基、雜環基氧基、雜環基羰基或橋接雜環基，R^h的每個環被R⁷和R⁸取代。C65. In embodiment C65, the compound as described in any one of embodiments C1 to C44 and_C60 to C64, or a pharmaceutically acceptable salt thereof, wherein^Rg and^R1 of the branched C4 to_C6 alkylene group of alk are hydrogen or fluorine (unless otherwise specified), and^Rh of the branched_C4 to_C6 alkylene group of alk is hydrogen, halogen, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclo, heterocyclooxy, heterocyclocarbonyl or bridged heterocyclo, and each ring of^Rh is substituted with^R7 and^R8 .

C66. 在實施方式C66中，如實施方式C1至C44和C60至C65中任一項所述之化合物或其藥學上可接受的鹽，其中alk的支鏈C₄至C₆伸烷基的R^g和Rⁱ係氫或氟，並且alk的支鏈C₄至C₆伸烷基的R^h係被R⁷和R⁸取代的氫、鹵代、烷氧基、羥基、二烷基胺基羰基、氰基或雜芳基。C66. In embodiment C66, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to_C44 and C60 to C65, wherein^Rg and^Ri of the branched C4 to_C6 alkylene group of alk are hydrogen or fluorine, and^Rh of the branched_C4 to_C6 alkylene group of alk is hydrogen, halogen, alkoxy, hydroxyl, dialkylaminocarbonyl, cyano or heteroaryl substituted with^R7 and^R8 .

C67. 在實施方式C67中，如實施方式C1至C44和C60至C66中任一項所述之化合物或其藥學上可接受的鹽，其中alk的支鏈C₄至C₆伸烷基的雜芳基、雜環基——本身或作為雜環基氧基、雜環基羰基的一部分、和橋接雜環基，當存在時，係五員或六員環，並且R^h的每個環被R⁷和R⁸取代。C67. In embodiment C67, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C44 and C60 to C66, wherein the branched_C4 to_C6 alkylene heteroaryl, heterocyclic group - itself or as part of a heterocyclic group, heterocyclic group carbonyl group, and bridged heterocyclic group of alk, when present, is a five-membered or six-membered ring, and each ring of^Rh is substituted by^R7 and^R8 .

C68. 在實施方式C68中，如實施方式C1至C44和C60至C67中任一項所述之化合物或其藥學上可接受的鹽，係alk的支鏈C₄至C₆伸烷基的R^g和Rⁱ係（除非另有說明）氫、氘或氟，並且alk的支鏈C₄至C₆伸烷基的R^h，除非另有說明，係氫、氘、氟、環丙基、環丁基、環丙基氧基、環丁基氧基、二氟甲氧基、三氟甲氧基、甲氧基、乙氧基、羥基、氰基、胺基羰基、甲基胺基羰基、二甲基胺基羰基、二乙基胺基羰基、甲基羰基胺基、乙基羰基胺基、苯基、吡唑基、噻唑基、呋喃基、吡啶基、吡咯啶基、2-側氧基吡咯啶基、哌啶基、哌𠯤基、四氫呋喃基，R^h的每個環被獨立地選自氫、氘、甲基、甲氧基、氟、二氟甲基、三氟甲基、二氟甲氧基、三氟甲基、羥基、胺基、甲基胺基、二甲基胺基和氰基的R⁷和R⁸取代，除非另有說明。C68. In embodiment C68, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments C1 to_C44 and C60 to C67 is wherein^Rg and^Ri of the branched C4 to_C6 alkylene group of alk are (unless otherwise specified) hydrogen, deuterium or fluorine, and^Rh of the branched_C4 to_C6 alkylene group of alk is , unless otherwise specified, is hydrogen, deuterium, fluorine, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, thiazolyl, furyl, pyridyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, piperonyl, tetrahydrofuranyl, and each ring of^R is substituted with R and R independently selected from hydrogen, deuterium, methyl, methoxy, fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino,^{dimethylamino} , and^cyano , unless otherwise specified.

C69. 在實施方式C69中，如實施方式C1至C44和C60至C68中任一項所述之化合物或其藥學上可接受的鹽，其中alk的支鏈C₄至C₆伸烷基的R^g和Rⁱ，除非另有說明，係氫或氟，並且alk的支鏈C₄至C₆伸烷基的R^h係氫、氟、羥基、甲氧基、氰基、吡唑基-1-基或甲基胺基羰基。C69. In embodiment C69, the compound as described in any one of embodiments C1 to C44 and C60 to C68, or a pharmaceutically acceptable salt thereof, wherein^Rg and^R1 of the branched_C4 to_C6 alkylene group of alk, unless otherwise specified, are hydrogen or fluorine, and^Rh of the branched_C4 to_C6 alkylene group of alk is hydrogen, fluorine, hydroxyl, methoxy, cyano, pyrazol-1-yl or methylaminocarbonyl.

C70. 在實施方式C70中，如實施方式C1至C44和C49中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，其中R^g和R^h附接至該C₃至C₆伸烷基的直鏈部分的相同碳或相鄰碳原子，並且R^g和R^h可與它們所附接的碳原子一起形成環伸烷基或雜亞環基，其中由R^g和R^h形成的該環伸烷基和雜亞環基被R⁹和R¹⁰取代。C70. In embodiment C70, the compound as described in any one of embodiments C1 to C44 and C49, or a pharmaceutically acceptable salt thereof, wherein alk is a C₃ to C₆ alkylene group substituted with R^g , R^h and Rⁱ , wherein R^g and R^h are attached to the same carbon or adjacent carbon atoms of the straight chain portion of the C₃ to C₆ alkylene group, and R^g and R^h may form a cycloalkylene group or a heterocycloalkylene group together with the carbon atoms to which they are attached, wherein the cycloalkylene group and the heterocycloalkylene group formed by R^g and R^h are substituted with R⁹ and R¹⁰ .

C71. 在實施方式C71中，如實施方式C1至C44、C49和C70中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，其中R^g和R^h附接至該C₃至C₆伸烷基的直鏈部分的相同碳原子並且可與它們所附接的碳原子一起形成被R⁹和R¹⁰取代的環伸烷基。C71. In embodiment C71, the compound as described in any one of embodiments C1 to C44, C49 and C70, or a pharmaceutically acceptable salt thereof, wherein alk is a C₃ to C₆ alkylene substituted with R^g , R^h and Rⁱ , wherein R^g and R^h are attached to the same carbon atom of the straight chain portion of the C₃ to C₆ alkylene and can form, together with the carbon atom to which they are attached, a cycloalkylene substituted with R⁹ and R¹⁰ .

C72. 在實施方式C72中，如實施方式C1至C44、C49和C70中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，其中R^g和R^h附接至該C₃至C₆伸烷基的直鏈部分的相同碳原子並且可與它們所附接的碳原子一起形成被R⁹和R¹⁰取代的雜亞環基。C72. In embodiment C72, the compound as described in any one of embodiments C1 to C44, C49 and C70, or a pharmaceutically acceptable salt thereof, wherein alk is a C₃ to C₆ alkylene substituted with R^g , R^h and Rⁱ , wherein R^g and R^h are attached to the same carbon atom of the straight chain portion of the C₃ to C₆ alkylene and may form, together with the carbon atom to which they are attached, a heterocycloalkylene substituted with R⁹ and R¹⁰ .

C73. 在實施方式C73中，如實施方式C1至C44、C49和C70中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，其中R^g和R^h附接至該C₃至C₆伸烷基的直鏈部分的相鄰碳原子並且可與它們所附接的碳原子一起形成被R⁹和R¹⁰取代的環伸烷基。C73. In embodiment C73, the compound as described in any one of embodiments C1 to C44, C49 and C70, or a pharmaceutically acceptable salt thereof, wherein alk is a C₃ to C₆ alkylene substituted with R^g , R^h and Rⁱ , wherein R^g and R^h are attached to adjacent carbon atoms of the straight chain portion of the C₃ to C₆ alkylene and can form a cycloalkylene substituted with R⁹ and R¹⁰ together with the carbon atoms to which they are attached.

C74. 在實施方式C74中，如實施方式C1至C44、C49和C70中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，其中R^g和R^h附接至該C₃至C₆伸烷基的直鏈部分的相鄰的相同碳原子並且可與它們所附接的碳原子一起形成被R⁹和R¹⁰取代的雜亞環基。C74. In embodiment C74, the compound as described in any one of embodiments C1 to C44, C49 and C70, or a pharmaceutically acceptable salt thereof, wherein alk is a C₃ to C₆ alkylene substituted with R^g , R^h and Rⁱ , wherein R^g and R^h are attached to adjacent identical carbon atoms of the linear portion of the C₃ to C₆ alkylene and may form, together with the carbon atoms to which they are attached, a heterocycloalkylene substituted with R⁹ and R¹⁰ .

C75. 在實施方式C75中，如實施方式C1至C44、C49和C70至C72中任一項所述之化合物或其藥學上可接受的鹽，其中R^g和R^h附接至該C₃至C₆伸烷基的直鏈部分的相同碳原子並且可與它們所附接的碳原子一起形成具有下式的環伸烷基：或具有下式的雜亞環基：其中上述環中之每一個被R⁹和R¹⁰取代，較佳的是R⁹係氫、鹵代、甲基或乙基，並且R¹⁰係氫。C75. In embodiment C75, the compound as described in any one of embodiments C1 to C44, C49, and C70 to C72, or a pharmaceutically acceptable salt thereof, wherein R^g and R^h are attached to the same carbon atom of the linear portion of the C₃ to C₆ alkylene group and can form, together with the carbon atom to which they are attached, a cycloalkylene group having the formula: or a heterocyclic group having the formula: Wherein each of the above rings is substituted by R⁹ and R¹⁰ , preferably R⁹ is hydrogen, halogen, methyl or ethyl, and R¹⁰ is hydrogen.

C76. 在實施方式C76中，如實施方式C1至C44、C49、C70、C73和C74中任一項所述之化合物或其藥學上可接受的鹽，其中R^g和R^h附接至該C₃至C₆伸烷基的直鏈部分的相鄰碳原子並且可與它們所附接的碳原子一起形成具有下式的環伸烷基：和具有下式的雜亞環基：其中上述環中之每一個被R⁹和R¹⁰取代，較佳的是R⁹係氫、鹵代、甲基或乙基，並且R¹⁰係氫。C76. In embodiment C76, the compound as described in any one of embodiments C1 to C44, C49, C70, C73 and C74, or a pharmaceutically acceptable salt thereof, wherein R^g and R^h are attached to adjacent carbon atoms of the linear portion of the C₃ to C₆ alkylene group and can form, together with the carbon atoms to which they are attached, a cycloalkylene group having the formula: and a heterocyclic group having the formula: Wherein each of the above rings is substituted by R⁹ and R¹⁰ , preferably R⁹ is hydrogen, halogen, methyl or ethyl, and R¹⁰ is hydrogen.

C77. 在實施方式C77中，如實施方式C1至C44中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆雜伸烷基。C77. In embodiment C77, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C44, wherein alk is a C₃ to C₆ heteroalkyl substituted with R^g , R^h and Rⁱ .

C78. 在實施方式C78中，如實施方式C1至C44和C77中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆雜伸烷基，其中R^g、R^h和Rⁱ係氫。C78. In embodiment C78, the compound as described in any one of embodiments C1 to C44 and C77, or a pharmaceutically acceptable salt thereof, wherein alk is a C₃ to C₆ heteroaryl alkyl substituted with R^g , R^h and Rⁱ , wherein R^g , R^h and Rⁱ are hydrogen.

C79. 在實施方式C79中，如實施方式C1至C44和C77中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆雜伸烷基，其中R^g、R^h和Rⁱ係氫或鹵代，條件係R^g、R^h和Rⁱ中之至少一個係鹵代。C79. In embodiment C79, the compound as described in any one of embodiments C1 to C44 and C77, or a pharmaceutically acceptable salt thereof, wherein alk is a C₃ to C₆ heteroaryl alkyl substituted with R^g , R^h and Rⁱ , wherein R^g , R^h and Rⁱ are hydrogen or halogenated, with the proviso that at least one of R^g , R^h and Rⁱ is halogenated.

C80. 在實施方式C80中，如實施方式C1至C44和C77中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆雜伸烷基，其中R^h不是氫並且Rⁱ係氫，或者當R^g和R^h附接至該C₃至C₆伸烷基的直鏈部分的相同碳或相鄰碳原子時，R^g和R^h可與它們所附接的碳原子一起形成環伸烷基或雜亞環基，其中由R^g和R^h形成的該環伸烷基和雜亞環基被R⁹和R¹⁰取代。C80. In embodiment C80, the compound as described in any one of embodiments C1 to C44 and C77, or a pharmaceutically acceptable salt thereof, wherein alk is a C₃ to C₆ heteroalkylene substituted with R^g , R^h and Rⁱ , wherein R^h is not hydrogen and Rⁱ is hydrogen, or when R^g and R^h are attached to the same carbon or adjacent carbon atoms of the straight chain portion of the C₃ to C₆ alkylene, R^g and R^h may be taken together with the carbon atom to which they are attached to form a cycloalkylene or heterocycloalkylene, wherein the cycloalkylene and heterocycloalkylene formed by^R g and^R h are substituted with R⁹ and R¹⁰ .

C81. 在實施方式C81中，如實施方式C1至C44和C80中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆雜伸烷基，其中R^h不是氫並且Rⁱ係氫。C81. In embodiment C81, the compound as described in any one of embodiments C1 to C44 and C80, or a pharmaceutically acceptable salt thereof, wherein alk is a C₃ to C₆ heteroalkylene substituted with R^g , R^h and Rⁱ , wherein R^h is not hydrogen and Rⁱ is hydrogen.

C82. 在實施方式C82中，如實施方式C1至C44和C77至C81中任一項所述之化合物或其藥學上可接受的鹽，其中alk的該C₃至C₆雜伸烷基係直鏈C₃至C₆雜伸烷基，並且為了清楚起見，由於該實施方式僅表徵alk的該C₃至C₆雜伸烷基在本質上係直鏈的，因此應理解為該直鏈C₃至C₆雜伸烷基被R^g、R^h和Rⁱ取代，如參考的實施方式所提供的。C82. In embodiment C82, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C44 and C77 to C81, wherein the C₃ to C₆ heteroalkyl group of alk is a linear C₃ to C₆ heteroalkyl group, and for the sake of clarity, since this embodiment only represents that the C₃ to C₆ heteroalkyl group of alk is linear in nature, it should be understood that the linear C₃ to C₆ heteroalkyl group is substituted by R^g , R^h and Rⁱ , as provided in the reference embodiment.

C83. 在實施方式C83中，如實施方式C1至C44、C51至C59、C62至C69和C77至C82中任一項所述之化合物或其藥學上可接受的鹽，其中alk的該直鏈C₃至C₆雜伸烷基係-CH₂CH₂X^aCH₂-、-CH₂X^aCH₂CH₂-、-CH₂CH₂CH₂X^a-、-X^aCH₂CH₂CH₂-、-X^yCH₂CH₂X^a-、-X^yCH₂CH₂X^aCH₂-、-CH₂CH₂CH₂X^aCH₂-、-CH₂X^aCH₂-、-X^aCH₂CH₂-、-CH₂CH₂X^a-、-CH₂CONR^qCH₂-、-CH₂SO₂NR^qCH₂-、-CH₂NR^qCOCH₂-、-CH₂NR^qSO₂CH₂-、-CH₂CH₂CH₂NR^qCO-、-CH₂CONR^q-、-CH₂SO₂NR^q-、-CH₂NR^qCO-、-CH₂NR^qSO₂-、-CONR^qCH₂-、-SO₂NR^qCH₂-、-NR^qCOCH₂-、或-NR^qSO₂CH₂，其被如其中所定義的R^g、R^h和Rⁱ取代，並且X^a係-NR^q-、-O-、-S-、-SO-、-SO₂-或-CO-。^C83_.^In_{embodimentC83,}^the compound or pharmaceutically acceptable salt thereof according to any one of embodiments_C1 to C44^,C51to C59,_C62toC69and^C77 to C82^,_wherein^the linear_C3^to_C6 heteroalkyl_{groupofalkis-CH2CH2XaCH2-}^{,-CH2XaCH2CH2-}_{,-CH2CH2CH2Xa-,-XaCH2CH2CH2-,-XyCH2CH2Xa-}^,_{-XyCH2CH2XaCH2-,-CH2CH2CH2XaCH2-,-CH2XaCH2-,-XaCH2CH2Xa-,-CH2CONRqCH2-}^,_{-CH2SO2NRqCH2-} ,_{-CH2NRqCOCH2-,}^{-CH2NRqSO2CH2-}_,^{-CH2CH2CH2NRqCO-}_,^-CH2CONRq-_{,-CH2SO2NRq-,}^-CH2NRqCO- , -CH2NRqSO2-,_-CONRqCH2-^,_-SO2NRqCH2-^,-NRqCOCH2-_{,or-NRqSO2CH2} ,_which are substituted_byRg^,RhandRi as defined herein, and^Xa is_-NRq-^{, -O-,}_-S-^,_-SO-^,_-SO2- , or_-CO-.

C84. 在實施方式C84中，如實施方式C1至C44、C51至C59、C62至C69和C77至C83中任一項所述之化合物或其藥學上可接受的鹽，其中R^q係氫、甲基、乙基、甲基羰基或甲磺醯基。C84. In embodiment C84, the compound as described in any one of embodiments C1 to C44, C51 to C59, C62 to C69 and C77 to C83, or a pharmaceutically acceptable salt thereof, wherein R^q is hydrogen, methyl, ethyl, methylcarbonyl or methylsulfonyl.

C85. 在實施方式C85中，如實施方式C1至C44、C51至C59、C62至C69和C77至C84中任一項所述之化合物或其藥學上可接受的鹽，其中alk的該直鏈C₃至C₆雜伸烷基係-CH₂X^aCH₂-、-X^aCH₂CH₂-、-CH₂CH₂X^a-、-CH₂CH(R^h)X^a-、-X^aCH(R^h)CH₂-、-CH₂CONR^q-、-CH₂SO₂NR^q-、-CH₂NR^qCO-、-CH₂NR^qSO₂-、-CONR^qCH₂-、-SO₂NR^qCH₂-、-NR^qCOCH₂-、或-NR^qSO₂CH₂-，其中X^a係-S-、-SO₂-、-O-或-NR^q-。C85. In embodiment C85, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments C1 to C44, C51 to C59, C62 to C69 and C77 to C84, wherein the linear C₃ to C₆ heteroalkyl group of alk is -CH₂ X^a CH₂ -, -X^a CH₂ CH₂ -, -CH₂ CH₂ X^a -, -CH₂ CH(R^h )X^a -, -X^a CH(R^h )CH₂ -, -CH₂ CONR^q -, -CH₂ SO₂ NR^q -, -CH₂ NR^q CO-, -CH₂ NR^q SO₂ -, -CONR^q CH₂ -, -SO₂ NR^q CH₂ -, -NR^q COCH₂ -, or -NR^q SO₂ CH₂ -, wherein X^a represents -S-, -SO₂ -, -O- or -NR^q -.

C86. 在實施方式C86中，如實施方式C1至C44、C51至C59、C62至C69和C77至C85中任一項所述之化合物或其藥學上可接受的鹽，其中alk的該直鏈C₃至C₆雜伸烷基係-CH₂CH₂CH₂X^a-或-CH₂CH₂X^a。C86. In embodiment C86, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments C1 to C44, C51 to C59, C62 to C69 and C77 to C85, wherein the linear C₃ to C₆ heteroalkyl group of alk is -CH₂ CH₂ CH₂ X^a - or -CH₂ CH₂ X^a .

C87. 在實施方式C87中，如實施方式C1至C44、C51至C59、C62至C69和C77至C86中任一項所述之化合物或其藥學上可接受的鹽，其中alk的直鏈C₃至C₆雜伸烷基的R^g係氫或鹵代（除非另有說明），並且alk的直鏈C₃至C₆雜伸烷基的R^h係（除非另有說明）氫、鹵代、鹵代烷氧基、環烷基、環烷基氧基、烷氧基、羥基、胺基羰基、烷基胺基羰基、二烷基胺基羰基、烷基羰基胺基、氰基、氰基烷基氧基、苯基、雜芳基、雜環基或橋接雜環基，R^h的每個環被R⁷和R⁸取代並且Rⁱ係氫。C87. In embodiment C87, the compound as described in any one of embodiments C1 to C44, C51 to C59, C62 to C69 and C77 to C86, or a pharmaceutically acceptable salt thereof, wherein^Rg of the linear_C3 to_C6 heteroalkyl group of alk is hydrogen or halogenated (unless otherwise specified), and^Rh of the linear_C3 to_C6 heteroalkyl group of alk is (unless otherwise specified) hydrogen, halogenated, halogenated alkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclic group or bridged heterocyclic group, each ring of^Rh is substituted with^R7 and^R8 , and Rⁱ is hydrogen.

C88. 在實施方式C88中，如實施方式C1至C44、C51至C59、C62至C69和C77至C87中任一項所述之化合物或其藥學上可接受的鹽，其中alk的直鏈C₃至C₆雜伸烷基的R^g係氫、氟（除非另有說明），並且alk的直鏈C₃至C₆雜伸烷基的R^h（除非另有說明）係被R⁷和R⁸取代的氫、鹵代、鹵代烷氧基、烷氧基、羥基、二烷基胺基羰基、氰基或雜芳基。C88. In embodiment C88, the compound as described in any one of embodiments C1 to C44, C51 to C59, C62 to C69 and C77 to C87, or a pharmaceutically acceptable salt thereof, wherein^Rg of the linear_C3 to_C6 heteroalkyl group of alk is hydrogen or fluorine (unless otherwise specified), and^Rh of the linear_C3 to_C6 heteroalkyl group of alk (unless otherwise specified) is hydrogen, halogenated, halogenated alkoxy, alkoxy, hydroxyl, dialkylaminocarbonyl, cyano or heteroaryl substituted with^R7 and^R8 .

C89. 在實施方式C89中，如實施方式C1至C44、C51至C59、C62至C69和C77至C88中任一項所述之化合物或其藥學上可接受的鹽，其中alk的直鏈C₃至C₆雜伸烷基的R^h的雜芳基、雜環基和橋接雜環基，當存在時，係五員或六員環，並且R^h的每個環被R⁷和R⁸取代。C89. In embodiment C89, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C44, C51 to C59, C62 to C69 and C77 to C88, wherein the heteroaryl, heterocyclic and bridged heterocyclic groups of^Rh of the linear_C3 to_C6 heteroalkylene group of alk, when present, are five-membered or six-membered rings, and each ring of^Rh is substituted by^R7 and^R8 .

C90. 在實施方式C90中，如實施方式C1至C44、C51至C59、C62至C69和C77至C89中任一項所述之化合物或其藥學上可接受的鹽，其中alk的直鏈C₃至C₆雜伸烷基的R^g，當存在時且除非另有說明，係氫、氘或氟，並且alk的直鏈C₃至C₆雜伸烷基的R^h，當存在時且除非另有說明，係氫、氘、氟、環丙基、環丁基、環丙基氧基、環丁基氧基、二氟甲氧基、三氟甲氧基、甲氧基、乙氧基、羥基、氰基、胺基羰基、甲基胺基羰基、二甲基胺基羰基、二乙基胺基羰基、甲基羰基胺基、乙基羰基胺基、苯基、吡唑基、噻唑基、呋喃基、吡啶基、吡咯啶基、2-側氧基吡咯啶基、哌啶基、哌𠯤基或四氫呋喃基，R^h的每個環被獨立地選自氫、氘、甲基、甲氧基、氟、二氟甲基、三氟甲基、二氟甲氧基、三氟甲基、羥基、胺基、甲基胺基、二甲基胺基和氰基的R⁷和R⁸取代。C90. In embodiment C90, a compound as described in any one of embodiments C1 to C44, C51 to C59, C62 to C69 and C77 to C89, or a pharmaceutically acceptable salt thereof, wherein^Rg of the linear_C3 to_C6 heteroaryl group of alk, when present and unless otherwise specified, is hydrogen, deuterium or fluorine, and^Rh of the linear_C3 to_C6 heteroaryl group of alk , when present and unless otherwise indicated, is hydrogen, deuterium, fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, thiazolyl, furanyl, pyridyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, piperonyl, or tetrahydrofuranyl, each ring of^R being substituted with R and R independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino,^{dimethylamino} , and^cyano .

C91. 在實施方式C91中，如實施方式C1至C44、C51至C59、C62至C69和C77至C90中任一項所述之化合物或其藥學上可接受的鹽，其中alk的直鏈C₃至C₆雜伸烷基的R^g係氫，並且alk的直鏈C₃至C₆雜伸烷基的R^h係氟、環丙基、環丙基氧基、二氟甲氧基、三氟甲氧基、甲氧基、乙氧基、羥基、氰基、甲基胺基羰基、二甲基胺基羰基、甲基羰基胺基、苯基、吡唑-1-基、吡唑-4-基、吡啶-4-基、吡咯啶-1-基或2-側氧基吡咯啶-1-基，R^h的每個環被獨立地選自氫、氘、甲基和氟的R⁷和R⁸取代。C91. In embodiment C91, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C44, C51 to C59, C62 to C69 and C77 to C90, wherein^Rg of the linear_C3 to_C6 heteroalkyl group of alk is hydrogen, and^Rh of the linear_C3 to_C6 heteroalkyl group of alk is fluoro, cyclopropyl, cyclopropyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonylamino, phenyl, pyrazol-1-yl, pyrazol-4-yl, pyridin-4-yl, pyrrolidin-1-yl or 2-oxopyrrolidin-1-yl, and each ring of^Rh is independently selected from hydrogen, deuterium, methyl and fluoro R⁷ and R⁸ are substituted.

C92. 在實施方式C92中，如實施方式C77至C91中任一項所述之化合物或其藥學上可接受的鹽，其中X^a係-NR^q-、-O-、-S-或-SO₂-，較佳的是-NR^q-、-O-或-S-。C92. In embodiment C92, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C77 to C91, wherein X^a is -NR^q -, -O-, -S-, or -SO₂ -, preferably -NR^q -, -O-, or -S-.

C93. 在實施方式C93中，如實施方式C77至C92中任一項所述之化合物或其藥學上可接受的鹽，其中X^a係-NR^q-，其中R^q係氫或甲基。C93. In embodiment C93, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C77 to C92, wherein X^a is -NR^q -, wherein R^q is hydrogen or methyl.

C94. 在實施方式C94中，如實施方式C77至C92中任一項所述之化合物或其藥學上可接受的鹽，其中X^a係-O-。C94. In embodiment C94, the compound as described in any one of embodiments C77 to C92 or a pharmaceutically acceptable salt thereof, wherein X^a is -O-.

C95. 在實施方式C95中，如實施方式C77至C92中任一項所述之化合物或其藥學上可接受的鹽，其中X^a係-S-。C95. In embodiment C95, the compound as described in any one of embodiments C77 to C92 or a pharmaceutically acceptable salt thereof, wherein X^a is -S-.

C96. 在實施方式C96中，如實施方式C77至C95中任一項所述之化合物或其藥學上可接受的鹽，其中X^y係-O-。C96. In embodiment C96, the compound as described in any one of embodiments C77 to C95 or a pharmaceutically acceptable salt thereof, wherein^Xy is -O-.

C97. 在實施方式C97中，如實施方式C77至C95中任一項所述之化合物或其藥學上可接受的鹽，其中X^y係-NH-或-NCH₃-。C97. In embodiment C97, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C77 to C95, wherein X^y is -NH- or -NCH₃ -.

C98. 在實施方式C98中，如實施方式C1至C44和C77至C81中任一項所述之化合物或其藥學上可接受的鹽，其中alk的該C₃至C₆雜伸烷基係支鏈C₄至C₆雜伸烷基，並且為了清楚起見，由於該實施方式僅表徵alk的該C₄至C₆雜伸烷基在本質上係支鏈的，因此應理解為該支鏈C₄至C₆雜伸烷基被R^g、R^h和Rⁱ取代，如參考的實施方式所提供的。C98. In embodiment C98, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C44 and C77 to C81, wherein the_C3 to_C6 heteroalkyl group of alk is a branched_C4 to_C6 heteroalkyl group, and for the sake of clarity, since this embodiment only represents that the_C4 to C6_heteroalkyl group of alk is branched in nature, it should be understood that the branched_C4 to_C6 heteroalkyl group is substituted by^Rg ,^Rh and^Ri , as provided in the reference embodiment.

C99. 在實施方式C99中，如實施方式C1至C44和C77至C81和C98中任一項所述之化合物或其藥學上可接受的鹽，其中alk的該支鏈C₄至C₆雜伸烷基係-CH₂X^aCH(CH₃)CH₂-、-CH₂X^yCH₂CH(CH₃)X^a-、-CH₂CH₂CH(CH₃)X^a-、-X^aCH(CH₃)CH₂CH₂-、-X^yCH₂CH(CH₃)X^a-、-X^yCH(CH₃)CH₂X^a-、-CH₂CH₂CH₂CH(CH₃)X^a-、-X^aCH(CH₂R^h)CH₂-、-CH₂CH(CH₂R^h)X^a-、-X^aCH(CH₂CH₂R^h)CH₂-、-CH₂CH(CH₂CH₂R^h)X^a-、-CH₂C(CH₃)(CH₃)X^a-、-X^aC(CH₃)(CH₃)CH₂-、-CH(CH₃)CH(CH₃)X^a-、-CONR^zCH₂CH(CH₃)X^a-、-CH₂NR^qCOCH(CH₃)CH₂-、或-NR^qCOCH(CH₃)CH₂-，其中X^a係-NR^q-、-O-、-S-、-SO-、-SO₂-或-CO-。C99. In embodiment C99, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments C1 to C44, C77 to C81 and C98, wherein the branched C₄ to C₆ heteroaryl alkyl group of alk is -CH₂ X^a CH(CH₃ )CH₂ -, -CH₂ X^y CH₂ CH(CH₃ )X^a -, -CH₂ CH₂ CH(CH₃ )X^a -, -X^a CH(CH₃ )CH₂ CH₂ -, -X^y CH₂ CH(CH₃ )X^a -, -X^y CH(CH₃ )CH₂ X^a -, -CH₂ CH_2CH (CH₃ )X^a -, -X^a CH(CH₂ R^h )CH₂ -, -CH₂ CH(CH₂ R^h )X^a -, -X^a CH(CH₂ CH₂ R^h )CH₂ -, -CH₂ CH(CH₂ CH₂ R^h )X^a -, -CH₂ C(CH₃ )(CH₃ )X^a -, -X^a C(CH₃ )(CH₃ )CH₂ -, -CH(CH₃ )CH(CH₃ )X^a -, -CONR^z CH₂ CH(CH₃ )X^a -, -CH₂ NR^q COCH(CH₃ )CH₂ -, or -NR^q COCH(CH₃ )CH₂ -, where X^a is -NR^q -, -O-, -S-, -SO-, -SO₂ - or -CO-.

C100.     在實施方式C100中，如實施方式C1至C44、C77至C81、C98和C99中任一項所述之化合物或其藥學上可接受的鹽，其中alk的該支鏈C₄至C₆雜伸烷基係-CH₂C(CH₃)(CH₃)X^a-、-CH(CH₃)(CHCH₃)X^a-、-X^aCH(CH₂CH₂R^h)CH₂-、-CH₂CH(CH₂CH₂R^h)X^a-、-X^aCH(CH₂R^h)CH₂-、或-CH₂CH(CH₂R^h)X^a-。C100. In embodiment C100, the compound as described in any one of embodiments C1 to C44, C77 to C81, C98 and C99, or a pharmaceutically acceptable salt thereof, wherein the branched C₄ to C₆ heteroalkyl group of alk is -CH₂ C(CH₃ )(CH₃ )X^a -, -CH(CH₃ )(CHCH₃ )X^a -, -X^a CH(CH₂ CH₂ R^h )CH₂ -, -CH₂ CH(CH₂ CH₂ R^h )X^a -, -X^a CH(CH₂ R^h )CH₂ -, or -CH₂ CH(CH₂ R^h )X^a -.

C101.     在實施方式C101中，如實施方式C1至C44、C77至C81和C98至C100中任一項所述之化合物或其藥學上可接受的鹽，其中alk的支鏈C₄至C₆雜伸烷基的R^g和Rⁱ係氫或鹵代（除非另有說明），並且alk的支鏈C₄至C₆雜伸烷基的R^h係氫、鹵代、鹵代烷氧基、環烷基、環烷基氧基、烷氧基、羥基、胺基羰基、烷基胺基羰基、二烷基胺基羰基、烷基羰基胺基、氰基、氰基烷基氧基、苯基、雜芳基、雜環基、雜環基氧基、雜環基羰基或橋接雜環基，R^h的每個環被R⁷和R⁸取代。C101. In embodiment C101, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to_C44 , C77 to C81 and C98 to C100, wherein^Rg and^R1 of the branched C4 to_C6 heteroalkyl group of alk are hydrogen or halogenated (unless otherwise specified), and^Rh of the branched_C4 to_C6 heteroalkyl group of alk is hydrogen, halogenated, halogenated alkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclic group, heterocyclic groupoxy, heterocyclic groupcarbonyl or bridged heterocyclic group, each ring of^Rh is replaced by R⁷ and R⁸ are substituted.

C102.     在實施方式C102中，如實施方式C1至C44、C77至C81和C98至C101中任一項所述之化合物或其藥學上可接受的鹽，其中alk的支鏈C₄至C₆雜伸烷基的R^g和Rⁱ係氫或氟（除非另有說明），並且R^h（除非另有說明）係氫、鹵代、環烷基、環烷基氧基、烷氧基、羥基、烷基胺基羰基、二烷基胺基羰基、烷基羰基胺基、氰基、苯基、雜芳基、雜環基、雜環基氧基、雜環基羰基或橋接雜環基，R^h的每個環被R⁷和R⁸取代。C102. In embodiment C102, the compound as described in any one of embodiments C1 to C44, C77 to C81, and C98 to C101, or a pharmaceutically acceptable salt thereof, wherein^Rg and^R1 of the branched_C4 to_C6 heteroalkylene group of alk are hydrogen or fluorine (unless otherwise specified), and^Rh (unless otherwise specified) is hydrogen, halogen, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclo, heterocyclooxy, heterocyclocarbonyl, or bridged heterocyclo, and each ring of^Rh is substituted with^R7 and^R8 .

C103.     在實施方式C103中，如實施方式C1至C44、C77至C81和C98至C102中任一項所述之化合物或其藥學上可接受的鹽，其中R^g和Rⁱ係氫，並且R^h係氫、雜芳基、烷基胺基羰基或氰基。C103. In embodiment C103, the compound as described in any one of embodiments C1 to C44, C77 to C81 and C98 to C102, or a pharmaceutically acceptable salt thereof, wherein R^g and Rⁱ are hydrogen, and R^h is hydrogen, heteroaryl, alkylaminocarbonyl or cyano.

C104.     在實施方式C104中，如實施方式C1至C44、C77至C81和C98至C103中任一項所述之化合物或其藥學上可接受的鹽，其中alk的支鏈C₄至C₆雜伸烷基的雜芳基、雜環基——本身或作為雜環基氧基、雜環基羰基的一部分、和橋接雜環基，當存在時，係五員或六員環，R^h的每個環被R⁷和R⁸取代。C104. In embodiment C104, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C44, C77 to C81 and C98 to C103, wherein the branched_C4 to_C6 heteroalkylene heteroaryl, heterocyclic group - itself or as part of a heterocyclicoxy group, heterocycliccarbonyl group, and bridged heterocyclic group of alk, when present, is a five-membered or six-membered ring, and each ring of^Rh is substituted by^R7 and^R8 .

C105.     在實施方式C105中，如實施方式C1至C44、C77至C81和C98至C104中任一項所述之化合物或其藥學上可接受的鹽，其中alk的支鏈C₄至C₆雜伸烷基的R^h，當存在時且除非另有說明，係氫、氘、氟、環丙基、環丁基、環丙基氧基、環丁基氧基、二氟甲氧基、三氟甲氧基、甲氧基、乙氧基、羥基、氰基、胺基羰基、甲基胺基羰基、二甲基胺基羰基、二乙基胺基羰基、甲基羰基胺基、乙基羰基胺基、苯基、吡唑基、噻唑基、呋喃基、吡咯啶基、吡啶基、哌啶基、哌𠯤基、四氫呋喃基，R^h的每個環被獨立地選自氫、氘、甲基、甲氧基、氟、二氟甲基、三氟甲基、二氟甲氧基、三氟甲基、羥基、胺基、甲基胺基、二甲基胺基和氰基的R⁷和R⁸取代。C105. In embodiment C105, the compound as described in any one of embodiments C1 to C44, C77 to C81 and C98 to C104, or a pharmaceutically acceptable salt thereof, wherein R^h of the branched C₄ to C₆ heteroalkyl group of alk, when present and unless otherwise indicated, is hydrogen, deuterium, fluorine, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxyl, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, thiazolyl, furyl, pyrrolidinyl, pyridyl, piperidinyl, piperonyl, tetrahydrofuranyl, R Each ring of^h is substituted with R⁷ and R 8 independently selected from hydrogen, deuterium, methyl, methoxy, fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxyl, amino, methylamino, dimethylamino, and^cyano .

C106.     在實施方式C106中，如實施方式C98至C105中任一項所述之化合物或其藥學上可接受的鹽，其中X^a係-NR^q-、-O-、-S-或-SO₂-，較佳的是-NR^q-或-O-。C106. In embodiment C106, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C98 to C105, wherein X^a is -NR^q -, -O-, -S-, or -SO₂ -, preferably -NR^q - or -O-.

C107.     在實施方式C107中，如實施方式C98至C106中任一項所述之化合物或其藥學上可接受的鹽，其中X^a係-NR^q-，其中R^q係氫或甲基。C107. In embodiment C107, the compound according to any one of embodiments C98 to C106, or a pharmaceutically acceptable salt thereof, wherein X^a is -NR^q -, wherein R^q is hydrogen or methyl.

C108.     在實施方式C108中，如實施方式C98至C106中任一項所述之化合物或其藥學上可接受的鹽，其中X^a係-O-。C108. In embodiment C108, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C98 to C106, wherein X^a is -O-.

C109.     在實施方式C109中，如實施方式C98至C106中任一項所述之化合物或其藥學上可接受的鹽，其中X^a係-S-。C109. In embodiment C109, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C98 to C106, wherein X^a is -S-.

C110.     在實施方式C110中，如實施方式C98至C109中任一項所述之化合物或其藥學上可接受的鹽，其中X^y係-O-。C110. In embodiment C110, the compound according to any one of embodiments C98 to C109, or a pharmaceutically acceptable salt thereof, wherein^Xy is -O-.

C111.     在實施方式C111中，如實施方式C98至C109中任一項所述之化合物或其藥學上可接受的鹽，其中X^y係-NH-或-NCH₃-。C111. In embodiment C111, the compound according to any one of embodiments C98 to C109, or a pharmaceutically acceptable salt thereof, wherein X^y is -NH- or -NCH₃ -.

C112.     在實施方式C112中，如實施方式C1至C111中任一項所述之化合物或其藥學上可接受的鹽，其中alk係：C112. In embodiment C112, the compound according to any one of embodiments C1 to C111, or a pharmaceutically acceptable salt thereof, wherein alk is:

C113.     在實施方式C113中，如實施方式C1至C112中任一項所述之化合物或其藥學上可接受的鹽，其中alk係：C113. In embodiment C113, the compound according to any one of embodiments C1 to C112, or a pharmaceutically acceptable salt thereof, wherein alk is:

C114.     在實施方式C114中，如實施方式C1至C113中任一項所述之化合物或其藥學上可接受的鹽，其中alk係：C114. In embodiment C114, the compound according to any one of embodiments C1 to C113, or a pharmaceutically acceptable salt thereof, wherein alk is:

C115.     在實施方式C115中，如實施方式C1至C114中任一項所述之化合物或其藥學上可接受的鹽，其中降解決定子係選自以下的E3泛素連接酶配位基：、、、、、、、、、、、和； 其中R^ee係氫、甲基、乙基、環丙基或2,2,2-三氟乙基，並且R^ff係氫、甲基、環丙基、氟、氰基、甲氧基、二氟甲氧基、三氟甲氧基或三氟甲基。C115. In embodiment C115, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments C1 to C114, wherein the degradation determinant is selected from the following E3 ubiquitin ligase ligands: 、 、 、 、 、 、 、 、 、 、 、 and wherein R^ee is hydrogen, methyl, ethyl, cyclopropyl or 2,2,2-trifluoroethyl, and R^ff is hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.

C116.     在實施方式C116中，如實施方式C1至C115中任一項所述之化合物或其藥學上可接受的鹽，其中降解決定子係選自以下的E3泛素連接酶配位基：、、、、、、、、、和； 其中R^ee係氫、甲基、乙基、環丙基或2,2,2-三氟乙基，並且R^ff係氫、甲基、環丙基、氟、氰基、甲氧基、二氟甲氧基、三氟甲氧基或三氟甲基。C116. In embodiment C116, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments C1 to C115, wherein the degradation determinant is selected from the following E3 ubiquitin ligase ligands: 、 、 、 、 、 、 、 、 、 and wherein R^ee is hydrogen, methyl, ethyl, cyclopropyl or 2,2,2-trifluoroethyl, and R^ff is hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.

C117.     在實施方式C117中，如實施方式C1至C116中任一項所述之化合物或其藥學上可接受的鹽，其中降解決定子係選自以下的E3連接酶配位基：C117. In embodiment C117, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments C1 to C116, wherein the degradation determinant is selected from the following E3 ligase ligands:

C118.     在實施方式C118中，如實施方式C1至C116中任一項所述之化合物或其藥學上可接受的鹽，其中降解決定子係E3泛素連接酶配位基，其中每個R^ee係氫、甲基、乙基、環丙基或2,2,2-三氟乙基，較佳的是甲基。C118. In embodiment C118, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C116, wherein the degradation determinant is an E3 ubiquitin ligase ligand , wherein each R^ee is hydrogen, methyl, ethyl, cyclopropyl or 2,2,2-trifluoroethyl, preferably methyl.

代表性的第一方面的化合物和具有式 (I) 的化合物示於下文化合物表1中： [表1]化合物#結構名稱MS (ES, m/z): [M+1]+1(R)-1-(1-甲基-6-(1-(2-甲基-3-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮768.32(S)-1-(1-甲基-6-(1-(2-甲基-3-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮768.341-(1-甲基-6-(1-(3-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮754.173-(5-(4-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌𠯤-1-基)-6-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮785.192-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈793.1101-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-7-氟-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮784.0111-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮767.1121-(1-甲基-6-(1-(2-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)丁基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮782.0131-(6-(1-(2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)丁基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮780.314(R)-1-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮766.615(S)-1-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮766.6164-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈791.2171-(1-甲基-6-(1-(2-甲基-3-(3-((4-((5-(三氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮784.4181-(6-(1-(3-(3-((4-((5-溴嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮780.3191-(1-甲基-6-(1-(2-甲基-3-(3-((4-((5-乙烯基嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮726.4202-((3-(4-(1-(2,6-二側氧基哌啶-3-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-4-基)哌啶-1-基)丙基)(甲基)胺基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈2,2,2-三氟乙酸鹽823.3213-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)哌啶-2,6-二酮765.322(S)-1-(6-(1-(2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮768.223(R)-1-(6-(1-(2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮768.4241-(6-(1-(3-(3-((4-((5-乙基嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮728.4251-(6-(1-(3-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氟苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮784.3263-(3-甲基-4-(1-(3-(甲基(2-(三氟甲基)-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)胺基)丙基)哌啶-4-基)-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮2,2,2-三氟乙酸鹽866.3274-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙氧基)苯甲腈747.2281-(6-(1-(3-(3-((4-((5-異丙基嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮742.5291-(6-(1-(2-((3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)胺基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮767.4301-(6-(1-(2-((3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)硫代)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮784.431(S)-1-(6-(1-(2-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮768.332(R)-1-(6-(1-(2-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮768.3334-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈759.3341-(6-(1-(2-(5-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氟苯氧基)乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮740.2351-(6-(1-(3-(4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮734.2364-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,6-二側氧基哌啶-3-基)-1-甲基-1H-吲哚-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈789.3374-((4-((5-(2,2-二氟乙氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈805.3385-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈791.3391-(6-(1-(2-((4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)胺基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮767.4404-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,6-二側氧基哌啶-3-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈790.3411-(6-(1-(2-(5-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟甲基)苯氧基)乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮790.2421-(6-(1-(2-((3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)(甲基)胺基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮781.2431-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮782.4441-(6-(1-(2-羥基-2-甲基-3-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮784.2451-(6-(1-(3-(3-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮750.4461-(6-(1-(2-((4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)(甲基)胺基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮781.4473-(4-(1-(3-((2-氟-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)(甲基)胺基)丙基)哌啶-4-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮甲酸鹽816.3481-(6-(1-((2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)環戊基)甲基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮792.3491-(6-(1-((2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)環戊基)甲基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮792.3501-(6-(1-((2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)環己基)甲基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮甲酸鹽806.3511-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氟苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮784.2522-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)-3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-N,N-二甲基丙醯胺823.3534-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-3,3-二氟哌啶-1-基)-2-甲基丙基)苯甲腈甲酸鹽827.2544-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-(2,2,2-三氟乙基)-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈859.3552-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)-4-((4-((5-(三氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈809.3564-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(4-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丁基)苯甲腈805.4574-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(1-(2,6-二側氧基哌啶-3-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-4-基)哌啶-1-基)-2-甲基丙基)苯甲腈774.2584-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙氧基)苯甲腈779.259(S)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈791.260(R)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈791.261(E)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙-1-烯-1-基)苯甲腈789.4621-(6-(1-(2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)烯丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮764.4631-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-羥基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮768.3642-(3-(4-(1-(2,6-二側氧基哌啶-3-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-4-基)哌啶-1-基)-2-甲基丙基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈808.2654-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(1-(2,6-二側氧基哌啶-3-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-4-基)哌啶-1-基)-2-甲基丙基)苯甲腈806.3664-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-7-氟-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈809.3671-(6-(1-(3-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氟苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮800.3681-(6-(1-(3-(5-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氟苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮768.2691-(6-(1-(3-(2-氟-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮802.3701-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丁基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮766.3713-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)-4-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁腈791.3721-(6-(1-(3-(3-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-5-氟苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮768.2731-(6-(1-(3-(3-氟-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮802.3741-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-5-氟苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮800.3755-(1-(3-(2-氰基-5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-N-(2,6-二側氧基哌啶-3-基)吡啶甲醯胺780.3763-(4-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮781.2775-(1-(3-(5-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氰基苯基)-2-甲基丙基)哌啶-4-基)-N-(2,6-二側氧基哌啶-3-基)吡啶甲醯胺748.2784-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)苯甲腈793.4795-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈758.9801-(6-(1-(3-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟甲基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮833.9811-(6-(1-(3-(4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氟苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮751.9821-(6-(1-(3-(2-氟-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮785.9834-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-羥基-2-甲基丙基)苯甲腈775.3844-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-羥基-2-甲基丙基)苯甲腈807.4852-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-羥基-2-甲基丙基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈809.3861-(6-(1-(3-(4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氟苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮768.4871-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氟苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮800.6881-(6-(1-(3-(2-氟-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮802.4891-(6-(1-(2-羥基-2-甲基-3-(2-(三氟甲基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮852.4901-(6-(1-(2-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟甲基)苯氧基)乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮821.9911-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟甲基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮834.0921-(6-(1-(3-(4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟甲基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮801.9931-(1-甲基-6-(1-(2-甲基-3-(2-(三氟甲基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮835.9941-(6-(1-(3-(4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮750.2951-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮782.2961-(6-(1-(2-羥基-2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮784.2971-(6-(1-(3-(4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟甲基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮818.3981-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟甲基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮850.699(E)-4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙-1-烯-1-基)苯甲腈757.51004-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)烯丙基)苯甲腈757.5101(E)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙-1-烯-1-基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈791.51022-(2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)烯丙基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈791.51034-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-((2R)-4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2-甲基哌啶-1-基)-2-甲基丙基)苯甲腈甲酸鹽805.01044-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(3-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-8-氮雜雙環[3.2.1]辛-8-基)-2-甲基丙基)苯甲腈817.21054-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁基)苯甲腈791.3106(E)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-1-烯-1-基)苯甲腈775.1107(E)-1-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基烯丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮764.3108(E)-1-(1-甲基-6-(1-(2-甲基-3-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)烯丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮766.3109(E)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁-1-烯-1-基)苯甲腈789.1110(E)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丁-1-烯-1-基)苯甲腈803.2111(E)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-3-甲基丁-1-烯-1-基)苯甲腈803.4112(E)-2-(3-(4-(3-(2,6-二側氧基哌啶-3-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙-1-烯-1-基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈790.4113(E)-1-(6-(1-(3-(2-(二氟甲基)-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)烯丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮802.1114(Z)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-1-烯-1-基)苯甲腈775.11151-(6-(1-(3-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(二氟甲基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮816.11164-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-((2S,6S)-4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2,6-二甲基哌啶-1-基)-2-甲基丙基)苯甲腈甲酸鹽819.31174-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙基)胺基)苯甲腈778.41184-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2-側氧基吡啶-1(2H)-基)-2-甲基丙基)苯甲腈801.21191-(6-(1-(2-(2-氟-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮2,2,2-三氟乙酸鹽774.21202-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)-3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-N-甲基丙醯胺809.41211-(6-(1-(2-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氟苯氧基)乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮772.21222-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙氧基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈781.21231-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-(1-甲基-1H-吡唑-4-基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮832.31244-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基-3-側氧基丙基)苯甲腈805.31254-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(4-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁-2-基)苯甲腈791.2126(R)-1-(1-甲基-6-(1-(2-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮770.4127(S)-1-(1-甲基-6-(1-(2-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮770.41284-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-羥基丙基)苯甲腈793.21292-(3-(3-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-8-氮雜雙環[3.2.1]辛-8-基)-2-甲基丙基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈819.31304-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-((2S)-4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2-甲基哌啶-1-基)-2-甲基丙基)苯甲腈805.31314-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙基)(甲基)胺基)苯甲腈792.41324-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙基)(甲基)胺基)苯甲腈760.41332-((2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙基)(甲基)胺基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈794.41344-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙基)硫代)苯甲腈795.5135(R)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)苯甲腈795.4136(S)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)苯甲腈795.41371-(6-(1-(3-(4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-3-氟苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮768.21381-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-3-氟苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮800.31391-(6-(1-(3-(3-氟-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮802.21404-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)苯乙氧基)苯甲腈772.21411-(6-(1-(2-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮754.41421-(6-(1-(2-(4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮722.31431-(1-甲基-6-(1-(2-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)乙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮756.41444-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-((2R)-4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2-甲基哌啶-1-基)乙氧基)苯甲腈793.21452-(3-((2R)-4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2-甲基哌啶-1-基)-2-甲基丙基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈807.21462-(3-((2S)-4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2-甲基哌啶-1-基)-2-甲基丙基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈807.21474-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(7-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-3-氧雜-9-氮雜雙環[3.3.1]壬-9-基)-2-甲基丙基)苯甲腈833.31484-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-3-甲基苯乙氧基)苯甲腈786.21491-(6-(1-(3-(2-(二氟甲基)-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮818.11501-(6-(1-(3-(5-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(二氟甲基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮784.11514-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-((2S)-4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2-甲基哌啶-1-基)乙氧基)苯甲腈793.21521-(6-(1-(3-(2-溴-5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮844.11531-(6-(1-(2-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(二氟甲基)苯氧基)乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮804.11544-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(6-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2-氮雜螺[3.3]庚-2-基)-2-甲基丙基)苯甲腈803.31554-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(3-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)四氫吖唉-1-基)-2-甲基丙基)苯甲腈763.31562-(3-氰基-2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)丙基)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈816.31571-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮甲酸鹽768.31584-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙氧基)苯甲腈793.31591-(6-(1-((1-((3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)甲基)環丙基)甲基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮794.31601-(6-(1-(3-(2-氯-5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮800.11611-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-3,3-二氟丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮788.31622-(4-氰基-3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁基)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈816.41634-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌𠯤-1-基)-2-甲基丙基)苯甲腈792.31644-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(3-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-3,8-二氮雜雙環[3.2.1]辛-8-基)-2-甲基丙基)苯甲腈818.41651-(6-(1-(4-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(二氟甲基)苯基)丁-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮816.21664-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-3-甲氧基丙-2-基)氧基)苯甲腈823.31673-(6-(1-(3-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(二氟甲基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)哌啶-2,6-二酮815.21681-(6-(1-(2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)-3,3,3-三氟丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮820.31691-(6-(1-(3-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-側氧基吡啶-1(2H)-基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮783.21704-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(1-(2,6-二側氧基哌啶-3-基)-1H-吲唑-5-基)哌啶-1-基)-2-甲基丙基)苯甲腈776.21714-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,6-二側氧基哌啶-3-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁基)苯甲腈790.21721-(1-甲基-6-(1-(2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮768.21731-(6-(1-(4-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丁-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮766.21744-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙氧基)苯甲腈793.11754-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙氧基)苯甲腈761.11762-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙氧基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈795.11771-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1-甲基-1H-咪唑-2-基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮770.41781-(6-(1-(2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)-4,4,4-三氟丁基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮834.11793-(6-(1-(4-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(二氟甲基)苯基)丁-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)哌啶-2,6-二酮815.31801-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-3,3-二氟-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮802.51814-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-(4-(3-(2,6-二側氧基哌啶-3-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙氧基)苯甲腈778.41822-(2-(4-(3-(2,6-二側氧基哌啶-3-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙氧基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈780.41831-(6-(4-(((3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)(甲基)胺基)甲基)環己基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮甲酸鹽766.21844-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-5-基)哌啶-1-基)丁基)苯甲腈791.11851-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(二氟甲基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮816.11864-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((2S)-3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丁基)苯甲腈805.51871-(6-(1-(4-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丁-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮780.51884-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(1-(2,6-二側氧基哌啶-3-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-4-基)哌啶-1-基)丁基)苯甲腈806.21891-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮756.21904-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(2-(2,6-二側氧基哌啶-3-基)-1,3-二側氧基異吲哚啉-5-基)哌啶-1-基)丁基)苯甲腈805.11914-((4-((5-環丙基嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈765.21924-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-(4-(1-(2,6-二側氧基哌啶-3-基)-1H-吲唑-5-基)哌啶-1-基)丙氧基)苯甲腈778.11934-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-3-甲基丁基)苯甲腈805.41941-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2,2-二氟丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮788.51954-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2,2-二氟丙基)苯甲腈813.31964-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)戊基)苯甲腈805.51974-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(4-((2,6-二側氧基哌啶-3-基)胺基)苯基)哌啶-1-基)-2-甲基丙基)苯甲腈751.21984-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-((2,6-二側氧基哌啶-3-基)胺基)苯基)哌啶-1-基)-2-甲基丙基)苯甲腈751.21994-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(1-(2,6-二側氧基哌啶-3-基)-3-甲基-1H-吲唑-5-基)哌啶-1-基)-2-甲基丙基)苯甲腈790.22001-(6-(1-(4-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-側氧基吡啶-1(2H)-基)丁-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮783.12014-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-(甲氧基甲基)丙基)苯甲腈821.62024-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-4,4,4-三氟丁基)苯甲腈845.52034-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,6-二側氧基哌啶-3-基)-1-(2,2,2-三氟乙基)-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈甲酸鹽858.12044-((4-((5-((二氟甲基)硫代)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈807.12051-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-側氧基吡啶-1(2H)-基)-2-甲基丙基)-哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮783.22062-(3-(4-(1-環丙基-3-(2,4-二側氧基-四氫嘧啶-1(2H)-基)-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)苯甲腈817.22072-(3-(4-(1-(2,6-二側氧基哌啶-3-基)-1H-吲唑-5-基)哌啶-1-基)丁基)-4-((4-((5-(三氟-甲基)嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)苯甲腈778.12084-((4-((5-(二氟甲氧基)-嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)-4-甲氧基丁基)苯甲腈835.32094-((4-((5-環丙基嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-(4-(3-(2,4-二側氧基四氫-嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-丙氧基)苯甲腈767.12104-((4-((5-(二氟甲氧基)-嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-(氧環丁烷-3-基)丙基)苯甲腈833.52111-(1-甲基-6-(1-(4-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丁-2-基)-哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮758.12122-(4-氰基-2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)丁基)-4-((4-((5-(二氟甲氧基)-嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈830.52131-(1-甲基-6-(1-(2-甲基-3-(5-甲基-4-((4-((5-(三氟甲基)-嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮772.22141-(1-甲基-6-(1-(2-甲基-3-(3-甲基-4-((4-((5-(三氟甲基)-嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮772.22154-((4-((5-(二氟甲氧基)-嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(1-(2,6-二側氧基哌啶-3-基)-1H-苯并-[d][1,2,3]三唑-5-基)-哌啶-1-基)-2-甲基丙基)-苯甲腈777.22161-(1-甲基-6-(1-(2-甲基-3-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮758.12171-(6-(1-(1-(2-氟-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯氧基)丙-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮788.1218(R)-4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫-嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)苯甲腈761.4219(R)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯甲腈793.4220(R)-4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)胺基)-苯甲腈2,2,2-三氟乙酸鹽760.4221(R)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)胺基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)苯甲腈2,2,2-三氟乙酸鹽794.42224-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)硫代)苯甲腈777.22232-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)硫代)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯甲腈811.3224(E)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁-1-烯-1-基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯甲腈791.12251-(1-甲基-6-(1-(2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)-1H-咪唑-1-基)-丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮758.22264-((4-((5-(二氟甲氧基)-嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-((4-(3-(2,6-二側氧基哌啶-3-基)-1-甲基-1H-吲唑-6-基)環己基)氧基)-乙基)苯甲腈777.52271-(1-甲基-6-(1-(2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)-1H-1,2,3-三唑-1-基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮759.1228N-(2-氰基-5-((4-((5-(二氟-甲氧基)嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)苯基)-2-(4-(3-(2,4-二側氧基四氫-嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-乙醯胺2,2,2-三氟乙酸鹽792.32294-((4-((5-(2,2-二氟環-丙基)嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)-苯甲腈801.22302-(4-氰基-2-((4-(3-(2,4-二側氧基-四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)丁基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯甲腈832.52314-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(4-氰基-2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)丁基)-苯甲腈798.52322-(2-環丙基-3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙基)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯甲腈817.52331-(1-甲基-6-(1-(2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)-1H-吡唑-1-基)-丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮758.2234分離的非鏡像異構物2-(3-(4-(3-(2,4-二側氧基四氫-嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丁基)-4-((4-((5-(三氟-甲基)嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)苯甲腈807.2235分離的非鏡像異構物2-(3-(4-(3-(2,4-二側氧基四氫-嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丁基)-4-((4-((5-(三氟-甲基)嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)苯甲腈807.2236(S)-2-((1-(4-(3-(2,4-二側氧基-四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯甲腈795.4237(S)-4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫-嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)苯甲腈761.4238(R)-4-((4-((5-環丙基嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)-苯甲腈765.3239(S)-4-((4-((5-環丙基嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)-苯甲腈765.3240(S)-4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)胺基)-苯甲腈760.2241(S)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)胺基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯甲腈794.32421-(6-(1-(1-(2-氯-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)苯氧基)丙-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮804.12434-((4-((5-環丙基嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁-2-基)氧基)苯甲腈781.32444-((4-((5-環丙基嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((2-(4-(3-(2,4-二側氧基四氫-嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙基)胺基)苯甲腈752.62452-((1-(4-(3-(2,4-二側氧基四氫-嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁-2-基)氧基)-4-((4-((5-(三氟甲基)-嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈809.4246(S)-1-(6-(1-(3-(5-((4-((5-環丙基嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)-2-(二氟甲基)苯基)-2-甲基-丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫-嘧啶-2,4(1H,3H)-二酮790.32471-(6-(1-(2-(2-氯-5-((4-((5-環丙基嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)苯氧基)-丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫-嘧啶-2,4(1H,3H)-二酮甲酸鹽776.32481-(6-(1-(1-(2-氯-5-((4-((5-環丙基嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯氧基)丙-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮甲酸鹽776.32491-(6-(1-(1-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)-2-(二氟甲基)苯氧基)丙-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮818.12502-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁氧基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈809.4Representative compounds of the first aspect and compounds having formula (I) are shown in the following compound table 1: [Table 1]Compound#structureNameMS (ES, m/z): [M+1]+ 1 (R)-1-(1-methyl-6-(1-(2-methyl-3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 768.3 2 (S)-1-(1-methyl-6-(1-(2-methyl-3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 768.3 4 1-(1-methyl-6-(1-(3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 754.1 7 3-(5-(4-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 785.1 9 2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 793.1 10 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-7-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 784.0 11 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 767.1 12 1-(1-methyl-6-(1-(2-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)butyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 782.0 13 1-(6-(1-(2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)butyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 780.3 14 (R)-1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 766.6 15 (S)-1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 766.6 16 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 791.2 17 1-(1-methyl-6-(1-(2-methyl-3-(3-((4-((5-(trifluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 784.4 18 1-(6-(1-(3-(3-((4-((5-bromopyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 780.3 19 1-(1-methyl-6-(1-(2-methyl-3-(3-((4-((5-vinylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 726.4 20 2-((3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)propyl)(methyl)amino)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 2,2,2-trifluoroacetate 823.3 twenty one 3-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione 765.3 twenty two (S)-1-(6-(1-(2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 768.2 twenty three (R)-1-(6-(1-(2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 768.4 twenty four 1-(6-(1-(3-(3-((4-((5-ethylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 728.4 25 1-(6-(1-(3-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 784.3 26 3-(3-methyl-4-(1-(3-(methyl(2-(trifluoromethyl)-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)amino)propyl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 2,2,2-trifluoroacetate 866.3 27 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethoxy)benzonitrile 747.2 28 1-(6-(1-(3-(3-((4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 742.5 29 1-(6-(1-(2-((3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)amino)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 767.4 30 1-(6-(1-(2-((3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)thio)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 784.4 31 (S)-1-(6-(1-(2-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 768.3 32 (R)-1-(6-(1-(2-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 768.3 33 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 759.3 34 1-(6-(1-(2-(5-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenoxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 740.2 35 1-(6-(1-(3-(4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 734.2 36 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,6-difluorooxypiperidin-3-yl)-1-methyl-1H-indol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 789.3 37 4-((4-((5-(2,2-difluoroethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 805.3 38 5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 791.3 39 1-(6-(1-(2-((4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)amino)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 767.4 40 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,6-difluorooxypiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 790.3 41 1-(6-(1-(2-(5-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 790.2 42 1-(6-(1-(2-((3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)(methyl)amino)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 781.2 43 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 782.4 44 1-(6-(1-(2-hydroxy-2-methyl-3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 784.2 45 1-(6-(1-(3-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 750.4 46 1-(6-(1-(2-((4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)(methyl)amino)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 781.4 47 3-(4-(1-(3-((2-fluoro-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)(methyl)amino)propyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dionecarboxylate 816.3 48 1-(6-(1-((2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)cyclopentyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 792.3 49 1-(6-(1-((2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)cyclopentyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 792.3 50 1-(6-(1-((2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dionecarboxylate 806.3 51 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 784.2 52 2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-N,N-dimethylpropionamide 823.3 53 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3-difluoropiperidin-1-yl)-2-methylpropyl)benzonitrile formate 827.2 54 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 859.3 55 2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)-4-((4-((5-(trifluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 809.3 56 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylbutyl)benzonitrile 805.4 57 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 774.2 58 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethoxy)benzonitrile 779.2 59 (S)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 791.2 60 (R)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 791.2 61 (E)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylprop-1-en-1-yl)benzonitrile 789.4 62 1-(6-(1-(2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)allyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 764.4 63 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-hydroxypropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 768.3 64 2-(3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-2-methylpropyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 808.2 65 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 806.3 66 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7-fluoro-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 809.3 67 1-(6-(1-(3-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 800.3 68 1-(6-(1-(3-(5-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 768.2 69 1-(6-(1-(3-(2-fluoro-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 802.3 70 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)butyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 766.3 71 3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butanenitrile 791.3 72 1-(6-(1-(3-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-5-fluorophenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 768.2 73 1-(6-(1-(3-(3-fluoro-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 802.3 74 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-5-fluorophenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 800.3 75 5-(1-(3-(2-cyano-5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-N-(2,6-difluorooxypiperidin-3-yl)picolinamide 780.3 76 3-(4-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 781.2 77 5-(1-(3-(5-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-cyanophenyl)-2-methylpropyl)piperidin-4-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide 748.2 78 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)benzonitrile 793.4 79 5-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 758.9 80 1-(6-(1-(3-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 833.9 81 1-(6-(1-(3-(4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 751.9 82 1-(6-(1-(3-(2-fluoro-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 785.9 83 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-hydroxy-2-methylpropyl)benzonitrile 775.3 84 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-hydroxy-2-methylpropyl)benzonitrile 807.4 85 2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-hydroxy-2-methylpropyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 809.3 86 1-(6-(1-(3-(4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 768.4 87 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 800.6 88 1-(6-(1-(3-(2-fluoro-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 802.4 89 1-(6-(1-(2-hydroxy-2-methyl-3-(2-(trifluoromethyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 852.4 90 1-(6-(1-(2-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 821.9 91 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 834.0 92 1-(6-(1-(3-(4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 801.9 93 1-(1-methyl-6-(1-(2-methyl-3-(2-(trifluoromethyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 835.9 94 1-(6-(1-(3-(4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 750.2 95 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 782.2 96 1-(6-(1-(2-hydroxy-2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 784.2 97 1-(6-(1-(3-(4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 818.3 98 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 850.6 99 (E)-4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylprop-1-en-1-yl)benzonitrile 757.5 100 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)allyl)benzonitrile 757.5 101 (E)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylprop-1-en-1-yl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 791.5 102 2-(2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)allyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 791.5 103 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-((2R)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2-methylpiperidin-1-yl)-2-methylpropyl)benzonitrile formate 805.0 104 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-methylpropyl)benzonitrile 817.2 105 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butyl)benzonitrile 791.3 106 (E)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)prop-1-en-1-yl)benzonitrile 775.1 107 (E)-1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylallyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 764.3 108 (E)-1-(1-methyl-6-(1-(2-methyl-3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)allyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 766.3 109 (E)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)but-1-en-1-yl)benzonitrile 789.1 110 (E)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylbut-1-en-1-yl)benzonitrile 803.2 111 (E)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-3-methylbut-1-en-1-yl)benzonitrile 803.4 112 (E)-2-(3-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylprop-1-en-1-yl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 790.4 113 (E)-1-(6-(1-(3-(2-(difluoromethyl)-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)allyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 802.1 114 (Z)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)prop-1-en-1-yl)benzonitrile 775.1 115 1-(6-(1-(3-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 816.1 116 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-((2S,6S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2,6-dimethylpiperidin-1-yl)-2-methylpropyl)benzonitrile formate 819.3 117 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((2-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethyl)amino)benzonitrile 778.4 118 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2-oxopyridin-1(2H)-yl)-2-methylpropyl)benzonitrile 801.2 119 1-(6-(1-(2-(2-fluoro-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-trifluoroacetate 774.2 120 2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-N-methylpropionamide 809.4 121 1-(6-(1-(2-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenoxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 772.2 122 2-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethoxy)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 781.2 123 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-(1-methyl-1H-pyrazol-4-yl)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 832.3 124 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methyl-3-oxopropyl)benzonitrile 805.3 125 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butan-2-yl)benzonitrile 791.2 126 (R)-1-(1-methyl-6-(1-(2-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 770.4 127 (S)-1-(1-methyl-6-(1-(2-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 770.4 128 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-hydroxypropyl)benzonitrile 793.2 129 2-(3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-methylpropyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 819.3 130 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-((2S)-4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2-methylpiperidin-1-yl)-2-methylpropyl)benzonitrile 805.3 131 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethyl)(methyl)amino)benzonitrile 792.4 132 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethyl)(methyl)amino)benzonitrile 760.4 133 2-((2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethyl)(methyl)amino)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 794.4 134 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethyl)thio)benzonitrile 795.5 135 (R)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)benzonitrile 795.4 136 (S)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)benzonitrile 795.4 137 1-(6-(1-(3-(4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-3-fluorophenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 768.2 138 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-3-fluorophenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 800.3 139 1-(6-(1-(3-(3-fluoro-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 802.2 140 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)phenethoxy)benzonitrile 772.2 141 1-(6-(1-(2-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 754.4 142 1-(6-(1-(2-(4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 722.3 143 1-(1-methyl-6-(1-(2-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)ethyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 756.4 144 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-((2R)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2-methylpiperidin-1-yl)ethoxy)benzonitrile 793.2 145 2-(3-((2R)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2-methylpiperidin-1-yl)-2-methylpropyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 807.2 146 2-(3-((2S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2-methylpiperidin-1-yl)-2-methylpropyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 807.2 147 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(7-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3-oxahio-9-azabicyclo[3.3.1]nonan-9-yl)-2-methylpropyl)benzonitrile 833.3 148 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3-methylphenethoxy)benzonitrile 786.2 149 1-(6-(1-(3-(2-(difluoromethyl)-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 818.1 150 1-(6-(1-(3-(5-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 784.1 151 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-((2S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2-methylpiperidin-1-yl)ethoxy)benzonitrile 793.2 152 1-(6-(1-(3-(2-bromo-5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 844.1 153 1-(6-(1-(2-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenoxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 804.1 154 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(6-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2-azaspiro[3.3]hept-2-yl)-2-methylpropyl)benzonitrile 803.3 155 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)tetrahydroazolidin-1-yl)-2-methylpropyl)benzonitrile 763.3 156 2-(3-cyano-2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)propyl)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 816.3 157 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dionecarboxylate 768.3 158 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propoxy)benzonitrile 793.3 159 1-(6-(1-((1-((3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 794.3 160 1-(6-(1-(3-(2-chloro-5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 800.1 161 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3,3-difluoropropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 788.3 162 2-(4-cyano-3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butyl)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 816.4 163 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 792.3 164 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylpropyl)benzonitrile 818.4 165 1-(6-(1-(4-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenyl)butan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 816.2 166 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-3-methoxypropan-2-yl)oxy)benzonitrile 823.3 167 3-(6-(1-(3-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione 815.2 168 1-(6-(1-(2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-3,3,3-trifluoropropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 820.3 169 1-(6-(1-(3-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-oxopyridin-1(2H)-yl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 783.2 170 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(1-(2,6-difluorooxypiperidin-3-yl)-1H-indazol-5-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 776.2 171 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,6-difluorooxypiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butyl)benzonitrile 790.2 172 1-(1-methyl-6-(1-(2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 768.2 173 1-(6-(1-(4-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)butan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 766.2 174 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propoxy)benzonitrile 793.1 175 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propoxy)benzonitrile 761.1 176 2-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propoxy)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 795.1 177 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1-methyl-1H-imidazol-2-yl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 770.4 178 1-(6-(1-(2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-4,4,4-trifluorobutyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 834.1 179 3-(6-(1-(4-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenyl)butan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione 815.3 180 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3,3-difluoro-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 802.5 181 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-(4-(3-(2,6-difluorooxypiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethoxy)benzonitrile 778.4 182 2-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethoxy)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 780.4 183 1-(6-(4-(((3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)(methyl)amino)methyl)cyclohexyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dionecarboxylate 766.2 184 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)butyl)benzonitrile 791.1 185 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 816.1 186 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((2S)-3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylbutyl)benzonitrile 805.5 187 1-(6-(1-(4-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylbutan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 780.5 188 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)butyl)benzonitrile 806.2 189 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 756.2 190 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-1-yl)butyl)benzonitrile 805.1 191 4-((4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 765.2 192 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-(4-(1-(2,6-difluorooxypiperidin-3-yl)-1H-indazol-5-yl)piperidin-1-yl)propoxy)benzonitrile 778.1 193 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-3-methylbutyl)benzonitrile 805.4 194 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2,2-difluoropropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 788.5 195 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2,2-difluoropropyl)benzonitrile 813.3 196 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)pentyl)benzonitrile 805.5 197 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(4-((2,6-difluorooxypiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-methylpropyl)benzonitrile 751.2 198 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-((2,6-difluorooxypiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-methylpropyl)benzonitrile 751.2 199 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(1-(2,6-difluorooxypiperidin-3-yl)-3-methyl-1H-indazol-5-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 790.2 200 1-(6-(1-(4-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-oxopyridin-1(2H)-yl)butan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 783.1 201 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-(methoxymethyl)propyl)benzonitrile 821.6 202 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-4,4,4-trifluorobutyl)benzonitrile 845.5 203 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,6-dioxopiperidin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile formate 858.1 204 4-((4-((5-((difluoromethyl)thio)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 807.1 205 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-oxopyridin-1(2H)-yl)-2-methylpropyl)-piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 783.2 206 2-(3-(4-(1-cyclopropyl-3-(2,4-dioxo-tetrahydropyrimidin-1(2H)-yl)-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 817.2 207 2-(3-(4-(1-(2,6-dioxopiperidin-3-yl)-1H-indazol-5-yl)piperidin-1-yl)butyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 778.1 208 4-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-((4-(3-(2,4-difluoromethoxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)-4-methoxybutyl)benzonitrile 835.3 209 4-((4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-(4-(3-(2,4-dioxotetrahydro-pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-propyloxy)benzonitrile 767.1 210 4-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-(oxobutan-3-yl)propyl)benzonitrile 833.5 211 1-(1-methyl-6-(1-(4-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)butan-2-yl)-piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 758.1 212 2-(4-cyano-2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)butyl)-4-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 830.5 213 1-(1-methyl-6-(1-(2-methyl-3-(5-methyl-4-((4-((5-(trifluoromethyl)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 772.2 214 1-(1-methyl-6-(1-(2-methyl-3-(3-methyl-4-((4-((5-(trifluoromethyl)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 772.2 215 4-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(1-(2,6-difluorooxypiperidin-3-yl)-1H-benzo-[d][1,2,3]triazol-5-yl)-piperidin-1-yl)-2-methylpropyl)-benzonitrile 777.2 216 1-(1-methyl-6-(1-(2-methyl-3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 758.1 217 1-(6-(1-(1-(2-fluoro-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-phenoxy)propan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 788.1 218 (R)-4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydro-pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)benzonitrile 761.4 219 (R)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzonitrile 793.4 220 (R)-4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)amino)benzonitrile 2,2,2-trifluoroacetate 760.4 221 (R)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)amino)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 2,2,2-trifluoroacetate 794.4 222 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)thio)benzonitrile 777.2 223 2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)thio)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzonitrile 811.3 224 (E)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)but-1-en-1-yl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzonitrile 791.1 225 1-(1-methyl-6-(1-(2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-imidazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 758.2 226 4-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-((4-(3-(2,6-difluorooxypiperidin-3-yl)-1-methyl-1H-indazol-6-yl)cyclohexyl)oxy)ethyl)benzonitrile 777.5 227 1-(1-methyl-6-(1-(2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-1,2,3-triazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 759.1 228 N-(2-cyano-5-((4-((5-(difluoro-methoxy)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)phenyl)-2-(4-(3-(2,4-dioxotetrahydro-pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-acetamide 2,2,2-trifluoroacetate 792.3 229 4-((4-((5-(2,2-difluorocyclopropyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)-benzonitrile 801.2 230 2-(4-cyano-2-((4-(3-(2,4-dioxo-tetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)butyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzonitrile 832.5 231 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-cyano-2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)butyl)-benzonitrile 798.5 232 2-(2-Cyclopropyl-3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propyl)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzonitrile 817.5 233 1-(1-methyl-6-(1-(2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 758.2 234 Separated non-mirror isomers 2-(3-(4-(3-(2,4-dioxotetrahydro-pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylbutyl)-4-((4-((5-(trifluoro-methyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 807.2 235 Separated non-mirror isomers 2-(3-(4-(3-(2,4-dioxotetrahydro-pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylbutyl)-4-((4-((5-(trifluoro-methyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 807.2 236 (S)-2-((1-(4-(3-(2,4-dioxo-tetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzonitrile 795.4 237 (S)-4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydro-pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)benzonitrile 761.4 238 (R)-4-((4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)-benzonitrile 765.3 239 (S)-4-((4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)-benzonitrile 765.3 240 (S)-4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)amino)-benzonitrile 760.2 241 (S)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)amino)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzonitrile 794.3 242 1-(6-(1-(1-(2-chloro-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 804.1 243 4-((4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butan-2-yl)oxy)benzonitrile 781.3 244 4-((4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((2-(4-(3-(2,4-dioxotetrahydro-pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethyl)amino)benzonitrile 752.6 245 2-((1-(4-(3-(2,4-Dioxotetrahydro-pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butan-2-yl)oxy)-4-((4-((5-(trifluoromethyl)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 809.4 246 (S)-1-(6-(1-(3-(5-((4-((5-cyclopropylpyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenyl)-2-methyl-propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydro-pyrimidine-2,4(1H,3H)-dione 790.3 247 1-(6-(1-(2-(2-chloro-5-((4-((5-cyclopropylpyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)phenoxy)-propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydro-pyrimidine-2,4(1H,3H)-dionecarboxylate 776.3 248 1-(6-(1-(1-(2-chloro-5-((4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-phenoxy)propan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dionecarboxylate 776.3 249 1-(6-(1-(1-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenoxy)propan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 818.1 250 2-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butoxy)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 809.4

預期的化合物揭露於下表2中： [表2]The expected compounds are disclosed in Table 2 below: [Table 2]

通用合成方案 具有式 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物）可以藉由下文所示的反應方案中描述的方法製備。General Synthesis SchemesCompounds of Formula (I) (and any embodiments thereof disclosed herein, including specific compounds) can be prepared by the methods described in the reaction schemes shown below.

用於製備該等化合物的起始材料和試劑係從商業供應商（如奧德里奇化工有限公司（Aldrich Chemical Co.）（密爾沃基，威斯康辛州）、巴亨公司（Bachem）（托倫斯，加利福尼州）或西格瑪公司（Sigma）（聖路易斯，密蘇里州））可獲得的，或係藉由熟悉該項技術者已知的方法、依照在以下參考文獻中所述之程序製備的，如Fieser and Fieser’s Reagents for Organic Synthesis [費塞爾和費塞爾的有機合成試劑], 第1-17卷（John Wiley and Sons [約翰·威利父子出版公司], 1991）；Rodd’s Chemistry of Carbon Compounds [羅德氏碳化合物化學], 第1-5卷以及增刊（Elsevier Science Publishers [愛思唯爾科學出版社], 1989）；Organic Reactions [有機反應], 第1-40卷（John Wiley and Sons [約翰·威利父子出版公司], 1991）；March’s Advanced Organic Chemistry [馬馳氏高等有機化學]（John Wiley and Sons [約翰·威利父子出版公司], 第4版）以及Larock’s Comprehensive Organic Transformations [拉羅克氏綜合有機轉化]（VCH Publishers Inc. [VCH出版公司], 1989）。該等方案僅僅是可以合成具有式 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物）的一些方法的說明，並且可以對該等方案進行各種修改，並且可以對該等方案做出不同修改並且熟悉該項技術者閱讀本揭露時將得到啟示。如果希望的話，該等起始材料和中間體以及反應的最終產物可以使用常規技術（包括但不限於過濾、蒸餾、結晶、層析法等）進行分離與純化。此類材料可以使用常規手段，包括物理常數以及光譜數據進行表徵。Starting materials and reagents used to prepare the compounds are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrance, California), or Sigma (St. Louis, Missouri), or are prepared by methods known to those skilled in the art according to the procedures described in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Vols. 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Vols. 1-5 and Supplements (Elsevier Science Publishers, 1991); 1989); Organic Reactions, Vols. 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry (John Wiley and Sons, 4th ed.); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some of the methods by which compounds of Formula (I) (and any embodiments thereof disclosed herein, including specific compounds) may be synthesized, and various modifications of these schemes may be made and will be apparent to those skilled in the art upon reading this disclosure. If desired, the starting materials and intermediates, as well as the final products of the reaction, can be isolated and purified using conventional techniques (including but not limited to filtration, distillation, crystallization, chromatography, etc.). Such materials can be characterized using conventional means, including physical constants and spectral data.

除非指出與此相反，否則本文所述之反應在大氣壓下，在從約-78°C至約150°C，如從約0°C至約125°C的溫度範圍下，並且進一步如在約室溫（或環境溫度），例如約20°C發生。Unless otherwise indicated, the reactions described herein occur at atmospheric pressure, at a temperature ranging from about -78°C to about 150°C, such as from about 0°C to about 125°C, and further such as at about room temperature (or ambient temperature), e.g., about 20°C.

具有式 (I) 的化合物（其中降解決定子係具有式 (i) 和 (ii) 的E3連接酶配位基，並且Hy、R¹、R²、R^2a、Ar、alk和Z如上文發明內容或其實施方式中所定義）可以如下文方案1中所述製備。Compounds of formula (I) (wherein the degron is an E3 ligase ligand of formula (i) and (ii), and Hy, R¹ , R² , R^2a , Ar, alk and Z are as defined above in the invention or its embodiments) can be prepared as described in Scheme 1 below.

方案1在合適的條件（如本領域熟知的酸性、鹼性或過渡金屬催化的反應條件）下，用具有式1-1的胺（其中降解決定子、Hy、R¹、R²、R^2a、Ar、alk和Z如上文發明內容或其實施方式中所定義）處理具有式1-2的嘧啶（其中A¹係鹵素，如氯或溴）提供了具有式 (I) 的化合物。Solution1 Treatment of a pyrimidine of formula 1-2 (wherein A1 is a halogen, such as chlorine or bromine) with an amine of formula1-1 (wherein the degator, Hy,^R1 ,^R2 ,^R2a , Ar, alk, and Z are as defined above in the present invention or its embodiments) under appropriate conditions (e.g., acidic,^basic , or transition metal- catalyzed reaction conditions well known in the art) provides a compound of formula (I).

可替代地，具有式 (I) 的化合物（例如，其中R¹、R²、Ar和alk如發明內容或其實施方式中所定義，R^2a係氫，Hy係1,4-哌啶二基，降解決定子係具有式 (i) 或 (ii) 的基團，並且Z係雜亞環基、橋接雜亞環基或螺雜亞環基，每個環含有至少一個氮原子）可以如下文方案2中所示和所述合成。Alternatively, compounds having formula (I) (e.g., wherein R¹ , R² , Ar, and alk are as defined in the present invention or its embodiments, R^2a is hydrogen, Hy is 1,4-piperidinediyl, the degron is a group having formula (i) or (ii), and Z is a heterocyclic group, a bridged heterocyclic group, or a spiroheterocyclic group, each ring containing at least one nitrogen atom) can be synthesized as shown and described in Scheme 2 below.

方案2在本領域熟知的條件下，例如在DIPEA（在三級丁醇中）的存在下，在升高的溫度下，用具有式2-2的哌啶胺處理具有式2-1的嘧啶（其中A¹係鹵素，如氯或溴，並且R¹和R²如上文發明內容或其實施方式中所定義）提供了具有式2-3的化合物。藉由以下方式將藉由在酸（如TFA）存在下去除2-3的Boc保護基團而製備的具有式2-4的胺化合物轉化為具有式2-6的磺醯胺化合物：用具有式2-5的磺醯基鹵化物（其中A²係鹵素（如氯），並且LG係合適的脫離基（如鹵代或甲磺醯基），並且Ar和alk如上文發明內容或其實施方式中所定義）處理它。在鹼性條件下，例如在DIPEA的存在下，用具有式2-7的胺化合物（其中係雜環基、橋接雜環基或螺雜環基，每個環含有至少一個氮原子，並且環A如上文發明內容或其實施方式中所定義）或用具有式2-8的化合物（其中Y^a、Z^a和環B如發明內容中所定義，並且如化合物2-7中所定義）處理具有式2-6的化合物提供了具有式 (I) 的化合物。Option2 Treatment of a pyrimidine of formula2-1 (wherein^A is a halogen, such as chloro or bromo, and R and^R are as defined^above in the present invention or its embodiments) with a piperidinamine of formula2-2 under conditions well known in the art, for example, in the presence of DIPEA (in tertiary butanol) at elevated temperature, provides a compound of formula2-3 . An amine compound of formula2-4 , prepared by removal of the Boc protecting group of2-3 in the presence of an acid (such as TFA), is converted to a sulfonamide compound of formula2-6 by treating it with a sulfonyl halide of formula2-5 (wherein^A is a halogen (such as chloro), LG is a suitable ionizing group (such as halo or mesylate), and Ar and alk are as defined above in the present invention or its embodiments). Under alkaline conditions, for example in the presence of DIPEA, an amine compound of formula2-7 (wherein is a heterocyclic group, a bridged heterocyclic group or a spiroheterocyclic group, each ring containing at least one nitrogen atom, and Ring A is as defined in the above invention or its embodiments) or a compound having Formula2-8 (wherein^Ya ,^Za and Ring B are as defined in the invention, and Treatment of a compound of formula2-6 with (as defined in compound2-7 ) provides a compound of formula (I).

具有式2-1、2-5、2-7和2-8的化合物係可商購的，或者它們可以藉由本領域已知的方法製備。Compounds of formula2-1 ,2-5 ,2-7 and2-8 are commercially available or they can be prepared by methods known in the art.

可替代地，具有式 (I) 的化合物（例如，其中R¹、R²、Ar和alk如發明內容或其實施方式中所定義，R^2a係氫、1,4-哌啶二基，降解決定子係具有式 (i) 的基團和具有式 (i) 或 (ii) 的降解決定子，並且Z係含有至少一個氮原子的雜亞環基、如4-哌啶-1-基）可以如下文方案3中所示和所述合成。Alternatively, compounds of formula (I) (e.g., wherein R¹ , R² , Ar, and alk are as defined in the present invention or its embodiments, R^2a is hydrogen, 1,4-piperidinediyl, the degron is a group of formula (i) and a degron of formula (i) or (ii), and Z is a heterocyclohexyl group containing at least one nitrogen atom, such as 4-piperidin-1-yl) can be synthesized as shown and described in Scheme 3 below.

方案3使具有式3-1的化合物（其中A¹係鹵素，並且環A如上文發明內容或其實施方式中所定義）與具有式3-2的四氫哌啶基（其中M係金屬，如硼酸酯或鋅）進行交叉偶合，提供了具有式3-3的化合物。該反應通常在鈀催化劑存在下進行；例如，當M係硼酸酯時，在Pd(dppf)Cl₂和Na₂CO₃存在下，在1,4-二㗁𠮿和水中進行鈴木反應。Option3 Cross-coupling of a compound of formula3-1 (wherein^A1 is a halogen and Ring A is as defined above in the present invention or its embodiments) with a tetrahydropiperidinyl group of formula3-2 (wherein M is a metal, such as a boronate or zinc) provides a compound of formula3-3 . This reaction is typically carried out in the presence of a palladium catalyst; for example, when M is a boronate, a Suzuki reaction is carried out in 1,4-dihydropyridine and_water in the presence of Pd(dppf)_Cl2 and_Na2CO3 .

在本領域熟知的條件下，例如在鈀催化劑存在下和在氫氣氣氛下，對化合物3-3中雙鍵進行還原提供了具有式3-4的化合物。在酸性條件下去除3-4的Boc保護基團，提供了具有式3-5的胺化合物。在本領域熟知的條件下，在還原劑、如NaBH(OAc)₃的存在下，在合適的溶劑、如DCM中，使3-5與具有式3-6的醛（其中Ar和-CH₂-[alk]_n-1係alk，各自如上文發明內容或其實施方式中所定義，其中Hy係如上文發明內容或其實施方式中所定義，並且-CH₂-(alk)_n-1係如上文發明內容或其實施方式中所定義的alk）進行反應，提供了具有式3-7的化合物。使用酸（如TFA）去除化合物3-7中的Boc保護基團，提供了具有式3-8的胺化合物。在合適的條件（如本領域熟知的酸性、鹼性或過渡金屬催化的反應條件）下，用具有式2-1的化合物處理化合物3-8，提供了具有式 (I) 的化合物。Reduction of the double bond in compound3-3 under conditions well known in the art, such as in the presence of a palladium catalyst and under a hydrogen atmosphere, provides compounds of formula3-4 . Removal of the Boc protecting group in3-4 under acidic conditions provides amine compounds of formula3-5 . Reaction of3-5 with an aldehydeof formula 3-6₍ wherein Ar and_-CH2- [alk]_n-1 are alk, each as defined above in the invention or its embodiments, wherein Hy is as defined above in the invention or its embodiments, and_-CH2- (alk)n-1 is alk as defined above in the invention or its embodiments) in the presence of a reducing agent such as NaBH(OAc)₃ in a suitable solvent such as DCM under conditions well known in the art provides compounds of formula3-7 . Removal of the Boc protecting group from compound3-7 using an acid (e.g., TFA) provides an amine compound of formula3-8 . Compound3-8 is treated with a compound of formula2-1 under appropriate conditions (e.g., acidic, alkaline, or transition metal-catalyzed reaction conditions well known in the art) to provide a compound of formula (I).

按照上文方案3中所述進行，但用具有式2-8的化合物代替具有式3-5的化合物，將得到具有式的化合物，然後可將其轉化為具有式 (I) 的化合物（其中降解決定子係具有式 (ii) 的基團）或其任何實施方式。Proceeding as described above in Scheme 3, but substituting a compound of formula2-8 for a compound of formula3-5 , will yield a compound of formula A compound of formula (I) wherein the degron is a group of formula (ii) or any embodiment thereof can be converted into a compound of formula (I) wherein the degron is a group of formula (ii) or any embodiment thereof.

具有式 (I) 的化合物或其實施方式（其中R¹、R²、Ar如發明內容或其實施方式中所定義，R^2a係氫，Hy係雜亞環（如1,4-哌啶二基），alk係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基，降解決定子係具有式 (ii) 的基團，並且Z係雜亞環基、橋接雜亞環基或螺雜亞環基，每個環含有至少一個氮原子）也可以如下文方案4中所示和所述合成。Compounds of formula (I) or embodiments thereof (wherein R¹ , R² , Ar are as defined in the invention or embodiments thereof, R^2a is hydrogen, Hy is a heterocyclic group (e.g., 1,4-piperidinyldiyl), alk is a C₃ to C₆ alkylene group substituted with R^g , R^h , and Rⁱ , the degrowth determinant is a group of formula (ii), and Z is a heterocyclic group, a bridged heterocyclic group, or a spiroheterocyclic group, each ring containing at least one nitrogen atom) can also be synthesized as shown and described in Scheme 4 below.

方案4藉由以下方式將具有式2-4的胺化合物轉化為具有式4-2的磺醯胺化合物：用具有式4-1的磺醯基鹵化物（其中A²係鹵素（如氯），並且A³係合適的鹵素（如溴），並且Ar如上文發明內容或其實施方式中所定義）處理它。在本領域已知的還原偶合條件下，例如在Mn、NiCl₂(DME)、吡啶-2-甲脒鹽酸鹽和NaI的組合存在下，用具有式4-3的酯（其中R係烷基，(alk)_n-1係被R^g、R^h和Rⁱ取代的C₂至C₅伸烷基，A⁴係鹵素（如碘））處理具有式4-2的化合物提供了具有式4-4的化合物，其在還原劑（如DIBAL-H）的存在下可以轉化為具有式4-5的醇。可以在還原胺化條件下用具有式2-8的化合物處理具有式4-6的醛化合物（其藉由用合適的氧化劑、如戴斯-馬丁過碘烷氧化4-5來合成）以產生具有式 (I) 的化合物（其中-CH₂-[alk]_n-1係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基）。Option4 An amine compound of formula2-4 is converted to a sulfonamide compound of formula4-2 by treating it with a sulfonyl halide of formula4-1 (wherein^A2 is a halogen (e.g., chlorine), and^A3 is a suitable halogen (e.g., bromine), and Ar is as defined above in the present invention or its embodiments). Treatment of a compound of formula 4-2 with an ester of formula4-3 (wherein R is alkyl, (alk)_n- 1 is a C2 to C5 alkylene substituted with^Rg , Rh, and^Ri , and^A4 is a halogen (e.g._, iodine)) under reductive coupling conditions known in the art, for example, in the presence of a combination of Mn, NiCl2(DME), pyridine_-2 -carboximidazole hydrochloride, and^NaI , provides a compoundof formula 4-4, which can be converted to an alcohol of formula4-5 in the presence of a reducing agent (e.g., DIBAL-H). Aldehyde compounds of formula4-6 (synthesized by oxidation of4-5 with a suitable oxidizing agent, such as Dess-Martin periodinane) can be treated with compounds of formula2-8 under reductive amination conditions to produce compounds of formula (I) (wherein_-CH2- [alk]_n-1 is a_C3 to_C6 alkylene substituted with^Rg ,^Rh , and^R1 ).

具有式 (I) 的化合物或其實施方式（其中R¹和R²如發明內容或其實施方式中所定義，Ar係單環雜伸芳基、雜亞環基、不飽和雜亞環基^X或其實施方式，R^2a係氫，Hy係雜亞環（如1,4-哌啶二基），降解決定子係具有式 (ii) 的基團，並且alk係C₃至C₆伸烷基）可以如下文方案5中所示和所述合成。Compounds of formula (I) or embodiments thereof (wherein R¹ and R² are as defined in the present invention or embodiments thereof, Ar is a monocyclic heteroaryl group, a heterocycloalkylene group, an unsaturated heterocycloalkylene group^X or embodiments thereof, R^2a is hydrogen, Hy is a heterocycloalkylene group (such as 1,4-piperidinyldiyl), the degration determinant is a group of formula (ii), and alk is a C₃ to C₆ alkylene group) can be synthesized as shown and described in Scheme 5 below.

方案5藉由以下方式將具有式2-4的胺化合物轉化為具有式5-2的磺醯胺化合物：用具有式5-1的磺醯基鹵化物（其中A²係鹵素（如氯），並且Ar係單環雜伸芳基、雜亞環基、不飽和雜亞環基^X或上文其實施方式）處理它。在鹼的存在下，在升高的溫度下，用具有式5-3的化合物（其中PG係合適的氧保護基團，(alk)_n-1係被R^g、R^h和Rⁱ取代的C₂至C₅伸烷基，並且A⁵係合適的脫離基（如鹵素或甲磺酸根））處理具有式5-2的化合物提供了具有式5-4的化合物。藉由用本領域已知的方法去除保護基團，可以將具有式5-4的化合物轉化為具有式5-5的醇。可以在還原胺化條件下用具有式2-8的化合物處理具有式5-6的醛（其藉由用合適的氧化劑、如戴斯-馬丁過碘烷氧化5-5來合成）以產生具有式 (I) 的化合物（其中-CH₂-[alk]_n-1係被R^g、R^h和Rⁱ取代的C₃至C₆伸烷基）。Option5 An amine compound of Formula2-4 is converted to a sulfonamide compound of Formula5-2 by treating it with a sulfonyl halide of Formula5-1 (wherein^A2 is a halogen (e.g., chlorine), and Ar is a monocyclic heteroaryl group, a heterocycloalkylene group, an unsaturated^{heterocycloalkylene} group, or an embodiment thereof as described above). Treatment of the compound of Formula 5-2 with a compound of Formula5-3 (wherein PG is a suitable oxygen protecting group, (alk)_n-1 is a_C2 to_C5 alkylene group substituted with^Rg ,^Rh , and^Ri , and^A5 is a suitable ionizing group (e.g., a halogen or mesylate)) in the presence of a base at elevated temperature provides a compoundof Formula 5-4. Compounds of formula5-4 can be converted to alcohols of formula5-5 by removing the protecting group using methods known in the art. Aldehydes of formula5-6 (synthesized by oxidation of5-5 with a suitable oxidizing agent, such as Dess-Martin periodinane) can be treated with compounds of formula2-8 under reductive amination conditions to produce compounds of formula (I) (wherein_-CH2- [alk]_n-1 is a_C3 to_C6 alkylene group substituted with^Rg ,^Rh , and^Ri ).

具有式 (I) 的化合物或其實施方式（其中R¹和R²如發明內容或其實施方式中所定義，Ar係芳基或單環雜芳基或其實施方式，R^2a係氫，Hy係雜亞環（如1,4-哌啶二基），降解決定子係具有式 (ii) 的基團，並且alk係被R^g、R^h和Rⁱ取代的C₃至C₆雜伸烷基（或其實施方式），其經由雜伸烷基的氧原子附接至Ar）可以如下文方案6中所示和所述合成。Compounds of formula (I) or embodiments thereof (wherein R¹ and R² are as defined in the invention or embodiments thereof, Ar is aryl or monocyclic heteroaryl or embodiments thereof, R^2a is hydrogen, Hy is a heterocyclic cycloalkylene (such as 1,4-piperidinyl), the degator is a group of formula (ii), and alk is a C₃ to C₆ heteroalkylene substituted with R^g , R^h and Rⁱ (or embodiments thereof), which is attached to Ar via the oxygen atom of the heteroalkylene) can be synthesized as shown and described in Scheme 6 below.

方案6藉由以下方式將具有式2-4的胺化合物轉化為具有式6-2的磺醯胺化合物：用具有式6-1的磺醯基鹵化物（其中A²係鹵素（如氯），並且Ar如上文發明內容或其實施方式中所定義）處理它。在本領域已知的光延（Mitsunobu）反應條件下，用具有式6-3的醇（其中R係烷基）處理具有式6-2的化合物提供了具有式6-4的化合物，按照與方案4中所述類似的方式進行可以將其轉化為具有式 (I) 的化合物（其中-CH₂-[alk]_n-2-O-係被R^g、R^h和Rⁱ取代的C₃至C₆雜伸烷基）。Option6 An amine compound of formula2-4 is converted to a sulfonamide compound of formula6-2 by treating it with a sulfonyl halide of formula6-1 (wherein^A is a halogen (e.g., chlorine) and Ar is as defined above in the present invention or its embodiments). Treatment of the compound of formula6-2 with an alcohol of formula6-3 (wherein R is an alkyl group) under art-known Mitsunobu reaction conditions provides a compound of formula6-4 , which can be converted to a compound of formula (I) (wherein_-CH2- [alk]_n-2- O- is a_C3 to_C6 heteroalkyl group substituted with^Rg ,^Rh , and Ri⁾ in a manner similar to that described in Scheme 4.

具有式 (I) 的化合物或其實施方式（其中R¹和R²如發明內容或其實施方式中所定義，Ar係芳基或單環雜芳基或其實施方式，R^2a係氫，Hy係雜亞環（如1,4-哌啶二基），降解決定子係具有式 (ii) 的基團，並且alk係被R^g、R^h和Rⁱ取代的C₃至C₆雜伸烷基（或其實施方式），其經由雜伸烷基的氮原子附接至Ar）可以如下文方案7中所示和所述合成。Compounds of formula (I) or embodiments thereof (wherein R¹ and R² are as defined in the invention or embodiments thereof, Ar is aryl or monocyclic heteroaryl or embodiments thereof, R^2a is hydrogen, Hy is a heterocyclic cycloalkylene (such as 1,4-piperidinyl), the degator is a group of formula (ii), and alk is a C₃ to C₆ heteroalkylene substituted with R^g , R^h and Rⁱ (or embodiments thereof), which is attached to Ar via the nitrogen atom of the heteroalkylene) can be synthesized as shown and described in Scheme 7 below.

方案7藉由以下方式將具有式2-4的胺化合物轉化為具有式7-2的磺醯胺化合物：用具有式7-1的磺醯基鹵化物（其中A²係鹵素（如氯），並且A³係合適的鹵素（如溴），並且Ar如上文發明內容或其實施方式中所定義）處理它。在本領域已知的布赫瓦爾德型偶合反應條件下，用具有式7-3的胺（其中R係烷基）處理具有式7-2的化合物提供了具有式7-4的化合物，按照與方案4中所述類似的方式進行可以將其轉化為具有式 (I) 的化合物（其中-CH₂-[alk]_n-2-NH-係被R^g、R^h和Rⁱ取代的C₃至C₆雜伸烷基）。Option7 An amine compound of formula2-4 is converted to a sulfonamide compound of formula7-2 by treating it with a sulfonyl halide of formula7-1 (wherein^A2 is a halogen (e.g., chlorine), and^A3 is a suitable halogen (e.g., bromine), and Ar is as defined above in the present invention or its embodiments. Treatment of the compound of formula7-2 with an amine of formula7-3 (wherein R is an alkyl group) under Buchwald-type coupling reaction conditions known in the art provides a compound of formula7-4 , which can be converted to a compound of formula (I) (wherein_-CH2- [alk]_n-2- NH- is a_C3 to C6 heteroalkyl group substituted with^Rg ,^Rh , and^Ri ) in a manner similar to that described in Scheme₄ .

效用 具有式 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物）可導致CDK2和CDK4蛋白的降解，因此可用於治療由CDK2和/或CDK4介導的疾病。UtilityCompounds of Formula (I) (and any embodiments thereof disclosed herein, including specific compounds) can cause degradation of CDK2 and CDK4 proteins and are therefore useful in treating diseases mediated by CDK2 and/or CDK4.

越來越多的證據表明，過度活化的CDK2和/或CDK4導致癌細胞中的異常細胞週期調節和增殖。雖然很少發現CDK2/4突變，但在人癌症中，CDK4/週期蛋白D、CDK2/週期蛋白E或CDK2/週期蛋白A複合物的激酶活性經由幾種機制升高。在許多人癌症中已經鑒定出了CDK4/週期蛋白D調節的異常。例如，在許多癌症中都發現了週期蛋白D1的擴增或過表現，包括乳腺浸潤性導管癌、浸潤性乳腺癌、膀胱尿路上皮癌、乳腺浸潤性小葉癌和肺腺癌。週期蛋白D1的易位、CDK4的擴增在脂肪肉瘤中很常見。在其他實性瘤和血液系統惡性腫瘤中也觀察到了較低頻率的CDK4擴增。CDK4抑制劑p16（CDKN2A）的缺失亦為許多癌症中的常見事件，包括多形性神經膠質母細胞瘤、頭頸部鱗狀細胞癌、胰臟腺癌、食道腺癌、間皮瘤、肺鱗狀細胞癌、膀胱尿路上皮癌、皮膚黑色素瘤、彌漫型大B細胞淋巴瘤、膽管癌、肺腺癌和胃腺癌。Accumulating evidence suggests that overactivation of CDK2 and/or CDK4 leads to aberrant cell cycle regulation and proliferation in cancer cells. Although CDK2/4 mutations are rare, the kinase activity of the CDK4/cyclin D, CDK2/cyclin E, or CDK2/cyclin A complexes is elevated in human cancers through several mechanisms. Abnormalities in CDK4/cyclin D regulation have been identified in numerous human cancers. For example, amplification or overexpression of cyclin D1 has been found in numerous cancers, including invasive ductal carcinoma of the breast, invasive breast cancer, urothelial carcinoma of the bladder, invasive lobular carcinoma of the breast, and lung adenocarcinoma. Translocation of cyclin D1 and amplification of CDK4 are common in liposarcoma. CDK4 amplification has also been observed at lower frequencies in other solid tumors and hematologic malignancies. Loss of the CDK4 inhibitor p16 (CDKN2A) is also a common event in many cancers, including glioblastoma multiforme, head and neck squamous cell carcinoma, pancreatic adenocarcinoma, esophageal adenocarcinoma, mesothelioma, lung squamous cell carcinoma, bladder urothelial carcinoma, cutaneous melanoma, diffuse large B-cell lymphoma, bile duct carcinoma, lung adenocarcinoma, and gastric adenocarcinoma.

已經發現，週期蛋白E在癌症（例如子宮癌、卵巢癌、胃癌和乳腺癌）中經常被擴增。在一些癌症類型中，控制週期蛋白E的周轉的FBXW7中的功能缺失突變或USP28的過表現導致週期蛋白E過表現和CDK2活化。可替代地，某些癌細胞表現過度活躍的截短形式的週期蛋白E或週期蛋白A。此外，在各種癌症如肝細胞癌、結直腸癌和乳腺癌中也報導了週期蛋白A的擴增和過表現。在一些腫瘤中，在內源性CDK2抑制劑p27或p21的表現缺失或位置改變、或p27的負調節劑SKP2的過表現後，CDK2的催化活性增加。此外，CDC25A和CDC25B（負責活化CDK2的去磷酸化的蛋白磷酸酶）在各種腫瘤中過表現。CDK2活化的該等不同機制已經使用癌細胞或小鼠癌症模型驗證。此外，CDK2/週期蛋白E使致癌Myc磷酸化以對抗ras誘導的衰老，突出了CDK2在myc/ras誘導的腫瘤形成中的重要性。已經表明CDK2的失活對myc過表現的癌細胞係合成致死的。在非整倍體癌細胞（例如KRAS突變肺癌）中，CDK2抑制導致後期災變和細胞凋亡。此外，抑制CDK2有效地誘導AML細胞系中的顆粒球分化，並阻滯AML小鼠模型中的腫瘤生長。Cyclin E has been found to be frequently amplified in cancers such as uterine, ovarian, gastric, and breast cancers. In some cancer types, loss-of-function mutations in FBXW7 or overexpression of USP28, which control cyclin E turnover, lead to overexpression of cyclin E and activation of CDK2. Alternatively, certain cancer cells express overactive, truncated forms of cyclin E or cyclin A. Furthermore, amplification and overexpression of cyclin A have been reported in various cancers, such as hepatocellular carcinoma, colorectal cancer, and breast cancer. In some tumors, CDK2 catalytic activity is increased following the loss or relocation of the endogenous CDK2 inhibitors p27 or p21, or the overexpression of SKP2, a negative regulator of p27. Furthermore, CDC25A and CDC25B (protein phosphatases responsible for dephosphorylation of activated CDK2) are overexpressed in various tumors. These diverse mechanisms of CDK2 activation have been validated using cancer cells and mouse cancer models. Furthermore, CDK2/cyclin E phosphorylates oncogenic Myc to antagonize Ras-induced senescence, highlighting the importance of CDK2 in Myc/Ras-induced tumorigenesis. Inactivation of CDK2 has been shown to be synthetically lethal in Myc-overexpressing cancer cells. In aneuploid cancer cells (e.g., KRAS-mutant lung cancer), CDK2 inhibition leads to late-stage catastrophe and apoptosis. Furthermore, CDK2 inhibition effectively induces granulocyte differentiation in AML cell lines and blocks tumor growth in AML mouse models.

由於週期蛋白E擴增或過表現而導致的CDK2活化也被鑒定為由CDK4/6抑制劑或曲妥珠單抗治療的HR+ 或HER2+ 乳腺癌的關鍵原發性或獲得性耐藥性途徑。因此，具有式 (I) 的化合物可以與CDK4/6抑制劑或抗HER2療法組合使用，以用於治療CDK4/6抑制劑或抗HER2療法難治的癌症。CDK2 activation due to amplification or overexpression of cyclin E has also been identified as a key primary or acquired resistance pathway in HR+ or HER2+ breast cancers treated with CDK4/6 inhibitors or trastuzumab. Therefore, compounds of Formula (I) can be used in combination with CDK4/6 inhibitors or anti-HER2 therapies to treat cancers refractory to CDK4/6 inhibitors or anti-HER2 therapies.

因此，本揭露之化合物可用於治療特徵在於以下的腫瘤：1) CDK2和/或CDK4的過表現；2) 週期蛋白D、週期蛋白E或週期蛋白A的擴增/過表現；3) CDK2（Thr160）或CDK4（Thr172）的過度磷酸化；4) FBXW7中的功能缺失突變、AMBRA1的耗竭、USP28的過表現、或CDC25A或/和CDC25B的擴增/過表現；5) 截短的週期蛋白E或週期蛋白A的表現；6) p16、p21或p27的失調，或SKP2的過表現；7) 過度活躍的MYC/RAS；8) 非整倍體癌症；9) CDK4和/或CDK6抑制劑難治性癌症；以及10) CCNE1的擴增和/或過表現。Therefore, the compounds disclosed herein can be used to treat tumors characterized by: 1) overexpression of CDK2 and/or CDK4; 2) amplification/overexpression of cyclin D, cyclin E, or cyclin A; 3) hyperphosphorylation of CDK2 (Thr160) or CDK4 (Thr172); 4) loss-of-function mutations in FBXW7, depletion of AMBRA1, overexpression of USP28, or amplification/overexpression of CDC25A or/and CDC25B; 5) expression of truncated cyclin E or cyclin A; 6) dysregulation of p16, p21, or p27, or overexpression of SKP2; 7) overactive MYC/RAS; 8) aneuploid cancers; 9) cancers refractory to CDK4 and/or CDK6 inhibitors; and 10) amplification and/or overexpression of CCNE1.

在一些實施方式中，癌症係卵巢癌（例如漿液性、透明細胞、子宮內膜樣和黏液性卵巢癌）、子宮癌（例如子宮內膜癌和子宮肉瘤）、胃癌（即胃部癌症）、肺癌（例如腺癌、小細胞肺癌和非小細胞肺癌、小細胞性和非小細胞性癌、支氣管癌、支氣管腺瘤、胸膜肺母細胞瘤）、腎癌（例如透明細胞腎細胞癌、乳頭狀腎細胞癌和嫌色腎細胞癌）、腦癌（包括星形細胞瘤、腦膜瘤和膠質母細胞瘤）、神經母細胞瘤、副神經節瘤、嗜鉻細胞瘤、胰臟神經內分泌腫瘤、生長抑素瘤、血管母細胞瘤、胃腸道間質瘤、垂體瘤、平滑肌瘤、平滑肌肉瘤、紅血球增多症、視網膜癌、遺傳性平滑肌瘤病、腎細胞癌、星形細胞瘤、皮膚癌（例如黑色素瘤、鱗狀細胞癌、卡波西肉瘤、默克爾細胞皮膚癌）、膀胱癌（包括膀胱尿路上皮癌）、宮頸癌、結直腸癌（例如小腸癌、結腸癌、直腸癌、肛門癌）、頭頸癌（例如喉癌、下咽癌、鼻咽癌、口咽癌、唇癌、舌癌和口腔癌）、肝癌（例如肝細胞癌和膽管細胞癌）、前列腺癌、睪丸癌、膽囊癌、胰臟癌（例如外分泌胰臟癌和神經內分泌胰臟癌）、甲狀腺癌和甲狀旁腺癌、輸卵管癌、腹膜癌、陰道癌、膽道癌、食道癌（例如食道鱗狀細胞癌和食道腺癌）、肉瘤（例如脂肪肉瘤和骨肉瘤）、骨癌、軟骨肉瘤、白血病（包括急性骨髓性白血病、急性淋巴球白血病、慢性骨髓性白血病和慢性淋巴球白血病）、淋巴瘤（例如非何杰金氏淋巴瘤NHL（包括套細胞淋巴瘤MCL）和何杰金氏淋巴瘤）以及多發性骨髓瘤。In some embodiments, the cancer is ovarian cancer (e.g., serous, clear cell, endometrioid, and mucinous ovarian cancer), uterine cancer (e.g., endometrial cancer and uterine sarcoma), gastric cancer (i.e., gastric cancer), lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung cancer, small cell and non-small cell carcinoma, bronchogenic carcinoma, bronchial adenoma, pleuropulmonary blastoma), renal cancer (e.g., clear cell renal carcinoma, papillary renal cell carcinoma, and chromophobe renal cell carcinoma), cell carcinoma), brain cancer (including astrocytoma, meningioma, and glioblastoma), neuroblastoma, paraganglioma, pheochromocytoma, pancreatic neuroendocrine tumor, somatostatinoma, hemangioblastoma, gastrointestinal stromal tumor, pituitary tumor, leiomyoma, leiomyosarcoma, polycythemia vera, retinal cancer, hereditary leiomyomatosis, renal cell carcinoma, astrocytoma, skin cancer (e.g., melanoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel's skin cancer), bladder cancer (including urothelial carcinoma of the bladder), cervical cancer, colorectal cancer (such as small intestine cancer, colon cancer, rectal cancer, anal cancer), head and neck cancer (such as laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip cancer, tongue cancer, and oral cancer), liver cancer (such as hepatocellular carcinoma and bile duct cell carcinoma), prostate cancer, testicular cancer, gallbladder cancer, pancreatic cancer (such as exocrine pancreatic cancer and neuroendocrine pancreatic cancer), thyroid cancer and parathyroid cancer, fallopian cancer Cancers of the pancreas and peritoneum include: esophageal cancer (e.g., esophageal squamous cell carcinoma and esophageal adenocarcinoma), sarcomas (e.g., liposarcoma and osteosarcoma), bone cancer, chondrosarcoma, leukemias (e.g., acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, and chronic lymphocytic leukemia), lymphomas (e.g., non-Hodgkin's lymphoma (NHL) (including mantle cell lymphoma (MCL)) and Hodgkin's lymphoma), and multiple myeloma.

在其他實施方式中，癌症係乳腺癌，包括例如ER陽性/HR陽性乳腺癌、HER2陰性乳腺癌、ER陽性/HR陽性乳腺癌、HER2陽性乳腺癌、ER陰性/HR陰性、HER2陽性乳腺癌、三陰性乳腺癌（TNBC）；或炎性乳腺癌。在一些實施方式中，乳腺癌係內分泌耐藥性乳腺癌、抗HER2療法（例如，曲妥珠單抗）耐藥性乳腺癌、或表現出對CDK4/CDK6抑制的原發性或獲得性耐藥性的乳腺癌。在一些實施方式中，乳腺癌係晚期或轉移性乳腺癌。在上述每一者的一些實施方式中，乳腺癌的特徵在於CCNE1和/或CCNE2的擴增或過表現。In other embodiments, the cancer is breast cancer, including, for example, ER-positive/HR-positive breast cancer, HER2-negative breast cancer, ER-positive/HR-positive breast cancer, HER2-positive breast cancer, ER-negative/HR-negative, HER2-positive breast cancer, triple-negative breast cancer (TNBC), or inflammatory breast cancer. In some embodiments, the breast cancer is endocrine-resistant breast cancer, breast cancer resistant to anti-HER2 therapy (e.g., trastuzumab), or breast cancer that exhibits primary or acquired resistance to CDK4/CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments of each of the foregoing, the breast cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2.

除了癌症之外，如發明內容中所述之如第一方面中所述之具有式 (I) 的化合物（或上文的其任一實施方式）可用於治療自體免疫性疾病自體免疫性疾病，例如類風濕性關節炎（RA）、全身性紅斑狼瘡（SLE）、原發性休格倫氏症候群（pSS）、多發性硬化（MS）、克羅恩病（CD）、痛風、眼色素層炎、尋常型天疱瘡和敗血症，並且還可以用作噪音誘導的、順鉑誘導的或抗生素誘導的或年齡相關的聽力損失的有希望的預防性治療。In addition to cancer, the compounds of formula (I) as described in the first aspect as described in the present invention (or any of its embodiments above) can be used to treat autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), multiple sclerosis (MS), Crohn's disease (CD), gout, uveitis, pemphigus vulgaris and sepsis, and can also be used as a promising preventive treatment for noise-induced, cisplatin-induced or antibiotic-induced or age-related hearing loss.

測試 本揭露之化合物的CDK2/4降解活性可以使用下文生物學實例中描述的體外測定來測試。AssaysThe CDK2/4 degradation activity of the compounds disclosed herein can be tested using the in vitro assays described in the biological examples below.

藥物組成物 通常，具有式 (I) 的化合物（除非另有說明，否則對其中的化合物/具有式 (I) 的化合物的提及包括本文所述之其任何實施方式或其藥學上可接受的鹽）將以治療有效量藉由針對用於相似效用的藥劑的可接受的投與模式中之任一項進行投與。具有式 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物）的治療有效量可以在約0.01至約500 mg/kg患者體重/天的範圍內，其可以以單一劑量或多個劑量投與。合適的劑量水平可為從約0.1至約250 mg/kg/天、約0.5至約100 mg/kg/天。合適的劑量水平可為約0.01至約250 mg/kg/天、約0.05至約100 mg/kg/天或約0.1至約50 mg/kg/天。在此範圍內，劑量可為約0.05至約0.5、約0.5至約5或約5至約50 mg/kg/天。對於口服投與，該等組成物可以以片劑形式提供，該等片劑含有約1.0至約1000毫克的活性成分，特別地約1、5、10、15、20、25、50、75、100、150、200、250、300、400、500、600、750、800、900和1000毫克的活性成分。具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物）（即，活性成分）的實際量將取決於許多因素，如待治療的疾病的嚴重程度、患者的年齡及相對健康、正在使用的化合物的效力、投與的途徑及形式以及其他因素。Pharmaceutical CompositionsGenerally, a compound of Formula (I) (unless otherwise specified, reference to a compound/compounds of Formula (I) includes any embodiment thereof described herein or a pharmaceutically acceptable salt thereof) will be administered in a therapeutically effective amount by any of the accepted modes of administration for similarly utilizable agents. A therapeutically effective amount of a compound of Formula (I) (and any embodiment thereof disclosed herein, including specific compounds) may range from about 0.01 to about 500 mg/kg of patient body weight per day, which may be administered in a single dose or in multiple doses. Suitable dosage levels may range from about 0.1 to about 250 mg/kg/day, or about 0.5 to about 100 mg/kg/day. Suitable dosage levels may be about 0.01 to about 250 mg/kg/day, about 0.05 to about 100 mg/kg/day, or about 0.1 to about 50 mg/kg/day. Within this range, the dosage may be about 0.05 to about 0.5, about 0.5 to about 5, or about 5 to about 50 mg/kg/day. For oral administration, the compositions may be provided in the form of tablets containing about 1.0 to about 1000 mg of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 mg of the active ingredient. The actual amount of the compound of formula (I) (or any embodiment thereof disclosed herein, including specific compounds) (i.e., the active ingredient) administered will depend on many factors, such as the severity of the disease being treated, the age and relative health of the patient, the potency of the compound being administered, the route and form of administration, and other factors.

通常，具有式 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物）將作為藥物組成物藉由以下途徑中之任一種投與：口服、全身（例如，經皮、鼻內或藉由栓劑）或腸胃外（例如，肌內、靜脈內或皮下）投與。較佳的投與方式係使用方便的日劑量方案口服，其可以根據患病程度進行調整。組成物可以採取片劑、丸劑、膠囊、半固體、粉末、緩釋配製物、溶液、混懸液、酏劑、噴霧劑或任何其他適當的組成物的形式。Typically, the compound of formula (I) (and any embodiments thereof disclosed herein, including specific compounds) will be administered as a pharmaceutical composition by any of the following routes: oral, systemic (e.g., transdermal, intranasal, or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous). The preferred route of administration is oral using a convenient daily dosage regimen that can be adjusted according to the severity of the disease. The composition can take the form of a tablet, pill, capsule, semisolid, powder, sustained-release formulation, solution, suspension, elixir, spray, or any other appropriate composition.

配製物的選擇取決於多種因素，如藥物投與模式（例如，對於口服投與，較佳的是呈片劑、丸劑或膠囊形式的配製物，包括腸溶包衣的或延遲釋放的片劑、丸劑或膠囊）以及原料藥的生體可用率。The choice of formulation depends on factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules, including enteric-coated or delayed-release tablets, pills, or capsules, are preferred) and the bioavailability of the drug substance.

組成物通常由具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物）與至少一種藥學上可接受的賦形劑的組合組成。可接受的賦形劑通常是無毒的，有助於投與，並且不會不利地影響具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物）的治療益處。這種賦形劑可為熟悉該項技術者通常可用的任何固體、液體、半固體或在噴霧劑組成物的情況下係氣態賦形劑。The compositions typically consist of a compound of Formula (I) (or any embodiment thereof disclosed herein, including specified compounds) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are generally non-toxic, facilitate administration, and do not adversely affect the therapeutic benefits of the compound of Formula (I) (or any embodiment thereof disclosed herein, including specified compounds). Such excipients can be any solid, liquid, semisolid, or, in the case of spray compositions, gaseous excipients commonly available to those skilled in the art.

固體藥物賦形劑包括澱粉、纖維素、滑石、葡萄糖、乳糖、蔗糖、明膠、麥芽、稻、麵粉、白堊、矽膠、硬脂酸鎂、硬脂酸鈉、單硬脂酸甘油酯、氯化鈉、脫脂乳粉等。液體和半固體賦形劑可以選自甘油、丙二醇、水、乙醇以及各種油，包括石油、動物、植物或合成來源的那些，例如，花生油、大豆油、礦物油、芝麻油等。較佳的液體載劑，特別是對於可注射溶液，包括水、鹽水、水性右旋糖和二醇。Solid drug adjuvants include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, skimmed milk powder, etc. Liquid and semi-solid adjuvants can be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, especially for injectable solutions, include water, saline, aqueous dextrose and glycols.

具有式 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物）可以配製用於藉由注射（例如藉由推注或連續輸注）進行腸胃外投與。注射用配製物可以以單位劑型提供，例如，在添加有防腐劑的安瓿中或在多劑量容器中。組成物可以採取例如以油性或水性媒介物中的混懸液、溶液或乳液的形式，並且可以含有配製劑（如混懸劑、穩定劑和/或分散劑）。配製物可以存在於單位劑量或多劑量容器（例如，密封的安瓿和小瓶）中，並且可以以粉末形式儲存或在冷凍乾燥（凍乾）條件下儲存，只需要在使用前即時添加無菌液體載劑（例如，鹽水或無菌的無熱原水）。臨時的注射溶液和混懸液可以由前述種類的無菌粉末、顆粒和片劑製備。Compounds of Formula (I) (and any embodiments thereof disclosed herein, including specific compounds) can be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Injectable formulations can be provided in unit dosage form, for example, in ampoules with added preservatives or in multi-dose containers. The composition can take the form of a suspension, solution, or emulsion, for example, in an oily or aqueous vehicle, and can contain a formulating agent (e.g., a suspending agent, a stabilizer, and/or a dispersing agent). The formulations can be presented in unit-dose or multi-dose containers (e.g., sealed ampoules and vials) and can be stored in powder form or in a freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier (e.g., saline or sterile, pyrogen-free water) immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the types described above.

用於腸胃外投與的配製物包括活性化合物的水性和非水性（油性）無菌注射溶液，其可以含有抗氧化劑、緩衝液、抑菌劑和使配製物與預期接受體的血液等滲的溶質；以及水性和非水性無菌混懸液，其可以包括混懸劑和增稠劑。合適的親脂性溶劑或媒介物包括脂肪油（如芝麻油）或合成的脂肪酸酯（如油酸乙酯或三酸甘油酯）或脂質體。水性注射混懸液可以含有增加混懸液的黏度的物質，如羧甲基纖維素鈉、山梨糖醇或聚葡萄糖。視需要地，混懸液還可以含有合適的穩定劑或增加化合物的溶解度的藥劑，以允許製備高度濃縮的溶液。Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils (such as sesame oil) or synthetic fatty acid esters (such as ethyl oleate or triglycerides) or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or polydextrose. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow the preparation of highly concentrated solutions.

除了先前描述的配製物之外，具有式 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物）還可以配製為貯庫製劑。此類長效型配製物可藉由植入（例如，皮下或肌內）或藉由肌內注射進行投與。因此，例如，該等化合物可以與合適的聚合物或疏水性材料（例如，作為在可接受的油中的乳液）或離子交換樹脂一起配製，或被配製成略微可溶的衍生物，例如被配製成略微可溶的鹽。In addition to the formulations described previously, the compounds of formula (I) (and any embodiments thereof disclosed herein, including specific compounds) can also be formulated as depot preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or ion exchange resin, or as a sparingly soluble derivative, such as a sparingly soluble salt.

對於經頰或舌下投與，該等組成物可以按常規方式採取片劑、錠劑、軟錠劑或凝膠的形式。此類組成物可以包含調味基料如蔗糖和阿拉伯膠或黃蓍膠中的活性成分。For buccal or sublingual administration, the compositions may take the form of tablets, troches, pastilles or gels in conventional manner. Such compositions may contain the active ingredient in a flavored base such as sucrose and gum arabic or tragacanth.

具有式 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物）還可以被配製成直腸組成物（如栓劑或保留灌腸劑），例如含有常規栓劑基質（如可可脂、聚乙二醇或其他甘油酯）。The compounds of formula (I) (and any embodiments thereof disclosed herein, including specific compounds) may also be formulated in rectal compositions such as suppositories or retention enemas, for example containing conventional suppository bases such as cocoa butter, polyethylene glycol or other glycerides.

某些具有式 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物）可以局部投與，即藉由非全身投與。這包括將具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物）外部投與於表皮或口腔以及將這種化合物滴入耳、眼以及鼻中，使得該化合物不顯著進入血流。相比之下，全身投與係指口服、靜脈內、腹膜內和肌內投與。Certain compounds of Formula (I) (and any embodiments thereof disclosed herein, including specific compounds) can be administered topically, i.e., by non-systemic administration. This includes topical administration of a compound of Formula (I) (or any embodiments thereof disclosed herein, including specific compounds) to the epidermis or oral cavity, as well as instillation of such a compound into the ear, eye, and nose, so that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

適於局部投與的配製物包括適於滲透藉由皮膚至炎症位點的液體或半液體製劑，如凝膠、擦劑、洗劑、乳膏、軟膏或糊劑，以及適於投與至眼、耳或鼻的滴劑。局部投與的活性成分可以構成例如配製物的從0.001%至10% w/w（按重量計）。在某些實施方式中，活性成分可以構成多達10% w/w。在其他實施方式中，其可以構成小於5% w/w。在某些實施方式中，活性成分可以構成從2% w/w至5% w/w。在其他實施方式中，其可以構成配製物的從0.1%至1% w/w。Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes, as well as drops suitable for administration to the eyes, ears or noses. The active ingredient for topical administration may constitute, for example, from 0.001% to 10% w/w (by weight) of the formulation. In certain embodiments, the active ingredient may constitute up to 10% w/w. In other embodiments, it may constitute less than 5% w/w. In certain embodiments, the active ingredient may constitute from 2% w/w to 5% w/w. In other embodiments, it may constitute from 0.1% to 1% w/w of the formulation.

對於藉由吸入進行的投與，具有式 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物）可以方便地從吹入器、噴霧器加壓包或遞送噴霧劑噴霧的其他方便方法遞送。加壓包可以包含合適的推進劑，如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其他合適的氣體。在加壓噴霧劑的情況下，劑量單位可以藉由提供用於遞送一個計量量的閥門來確定。可替代地，對於藉由吸入或吹入進行的投與，具有式 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物）可以採取乾粉末組成物的形式，例如化合物與合適的粉末基質（如乳糖或澱粉）的粉末混合物。粉末組成物可以按單位劑型呈現在例如膠囊、藥筒、明膠或泡鼓包裝中，粉末從中可以藉助於吸入器或吹入器投與。其他合適的藥物賦形劑及其配製物描述在由E. W. Martin編輯的Remington’s Pharmaceutical Sciences [雷明頓藥物科學]（Mack Publishing Company [馬克出版公司], 第20版, 2000）中。For administration by inhalation, the compound of formula (I) (and any embodiments thereof disclosed herein, including specific compounds) can be conveniently delivered from an insufflator, a nebulizer pressurized pack, or other convenient means of delivering an aerosol spray. The pressurized pack may contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve for delivering a metered amount. Alternatively, for administration by inhalation or insufflation, the compound of formula (I) (and any embodiments thereof disclosed herein, including specific compounds) can be in the form of a dry powder composition, for example, a powder mix of the compound and a suitable powder base (such as lactose or starch). The powder composition can be presented in unit dose form, for example, in capsules, cartridges, gelatin, or blister packs, from which the powder can be administered with the aid of an inhaler or insufflator. Other suitable drug formulations and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th edition, 2000).

具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物）在配製物中的水平可以在熟悉該項技術者採用的全範圍內變化。典型地，配製物將含有（基於重量百分比（wt.%））基於總配製物的從約0.01-99.99 wt. %的具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物），其餘的是一或多種合適的藥物賦形劑。例如，化合物以約1-80 wt. %的水平存在。The level of the compound of formula (I) (or any of the embodiments thereof disclosed herein, including specified compounds) in a formulation can vary within a full range employed by those skilled in the art. Typically, the formulation will contain (on a weight percentage (wt.%) basis) from about 0.01-99.99 wt.% of the compound of formula (I) (or any of the embodiments thereof disclosed herein, including specified compounds), based on the total formulation, with the remainder being one or more suitable drug excipients. For example, the compound is present at a level of about 1-80 wt.%.

組合和組合療法 具有式 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物）可以與一或多種其他藥物組合用於治療疾病或病症，對於該等疾病或病症具有式 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物）或其他藥物可具有效用。此類其他藥物可以藉由一種途徑以及其常用的量與具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物）同時地或依序地投與。當具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物）與一或多種其他藥物同時使用時，較佳的是含有此類其他藥物和具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物）的單位劑型的藥物組成物。然而，組合療法還可以包括其中具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物）和一或多種其他藥物以不同的重疊時間表投與的療法。還考慮了當與一或多種其他活性成分組合使用時，具有式 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物）和其他活性成分可以以比各自單獨使用時更低的劑量使用。Combinations and Combination TherapiesCompounds of Formula (I) (and any embodiments thereof disclosed herein, including specific compounds) can be used in combination with one or more other drugs for the treatment of diseases or conditions for which the compound of Formula (I) (and any embodiments thereof disclosed herein, including specific compounds) or other drugs may be effective. Such other drugs can be administered simultaneously or sequentially with the compound of Formula (I) (or any embodiments thereof disclosed herein, including specific compounds) by a route and in an amount commonly used therefor. When a compound of Formula (I) (or any embodiments thereof disclosed herein, including specific compounds) is used concurrently with one or more other drugs, a pharmaceutical composition containing such other drugs and the compound of Formula (I) (or any embodiments thereof disclosed herein, including specific compounds) in a unit dosage form is preferred. However, combination therapy may also include regimens in which the compound of Formula (I) (or any embodiment thereof disclosed herein, including specific compounds) and one or more other drugs are administered on different, overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compound of Formula (I) (and any embodiment thereof disclosed herein, including specific compounds) and the other active ingredient may be used in lower doses than when each is used alone.

因此，本揭露之藥物組成物還包括除了具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物）之外還含有一或多種其他藥物的那些。Thus, the pharmaceutical compositions of the present disclosure also include those containing one or more additional drugs in addition to a compound of formula (I) (or any embodiment thereof disclosed herein, including specific compounds).

上述組合不僅包括具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物）與一種其他藥物的組合，還包括與兩種或更多種其他活性藥物的組合。同樣地，具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物）可以與用於預防、治療、控制、改善疾病或病症或降低疾病或病症的風險的其他藥物組合使用，對於該等疾病或病症具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物）係有用的。此類其他藥物可以藉由一種途徑以及其常用的量與具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物）同時地或依序地投與。當具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物）與一或多種其他藥物同時使用時，可以使用含有此類其他藥物以及具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物）的藥物組成物。因此，本揭露之藥物組成物還包括除了具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物）之外還含有一或多種其他活性成分的那些。本揭露之化合物與第二活性成分的重量比可以變化，並且將取決於每種成分的有效劑量。通常，將使用各自的有效劑量。The above combinations include not only combinations of compounds of Formula (I) (or any of its embodiments disclosed herein, including specific compounds) with one other drug, but also combinations with two or more other active drugs. Similarly, compounds of Formula (I) (or any of its embodiments disclosed herein, including specific compounds) can be used in combination with other drugs used to prevent, treat, control, ameliorate, or reduce the risk of diseases or conditions for which compounds of Formula (I) (or any of its embodiments disclosed herein, including specific compounds) are useful. Such other drugs can be administered simultaneously or sequentially with compounds of Formula (I) (or any of its embodiments disclosed herein, including specific compounds) by a route and in an amount commonly used. When a compound of Formula (I) (or any embodiment thereof disclosed herein, including specified compounds) is used concomitantly with one or more other drugs, a pharmaceutical composition containing such other drugs along with the compound of Formula (I) (or any embodiment thereof disclosed herein, including specified compounds) can be used. Thus, pharmaceutical compositions disclosed herein also include those containing one or more other active ingredients in addition to the compound of Formula (I) (or any embodiment thereof disclosed herein, including specified compounds). The weight ratio of the compound of the disclosure to the second active ingredient can vary and will depend on the effective dose of each ingredient. Generally, effective doses of each will be used.

在有需要的受試者患有癌症或有患癌症的風險的情況下，可以用具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物）與一或多種其他抗癌劑的任何組合治療受試者，該一或多種其他抗癌劑包括但不限於：MAP激酶途徑（RAS/RAF/MEK/ERK）抑制劑，其包括但不限於：維莫非尼（PLX4032）、達拉菲尼、恩拉非尼（LGX818）、TQ-B3233、XL-518（Cas號1029872-29-4，可從ACC公司（ACC Corp）獲得）；曲美替尼、司美替尼（AZD6244）、TQ-B3234、PD184352、PD325901、TAK-733、佩米替尼（pimasertinib）、比美替尼、瑞美替尼、考美替尼（GDC-0973）、AZD8330、BVD-523、LTT462、來那替尼、AMG510、ARS853和揭露於專利WO 2016049565、WO 2016164675、WO 2016168540、WO 2017015562、WO 2017058728、WO 2017058768、WO 2017058792、WO 2017058805、WO 2017058807、WO 2017058902、WO 2017058915、WO 2017070256、WO 2017087528、WO 2017100546、WO 2017172979、WO 2017201161、WO 2018064510、WO 2018068017、WO 2018119183中之任何RAS抑制劑； CSF1R抑制劑（PLX3397、LY3022855等）和CSF1R抗體（IMC-054、RG7155）TGFβ受體激酶抑制劑如LY2157299； BTK抑制劑，如依魯替尼；BCR-ABL抑制劑：伊馬替尼（Gleevec®）；鹽酸尼洛替尼（Inilotinib hydrochloride）；尼洛替尼（Tasigna®）；達沙替尼（BMS-345825）；博舒替尼（SKI-606）；普納替尼（AP24534）；巴非替尼（INNO406）；達魯舍替尼（Danusertib）（PHA-739358）、AT9283（CAS 1133385-83-7）；塞卡替尼（AZD0530）；和N-[2-[(1S,4R)-6-[[4-環丁基胺基)-5-(三氟甲基)-2-嘧啶基]胺基]-l,2,3,4-四氫化萘-l,4-亞胺-9-基]-2-側氧基乙基]-乙醯胺（PF-03814735，CAS 942487-16-3）； ALK抑制劑：PF-2341066（XALKOPJ®；克唑替尼）；5-氯-N4-(2-(異丙基-磺醯基)苯基)-N2-(2-甲氧基-4-(4-(4-甲基哌𠯤-l-基)哌啶-l-基)苯基)嘧啶-2,4-二胺；GSK1838705 A；CH5424802；色瑞替尼（ZYKADIA）；TQ-B3139、TQ-B3101 PI3K抑制劑：4-[2-(lH-吲唑-4-基)-6-[[4-(甲磺醯基)哌𠯤-l-基]甲基]噻吩并[3,2-d]嘧啶-4-基]𠰌啉（也稱為GDC 0941並且描述於PCT公開案號WO 09/036082和WO 09/055730中）、2-甲基-2-[4-[3-甲基-2-側氧基-8-(喹啉-3-基)-2,3-二氫咪唑并[4,5-c]喹啉-l-基]苯基]丙腈（也稱為BEZ 235或NVP-BEZ 235，並且描述於PCT公開案號WO 06/122806中）； 血管內皮生長因子（VEGF）受體抑制劑：貝伐單抗（由基因泰克公司（Genentech）/羅氏公司（Roche）以商標名Avastin®銷售）、阿昔替尼（N-甲基-2-[[3-[(E)-2-吡啶-2-基乙烯基]-lH-吲唑-6-基]氫硫基]苯甲醯胺，也稱為AG013736並且描述於PCT公開案號WO 01/002369中）、丙胺酸布立尼布（(S)-((R)-l-(4-(4-氟-2-甲基-lH-吲哚-5-基氧基)-5-甲基吡咯并[2,l-f][l,2,4]三𠯤-6-基氧基)丙-2-基)2-胺基丙酸酯，也稱為BMS-582664）、莫特塞尼（N-(2,3-二氫-3,3-二甲基-lH-吲哚-6-基)-2-[(4-吡啶基甲基)胺基]-3-吡啶甲醯胺，並且描述於PCT公開案號WO 02/066470中）、帕瑞肽（也稱為SOM230，並且描述於PCT公開案號WO 02/010192中）、索拉非尼（以商標名Nexavar®銷售）；AL-2846 MET抑制劑，如福瑞替尼、卡博替尼或克唑替尼； FLT3抑制劑 - 蘋果酸舒尼替尼（由輝瑞公司（Pfizer）以商標名Sutent®銷售）；PKC412（米哚妥林）；坦度替尼（tanutinib）、索拉非尼、來他替尼、KW-2449、奎紮替尼（AC220）和克瑞拉尼； 上皮生長因子受體（EGFR）抑制劑：吉非替尼（Gefitnib）（以商標名Iressa®銷售）、N-[4-[(3-氯-4-氟苯基)胺基]-7-[[(3"S")-四氫-3-呋喃基]氧基]-6-喹唑啉基]-4(二甲基胺基)-2-丁醯胺（由勃林格殷格翰公司（Boehringer Ingelheim）以商標名Tovok®銷售）、西妥昔單抗（由百時美施貴寶公司（Bristol-Myers Squibb）以商標名Erbitux®銷售）、帕尼單抗（由安進公司（Amgen）以商標名Vectibix®銷售）； HER2受體抑制劑：曲妥珠單抗（由基因泰克公司/羅氏公司以商標Herceptin®銷售）、來那替尼（也稱為HKI-272，(2E)-N-[4-[[3-氯-4-[(吡啶-2-基)甲氧基]苯基]胺基]-3-氰基-7-乙氧基喹啉-6-基]-4-(二甲基胺基)丁-2-烯醯胺，並且描述於PCT公開案號WO 05/028443中）、拉帕替尼或二甲苯磺酸拉帕替尼（由葛蘭素史克公司（GlaxoSmithKline）以商標Tykerb®銷售）；曲妥珠單抗恩他新（在美國，阿多-曲妥珠單抗恩他新，商標名Kadcyla）- 一種由與細胞毒性劑美登素（mertansine）（DM1）連接的單株抗體曲妥珠單抗（赫賽汀）組成的抗體-藥物綴合物；曲妥珠單抗-德魯替康（Trastuzumab deruxtecan）（商標名Enhertu）； HER二聚抑制劑：帕妥珠單抗（由基因泰克公司以商標Omnitarg®銷售）； CD20抗體：利妥昔單抗（由基因泰克公司/羅氏公司以商標Riuxan®和MabThera®銷售）、托西莫單抗（由葛蘭素史克公司以商標Bexxar®銷售）、奧法木單抗（由葛蘭素史克公司以商標Arzerra®銷售）； 酪胺酸激酶抑制劑：鹽酸厄洛替尼（由基因泰克公司/羅氏公司以商標名Tarceva®銷售）、利尼伐尼（Linifanib）（N-[4-(3-胺基-lH-吲唑-4-基)苯基]-N'-(2-氟-5-甲基苯基)脲，也稱為ABT 869，可從基因泰克公司獲得）、蘋果酸舒尼替尼（由輝瑞公司以商標名Sutent®銷售）、博舒替尼（4-[(2,4-二氯-5-甲氧基苯基)胺基]-6-甲氧基-7-[3-(4-甲基哌𠯤-l-基)丙氧基]喹啉-3-甲腈，也稱為SKI-606，並且描述於美國專利案號6,780,996中）、達沙替尼（百時美施貴寶公司以商標名Sprycel®銷售）、維全特（armala）（也稱為帕唑帕尼，由葛蘭素史克公司以商標名Votrient®銷售）、伊馬替尼以及甲磺酸伊馬替尼（由諾華公司（Novartis）以商標名Gilvec®和Gleevec®銷售）； DNA合成抑制劑：卡培他濱（由羅氏公司以商標名Xeloda®銷售）、鹽酸吉西他濱（由禮來公司（Eli Lilly and Company）以商標名Gemzar®銷售）、奈拉濱（nelarabine）（(2R3S,4R,5R)-2-(2-胺基-6-甲氧基-嘌呤-9-基)-5-(羥基甲基)氧戊環-3,4-二醇，由葛蘭素史克公司以商標名Arranon®和Atriance®銷售）； 抗腫瘤劑：奧沙利鉑（由賽諾菲-安萬特集團（Sanofi-Aventis）以商標名Eloxatin®銷售並且描述於美國專利案號4,169,846中）； 人顆粒球群落刺激因子（G-CSF）調節劑：非格司亭（由安進公司以商標名Neupogen®銷售）； 免疫調節劑：阿托珠單抗（Afutuzumab）（可從Roche®獲得）、培非格司亭（由安進公司以商標名Neulasta®銷售）、來那度胺（也稱為CC-5013，以商標名Revlimid®銷售）、沙利度胺（以商標名Thalomid®銷售）； CD40抑制劑：達西珠單抗（也稱為SGN-40或huS2C6，可從西雅圖遺傳學公司（Seattle Genetics, Inc）獲得）；促凋亡受體促效劑（PARA）：杜拉樂明（也稱為AMG-951，可從安進公司/基因泰克公司獲得）； Hedgehog拮抗劑：2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲磺醯基)-苯甲醯胺（也稱為GDC-0449，並且描述於PCT公開案號WO 06/028958中）； 磷脂酶A2抑制劑：阿那格雷（以商標名Agrylin®銷售）； BCL-2抑制劑：4-[4-[[2-(4-氯苯基)-5,5-二甲基-l-環己烯-l-基]甲基]-l-哌𠯤基]-N-[[4-[[(1R)-3-(4-𠰌啉基)-l-[(苯硫基)甲基]丙基]胺基]-3-[(三氟甲基)磺醯基]苯基]磺醯基]苯甲醯胺（也稱為ABT-263並且描述於PCT公開案號WO 09/155386中）； MCl-1抑制劑：MIK665、S64315、AMG 397和AZD5991； 芳香化酶抑制劑：伊析美斯坦（由輝瑞公司以商標名Aromasin®銷售）、利妥唑（由諾華公司以商標名Femara®銷售）；阿那曲唑（以商標名Arimidex®銷售）； 拓樸異構酶I抑制劑：伊立替康（由輝瑞公司以商標名Camptosar®銷售）、鹽酸拓撲替康（由葛蘭素史克公司以商標名Hycamtin®銷售）； 拓樸異構酶II抑制劑：依托泊苷（也稱為VP-16和磷酸依托泊苷，以商標名Toposar®、VePesid®和Etopophos®銷售）、替尼泊苷（也稱為VM-26，以商標名Vumon®銷售）； mTOR抑制劑：坦羅莫司（由輝瑞公司以商標名Torisel®銷售）、利羅莫司（先前稱為德菲莫司（deferolimus），(lR,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-l,18-二羥基-19,30-二甲氧基-15,17,21,23,29,35-六甲基-2,3,10,14,20-五側氧基-11,36-二氧雜-4-氮雜三環[30.3.1.0 4 ' 9]三十六-16,24,26,28-四烯-12-基]丙基]-2-甲氧基環己基二甲基次膦酸鹽，也稱為AP23573和MK8669並且描述於PCT公開案號WO 03/064383中）、依羅莫司（由諾華公司以商標名Afinitor®銷售）； 蛋白酶體抑制劑，如卡非佐米、MLN9708、地拉米或硼替佐米； BET抑制劑，如INCB054329、OTX015和CPI-0610； LSD1抑制劑，如GSK2979552和INCB059872； KAT6抑制劑，如PF-07248144； HIF-2α抑制劑，如PT2977、PT2385、伊達替芬（imdatifan）和卡達替芬（casdatifan）； 破骨性骨吸收抑制劑：l-羥基-2-咪唑-l-基-膦醯基乙基)膦酸一水化物（由諾華公司以商標名Zometa®銷售）；CD33抗體藥物綴合物：吉妥珠單抗奧唑米星（由輝瑞公司/惠氏公司（Wyeth）以商標名Mylotarg®銷售）； CD22抗體藥物綴合物：奧英妥珠單抗（也稱為CMC-544和WAY-207294，可從杭州賽盛化工有限公司（Hangzhou Sage Chemical Co., Ltd.）獲得）； CD20抗體藥物綴合物：替伊莫單抗（以商標名Zevalin®銷售）； 生長抑素類似物：奧曲肽（也稱為醋酸奧曲肽，以商標名Sandostatin®和Sandostatin LAR®銷售）； 合成白介素11（IL-11）：奧普瑞白介素（oprelvekin）（由輝瑞公司/惠氏公司以商標名Neumega®銷售）； 合成促紅血球生成素：達依泊汀α（由安進公司以商標名Aranesp®銷售）； 核因子κ B受體活化劑（RANK）抑制劑：地諾單抗（由安進公司以商標名Prolia®銷售）； 血小板生成素模擬肽：羅米司亭（由安進公司以商標名Nplate®銷售）； 細胞生長刺激物：帕立非明（由安進公司以商標名Kepivance®銷售）； 抗似胰島素生長因子-1受體（IGF-1R）抗體：芬妥木單抗（Figitumumab）（也稱為CP-751,871，可從ACC公司獲得）、羅妥木單抗（robatumumab）（CAS號934235-44-6）； 抗CSl抗體：艾洛珠單抗（Elotuzumab）（HuLuc63，CAS號915296-00-3）； CD52抗體：阿侖單抗（以商標名Campath®銷售）； 組蛋白脫乙醯酶抑制劑（HDI）：伏立諾他（Voninostat）（由默克公司（Merck）以商標名Zolinza®銷售）； 烷基化劑：替莫唑胺（由先靈葆雅公司（Schering-Plough）/默克公司以商標名Temodar®和Temodal®銷售）、更生黴素（也稱為放線菌素D並以商標名Cosmegen®銷售）、美法侖（也稱為L-PAM、L-溶肉瘤素和苯丙胺酸氮芥，以商標名Alkeran®銷售）、六甲蜜胺（也稱為六甲嘧胺（HMM），以商標名Hexalen®銷售）、雙氯乙基亞硝脲（以商標名BiCNU®銷售）、苯達莫司汀（以商標名Treanda®銷售）、白消安（以商標名Busulfex®和Myleran®銷售）、卡鉑（以商標名Paraplatin®銷售）、羅氮芥（也稱為CCNU，以商標名CeeNU®銷售）、順鉑（也稱為CDDP，以商標名Platinol®和Platinol®-AQ銷售）、氯芥苯丁酸（以商標名Leukeran®銷售）、環磷醯胺（以商標名Cytoxan®和Neosar®銷售）、達卡巴𠯤（也稱為DTIC、DIC和咪唑羧醯胺，以商標名DTIC-Dome®銷售）、六甲蜜胺（也稱為六甲嘧胺（HMM），以商標名Hexalen®銷售）、異環磷醯胺（以商標名Ifex®銷售）、丙卡肼（以商標名Matulane®銷售）、二氯甲基二乙胺（也稱為雙氯乙基甲胺（nitrogen mustard）、氮芥（mustine）和鹽酸氮芥（mechloroethamine hydrochloride），以商標名Mustargen®銷售）、鏈脲佐菌素（以商標名Zanosar®銷售）、噻替派（也稱為硫代磷酸醯胺、TESPA和TSPA，以商標名Thioplex®銷售；生物響應調節劑：卡介苗（以商標名theraCys®和TICE® BCG銷售）、地尼白介素（以商標名Ontak®銷售）； 抗腫瘤抗生素：阿德力黴素（以商標名Adriamycin®和Rubex®銷售）、吉歐黴素（以商標名lenoxane®銷售）、道諾黴素（也稱為鹽酸道諾黴素、正定黴素和鹽酸道諾黴素，以商標名Cerubidine®銷售），道諾黴素脂質體（檸檬酸道諾黴素脂質體，以商標名DaunoXome®銷售）、米托蒽醌（也稱為DHAD，以商標名Novantrone®銷售）、表柔比星（以商標名Ellence™銷售）、伊達比星（以商標名Idamycin®、Idamycin PFS®銷售）、絲裂黴素C（以商標名Mutamycin®銷售）； 抗微管劑：雌莫司汀（以商標名Emcyl®銷售）； 組織蛋白酶K抑制劑：奧當卡替（Odanacatib）（也稱為MK-0822，N-(l-氰基環丙基)-4-氟-N-2-{(1S)-2,2,2-三氟-l-[4'-(甲磺醯基)聯苯-4-基]乙基}-L-亮胺醯胺，從蘭州化工股份有限公司（Lanzhou Chon Chemicals）、ACC公司和ChemieTek獲得，並且描述於PCT公開案號WO 03/075836中）；埃博黴素B類似物：伊沙匹隆（由百時美施貴寶公司以商標名Lxempra®銷售）； 熱激蛋白（HSP）抑制劑：坦螺旋黴素（Tanespimycin）（17-烯丙基胺基-17-脫甲氧基格爾德黴素，也稱為KOS-953和17-AAG，可從西格瑪公司（SIGMA）獲得，並且描述於美國專利案號4,261,989中）、NVP-HSP990、AUY922、AT13387、STA-9090、Debio 0932、KW-2478、XL888、CNF2024、TAS-116 TpoR促效劑：艾曲波帕（由葛蘭素史克公司以商標名Promacta®和Revolade®銷售）； 抗有絲分裂劑：多西他賽（由賽諾菲-安萬特集團以商標名Taxotere®銷售）；腎上腺類固醇抑制劑：胺麩精（以商標名Cytadren®銷售）； 抗雄性素：尼魯米特（以商標名Nilandron®和Anandron®銷售）、比卡魯胺（以商標名Casodex®銷售）、氟他胺（以商標名Fulexin™銷售）； 雄性素：氟甲睪酮（以商標名Halotestin®銷售）； CDK（CDK1、CDK2、CDK3、CDK5、CDK7、CDK8、CDK9、CDK11/12或CDK16）抑制劑，包括但不限於阿伏西地（Alvocidib）（pan-CDK抑制劑，也稱為夫拉平度（flovopirdol）或HMR-1275，2-(2-氯苯基)-5,7-二羥基-8-[(3S,4R)-3-羥基-l-甲基-4-哌啶基]-4-苯并哌喃酮（chromenone），並且描述於美國專利案號5,621,002中）； CDK4/6抑制劑帕博西尼、瑞博西尼、阿貝西利和曲拉西利；CDK9抑制劑AZD 4573、P276-00、AT7519M、TP-1287；CDK2/4/6抑制劑，如PF-06873600； SHP-2抑制劑，如TNO155； MDM2/MDMX、MDM2/p53和/或MDMX/p53調節劑； 促性腺激素釋放激素（GnRH）受體促效劑：亮丙瑞林或醋酸亮丙瑞林（由拜耳公司（Bayer AG）以商標名Viadure®、由賽諾菲-安萬特集團以Eligard®和由雅培公司（Abbott Lab）以Lupron®銷售）； 紫杉烷抗腫瘤劑：卡巴他賽（l-羥基-7,10-二甲氧基-9-側氧基-5,20-環氧紫杉-ll-烯-2a,4,13a-三基-4-乙酸酯-2-苯甲酸酯-13-[(2R,3S)-3-{[(三級丁氧基)羰基]胺基}-2-羥基-3-苯基丙酸酯）、拉洛他賽（(2α,3ξ,4α,5β,7α,10β,13α)-4,10-雙(乙醯基氧基)-13-({(2R,3S)-3-[(三級丁氧基羰基)胺基]-2-羥基-3-苯基丙醯基}氧基)-l-羥基-9-側氧基-5,20-環氧-7,19-環紫杉-ll-烯-2-基苯甲酸酯）； 5HTla受體促效劑：紮利羅登（也稱為SR57746，l-[2-(2-萘基)乙基]-4-[3-(三氟甲基)苯基]-l,2,3,6-四氫吡啶，並且描述於美國專利案號5,266,573中）；HPC疫苗：由葛蘭素史克公司銷售的Cervarix®、由默克公司銷售的Gardasil®；鐵螯合劑：地拉羅司（由諾華公司以商標名Exjade®銷售）； 抗代謝藥：克拉屈濱（2-氯去氧腺苷，以商標名leustatin®銷售）、5-氟尿嘧啶（以商標名Adrucil®銷售）、6-硫鳥嘌呤（以商標名Purinethol®銷售）、培美曲塞（以商標名Alimta®銷售）、阿糖孢苷（也稱為阿糖胞嘧啶（Ara-C），以商標名Cytosar-U®銷售）、阿糖胞苷脂質體（也稱為脂質體Ara-C，以商標名DepoCyt™銷售）、地西他濱（以商標名Dacogen®銷售）、羥基脲（以商標名Hydrea®、Droxia™和Mylocel™銷售）、氟達拉濱（以商標名Fludara®銷售）、氟尿苷（以商標名FUDR®銷售）、克拉屈濱（也稱為2-氯去氧腺苷（2-CdA），以商標名Leustatin™銷售）、胺甲喋呤（也稱為胺甲喋呤、胺甲喋呤鈉（MTX），以商標名Rheumatrex®和Trexall™銷售）、噴司他丁（以商標名Nipent®銷售）； 雙膦酸鹽：帕米膦酸鹽（以商標名Aredia®銷售）、唑來膦酸（以商標名Zometa®銷售）；去甲基化劑：5-阿紮胞苷（以商標名Vidaza®銷售）、地西他濱（以商標名Dacogen®銷售）； 植物生物鹼類：紫杉醇蛋白結合型（以商標名Abraxane®銷售）、長春鹼（也稱為硫酸長春鹼、長春質鹼和VLB，以商標名Alkaban-AQ®和Velban®銷售）、長春新鹼（也稱為硫酸長春新鹼、LCR和VCR，以商標名Oncovin®和Vincasar Pfs®銷售）、長春瑞濱（以商標名Navelbine®銷售）、紫杉醇（以商標名Taxol和Onxal™銷售）； 類視黃醇：阿利維A酸（以商標名Panretin®銷售）、視網酸（全反式視網酸，也稱為ATRA，以商標名Vesanoid®銷售）、異視網酸（13-順視網酸，以商標名Accutane®、Amnesteem®、Claravis®、Clarus®、Decutan®、Isotane®、Izotech®、Oratane®、Isotret®和Sotret®銷售）、蓓薩羅丁（以商標名Targretin®銷售）； 糖皮質激素：氫化可的松（也稱為可的松、氫化可的松琥珀酸鈉、氫化可的松磷酸鈉，並且以商標名Ala-Cort®、磷酸氫化可的松、Solu-Cortef®、Hydrocort Acetate®和Lanacort®銷售）、迪皮質醇（(8S,9R,10S,l lS,13S,14S,16R,17R)-9-氟-ll,17-二羥基-17-(2-羥基乙醯基)-10,13,16-三甲基-6,7,8,9,10,l l,12,13,14,15,16,17-十二氫-3H-環戊二烯并[a]菲-3-酮）、去氫皮質醇（以商標名Delta-Cortel®、Orapred®、Pediapred®和Prelone®銷售）、強體松（以商標名Deltasone®、Liquid Red®、Meticorten®和Orasone®銷售）、甲基去氫皮質醇（也稱為6-甲基去氫皮質醇、醋酸甲基去氫皮質醇、甲氫去氫皮質醇琥珀酸鈉，以商標名Duralone®、Medralone®、Medrol®、M-Prednisol®和Solu-Medrol®銷售）； 細胞介素：白介素-2（也稱為阿地白介素和IL-2，以商標名Proleukin®銷售）、白介素-11（也稱為奧普瑞白介素，以商標名Neumega®銷售）、α干擾素α（也稱為IFN-α，以商標名Intron® A和Roferon-A®銷售）；雌激素受體下調劑：氟維司群（以商標名Faslodex®銷售）； 抗雌激素：他莫昔芬（以商標名Novaldex®銷售）；托瑞米芬（以商標名Fareston®銷售）； 選擇性雌激素受體調節劑（SERM）：雷洛昔芬（以商標名Evista®銷售）； 雌激素受體PROTAC：維普地格斯特（Vepdegestrant）（ARV-471）； 白血球化激素釋放激素（LHRH）促效劑：戈舍瑞林（以商標名Zoladex®銷售）；孕酮：甲地孕酮（也稱為醋酸甲地孕酮，以商標名Megace®銷售）； 雜類細胞毒性劑：三氧化二砷（以商標名Trisenox®銷售）、天冬醯胺酶（也稱為L-天冬醯胺酶，歐文氏菌L-天冬醯胺酶，以商標名Elspar®和Kidrolase®銷售）； 一或多種免疫檢查點抑制劑CD27、CD28、CD40、CD122、CD96、CD73、CD39、CD47、OX40、GITR、CSF1R、JAK、PI3Kδ、PI3Kγ、TAM激酶、精胺酸酶、CD137（也稱為4-1BB）、ICOS、A2AR、A2BR、HIF-2α、B7-H3、B7-H4、BTLA、CTLA-4、LAG3、TIM3、VISTA、CD96、TIGIT、PD-1、PD-L1和PD-L2。在一些實施方式中，免疫檢查點分子係刺激性檢查點分子，該刺激性檢查點分子選自CD27、CD28、CD40、ICOS、OX40、GITR、CD137和STING。在一些實施方式中，免疫檢查點分子係抑制性檢查點分子，該抑制性檢查點分子選自B7-H3、B7-H4、BTLA、CTLA-4、IDO、TDO、精胺酸酶、KIR、LAG3、PD-1、TIM3、CD96、TIGIT和VISTA。在一些實施方式中，本文提供的化合物可以與一或多種藥劑組合使用，該一或多種藥劑選自KIR抑制劑、TIGIT抑制劑、LAIR1抑制劑、CD160抑制劑、2B4抑制劑和TGFRβ抑制劑。 Where a subject in need thereof has cancer or is at risk of developing cancer, the subject may be treated with any combination of a compound of formula (I) (or any embodiment thereof disclosed herein, including specific compounds) and one or more other anticancer agents, including but not limited to: MAP kinase pathway (RAS/RAF/MEK/ERK) inhibitors, including but not limited to: vemurafenib (PLX4032), dabrafenib, enrafenib (LGX818), TQ-B3233, XL-518 (Cas No. 1029872-29-4, available from ACC Corporation (ACC) Corp); trametinib, selumetinib (AZD6244), TQ-B3234, PD184352, PD325901, TAK-733, pimasertinib, bimetinib, rameltinib, cometinib (GDC-0973), AZD8330, BVD-523, LTT462, neratinib, AMG510, ARS853 and disclosed in patents WO 2016049565, WO 2016164675, WO 2016168540, WO 2017015562, WO 2017058728, WO 2017058768, WO 2017058792, WO 2017058805, WO Any RAS inhibitors described in WO 2017058807, WO 2017058902, WO 2017058915, WO 2017070256, WO 2017087528, WO 2017100546, WO 2017172979, WO 2017201161, WO 2018064510, WO 2018068017, and WO 2018119183; CSF1R inhibitors (PLX3397, LY3022855, etc.) and CSF1R antibodies (IMC-054, RG7155); TGFβ receptor kinase inhibitors such as LY2157299; BTK inhibitors, such as ibrutinib; BCR-ABL inhibitors: imatinib (Gleevec®); nilotinib hydrochloride; nilotinib (Tasigna®); dasatinib (BMS-345825); bosutinib (SKI-606); ponatinib (AP24534); bafitinib (INNO406); darucitinib (PHA-739358), AT9283 (CAS 1133385-83-7); saracatinib (AZD0530); and N-[2-[(1S,4R)-6-[[4-cyclobutylamino)-5-(trifluoromethyl)-2-pyrimidinyl]amino]-1,2,3,4-tetrahydronaphthalene-1,4-imino-9-yl]-2-oxoethyl]-acetamide (PF-03814735, CAS 942487-16-3); ALK inhibitors: PF-2341066 (XALKOPJ®; crizotinib); 5-chloro-N4-(2-(isopropyl-sulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiperidin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine; GSK1838705 A; CH5424802; Ceritinib (ZYKADIA); TQ-B3139, TQ-B3101 PI3K inhibitors: 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperidin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]thiophene (also known as GDC) 0941 and described in PCT Publication Nos. WO 09/036082 and WO 09/055730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235 and described in PCT Publication No. WO 06/122806); Vascular endothelial growth factor (VEGF) receptor inhibitors: bevacizumab (sold by Genentech/Roche under the trade name Avastin®), axitinib (N-methyl-2-[[3-[(E)-2-pyridin-2-ylvinyl]-1H-indazol-6-yl]thio]benzamide, also known as AG013736 and described in PCT Publication No. WO 01/002369), brivanib alanine ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triox-6-yloxy)propan-2-yl) 2-aminopropionate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridylmethyl)amino]-3-pyridinecarboxamide, and described in PCT Publication No. WO 02/066470), pasireotide (also known as SOM230, and described in PCT Publication No. WO 02/010192), sorafenib (sold under the brand name Nexavar®); AL-2846 MET inhibitors, such as foretinib, cabozantinib, or crizotinib; FLT3 inhibitors - sunitinib appletate (sold by Pfizer under the brand name Sutent®); PKC412 (midostaurin); tanutinib, sorafenib, lestaurinib, KW-2449, quizartinib (AC220), and crelanib; Epidermal growth factor receptor (EGFR) inhibitors: Gefitnib (sold under the trademark Iressa®), N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3"S")-tetrahydro-3-furyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butyramide (sold under the trademark Tovok® by Boehringer Ingelheim), Cetuximab (sold under the trademark Erbitux® by Bristol-Myers Squibb), Panitumumab (sold under the trademark Vectibix® by Amgen); HER2 receptor inhibitors: trastuzumab (sold by Genentech/Roche under the trademark Herceptin®), neratinib (also known as HKI-272, (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide, and described in PCT Publication No. WO 05/028443), lapatinib or lapatinib ditosylate (sold by GlaxoSmithKline under the trademark Tykerb®); trastuzumab emtansine (in the United States, ado-trastuzumab emtansine, trademarked Kadcyla) - An antibody-drug conjugate consisting of the monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent mertansine (DM1); trastuzumab deruxtecan (trade name Enhertu); HER dimerization inhibitor: pertuzumab (marketed by Genentech under the trademark Omnitarg®); CD20 antibodies: rituximab (marketed by Genentech/Roche under the trademarks Riuxan® and MabThera®), tositumomab (marketed by GlaxoSmithKline under the trademark Bexxar®), ofatumumab (marketed by GlaxoSmithKline under the trademark Arzerra®); Tyrosine kinase inhibitors: Erlotinib hydrochloride (sold by Genentech/Roche under the trademark Tarceva®), Linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT 869, available from Genentech), sunitinib appletate (sold by Pfizer under the trademark Sutent®), bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606 and described in U.S. Patent No. 6,780,996), dasatinib (sold by Bristol-Myers Squibb under the trademark Sprycel®), armala (also known as pazopanib, sold by GlaxoSmithKline under the trademark Votrient®), imatinib, and imatinib mesylate (sold by Novartis under the trademarks Gilvec® and Gleevec®); DNA synthesis inhibitors: capecitabine (sold by Roche under the trademark Xeloda®), gemcitabine hydrochloride (sold by Eli Lilly and Company under the trademark Gemzar®), nelarabine ((2R3S,4R,5R)-2-(2-amino-6-methoxy-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol, sold by GlaxoSmithKline under the trademarks Arranon® and Atriance®); antitumor agent: oxaliplatin (sold by Sanofi-Aventis under the trademark Eloxatin® and described in U.S. Patent No. 4,169,846); Human granulocyte colony-stimulating factor (G-CSF) regulator: filgrastim (marketed by Amgen as Neupogen®); Immunomodulators: Afutuzumab (available from Roche®), pegfilgrastim (marketed by Amgen as Neulasta®), lenalidomide (also known as CC-5013, marketed as Revlimid®), thalidomide (marketed as Thalomid®); CD40 inhibitor: daclizumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc); Pro-apoptotic receptor agonist (PARA): Duramin (also known as AMG-951, available from Amgen/Genentech); Hedgehog antagonist: 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)-benzamide (also known as GDC-0449 and described in PCT Publication No. WO 06/028958); Phospholipase A2 inhibitor: anagrelide (sold under the trademark Agrylin®); BCL-2 inhibitor: 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperidinyl]-N-[[4-[[(1R)-3-(4-thiophenyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in PCT Publication No. WO 09/155386); MCl-1 inhibitors: MIK665, S64315, AMG 397, and AZD5991; Aromatase inhibitors: izomestan (sold by Pfizer under the trademark Aromasin®), rituximab (sold by Novartis under the trademark Femara®), anastrozole (sold under the trademark Arimidex®); Topoisomerase I inhibitors: irinotecan (sold by Pfizer under the trademark Camptosar®), toponotecan hydrochloride (sold by GlaxoSmithKline under the trademark Hycamtin®); Topoisomerase II inhibitors: etoposide (also known as VP-16 and etoposide phosphate, sold under the trademarks Toposar®, VePesid®, and Etopophos®), teniposide (also known as VM-26, sold under the trademark Vumon®); mTOR inhibitors: temsirolimus (marketed by Pfizer under the trade name Torisel®), lirosolimus (formerly known as deferolimus), (1R,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxy-11,36-dioxa-4-azatricyclo[30.3.1.0 4 ' [9] hexatricarborate-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyldimethylphosphinate, also known as AP23573 and MK8669 and described in PCT Publication No. WO 03/064383), irolimus (sold by Novartis under the trademark Afinitor®); proteasome inhibitors such as carfilzomib, MLN9708, delamido, or bortezomib; BET inhibitors such as INCB054329, OTX015, and CPI-0610; LSD1 inhibitors such as GSK2979552 and INCB059872; KAT6 inhibitors such as PF-07248144; HIF-2α inhibitors, such as PT2977, PT2385, imdatifan, and casdatifan; osteoclastic bone resorption inhibitor: l-hydroxy-2-imidazol-l-yl-phosphonylethylphosphonic acid monohydrate (sold by Novartis under the trade name Zometa®); CD33 antibody-drug conjugate: gemtuzumab ozogamicin (sold by Pfizer/Wyeth under the trade name Mylotarg®); CD22 antibody-drug conjugate: inotuzumab (also known as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.) CD20 antibody-drug conjugate: ibritumomab tiuxetan (sold under the brand name Zevalin®); somatostatin analog: octreotide (also known as octreotide acetate, sold under the brand names Sandostatin® and Sandostatin LAR®); synthetic interleukin-11 (IL-11): oprelvekin (sold under the brand name Neumega® by Pfizer/Wyeth); synthetic erythropoietin: darbepoetin alfa (sold under the brand name Aranesp® by Amgen); nuclear factor kappa B receptor activator (RANK) inhibitor: denosumab (sold under the brand name Prolia® by Amgen); thrombopoietin mimetic peptide: romiplostim (sold under the brand name Nplate® by Amgen); Cell growth stimulator: Parifiramine (marketed by Amgen under the trademark Kepivance®); Anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies: Figitumumab (also known as CP-751,871, available from ACC), robatumumab (CAS No. 934235-44-6); Anti-CS1 antibody: Elotuzumab (HuLuc63, CAS No. 915296-00-3); CD52 antibody: Alemtuzumab (marketed under the trademark Campath®); Histone deacetylase inhibitor (HDI): Vorinostat (marketed by Merck under the trademark Zolinza®); Alkylating agents: temozolomide (sold under the trademarks Temodar® and Temodal® by Schering-Plough/Merck), dactinomycin (also known as actinomycin D and sold under the trademark Cosmegen®), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the trademark Alkeran®), hexamethylmelamine (also known as hexamethonium (HMM), sold under the trademark Hexalen®), bischloroethyl nitrosourea (sold under the trademark BiCNU®), bendamustine (sold under the trademark Treanda®), busulfan (sold under the trademarks Busulfex® and Myleran®), carboplatin (sold under the trademark Paraplatin®). (sold under the trade name CeeNU®), chlorambucil (also known as CCNU, sold under the trade name CeeNU®), cis-platinum (also known as CDDP, sold under the trade names Platinol® and Platinol®-AQ), chlorambucil (sold under the trade name Leukeran®), cyclophosphamide (sold under the trade names Cytoxan® and Neosar®), dacarbazine (also known as DTIC, DIC, and imidazolecarboxamide, sold under the trade name DTIC-Dome®), hexamethylmelamine (also known as hexamethonium (HMM), sold under the trade name Hexalen®), isocyclophosphamide (sold under the trade name Ifex®), procarbazine (sold under the trade name Matulane®), dichloromethyldiethylamine (also known as bischloroethylmethylamine (nitrogen)), and methylaminobenzene (also known as methylaminobenzene). mustard), mustine and mechloroethamine hydrochloride (sold under the brand name Mustarden®), streptozotocin (sold under the brand name Zanosar®), thiotepa (also known as phosphorothioate amide, TESPA, and TSPA, sold under the brand name Thioplex®); biological response modifiers: Bacillus Calmette-Guérin (sold under the brand names theraCys® and TICE® BCG), denileukin (sold under the brand name Ontak®); Antitumor antibiotics: Adriamycin (sold under the trademarks Adriamycin® and Rubex®), Zeocin (sold under the trademark lenoxane®), Daunocin (also known as daunomycin hydrochloride, normidomycin, and daunomycin hydrochloride, sold under the trademark Cerubidine®), Daunocin liposomes (daunomycin citrate liposomes, sold under the trademark DaunoXome®), Mitoxantrone (also known as DHAD, sold under the trademark Novantrone®), Epirubicin (sold under the trademark Ellence™), Idarubicin (sold under the trademarks Idamycin®, Idamycin PFS®), Mitomycin C (sold under the trademark Mutamycin®); Antimicrotubule agent: estramustine (sold under the trade name Emcyl®); Cathepsin K inhibitor: Odanacatib (also known as MK-0822, N-(l-cyanocyclopropyl)-4-fluoro-N-2-{(1S)-2,2,2-trifluoro-l-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide, obtained from Lanzhou Chon Chemicals, ACC, and ChemieTek, and described in PCT Publication No. WO 03/075836); Ibomycin B analog: Ixabepilone (sold under the trade name Lxempra® by Bristol-Myers Squibb); Heat shock protein (HSP) inhibitors: Tanespimycin (17-allylamino-17-demethoxygeldermycin, also known as KOS-953 and 17-AAG, available from Sigma and described in U.S. Patent No. 4,261,989), NVP-HSP990, AUY922, AT13387, STA-9090, Debio 0932, KW-2478, XL888, CNF2024, TAS-116 TpoR agonist: Eltrombopag (sold by GlaxoSmithKline under the trademarks Promacta® and Revolade®); Antimitotic agent: docetaxel (sold by Sanofi-Aventis under the brand name Taxotere®); Adrenal steroid inhibitor: glutathione (sold under the brand name Cytadren®); Antiandrogen: nilutamide (sold under the brand names Nilandron® and Anandron®), bicalutamide (sold under the brand name Casodex®), flutamide (sold under the brand name Fulexin™); Androgen: flumethasone (sold under the brand name Halotestin®); CDK (CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, CDK11/12, or CDK16) inhibitors, including but not limited to Alvocidib (a pan-CDK inhibitor also known as flovopirdol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-l-methyl-4-piperidinyl]-4-chromenone, and described in U.S. Patent No. 5,621,002); the CDK4/6 inhibitors palbociclib, ribociclib, abemaciclib, and tricrazil; and the CDK9 inhibitor AZD 4573, P276-00, AT7519M, TP-1287; CDK2/4/6 inhibitors, such as PF-06873600; SHP-2 inhibitors, such as TNO155; MDM2/MDMX, MDM2/p53, and/or MDMX/p53 modulators; gonadotropin-releasing hormone (GnRH) receptor agonists: leuprolide or leuprolide acetate (marketed by Bayer AG under the trademark Viadure®, by Sanofi-Aventis as Eligard®, and by Abbott Labs as Lupron®); Taxane antitumor agents: Cabazitaxel (l-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-ll-ene-2a,4,13a-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{[(tert-butyloxy)carbonyl]amino}-2-hydroxy-3-phenylpropionate), larotaxel ((2 (α,3ξ,4α,5β,7α,10β,13α)-4,10-bis(acetyloxy)-13-({(2R,3S)-3-[(t-butyloxycarbonyl)amino]-2-hydroxy-3-phenylpropionyl}oxy)-1-hydroxy-9-oxo-5,20-epoxy-7,19-cyclotaxane-11-en-2-yl benzoate); 5HT1a receptor agonist: Zaliroden (also known as SR57746, 1-[2-(2-naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine, and described in U.S. Patent No. 5,266,573); HPC vaccines: Cervarix® marketed by GlaxoSmithKline, Gardasil® marketed by Merck; Iron chelator: Deferasirox (marketed by Novartis under the trademark Exjade®); Antimetabolic drugs: Cladribine (2-chlorodeoxyadenosine, sold as leustatin®), 5-fluorouracil (sold as Adrucil®), 6-thioguanine (sold as Purinethol®), pemetrexed (sold as Alimta®), cytarabine (also known as cytosine arabinoside (Ara-C), sold as Cytosar-U®), liposomal cytarabine (also known as liposomal Ara-C, sold as DepoCyt™), decitabine (sold as Dacog en®), hydroxyureas (sold under the trade names Hydrea®, Droxia™, and Mylocel™), fludarabine (sold under the trade name Fludara®), floxuridine (sold under the trade name FUDR®), cladribine (also known as 2-chlorodeoxyadenosine (2-CdA), sold under the trade name Leustatin™), methotrexate (also known as methotrexate, methotrexate sodium (MTX), sold under the trade names Rheumatrex® and Trexall™), and pentostatin (sold under the trade name Nipent®); Bisphosphonates: Pamidronate (sold under the brand name Aredia®), Zoledronic acid (sold under the brand name Zometa®); Demethylating agents: 5-Azacitidine (sold under the brand name Vidaza®), Decitabine (sold under the brand name Dacogen®); Plant-based alkaloids: Paclitaxel protein-bound (sold under the brand name Abraxane®), Vinblastine (also known as vinblastine sulfate, vinblastine, and VLB, sold under the brand names Alkaban-AQ® and Velban®), Vincristine (also known as vincristine sulfate, LCR, and VCR, sold under the brand names Oncovin® and Vincasar Pfs®), Vinorelbine (sold under the brand name Navelbine®), Paclitaxel (sold under the brand names Taxol and Onxal™); Retinoids: alitretinoin (sold under the brand name Panretin®), retinoic acid (all-trans retinoic acid, also known as ATRA, sold under the brand name Vesanoid®), isoretinoic acid (13-cis-retinoic acid, sold under the brand names Accutane®, Amnesteem®, Claravis®, Clarus®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), bexarotene (sold under the brand name Targretin®); Glucocorticoids: hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the brand names Ala-Cort®, hydrocortisone phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort®), dehydrocortisone ((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one), dehydrocortisone (sold under the trade names Delta-Cortel®, Orapred®, Pediapred®, and Prelone®), prednisone (sold under the trade names Deltasone®, Liquid Red®, Meticorten®, and Orasone®), methyldehydrocortisol (also known as 6-methyldehydrocortisol, methyldehydrocortisol acetate, methyldehydrocortisol sodium succinate, sold under the trade names Duralone®, Medralone®, Medrol®, M-Prednisol®, and Solu-Medrol®); interleukins: interleukin-2 (also known as aldesleukin and IL-2, sold under the trade name Proleukin®), interleukin-11 (also known as oprelewkin, sold under the trade name Neumega®), interferon alpha (also known as IFN-α, sold under the trade names Intron® A and Roferon-A®); estrogen receptor downregulator: fulvestrant (sold under the trade name Faslodex®); Antiestrogens: Tamoxifen (sold as Novaldex®); Toremifene (sold as Fareston®); Selective estrogen receptor modulator (SERM): Raloxifene (sold as Evista®); Estrogen receptor PROTAC: Vepdegestrant (ARV-471); Leukocyte stimulating hormone-releasing hormone (LHRH) agonist: Goserelin (sold as Zoladex®); Progesterone: Megestrol acetate (also known as megestrol acetate, sold as Megace®). Heterotoxic agents: Arsenic trioxide (sold under the trade name Trisenox®), asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the trade names Elspar® and Kidrolase®); One or more immune checkpoint inhibitors CD27, CD28, CD40, CD122, CD96, CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3Kδ, PI3Kγ, TAM kinase, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, HIF-2α, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from C D27, CD28, CD40, ICOS, OX40, GITR, CD137, and STING. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, arginine kinase, KIR, LAG3, PD-1, TIM3, CD96, TIGIT, and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFRβ inhibitors.

在一些實施方式中，免疫檢查點分子的抑制劑係PD-1的抑制劑，例如，抗PD-1單株抗體。在一些實施方式中，抗PD-1單株抗體係納武單抗、派姆單抗（也稱為MK-3475）、匹地利珠單抗（pidilizumab）、SHR-1210、PDR001或AMP-224。在一些實施方式中，抗PD-1單株抗體係納武單抗或派姆單抗或PDR001。在一些實施方式中，抗PD1抗體係派姆單抗。In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, for example, an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab, or PDR001. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

在一些實施方式中，免疫檢查點分子的抑制劑係PD-L1的抑制劑，例如，抗PD-L1單株抗體。在一些實施方式中，抗PD-L1單株抗體係BMS-935559、MEDI4736、MPDL3280A（也稱為RG7446）或MSB0010718C。在一些實施方式中，抗PD-L1單株抗體係MPDL3280A（阿特利珠單抗）或MEDI4736（度伐魯單抗）。In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, for example, an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A (atelizumab) or MEDI4736 (durvalumab).

在一些實施方式中，免疫檢查點分子的抑制劑係CTLA-4的抑制劑，例如，抗CTLA-4抗體。在一些實施方式中，抗CTLA-4抗體係伊匹單抗或曲美木單抗。在一些實施方式中，免疫檢查點分子的抑制劑係LAG3的抑制劑，例如，抗LAG3抗體。在一些實施方式中，抗LAG3抗體係BMS-986016或LAG525。在一些實施方式中，免疫檢查點分子的抑制劑係GITR的抑制劑，例如，抗GITR抗體。在一些實施方式中，抗GITR抗體係TRX518或MK-4166、INCAGN01876或MK-1248。在一些實施方式中，免疫檢查點分子的抑制劑係OX40的抑制劑，例如，抗OX40抗體或OX40L融合蛋白。在一些實施方式中，抗OX40抗體係MEDI0562或INCAGN01949、GSK2831781、GSK-3174998、MOXR-0916、PF-04518600或LAG525。在一些實施方式中，OX40L融合蛋白係MEDI6383。In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN01876, or MK-1248. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562 or INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600, or LAG525. In some embodiments, the OX40L fusion protein is MEDI6383.

具有式 (I) 的化合物（以及本文揭露的其任何實施方式，包括特定的化合物）還可以用於增加或增強免疫響應，包括增加對抗原的免疫響應；改善免疫接種，包括增加疫苗功效；以及增加炎症。在一些實施方式中，本發明的化合物可被用於增強對疫苗的免疫響應，該等疫苗包括但不限於李斯特菌屬（Listeria）疫苗、溶瘤細胞病毒疫苗及癌症疫苗，如GVAX®（顆粒球-巨噬細胞群落刺激因子（GM-CF）基因轉染的腫瘤細胞疫苗）。抗癌疫苗包括樹突細胞、合成肽、DNA疫苗以及重組病毒。其他免疫調節劑還包括阻斷免疫細胞遷移的那些，如趨化介素受體（包括CCR2和CCR4）的拮抗劑；Sting促效劑和Toll受體促效劑。Compounds of Formula (I) (and any embodiments thereof disclosed herein, including specific compounds) can also be used to increase or enhance immune responses, including increasing immune responses to antigens; improving vaccination, including increasing vaccine efficacy; and increasing inflammation. In some embodiments, the compounds of the present invention can be used to enhance the immune response to vaccines, including, but not limited to, Listeria vaccines, oncolytic virus vaccines, and cancer vaccines such as GVAX® (a granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine). Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses. Other immunomodulators include those that block immune cell migration, such as antagonists of interleukin receptors (including CCR2 and CCR4); Sting agonists; and Toll receptor agonists.

其他抗癌劑還包括增強免疫系統的那些，如佐劑或過繼性T細胞轉移物。本申請的化合物在與CAR（嵌合抗原受體）T細胞治療組合作為T細胞活化的加強劑方面可為有效的。Other anticancer agents include those that enhance the immune system, such as adjuvants or secondary T cell transfer agents. The compounds of the present application may be effective in combination with CAR (chimeric antigen receptor) T cell therapy as enhancers of T cell activation.

具有式 (I) 的化合物（或本文揭露的其任何實施方式，包括特定的化合物）還可以用於與以下輔助療法組合：抗噁心藥：NK-1受體拮抗劑：卡索吡坦（由葛蘭素史克公司以商標名Rezonic®和Zunrisa®銷售）；以及 細胞保護劑：氨磷汀（Amifostine）（以商標名Ethyol®銷售）、亞葉酸（leucovorin）（也稱為亞葉酸鈣、嗜橙菌因子和亞葉酸（folinic acid））。實例Compounds of formula (I) (or any embodiment thereof disclosed herein, including specific compounds) may also be used in combination with the following adjunctive therapies: antinauseants: NK-1 receptor antagonists: casopitant (sold by GlaxoSmithKline under the trade names Rezonic® and Zunrisa®); and cytoprotectants: Amifostine (sold under the trade name Ethyol®), leucovorin (also known as folinic acid, leucovorin, and folinic acid).Examples

給出中間體（參考物）和具有式 (I) 的化合物（實例）的以下製備，以使熟悉該項技術者能夠更清楚地理解和實踐本揭露。不應該認為它們限制本揭露之範圍，而僅僅是作為其說明和代表。The following preparations of intermediates (references) and compounds of formula (I) (examples) are given to enable those skilled in the art to more clearly understand and practice the present disclosure. They should not be considered to limit the scope of the present disclosure, but are merely illustrative and representative thereof.

參考物1 3-(5-(四氫吖唉-3-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮2,2,2-三氟乙酸鹽的合成步驟1：(1-(三級丁氧基羰基)四氫吖唉-3-基)碘化鋅(II)向Zn粉（300 mg，4.59 mmol，1.30當量）在DMA（3.0 mL）中的混合物中添加1,2-二溴乙烯（66 mg，0.35 mmol，0.10當量）並將混合物在65°C在N₂下攪拌30 min。使混合物冷卻至室溫並且添加TMSCl（38 mg，0.35 mmol，0.10當量）。在攪拌混合物30 min後，逐滴添加3-碘四氫吖唉-1-甲酸三級丁酯（1.00 g，3.53 mmol，1.00當量）在DMA（1.0 mL）中的溶液。將混合物在65°C在N₂下攪拌2 h，然後冷卻至室溫。將溶液不經進一步純化而用於下一步驟。Reference 1 Synthesis of 3-(5-(tetrahydroazide-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 2,2,2-trifluoroacetate Step 1: (1-(tert-butyloxycarbonyl)tetrahydroacryl-3-yl)zinc(II) iodide To a mixture of Zn powder (300 mg, 4.59 mmol, 1.30 equiv) in DMA (3.0 mL) was added 1,2-dibromoethylene (66 mg, 0.35 mmol, 0.10 equiv), and the mixture was stirred at 65°C under_N₂ for 30 min. The mixture was cooled to room temperature, and TMSCl (38 mg, 0.35 mmol, 0.10 equiv) was added. After stirring the mixture for 30 min, a solution of tributyl 3-iodotetrahydroazolidinone-1-carboxylate (1.00 g, 3.53 mmol, 1.00 equiv) in DMA (1.0 mL) was added dropwise. The mixture was stirred at 65°C under_N₂ for 2 h, then cooled to room temperature. The solution was used in the next step without further purification.

步驟2：3-(2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-5-基)四氫吖唉-1-甲酸三級丁酯將(1-(三級丁氧基羰基)四氫吖唉-3-基)碘化鋅(II)（600 mg，1.72 mmol，3.00當量）在DMA中的溶液緩慢添加至3-(5-溴-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮（185 mg，0.57 mmol，1.00當量）、CuI（12 mg，0.06 mmol，0.10當量）、Pd(dppf)Cl₂（44 mg，0.06 mmol，0.10當量）在DMA（2.0 mL）中的混合物中。將混合物在90°C在N₂下攪拌過夜。將混合物濃縮並藉由矽膠柱層析法（EtOAc）純化，以給出呈棕色固體的標題化合物。Step 2: 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)tetrahydroacalazine-1-carboxylic acid tributyl ester A solution of (1-(tert-butyloxycarbonyl)tetrahydroazide-3-yl)zinc(II) iodide (600 mg, 1.72 mmol, 3.00 equiv) in DMA was slowly added to a mixture of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (185 mg, 0.57 mmol, 1.00 equiv), CuI (12 mg, 0.06 mmol, 0.10 equiv), and Pd(dppf)_Cl₂ (44 mg, 0.06 mmol, 0.10 equiv) in DMA (2.0 mL). The mixture was stirred at 90°C under_N₂ overnight. The mixture was concentrated and purified by silica gel column chromatography (EtOAc) to give the title compound as a brown solid.

步驟3：3-(5-(四氫吖唉-3-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮2,2,2-三氟乙酸鹽向3-(2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-5-基)四氫吖唉-1-甲酸三級丁酯（44 mg，0.11 mmol，1.00當量）在DCM（1.0 mL）中的溶液中逐滴添加TFA（0.2 mL）並將溶液攪拌3 h。將所得混合物濃縮以給出呈棕色油狀物的標題產物。Step 3: 3-(5-(tetrahydroazide-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 2,2,2-trifluoroacetate To a solution of tributyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)tetrahydroazolidin-1-carboxylate (44 mg, 0.11 mmol, 1.00 equiv) in DCM (1.0 mL) was added TFA (0.2 mL) dropwise, and the solution was stirred for 3 h. The resulting mixture was concentrated to give the title product as a brown oil.

參考物2 3-(4-(四氫吖唉-3-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮2,2,2-三氟乙酸鹽的合成步驟1：3-(1-(2,6-二側氧基哌啶-3-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]-咪唑-4-基)四氫吖唉-1-甲酸三級丁酯將(1-(三級丁氧基羰基)四氫吖唉-3-基)碘化鋅(II)（600 mg，1.72 mmol，3.00當量）在DMA中的溶液緩慢添加至在DMA（2.0 mL）中的3-(4-溴-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮（193 mg，0.57 mmol，1.00當量）、CuI（12 mg，0.06 mmol，0.10當量）和Pd(dppf)Cl₂（44 mg，0.06 mmol，0.10當量）的混合物中。將混合物在90°C在N₂下攪拌過夜。將混合物濃縮並藉由矽膠柱層析法（EtOAc）純化，以得到呈黃色固體的標題化合物。Reference 2 Synthesis of 3-(4-(tetrahydroazolidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 2,2,2-trifluoroacetate Step 1: 3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]-imidazol-4-yl)tetrahydroacrylamide-1-carboxylic acid tributyl ester A solution of (1-(tert-butyloxycarbonyl)tetrahydroazide-3-yl)zinc(II) iodide (600 mg, 1.72 mmol, 3.00 equiv) in DMA was slowly added to a mixture of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (193 mg, 0.57 mmol, 1.00 equiv), CuI (12 mg, 0.06 mmol, 0.10 equiv), and Pd(dppf)_Cl₂ (44 mg, 0.06 mmol, 0.10 equiv) in DMA (2.0 mL). The mixture was stirred at 90° C. under_N₂ overnight. The mixture was concentrated and purified by silica gel column chromatography (EtOAc) to give the title compound as a yellow solid.

步驟2：3-(4-(四氫吖唉-3-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮2,2,2-三氟乙酸鹽向3-(1-(2,6-二側氧基哌啶-3-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-4-基)四氫吖唉-1-甲酸三級丁酯（23 mg，0.055 mmol，1.00當量）在DCM（1.0 mL）中的溶液中逐滴添加TFA（0.2 mL）並將溶液在室溫攪拌3 h。將所得混合物濃縮以給出呈棕色油狀物的標題化合物。Step 2: 3-(4-(tetrahydroazolidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 2,2,2-trifluoroacetate To a solution of tributyl 3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)tetrahydroazolidin-1-carboxylate (23 mg, 0.055 mmol, 1.00 equiv) in DCM (1.0 mL) was added TFA (0.2 mL) dropwise, and the solution was stirred at room temperature for 3 h. The resulting mixture was concentrated to give the title compound as a brown oil.

參考物3 3-(1-側氧基-5-(哌𠯤-1-基)異吲哚啉-2-基)哌啶-2,6-二酮2,2,2-三氟乙酸鹽的合成步驟1：4-(3-氰基-4-(甲氧基羰基)苯基)哌𠯤-1-甲酸三級丁酯向2-氰基-4-氟苯甲酸甲酯（10.00 g，55.80 mmol，1.00當量）在DMSO（150.0 mL）中的攪拌溶液中添加哌𠯤-1-甲酸三級丁酯（11.40 g，61.38 mmol，1.10當量）和DIEA（34.70 g，268.96 mmol，4.80當量），並將所得混合物在110°C攪拌12 h。將混合物用水稀釋並用EtOAc萃取，並且將合併的有機層用鹽水洗滌，經Na₂SO₄乾燥。過濾後，將濾液濃縮並藉由矽膠柱層析法（用PE/EtOAc（3:1）洗脫）純化，以給出呈黃色固體的標題化合物。Reference 3 Synthesis of 3-(1-oxo-5-(piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione 2,2,2-trifluoroacetate Step 1: 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperidin-1-carboxylic acid tributyl ester To a stirred solution of methyl 2-cyano-4-fluorobenzoate (10.00 g, 55.80 mmol, 1.00 equiv) in DMSO (150.0 mL) was added tributylpiperidinium-1-carboxylate (11.40 g, 61.38 mmol, 1.10 equiv) and DIEA (34.70 g, 268.96 mmol, 4.80 equiv), and the resulting mixture was stirred at 110°C for 12 h. The mixture was diluted with water and extracted with EtOAc, and the combined organic layers were washed with brine_and dried over_Na2SO4 . After filtration, the filtrate was concentrated and purified by silica gel column chromatography (eluted with PE/EtOAc (3:1)) to give the title compound as a yellow solid.

步驟2：4-(3-甲醯基-4-(甲氧基羰基)苯基)哌𠯤-1-甲酸三級丁酯將4-(3-氰基-4-(甲氧基羰基)苯基)哌𠯤-1-甲酸三級丁酯（8.00 g，23.20 mmol，1.00當量）、NaH₂PO₂·H₂O（5.20 g，48.70 mmol，2.10當量）和雷尼鎳（5.10 g）在吡啶:H₂O:AcOH = 2:1:1（80.0 mL）中的混合物在70°C攪拌12 h。將混合物用NaHCO₃（水性）調節至pH = 7-8，並將混合物過濾並用EtOAc萃取。將有機層用鹽水洗滌，經Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由矽膠柱層析法（用PE/EtOAc（3:1）洗脫）純化，以給出呈黃色固體的標題化合物。Step 2: 4-(3-methylyl-4-(methoxycarbonyl)phenyl)piperidin-1-carboxylic acid tributyl ester A mixture of tributyl 4-(3-cyano_- 4-(methoxycarbonyl)phenyl)piperidinium-1-carboxylate (8.00 g, 23.20 mmol, 1.00 equiv),_NaH₂PO₂ ·_H₂O (5.20 g, 48.70 mmol, 2.10 equiv), and ranyl nickel (5.10 g) in pyridine:_H₂O :AcOH = 2:1:1 (80.0 mL) was stirred at 70°C for 12 h. The mixture was adjusted to pH 7-8 with_NaHCO₃ (aq), filtered, and extracted with EtOAc. The organic layer was washed with brine and dried_{overNa₂SO₄} . After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (eluted with PE/EtOAc (3:1)) to give the title compound as a yellow solid.

步驟3：4-(2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-5-基)哌𠯤-1-甲酸三級丁酯將3-胺基哌啶-2,6-二酮鹽酸鹽（2.60 g，15.50 mmol，1.20當量）、DIEA（4.03 g，31.22 mmol，2.42當量）、AcOH（10.63 g，188.76 mmol，13.78當量）和4-(3-甲醯基-4-(甲氧基羰基)苯基)哌𠯤-1-甲酸三級丁酯（4.50 g，12.90 mmol，1.00當量）在DCM（50.0 mL）中的混合物在35°C攪拌4 h，然後將NaBH(OAc)₃（8.20 g，38.70 mmol，3.00當量）添加至上述混合物中，並將混合物在40°C攪拌12 h。將混合物用水稀釋並用EtOAc萃取。將有機層用鹽水洗滌，經Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由矽膠柱層析法（用PE/EtOAc（1:2）洗脫）純化，以給出呈白色固體的標題化合物。Step 3: 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-carboxylic acid tributyl ester A mixture of 3-aminopiperidine-2,6-dione hydrochloride (2.60 g, 15.50 mmol, 1.20 equiv), DIEA (4.03 g, 31.22 mmol, 2.42 equiv), AcOH (10.63 g, 188.76 mmol, 13.78 equiv) and tert-butyl 4-(3-formyl-4-(methoxycarbonyl)phenyl)piperidinium-1-carboxylate (4.50 g, 12.90 mmol, 1.00 equiv) in DCM (50.0 mL) was stirred at 35 ° C for 4 h, and then NaBH (OAc)₃ (8.20 g, 38.70 mmol, 3.00 equiv) was added to the above mixture, and the mixture was stirred at 40 ° C for 12 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over Na₂ SO₄ . After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (eluted with PE/EtOAc (1:2)) to give the title compound as a white solid.

步驟4：3-(1-側氧基-5-(哌𠯤-1-基)異吲哚啉-2-基)哌啶-2,6-二酮2,2,2-三氟乙酸鹽向4-(2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-5-基)哌𠯤-1-甲酸三級丁酯（72 mg，0.17 mmol，1.00當量）在DCM（4.0 mL）中的溶液中添加TFA（1.0 mL）。將所得混合物在室溫攪拌2 h，然後濃縮，以給出呈黃色油狀物的標題化合物。Step 4: 3-(1-oxo-5-(piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione 2,2,2-trifluoroacetate To a solution of tributyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-carboxylate (72 mg, 0.17 mmol, 1.00 equiv) in DCM (4.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at room temperature for 2 h and then concentrated to afford the title compound as a yellow oil.

藉由與參考物3中所述類似的方式進行來合成以下參考化合物。參考物#結構參考物4The following reference compounds were synthesized by proceeding in a similar manner to that described in Reference 3. References# structure Reference 4

參考物5 1-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮2,2,2-2,2,2-三氟乙酸鹽的合成步驟1：6-溴-1-甲基-1H-吲唑-3-胺向4-溴-2-氟苯甲腈（10 g，0.05 mol，1.00當量）在EtOH（50.0 mL）中的攪拌溶液中添加甲基肼（57 g，0.50 mol，10.00當量），並將混合物在100°C在密封管中攪拌30 h。然後將混合物濃縮並用水稀釋。將混合物過濾以給出呈淺黃色固體的標題化合物。Reference 5 Synthesis of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-2,2,2-trifluoroacetate Step 1: 6-Bromo-1-methyl-1H-indazol-3-amine To a stirred solution of 4-bromo-2-fluorobenzonitrile (10 g, 0.05 mol, 1.00 equiv) in EtOH (50.0 mL) was added methylhydrazine (57 g, 0.50 mol, 10.00 equiv), and the mixture was stirred at 100 ° C in a sealed tube for 30 h. The mixture was then concentrated and diluted with water. The mixture was filtered to give the title compound as a light yellow solid.

步驟2：3-((6-溴-1-甲基-1H-吲唑-3-基)胺基)丙酸甲酯在0°C將丙烯酸甲酯（209.00 g，2.43 mol，10.00當量）添加至6-溴-1-甲基-1H-吲唑-3-胺（55.00 g，0.24 mol，1.00當量）、DBU（55.00 g，0.36 mol，1.50當量）、乳酸（33.00 g，0.36 mol，1.50當量）的溶液中，並將混合物在90°C在N₂下攪拌20 h。將混合物在減壓下濃縮並將殘餘物藉由矽膠柱層析法（EtOAc:PE = 0至100%）純化，以給出呈黃色固體的標題化合物。Step 2: Methyl 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propanoate Methyl acrylate (209.00 g, 2.43 mol, 10.00 equiv) was added to a solution of 6-bromo-1-methyl-1H-indazol-3-amine (55.00 g, 0.24 mol, 1.00 equiv), DBU (55.00 g, 0.36 mol, 1.50 equiv), and lactic acid (33.00 g, 0.36 mol, 1.50 equiv) at 0°C, and the mixture was stirred at 90°C under_N2 for 20 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc:PE = 0 to 100%) to give the title compound as a yellow solid.

步驟3：3-(1-(6-溴-1-甲基-1H-吲唑-3-基)脲基)丙酸甲酯將NaOCN（26.00 g，0.32 mol，2.00當量）添加至3-((6-溴-1-甲基-1H-吲唑-3-基)胺基)丙酸甲酯（50.00 g，0.16 mol，1.00當量）在AcOH（500.0 mL）中的溶液中，並將混合物在80°C在N₂下攪拌20 h。將混合物用水稀釋並用EtOAc萃取。將有機層用鹽水洗滌，經Na₂SO₄乾燥。過濾後，將濾液濃縮以給出呈黃色固體的標題化合物。Step 3: Methyl 3-(1-(6-bromo-1-methyl-1H-indazol-3-yl)ureido)propanoate NaOCN (26.00 g, 0.32 mol, 2.00 equiv) was added to a solution of methyl 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propanoate (50.00 g, 0.16 mol, 1.00 equiv) in AcOH (500.0 mL), and the mixture was stirred at 80 ° C under N₂ for 20 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over Na₂ SO_4. After filtration, the filtrate was concentrated to give the title compound as a yellow solid.

步驟4：1-(6-溴-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮向3-(1-(6-溴-1-甲基-1H-吲唑-3-基)脲基)丙酸甲酯（56.00 g，0.16 mol，1.00當量）在MeCN（500.0 mL）中的溶液中添加Tirton-B（7.90 g，0.05 mol，0.30當量）並在室溫在N₂下攪拌20 h。將混合物濃縮，然後用水稀釋。將混合物過濾，並將固體用水洗滌，風乾，以給出呈淺黃色固體的標題化合物。Step 4: 1-(6-Bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione To a solution of methyl 3-(1-(6-bromo-1-methyl-1H-indazol-3-yl)ureido)propanoate (56.00 g, 0.16 mol, 1.00 equiv) in MeCN (500.0 mL) was added Tirton-B (7.90 g, 0.05 mol, 0.30 equiv) and stirred at room temperature under_N₂ for 20 h. The mixture was concentrated and then diluted with water. The mixture was filtered, and the solid was washed with water and air-dried to give the title compound as a light yellow solid.

步驟5：4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-5,6-二氫吡啶-1(2H)-甲酸三級丁酯向1-(6-溴-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮（1.10 g，3.41 mmol，1.00當量）在1,4-二㗁𠮿/H₂O（10 mL/1 mL）中的混合物中添加4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-5,6-二氫吡啶-1(2H)-甲酸三級丁酯（1.60 g，5.11 mmol，1.50當量）、K₃PO₄（2.20 g，10.22 mmol，3.00當量）和X-Phos-Pd G3（289 mg，0.34 mmol，0.10當量），並將混合物在60°C在N₂下攪拌3 h。將混合物用DCM稀釋，並將有機層用鹽水洗滌，經Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由矽膠柱層析法（DCM:MeOH = 20 : 1）純化，以給出呈黃色固體的標題化合物。Step 5: 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tributyl ester To a mixture of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.10 g, 3.41 mmol, 1.00 equiv) in 1,4-dioxadiazole/H₂ O (10 mL/1 mL) were added tributyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.60 g, 5.11 mmol, 1.50 equiv), K₃ PO₄ (2.20 g, 10.22 mmol, 3.00 equiv) and X-Phos-Pd G3 (289 mg, 0.34 mmol, 0.10 equiv), and the mixture was heated at 60°C under N The mixture was stirred at_4° C for 3 h. The mixture was diluted with DCM, and the organic layer was washed with brine and dried over Na₂ SO₄ . After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give the title compound as a yellow solid.

步驟6：4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-甲酸三級丁酯將4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-5,6-二氫吡啶-1(2H)-甲酸三級丁酯（300 mg，0.71 mmol，1.00當量）、Pd/C（150 mg，50% wt）和Pd(OH)₂（150 mg，50% wt）在THF（20.0 mL）中的混合物在50°C和50 psi下在H₂下攪拌過夜。將混合物過濾，並且將濾液濃縮並藉由矽膠柱層析法（PE:EtOAc = 1 : 1）純化，以給出呈黃色固體的標題化合物。Step 6: 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylic acid tributyl ester A mixture of tributyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (300 mg, 0.71 mmol, 1.00 equiv), Pd/C (150 mg, 50% wt), and Pd(OH)₂ (150 mg, 50% wt) in THF (20.0 mL) was stirred at 50°C and 50 psi under_H2 overnight. The mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (PE:EtOAc = 1:1) to give the title compound as a yellow solid.

步驟7：1-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮2,2,2-2,2,2-三氟乙酸鹽將4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-甲酸三級丁酯（100 mg，0.25 mmol，1.00當量）在TFA/DCM（0.5 mL/2.0 mL）中的混合物在室溫攪拌2 h。將混合物濃縮，以給出呈棕色油狀物的標題化合物。Step 7: 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-2,2,2-trifluoroacetate A mixture of tributyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate (100 mg, 0.25 mmol, 1.00 equiv) in TFA/DCM (0.5 mL/2.0 mL) was stirred at room temperature for 2 h. The mixture was concentrated to give the title compound as a brown oil.

藉由與參考物5中所述類似的方式進行來合成以下參考化合物。參考物#結構參考物6參考物7The following reference compounds were synthesized by proceeding in a similar manner to that described in Reference 5. References# structure Reference 6 Reference 7

參考物8 3-((4-(哌啶-4-基)苯基)胺基)哌啶-2,6-二酮2,2,2-三氟乙酸鹽的合成步驟1：4-(4-硝基苯基)-5,6-二氫吡啶-1(2H)-甲酸三級丁酯將1-溴-4-硝基苯（1.0 g，4.95 mmol，1.00當量）、4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-5,6-二氫吡啶-1(2H)-甲酸三級丁酯（2.30 g，7.43 mmol，1.50當量）、K₂CO₃（1.37 g，9.90 mmol，2.00當量）和Pd(dppf)Cl₂（724 mg，0.99 mmol，0.20當量）在二㗁𠮿/H₂O（15 mL，5/1）中的混合物在100°C攪拌4 h。將混合物過濾並用EtOAc萃取。將合併的有機層經無水Na₂SO₄乾燥。過濾後，將濾液濃縮。將殘餘物藉由二氧化矽快速柱PE/EtOAc（10:1）純化，以給出呈黃色固體的標題化合物。Reference 8 Synthesis of 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione 2,2,2-trifluoroacetate Step 1: 4-(4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tributyl ester A mixture of 1-bromo-4-nitrobenzene (1.0 g, 4.95 mmol, 1.00 equiv), tributyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (_2.30 g, 7.43 mmol, 1.50 equiv),_K2CO3 (1.37 g, 9.90 mmol, 2.00 equiv), and Pd(dppf)_Cl2 (724 mg, 0.99 mmol, 0.20 equiv) in dioxane/_H2O (15 mL, 5/1) was stirred at 100°C for 4 h. The mixture was filtered and extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂ SO₄ . After filtration, the filtrate was concentrated. The residue was purified by silica flash column PE/EtOAc (10:1) to give the title compound as a yellow solid.

步驟2：4-(4-胺基苯基)哌啶-1-甲酸三級丁酯將4-(4-硝基苯基)-5,6-二氫吡啶-1(2H)-甲酸三級丁酯（1.20 g，3.95 mmol，1.00當量）、Pd/C（360 mg，10% w/w）在MeOH/THF（30 mL，1:1）中的混合物在45°C在H₂下攪拌過夜。將混合物過濾，並且將濾液濃縮。將殘餘物藉由二氧化矽快速柱PE/EtOAc（3:1）純化，以給出呈黃色固體的標題化合物。Step 2: 4-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester A mixture of tributyl 4-(4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (1.20 g, 3.95 mmol, 1.00 equiv) and Pd/C (360 mg, 10% w/w) in MeOH/THF (30 mL, 1:1) was stirred at 45°C under_H₂ overnight. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica flash column PE/EtOAc (3:1) to afford the title compound as a yellow solid.

步驟3：4-(4-((2,6-二側氧基哌啶-3-基)胺基)苯基)哌啶-1-甲酸三級丁酯將4-(4-胺基苯基)哌啶-1-甲酸三級丁酯（332 mg，1.20 mmol，1.00當量）、3-溴哌啶-2,6-二酮（242 mg，1.26 mmol，1.05當量）和NaHCO₃（302 mg，3.60 mmol，3.00當量）在DMF（4.0 mL）中的混合物在70°C攪拌過夜。將混合物用水稀釋並用EtOAc萃取。將合併的有機層經無水Na₂SO₄乾燥，過濾，然後濃縮。將殘餘物藉由二氧化矽快速柱PE/EtOAc（1:1）純化，以給出呈黃色固體的標題化合物。Step 3: 4-(4-((2,6-dioxypiperidin-3-yl)amino)phenyl)piperidine-1-carboxylic acid tributyl ester A mixture of tributyl 4-(4-aminophenyl)piperidine-1-carboxylate (332 mg, 1.20 mmol, 1.00 equiv), 3-bromopiperidine-2,6-dione (242 mg, 1.26 mmol, 1.05 equiv), and_NaHCO₃ (302 mg, 3.60 mmol, 3.00 equiv) in DMF (4.0 mL) was stirred at 70°C overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over_{anhydrousNa₂SO₄} , filtered, and then concentrated. The residue was purified by silica flash column PE/EtOAc (1:1) to afford the title compound as a yellow solid.

步驟4：3-((4-(哌啶-4-基)苯基)胺基)哌啶-2,6-二酮2,2,2-三氟乙酸鹽將TFA（0.5 mL）添加至4-(4-((2,6-二側氧基哌啶-3-基)胺基)苯基)哌啶-1-甲酸三級丁酯（100 mg，0.26 mmol，1.00當量）在DCM（2.0 mL）中的混合物中並將混合物在室溫攪拌2 h。將混合物濃縮，以給出呈黃色固體的標題化合物。Step 4: 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione 2,2,2-trifluoroacetate TFA (0.5 mL) was added to a mixture of tributyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate (100 mg, 0.26 mmol, 1.00 equiv) in DCM (2.0 mL), and the mixture was stirred at room temperature for 2 h. The mixture was concentrated to give the title compound as a yellow solid.

參考物9 3-(4-(哌𠯤-1-基)苯基)哌啶-2,6-二酮2,2,2-三氟乙酸鹽的合成步驟1：2,6-雙(苄基氧基)-3-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)吡啶將2,6-雙(苄基氧基)-3-溴吡啶（19.00 g，0.05 mol，1.00當量）、4,4,4',4',5,5,5',5'-八甲基-2,2'-雙(1,3,2-二氧雜環戊硼烷)（19.60 g，0.08 mol，1.50當量）、KOAc（10.00 g，0.10 mol，2.00當量）和Pd(dppf)Cl₂（3.7 g，5.00 mmol，0.10當量）在1,4-二㗁𠮿（200.0 mL）中的混合物在100°C在N₂下攪拌25 h。將混合物用水稀釋並用EtOAc萃取，並且將合併的有機層用鹽水洗滌，經Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由矽膠柱層析法（用EtOAc:PE= 0至100%洗脫）純化，以給出呈黃色固體的標題化合物。Reference 9 Synthesis of 3-(4-(piperidin-1-yl)phenyl)piperidine-2,6-dione 2,2,2-trifluoroacetate Step 1: 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine A mixture of 2,6-bis(benzyloxy)-3-bromopyridine (19.00 g, 0.05 mol, 1.00 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (19.60 g, 0.08 mol, 1.50 equiv), KOAc (10.00 g, 0.10 mol, 2.00 equiv) and Pd(dppf)_Cl2 (3.7 g, 5.00 mmol, 0.10 equiv) in 1,4-dioxaborolan (200.0 mL) was stirred at 100 °C under_N2 for 25 h. The mixture was diluted with water and extracted with EtOAc, and the combined organic layers were washed with brine and dried over Na₂ SO_4. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (eluted with EtOAc:PE = 0 to 100%) to give the title compound as a yellow solid.

步驟4：2,6-雙(苄基氧基)-3-(4-溴苯基)吡啶將2,6-雙(苄基氧基)-3-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)吡啶（4.42 g，10.60 mmol，1.20當量）、1-溴-4-碘苯（2.50 g，8.83 mol，1.00當量）、K₃PO₄（5.63 g，26.50 mmol，3.00當量）和Pd(PPh₃)₄（510 mg，0.44 mmol，0.05當量）在1,4-二㗁𠮿/H₂O = 10:1（40.0 mL）中的混合物在100°C在N₂下攪拌16 h。將混合物用水稀釋並用EtOAc萃取，並且將合併的有機層用鹽水洗滌，經Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由矽膠柱層析法（用EtOAc:PE= 0至100%洗脫）純化，以給出呈黃色固體的標題化合物。Step 4: 2,6-Bis(benzyloxy)-3-(4-bromophenyl)pyridine A mixture of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.42 g, 10.60 mmol, 1.20 equiv), 1-bromo-4-iodobenzene (2.50 g, 8.83 mol, 1.00 equiv), K₃ PO₄ (5.63 g, 26.50 mmol, 3.00 equiv) and Pd(PPh₃ )₄ (510 mg, 0.44 mmol, 0.05 equiv) in 1,4-dioxathiol/H₂ O = 10:1 (40.0 mL) was stirred at 100 °C under N₂ for 16 h. The mixture was diluted with water and extracted with EtOAc, and the combined organic layers were washed with brine and dried over Na₂ SO_4. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (eluted with EtOAc:PE = 0 to 100%) to give the title compound as a yellow solid.

步驟5：4-(4-(2,6-雙(苄基氧基)吡啶-3-基)苯基)哌𠯤-1-甲酸三級丁酯將2,6-雙(苄基氧基)-3-(4-溴苯基)吡啶（500 mg，1.12 mmol，1.00當量）、哌𠯤-1-甲酸三級丁酯（417 mg，2.24 mmol，2.00當量）、Cs₂CO₃（730 mg，2.24 mmol，2.00當量）、Pd₂(dba)₃（51 mg，0.06 mmol，0.05當量）和RuPhos（52 mg，0.11 mmol，0.10當量）在甲苯（15.0 mL）中的混合物在110^oC在N₂下攪拌20 h。將混合物用水稀釋並用EtOAc萃取，並且將合併的有機層用鹽水洗滌，經Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由矽膠柱層析法（用EtOAc:PE= 0至100%洗脫）純化，以給出呈黃色固體的標題化合物。Step 5: Tributyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-1-carboxylate A mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (500 mg, 1.12 mmol, 1.00 equiv), tributylpiperidinium-1-carboxylate (417 mg, 2.24 mmol, 2.00 equiv), Cs₂ CO₃ (730 mg, 2.24 mmol, 2.00 equiv), Pd₂ (dba)₃ (51 mg, 0.06 mmol, 0.05 equiv), and RuPhos (52 mg, 0.11 mmol, 0.10 equiv) in toluene (15.0 mL) was stirred at 110^° C. under N₂ for 20 h. The mixture was diluted with water and extracted with EtOAc, and the combined organic layers were washed with brine and dried over Na₂ SO₄ . After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (eluted with EtOAc:PE = 0 to 100%) to give the title compound as a yellow solid.

步驟6：4-(4-(2,6-二側氧基哌啶-3-基)苯基)哌𠯤-1-甲酸三級丁酯將4-(4-(2,6-雙(苄基氧基)吡啶-3-基)苯基)哌𠯤-1-甲酸三級丁酯（260 mg，0.47 mmol，1.00當量）、10% Pd/C（260 mg）在EtOAc（5.0 mL）和1,4-二㗁𠮿（5.0 mL）中的混合物在室溫在H₂下攪拌20 h。將混合物過濾並將濾液濃縮，以給出呈黃色油狀物的標題化合物。Step 6: 4-(4-(2,6-dioxypiperidin-3-yl)phenyl)piperidin-1-carboxylic acid tributyl ester A mixture of tributyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-1-carboxylate (260 mg, 0.47 mmol, 1.00 equiv), 10% Pd/C (260 mg) in EtOAc (5.0 mL) and 1,4-dioxathiol (5.0 mL) was stirred at room temperature under_H₂ for 20 h. The mixture was filtered and the filtrate was concentrated to give the title compound as a yellow oil.

步驟7：3-(4-(哌𠯤-1-基)苯基)哌啶-2,6-二酮2,2,2-三氟乙酸鹽將TFA（0.5 mL）添加至4-(4-(2,6-二側氧基哌啶-3-基)苯基)哌𠯤-1-甲酸三級丁酯（160 mg，0.43 mmol，1.00當量）在DCM（2.0 mL）中的攪拌溶液中，並將混合物在室溫在N₂下攪拌2 h。將混合物濃縮，以給出呈黃色油狀物的標題化合物。Step 7: 3-(4-(piperidin-1-yl)phenyl)piperidine-2,6-dione 2,2,2-trifluoroacetate TFA (0.5 mL) was added to a stirred solution of tributyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-1-carboxylate (160 mg, 0.43 mmol, 1.00 equiv) in DCM (2.0 mL), and the mixture was stirred at room temperature under_N2 for 2 h. The mixture was concentrated to give the title compound as a yellow oil.

參考物10 2-氯-5-(二氟甲基)嘧啶的合成在0°C向2-氯嘧啶-5-甲醛（250 mg，1.60 mmol，1.00當量）在DCM（3.0 mL）中的溶液中添加DAST（45 mg，31.93 mmol，20.00當量），並將混合物在室溫攪拌過夜。將混合物用水稀釋並用DCM萃取。將有機層用鹽水洗滌，經Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由急速層析法（PE:EtOAc=10:1）純化，以給出呈白色固體的標題化合物。Reference 10 Synthesis of 2-chloro-5-(difluoromethyl)pyrimidine To a solution of 2-chloropyrimidine-5-carbaldehyde (250 mg, 1.60 mmol, 1.00 equiv) in DCM (3.0 mL) at 0°C was added DAST (45 mg, 31.93 mmol, 20.00 equiv), and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with DCM. The organic layer was washed with brine and dried_{overNa₂SO₄} . After filtration, the filtrate was concentrated, and the residue was purified by flash chromatography (PE:EtOAc = 10:1) to afford the title compound as a white solid.

藉由與參考物10中所述類似的方式進行來製備以下參考化合物。參考物#結構參考物10aThe following reference compounds were prepared by proceeding in a manner similar to that described in Reference 10. References# structure Reference 10a

參考物11 2-氯-5-(二氟甲氧基)嘧啶的合成將2-氯嘧啶-5-醇（1.00 g，7.69 mmol，1.00當量）、2-氯-2,2-二氟乙酸甲酯（3.32 g，23.08 mmol，3.00當量）和Cs₂CO₃（3.01 g，9.23 mmol，1.20當量）在DMF（10.0 mL）中的混合物在100°C在N₂下攪拌1 h。將混合物倒入水中，並將所得混合物用DCM萃取。將合併的有機層經Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由矽膠柱層析法（PE : EtOAc = 20:1）純化，給出呈黃色油狀物的標題化合物。Reference 11 Synthesis of 2-chloro-5-(difluoromethoxy)pyrimidine A mixture of 2-chloropyrimidin-5-ol (1.00 g, 7.69 mmol, 1.00 equiv), methyl 2-chloro-2,2-difluoroacetate (3.32 g, 23.08 mmol, 3.00 equiv), and Cs₂ CO₃ (3.01 g, 9.23 mmol, 1.20 equiv) in DMF (10.0 mL) was stirred at 100°C under N₂ for 1 h. The mixture was poured into water, and the resulting mixture was extracted with DCM. The combined organic layers were dried over Na₂ SO_4. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (PE:EtOAc = 20:1) to afford the title compound as a yellow oil.

參考物12 1-(6-(哌啶-4-基)-1-(2,2,2-三氟乙基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮2,2,2-三氟乙酸鹽的合成步驟1：6-溴-1-(2,2,2-三氟乙基)-1H-吲唑-3-胺在0°C將NaH（2.10 g，52.83 mmol，2.00當量）添加至6-溴-1H-吲唑-3-胺（5.60 g，26.42 mmol，1.00當量）在DMF（20.0 mL）中的攪拌溶液中，並將混合物在0°C攪拌1 h。添加三氟甲磺酸2,2,2-三氟乙酯（6.7 g，29.06 mmol，1.10當量），並將混合物在室溫在N₂下攪拌3 h。將混合物倒入冷水中並過濾。將固體用水洗滌並乾燥，以給出呈黃色固體的標題化合物。Reference 12 Synthesis of 1-(6-(piperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-trifluoroacetate Step 1: 6-Bromo-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine NaH (2.10 g, 52.83 mmol, 2.00 equiv) was added to a stirred solution of 6-bromo-1H-indazol-3-amine (5.60 g, 26.42 mmol, 1.00 equiv) in DMF (20.0 mL) at 0°C, and the mixture was stirred at 0°C for 1 h. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (6.7 g, 29.06 mmol, 1.10 equiv) was added, and the mixture was stirred at room temperature under_N₂ for 3 h. The mixture was poured into cold water and filtered. The solid was washed with water and dried to give the title compound as a yellow solid.

步驟2：1-(6-(哌啶-4-基)-1-(2,2,2-三氟乙基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮2,2,2-三氟乙酸鹽藉由與參考物5的步驟2-7中所述類似的方式進行來合成標題化合物。Step 2: 1-(6-(piperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-trifluoroacetate The title compound was synthesized by proceeding in a similar manner to that described in steps 2-7 of reference 5.

參考物13 1-(1-甲基-6-(哌𠯤-1-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮的合成步驟1：4-(4-氰基-3-氟苯基)哌𠯤-1-甲酸苄酯將2,4-二氟苯甲腈（18.95 g，136.20 mmol，1.50當量）、哌𠯤-1-甲酸苄酯（20 g，90.80 mmol，1.00當量）和碳酸鉀（25.10 g，181.6 mmol，2.00當量）在ACN（200.0 mL）中的混合物在80°C在N₂下攪拌16 h。將混合物過濾，並且將濾液濃縮。將殘餘物藉由矽膠柱層析法（用PE/EtOAc（3:1）洗脫）純化，以給出呈白色固體的標題化合物。Reference 13 Synthesis of 1-(1-methyl-6-(piperidin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Benzyl 4-(4-cyano-3-fluorophenyl)piperidin-1-carboxylate A mixture of 2,4-difluorobenzonitrile (18.95 g, 136.20 mmol, 1.50 equiv), benzyl piperidine-1-carboxylate (20 g, 90.80 mmol, 1.00 equiv), and potassium carbonate (25.10 g, 181.6 mmol, 2.00 equiv) in ACN (200.0 mL) was stirred at 80 °C under_N₂ for 16 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluted with PE/EtOAc (3:1)) to give the title compound as a white solid.

步驟2：4-(3-胺基-1H-吲唑-6-基)哌𠯤-1-甲酸苄酯將4-(4-氰基-3-氟苯基)哌𠯤-1-甲酸苄酯（11.00 g，32.40 mmol，1.00當量）和N₂H₄/H₂O（10.14 g，161.99 mmol，5.00當量）在BuOH（100.0 mL）中的混合物在100°C在N₂下攪拌16 h。將混合物濃縮並藉由急速層析法純化，以給出呈黃色固體的標題化合物。Step 2: Benzyl 4-(3-amino-1H-indazol-6-yl)piperidin-1-carboxylate A mixture of benzyl 4-(4-cyano-3-fluorophenyl)piperidinium-1-carboxylate (11.00 g, 32.40 mmol, 1.00 equiv) and_N2H4 /_H2O (10.14 g, 161.99 mmol, 5.00 equiv) in BuOH (100.0 mL) was stirred at 100 °C under_N2 for 16 h. The mixture was concentrated and purified by flash chromatography to give_the title compound as a yellow solid.

步驟3：4-(3-胺基-1-甲基-1H-吲唑-6-基)哌𠯤-1-甲酸苄酯在0°C在N₂下向4-(3-胺基-1H-吲唑-6-基)哌𠯤-1-甲酸苄酯（4.00 g，11.40 mmol，1.00當量）在乾DMF（50.0 mL）中的溶液中添加NaH（0.91 g，22.80 mmol，2.00當量），並將混合物在室溫攪拌30 min。將混合物冷卻至0°C，逐滴添加乾DMF（10.0 mL）中的CH₃I（1.78 g，12.54 mmol，1.10當量），並將混合物攪拌3 h。將混合物用水淬滅，用EtOAc萃取。將合併的有機層用鹽水洗滌，用Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由矽膠柱層析法（用DCM/MeOH = （50:1）洗脫）純化，以給出呈黃色固體的標題化合物。Step 3: Benzyl 4-(3-amino-1-methyl-1H-indazol-6-yl)piperidin-1-carboxylate To a solution of benzyl 4-(3-amino-1H-indazol-6-yl)piperidinium-1-carboxylate (4.00 g, 11.40 mmol, 1.00 equiv) in dry DMF (50.0 mL) at 0°C under_N₂ was added NaH (0.91 g, 22.80 mmol, 2.00 equiv), and the mixture was stirred at room temperature for 30 min. The mixture was cooled to 0°C, and_CH₃I (1.78 g, 12.54 mmol, 1.10 equiv) in dry DMF (10.0 mL) was added dropwise, and the mixture was stirred for 3 h. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine and dried_{overNa₂SO₄} . After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (eluted with DCM/MeOH = (50:1)) to give the title compound as a yellow solid.

步驟4：4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-哌𠯤-1-甲酸苄酯藉由與參考物5的步驟2-4中所述類似的方式進行來合成標題化合物。Step 4: 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-piperidin-1-carboxylic acid benzyl ester The title compound was synthesized by proceeding in a similar manner to that described in steps 2-4 of reference 5.

步驟5：1-(1-甲基-6-(哌𠯤-1-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮將4-[3-(2,4-二側氧基-1,3-二氮雜己環烷（diazinan）-1-基)-1-甲基吲唑-6-基]哌𠯤-1-甲酸苄酯（500 mg，1.08 mmol，1.00當量）、10% Pd/C（400 mg）和甲酸銨（682 mg，10.81 mmol，10.00當量）在MeOH（20.0 mL）中的混合物在60°C在N₂下攪拌16 h。將混合物過濾並將濾液濃縮，以給出呈白色固體的標題化合物。Step 5: 1-(1-methyl-6-(piperidin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of benzyl 4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methylindazol-6-yl]piperidinium-1-carboxylate (500 mg, 1.08 mmol, 1.00 equiv), 10% Pd/C (400 mg), and ammonium formate (682 mg, 10.81 mmol, 10.00 equiv) in MeOH (20.0 mL) was stirred at 60 °C under_N2 for 16 h. The mixture was filtered and the filtrate was concentrated to give the title compound as a white solid.

藉由與參考物13中所述類似的方式進行來合成以下參考化合物。參考物#結構參考物14The following reference compounds were synthesized by proceeding in a similar manner to that described in reference 13. References# structure Reference 14

參考物15 1-(6-(3,3-二氟哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮2,2,2-2,2,2-三氟乙酸鹽的合成步驟1：1-(1-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮將1-(6-溴-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮（626 mg，2.00 mmol，1.00當量）、4,4,4',4',5,5,5',5'-八甲基-2,2'-雙(1,3,2-二氧雜環戊硼烷)（762 mg，3.00 mmol，1.50當量）、KOAc（589 mg，6.00 mmol，3.00當量）和Pd(dppf)Cl₂（146 mg，0.20 mmol，0.10當量）在1,4-二㗁𠮿（10 mL）中的混合物在85°C在N₂下攪拌過夜。將混合物過濾，並且將濾液濃縮。將殘餘物藉由矽膠柱層析法（DCM:MeOH = 100 : 1）純化，以給出呈黃色固體的標題化合物。Reference 15 Synthesis of 1-(6-(3,3-difluoropiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-2,2,2-trifluoroacetate Step 1: 1-(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (626 mg, 2.00 mmol, 1.00 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (762 mg, 3.00 mmol, 1.50 equiv), KOAc (589 mg, 6.00 mmol, 3.00 equiv), and Pd(dppf)_Cl2 (146 mg, 0.20 mmol, 0.10 equiv) in 1,4-dioxaborolan (10 mL) was stirred at 85°C under_N2 overnight. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:1) to give the title compound as a yellow solid.

步驟2：4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-3,3-二氟-3,6-二氫吡啶-1(2H)-甲酸三級丁酯將1-(1-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮（800 mg，2.00 mmol，1.00當量）、3,3-二氟-4-(((三氟甲基)磺醯基)氧基)-3,6-二氫吡啶-1(2H)-甲酸三級丁酯（1.10 g，3.00 mmol，1.50當量）、Na₂CO₃（636 mg，6.00 mmol，3.00當量）、Pd(dppf)Cl₂（146 mg，0.20 mmol，0.1當量）和H₂O（2.5 mL）在1,4-二㗁𠮿（10.0 mL）中的混合物在55°C在N₂下攪拌過夜。將混合物過濾，並且將濾液濃縮。將殘餘物藉由矽膠柱層析法（DCM:MeOH = 120 : 1）純化，以給出呈黃色固體的標題化合物。Step 2: 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3-difluoro-3,6-dihydropyridine-1(2H)-carboxylic acid tributyl ester 1-(1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (800 mg, 2.00 mmol, 1.00 equiv), 3,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tributyl ester (1.10 g, 3.00 mmol, 1.50 equiv), Na₂ CO₃ (636 mg, 6.00 mmol, 3.00 equiv), Pd(dppf)Cl₂ (146 mg, 0.20 mmol, 0.1 equiv) and H₂ O (2.5 A mixture of 4-nitropropane (3-nitropropane) (10.0 mL) in 1,4-dioxane (10.0 mL) was stirred at 55°C under_N2 overnight. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 120:1) to give the title compound as a yellow solid.

步驟3：4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-3,3-二氟哌啶-1-甲酸三級丁酯將4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-3,3-二氟-3,6-二氫吡啶-1(2H)-甲酸三級丁酯（940 mg，2.00 mmol，1.00當量）、10% Pd/C（900 mg）和Pd(OH)₂（900 mg）在MeOH（10.0 mL）中的混合物在50°C在H₂（50 PSI）下攪拌過夜。將混合物過濾，並且將濾液濃縮。將殘餘物藉由矽膠柱層析法（DCM:MeOH = 1 : 1）純化，以給出呈黃色固體的標題。Step 3: 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3-difluoropiperidine-1-carboxylic acid tributyl ester A mixture of tributyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3-difluoro-3,6-dihydropyridine-1(2H)-carboxylate (940 mg, 2.00 mmol, 1.00 equiv), 10% Pd/C (900 mg), and Pd(OH)_₂ (900 mg) in MeOH (10.0 mL) was stirred at 50°C under_H₂ (50 PSI) overnight. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 1:1) to give the title compound as a yellow solid.

步驟4：1-(6-(3,3-二氟哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮2,2,2-2,2,2-三氟乙酸鹽將4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-3,3-二氟哌啶-1-甲酸三級丁酯（102 mg，0.22 mmol，1.00當量）在TFA/DCM（0.5 mL/2.0 mL）中的混合物在室溫攪拌2 h。將混合物濃縮，以給出呈棕色油狀物的標題化合物。Step 4: 1-(6-(3,3-difluoropiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-2,2,2-trifluoroacetate A mixture of tributyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3-difluoropiperidine-1-carboxylate (102 mg, 0.22 mmol, 1.00 equiv) in TFA/DCM (0.5 mL/2.0 mL) was stirred at room temperature for 2 h. The mixture was concentrated to give the title compound as a brown oil.

參考物16 6-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2,6-二氮雜螺[3.3]庚烷-2-甲酸三級丁酯2,2,2-三氟乙酸鹽的合成步驟1：6-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2,6-二氮雜螺[3.3]庚烷-2-甲酸三級丁酯將1-(6-溴-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮（300 mg，0.93 mmol，1.00當量）、2,6-二氮雜螺[3.3]庚烷-2-甲酸三級丁酯（570 mg，2.32 mmol，2.50當量）、t-BuOK（627 mg，5.6 mmol，6.00當量）、t-BuBrettphos Pd G3（81 mg，0.093 mmol，0.10當量）和t-BuXphos（76 mg，0.186 mmol，0.20當量）在1,4-二㗁𠮿（6 mL）中的混合物在100°C在N₂下攪拌3 h。將混合物用DCM稀釋，並將有機層用水和鹽水洗滌，經Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由矽膠柱層析法（DCM:MeOH = 20 : 1）純化，以給出呈黃色固體的標題化合物。Reference 16 Synthesis of 6-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tributyl ester 2,2,2-trifluoroacetate Step 1: 6-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tributyl ester A mixture of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (300 mg, 0.93 mmol, 1.00 equiv), tributyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (570 mg, 2.32 mmol, 2.50 equiv), t-BuOK (627 mg, 5.6 mmol, 6.00 equiv), t-BuBrettphos Pd G3 (81 mg, 0.093 mmol, 0.10 equiv) and t-BuXphos (76 mg, 0.186 mmol, 0.20 equiv) in 1,4-dioxathiol (6 mL) was stirred at 100 °C under_N2 for 3 h. The mixture was diluted with DCM, and the organic layer was washed with water and brine, and dried over Na₂ SO₄ . After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give the title compound as a yellow solid.

步驟2：1-(1-甲基-6-(2,6-二氮雜螺[3.3]庚-2-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮2,2,2-2,2,2-三氟乙酸鹽將6-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2,6-二氮雜螺[3.3]庚烷-2-甲酸三級丁酯（90 mg，0.204 mmol，1.00當量）在TFA/DCM（0.5 mL/2 mL）中的混合物在室溫攪拌2 h。將混合物濃縮，以給出呈棕色油狀物的標題化合物。Step 2: 1-(1-methyl-6-(2,6-diazaspiro[3.3]hept-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-2,2,2-trifluoroacetate A mixture of tributyl 6-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (90 mg, 0.204 mmol, 1.00 equiv) in TFA/DCM (0.5 mL/2 mL) was stirred at room temperature for 2 h. The mixture was concentrated to give the title compound as a brown oil.

參考物17 1-(6-(1-(3-(3-((4-胺基哌啶-1-基)磺醯基)苯基)-2,2-二甲基丙基) 哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽的合成步驟1：(1-((3-(2,2-二甲基-3-側氧基丙基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在氬氣氣氛下將N-[1-[3-(溴甲基)苯基]磺醯基-4-哌啶基]胺基甲酸三級丁酯（1.0 g，2.31 mmol）、2-甲基丙醛（416 mg，5.77 mmol）、四丁基碘化銨（85.24 mg，0.23 mmol）和氫氧化鈉（323.06 mg，8.08 mmol）在1,4-二㗁𠮿（10 mL）中的混合物加熱至70°C並攪拌3 h。冷卻後，將混合物用水稀釋並用乙酸乙酯萃取。將合併的有機層用水、鹽水洗滌，並經無水硫酸鈉乾燥。過濾後，將濾液濃縮並將殘餘物藉由矽膠層析法（用乙酸乙酯/石油醚（0-20%，具有5%二氯甲烷）洗脫）純化，以得到呈白色固體的標題化合物。Reference 17 Synthesis of 1-(6-(1-(3-(3-((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2,2-dimethylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride Step 1: Tributyl (1-((3-(2,2-dimethyl-3-hydroxypropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate A mixture of tributyl N-[1-[3-(bromomethyl)phenyl]sulfonyl-4-piperidinyl]carbamate (1.0 g, 2.31 mmol), 2-methylpropanal (416 mg, 5.77 mmol), tetrabutylammonium iodide (85.24 mg, 0.23 mmol), and sodium hydroxide (323.06 mg, 8.08 mmol) in 1,4-dioxane (10 mL) was heated to 70°C and stirred for 3 hours under an atmosphere of nitrogen. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the residue was purified by silica gel chromatography, eluting with ethyl acetate/petroleum ether (0-20% with 5% dichloromethane) to give the title compound as a white solid.

步驟2：(1-((3-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2,2-二甲基丙基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯將鈦酸四異丙酯（1.24 g，4.37 mmol）添加至(1-((3-(2,2-二甲基-3-側氧基丙基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（530 mg，1.25 mmol）和1-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽（408.7 mg，1.25 mmol）在無水N-甲基-2-吡咯啶酮（5.3 mL）中的混合物中，並將混合物在氬氣氣氛下加熱至90°C，持續3 h。將混合物冷卻至室溫並添加氰基硼氫化鈉（274.56 mg，4.37 mmol），並將混合物在25°C攪拌1 h。將混合物用水稀釋並用乙酸乙酯萃取。將合併的有機層用水、鹽水洗滌，經無水硫酸鈉乾燥。過濾後，將濾液濃縮並將殘餘物藉由矽膠層析法（用甲醇/二氯甲烷（0-5%）洗脫）純化，以得到呈白色固體的標題化合物。Step 2: Tributyl (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2,2-dimethylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate Tetraisopropyl titanium ester (1.24 g, 4.37 mmol) was added to a mixture of tributyl (1-((3-(2,2-dimethyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (530 mg, 1.25 mmol) and 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (408.7 mg, 1.25 mmol) in anhydrous N-methyl-2-pyrrolidone (5.3 mL), and the mixture was heated to 90 ° C under an hydrogen atmosphere for 3 h. The mixture was cooled to room temperature, and sodium cyanoborohydride (274.56 mg, 4.37 mmol) was added, and the mixture was stirred at 25°C for 1 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel chromatography (eluting with methanol/dichloromethane (0-5%)) to provide the title compound as a white solid.

步驟3：1-(6-(1-(3-(3-((4-胺基哌啶-1-基)磺醯基)苯基)-2,2-二甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽在0°C向(1-((3-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2,2-二甲基丙基)苯基) 磺醯基)哌啶-4-基)胺基甲酸三級丁酯（280 mg，0.38 mmol）在二氯甲烷（3 mL）中的攪拌溶液中添加二㗁𠮿中的4 M氯化氫（1.5 mL）並攪拌1 h。將混合物在減壓下濃縮，以得到呈白色固體的標題化合物。Step 3: 1-(6-(1-(3-(3-((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2,2-dimethylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride To a stirred solution of tributyl (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2,2-dimethylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (280 mg, 0.38 mmol) in dichloromethane (3 mL) was added 4 M hydrogen chloride in dichloromethane (1.5 mL) at 0°C and stirred for 1 h. The mixture was concentrated under reduced pressure to give the title compound as a white solid.

參考物18 (1-((3-溴-4-氯苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯的合成步驟1：3-溴-4-氯苯磺醯氯在0°C向3-溴-4-氯苯胺（5.00 g，24.22 mmol，1.00當量）在濃HCl（50.0 mL）中的攪拌溶液中添加NaNO₂（3.34 g，48.44 mmol，2.00當量），隨後在0°C添加五水硫酸銅（0.60 g，2.42 mmol，0.10當量），然後係NaHSO₃（水性）（25.20 g，242.20 mmol，10.00當量）。將反應混合物在0°C在氮氣下攪拌1 h。將反應混合物用EA萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾和濃縮後，將殘餘物藉由矽膠柱層析法（PE : EA = 10 : 1）純化，以給出呈棕色油狀物的標題化合物。Reference 18 Synthesis of tert-butyl (1-((3-bromo-4-chlorophenyl)sulfonyl)piperidin-4-yl)carbamate Step 1: 3-Bromo-4-chlorobenzenesulfonyl chloride To a stirred solution of 3-bromo-4-chloroaniline (5.00 g, 24.22 mmol, 1.00 equiv) in concentrated HCl (50.0 mL) at 0°C was added_NaNO₂ (3.34 g, 48.44 mmol, 2.00 equiv), followed by copper sulfate pentahydrate (0.60 g, 2.42 mmol, 0.10 equiv) at 0°C, and then_NaHSO₃ (aq) (25.20 g, 242.20 mmol, 10.00 equiv). The reaction mixture was stirred at 0°C under nitrogen for 1 h. The reaction mixture was extracted with EA. The combined organic layers were washed with brine and dried_over anhydrous_Na₂SO₄ . After filtration and concentration, the residue was purified by silica gel column chromatography (PE:EA = 10:1) to give the title compound as a brown oil.

步驟2：(1-((3-溴-4-氯苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在0^oC向哌啶-4-基胺基甲酸三級丁酯（3.97 g，19.83 mmol，1.15當量）和TEA（6.98 g，68.96 mmol，4.00當量）在DCM（50.0 mL）中的攪拌溶液中緩慢添加3-溴-4-氯苯磺醯氯（5.00 g，17.24 mmol，1.00當量）。將所得混合物在室溫在氮氣下攪拌1 h，用水稀釋並用DCM萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾和濃縮後，將殘餘物藉由矽膠柱層析法（DCM:MeOH = 20 : 1）純化，以給出呈黃色固體的標題化合物。Step 2: Tributyl (1-((3-bromo-4-chlorophenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of tert-butyl piperidin-4-ylcarbamate (3.97 g, 19.83 mmol, 1.15 equiv) and TEA (6.98 g, 68.96 mmol, 4.00 equiv) in DCM (50.0 mL) at 0^° C was slowly added 3-bromo-4-chlorobenzenesulfonyl chloride (5.00 g, 17.24 mmol, 1.00 equiv). The resulting mixture was stirred at room temperature under nitrogen for 1 h, diluted with water, and extracted with DCM. The combined organic layers were washed with brine and dried over_{anhydrousNa₂SO₄} . After filtration and concentration, the residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give the title compound as a yellow solid.

實例11-(6-(1-(2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)丁基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮的合成步驟1：(E)-2-(3-((4-((三級丁氧基羰基)胺基)哌啶-1-基)磺醯基)亞苄基)-丁酸乙酯在0°C將2-(二乙氧基磷醯基)丁酸乙酯（412 mg，1.63 mmol，1.20當量）添加至NaH（60%在礦物油中，82 mg，2.04 mmol，1.50當量）在THF（10.0 mL）中的攪拌溶液中，並將該混合物在0°C攪拌30 min。然後添加THF（10.0 mL）中的(1-((3-甲醯基苯基)-磺醯基)哌啶-4-基)胺基甲酸三級丁酯（500 mg，1.36 mmol，1.00當量）。將該混合物在0°C攪拌30 min，然後緩慢加溫至室溫並攪拌12 h。將混合物在0°C用H₂O淬滅並用EtOAc萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮並將殘餘物藉由矽膠柱層析法（用DCM:MeOH（0-5%）洗脫）純化，以得到呈白色固體的標題化合物。Example1 Synthesis of 1-(6-(1-(2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)butyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Ethyl (E)-2-(3-((4-((tert-butyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)benzylidene)butyrate Ethyl 2-(diethoxyphosphatyl)butyrate (412 mg, 1.63 mmol, 1.20 equiv) was added to a stirred solution of NaH (60% in mineral oil, 82 mg, 2.04 mmol, 1.50 equiv) in THF (10.0 mL) at 0°C, and the mixture was stirred at 0°C for 30 min. Then, tributyl (1-((3-formylphenyl)-sulfonyl)piperidin-4-yl)carbamate (500 mg, 1.36 mmol, 1.00 equiv) in THF (10.0 mL) was added. The mixture was stirred at 0°C for 30 min, then slowly warmed to room temperature and stirred for 12 h. The mixture was quenched with_H₂O at 0°C and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na₂ SO_4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with DCM:MeOH (0-5%) to give the title compound as a white solid.

步驟2：2-(3-((4-((三級丁氧基羰基)胺基)哌啶-1-基)磺醯基)苄基)丁酸乙酯將(E)-2-(3-((4-((三級丁氧基羰基)胺基)哌啶-1-基)-磺醯基)亞苄基)丁酸乙酯（400 mg，0.86 mmol，1.00當量）、10% Pd/C（200 mg）在MeOH（10.0 mL）中的混合物在室溫在1 atm H₂下攪拌12 h。將混合物過濾，並且將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用DCM:MeOH（0-5%）洗脫）純化，以得到呈淺黃色油狀物的標題化合物。Step 2: Ethyl 2-(3-((4-((tert-butyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)benzyl)butanoate A mixture of ethyl (E)-2-(3-((4-((tert-butyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)benzylidene)butanoate (400 mg, 0.86 mmol, 1.00 equiv) and 10% Pd/C (200 mg) in MeOH (10.0 mL) was stirred at room temperature under 1 atm_H₂ for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM:MeOH (0-5%) to give the title compound as a light yellow oil.

步驟3：(1-((3-(2-(羥基甲基)丁基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在-10°C將LiAlH₄（2.5 M在THF中，1.15 mL，2.88 mmol，3.00當量）添加至2-(3-((4-((三級丁氧基羰基)胺基)哌啶-1-基)磺醯基)苄基)-丁酸乙酯（450 mg，0.96 mmol，1.00當量）在THF（20.0 mL）中的攪拌溶液中，並將混合物攪拌3 h。將混合物用DCM稀釋，用H₂O淬滅，並將所得混合物在室溫攪拌30 min。將混合物過濾，並且將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用DCM:MeOH（0-5%）洗脫）純化，以得到呈淺黃色固體的標題化合物。Step 3: Tert-butyl (1-((3-(2-(hydroxymethyl)butyl)phenyl)sulfonyl)piperidin-4-yl)carbamate_LiAlH₄ (2.5 M in THF, 1.15 mL, 2.88 mmol, 3.00 equiv) was added to a stirred solution of ethyl 2-(3-((4-((tert-butyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)benzyl)butyrate (450 mg, 0.96 mmol, 1.00 equiv) in THF (20.0 mL) at -10°C, and the mixture was stirred for 3 h. The mixture was diluted with DCM, quenched with_H₂O , and the resulting mixture was stirred at room temperature for 30 min. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM:MeOH (0-5%) to give the title compound as a light yellow solid.

步驟4：(1-((3-(2-甲醯基丁基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在0°C向(1-((3-(2-(羥基甲基)丁基)苯基)磺醯基)-哌啶-4-基)胺基甲酸三級丁酯（150 mg，0.35 mmol，1.00當量）在DCM（7.0 mL）中的攪拌溶液中添加戴斯-馬丁過碘烷（223 mg，0.53 mmol，1.50當量），並將混合物在N₂下攪拌2 h。將混合物過濾並在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用DCM: MeOH（0-2%）洗脫）純化，以得到呈淺黃色固體的標題化合物。Step 4: tert-butyl (1-((3-(2-methylbutyl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of tributyl (1-((3-(2-(hydroxymethyl)butyl)phenyl)sulfonyl)-piperidin-4-yl)carbamate (150 mg, 0.35 mmol, 1.00 equiv) in DCM (7.0 mL) at 0°C was added Dess-Martin periodinane (223 mg, 0.53 mmol, 1.50 equiv), and the mixture was stirred under_N₂ for 2 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM:MeOH (0-2%) to give the title compound as a light yellow solid.

步驟5：(1-((3-(2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)丁基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在0°C將DMA（2.0 mL）中的NaBH(OAc)₃（180 mg，0.85 mmol，2.5當量）添加至1-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽（127 mg，0.35 mmol，1.00當量）、TEA（106 mg，1.05 mmol，3.00當量）和(1-((3-(2-甲醯基丁基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（149 mg，0.35 mmol，1.00當量）在DMA（6.0 mL）中的混合物中，並將混合物在室溫攪拌12 h。將混合物用水稀釋並用EtOAc萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮並將殘餘物藉由矽膠柱層析法（用DCM:MeOH（0-5%）洗脫）純化，以得到呈淺黃色固體的標題化合物。Step 5: Tributyl (1-((3-(2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)butyl)phenyl)sulfonyl)piperidin-4-yl)carbamate NaBH(OAc)₃ (180 mg, 0.85 mmol, 2.5 equiv) in DMA (2.0 mL) was added to a mixture of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (127 mg, 0.35 mmol, 1.00 equiv), TEA (106 mg, 1.05 mmol, 3.00 equiv), and tert-butyl (1-((3-(2-formylbutyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (149 mg, 0.35 mmol, 1.00 equiv) in DMA (6.0 mL) at 0°C, and the mixture was stirred at room temperature for 12 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na₂ SO_4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with DCM:MeOH (0-5%) to give the title compound as a light yellow solid.

步驟6：1-(6-(1-(2-(3-((4-胺基哌啶-1-基)磺醯基)苄基)丁基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽在室溫將EtOAc中的HCl（2 M，5.0 mL）添加至(1-((3-(2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)丁基)-苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（170 mg，0.23 mmol，1.00當量）中並將它攪拌3 h。將混合物在減壓下濃縮，以得到呈淺黃色固體的標題化合物。Step 6: 1-(6-(1-(2-(3-((4-aminopiperidin-1-yl)sulfonyl)benzyl)butyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride HCl in EtOAc (2 M, 5.0 mL) was added to tributyl (1-((3-(2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)butyl)-phenyl)sulfonyl)piperidin-4-yl)carbamate (170 mg, 0.23 mmol, 1.00 equiv) at room temperature and stirred for 3 h. The mixture was concentrated under reduced pressure to give the title compound as a light yellow solid.

步驟7：1-(6-(1-(2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)丁基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮將1-(6-(1-(2-(3-((4-胺基哌啶-1-基)磺醯基)苄基)丁基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽（155 mg，0.23 mmol，1.00當量）、DIEA（149 mg，1.15 mmol，5.00當量）、CsF（70 mg，0.46 mmol，2.00當量）和2-氯-5-(二氟甲氧基)嘧啶（83 mg，0.46 mmol，2.00當量）在DMSO（7.0 mL）中的混合物在50°C在N₂下攪拌12 h。將混合物用水稀釋並用EtOAc萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥並過濾。將濾液在減壓下濃縮並將殘餘物藉由製備型HPLC純化，以得到呈白色固體的標題化合物。MS (ES, m/z): [M+1]⁺= 780.4Step 7: 1-(6-(1-(2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)butyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of 1-(6-(1-(2-(3-((4-aminopiperidin-1-yl)sulfonyl)benzyl)butyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (155 mg, 0.23 mmol, 1.00 equiv), DIEA (149 mg, 1.15 mmol, 5.00 equiv), CsF (70 mg, 0.46 mmol, 2.00 equiv), and 2-chloro-5-(difluoromethoxy)pyrimidine (83 mg, 0.46 mmol, 2.00 equiv) in DMSO (7.0 mL) was stirred at 50° C. under N₂ for 12 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂ SO₄ and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC to give the title compound as a white solid. MS (ES, m/z): [M+1]⁺ = 780.4

藉由與實例1中所述類似的方式進行來合成以下化合物。實例#結構實例 2The following compounds were synthesized in a similar manner to that described in Example 1.Example#structure Example 2

實例34-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈的合成步驟1：3-溴-4-氰基苯磺醯氯將4-胺基-2-溴苯甲腈（5.0 g，25.38 mmol，1.00當量）在濃HCl/H₂O（60.0 mL/225.0 mL）中的混合物加溫至90°C直至完全溶解。將混合物冷卻至0°C-5°C。將NaNO₂（1.9 g，27.54 mmol，1.08當量）在H₂O（5 mL）中的溶液逐滴添加至上述混合物中，然後隨後在0°C-5°C逐滴添加SOCl₂/H₂O（8.0 mL/50.0 mL）中的CuCl（0.2 g，2.02 mmol，0.08當量）。將所得混合物在0°C-5°C攪拌1 h。將混合物用水稀釋並用EtOAc萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥並過濾。將濾液在減壓下濃縮並將殘餘物藉由矽膠柱層析法（用PE:EtOAc = 4:1洗脫）純化，以得到呈白色油狀物的標題化合物。Example3 Synthesis of 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile Step 1: 3-Bromo-4-cyanobenzenesulfonyl chloride A mixture of 4-amino-2-bromobenzonitrile (5.0 g, 25.38 mmol, 1.00 equiv) in concentrated HCl/_H₂O (60.0 mL/225.0 mL) was warmed to 90°C until completely dissolved. The mixture was cooled to 0°C-5°C. A solution of_NaNO₂ (1.9 g, 27.54 mmol, 1.08 equiv) in_H₂O (5 mL) was added dropwise to the mixture, followed by the dropwise addition of CuCl (0.2 g, 2.02 mmol, 0.08 equiv) in_SOCl₂ /_H₂O (8.0 mL/50.0 mL) at 0°C-5°C. The resulting mixture was stirred at 0°C-5°C for 1 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na₂ SO₄ and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE:EtOAc = 4:1) to give the title compound as a white oil.

步驟2：(1-((3-溴-4-氰基苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在0°C將DCM（5.0 mL）中的3-溴-4-氰基苯磺醯氯（500 mg，1.79 mmol，1.00當量）逐滴添加至哌啶-4-基胺基甲酸三級丁酯（359.2 mg，1.79 mmol，1.00當量）和TEA（542.4 mg，5.37 mmol，3.00當量）在DCM（5.0 mL）中的攪拌溶液中。將混合物在室溫攪拌2 h。將混合物倒入水中並用DCM萃取。將合併的有機層用水和鹽水洗滌，經Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由急速層析法純化，以給出呈棕色固體的標題化合物。Step 2: Tributyl (1-((3-bromo-4-cyanophenyl)sulfonyl)piperidin-4-yl)carbamate 3-Bromo-4-cyanobenzenesulfonyl chloride (500 mg, 1.79 mmol, 1.00 equiv) in DCM (5.0 mL) was added dropwise to a stirred solution of tributyl piperidin-4-ylcarbamate (359.2 mg, 1.79 mmol, 1.00 equiv) and TEA (542.4 mg, 5.37 mmol, 3.00 equiv) in DCM (5.0 mL) at 0°C. The mixture was stirred at room temperature for 2 h. The mixture was poured into water and extracted with DCM. The combined organic layers were washed with water and brine and dried_{overNa₂SO₄} . After filtration, the filtrate was concentrated and the residue was purified by flash chromatography to give the title compound as a brown solid.

步驟3：(1-((4-氰基-3-(2-甲基-3-側氧基丙基)苯基)磺醯基)哌啶-4-基)-胺基甲酸三級丁酯向(1-((3-溴-4-氰基苯基)磺醯基)哌啶-4-基)-胺基甲酸三級丁酯（400 mg，0.90 mmol，1.00當量）在DMF（8.0 mL）中的攪拌溶液中添加2-(二-三級丁基-膦醯基)-1-苯基-1H-吲哚（20 mg，0.06 mmol，0.06當量）、N-環己基-N-甲基環-己胺（194.4 mg，1.17 mmol，1.1當量）、2-甲基丙-2-烯-1-醇（130 mg，1.8 mmol，2.00當量）和Pd₂(dba)₃（16.8 mg，0.02 mmol，0.02當量）。將混合物用N₂吹掃並在100°C攪拌5 h。將混合物倒入水中，用EtOAc萃取，並將合併的有機層用水和鹽水洗滌，經Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由急速層析法純化，以給出呈白色固體的標題化合物。Step 3: (1-((4-cyano-3-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)-carbamic acid tert-butyl ester To a stirred solution of tert-butyl (1-((3-bromo-4-cyanophenyl)sulfonyl)piperidin-4-yl)-carbamate (400 mg, 0.90 mmol, 1.00 equiv) in DMF (8.0 mL) were added 2-(di-tert-butyl-phosphinoyl)-1-phenyl-1H-indole (20 mg, 0.06 mmol, 0.06 equiv), N-cyclohexyl-N-methylcyclohexylamine (194.4 mg, 1.17 mmol, 1.1 equiv), 2-methylprop-2-en-1-ol (130 mg, 1.8 mmol, 2.00 equiv) and_Pd2 (dba)₃ (16.8 mg, 0.02 mmol, 0.02 equiv). The mixture was purged with_N2 and stirred at 100 °C for 5 h. The mixture was poured into water, extracted with EtOAc, and the combined organic layers were washed with water and brine,_and dried over_Na2SO4 . After filtration, the filtrate was concentrated and the residue was purified by flash chromatography to give the title compound as a white solid.

步驟4：4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基-丙基)苯甲腈藉由與實例1的步驟5-7中所述類似的方式進行來合成標題化合物。MS (ES, m/z): [M+1]⁺= 791.3。Step 4: 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methyl-propyl)benzonitrile The title compound was synthesized in a manner similar to that described in Steps 5-7 of Example 1. MS (ES, m/z): [M+1]⁺ = 791.3.

藉由與實例3中所述類似的方式進行來合成以下化合物。實例#結構實例 4實例5The following compounds were synthesized in a similar manner to that described in Example 3.Example#structure Example 4 Example 5

實例6(S)-1-(6-(1-(2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮的合成步驟1：(1-((3-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯基)磺醯基)哌啶-4-基) 胺基甲酸三級丁酯在室溫在氮氣氣氛下向(1-((3-溴苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（5 g，11.92 mmol，1當量）和4,4,4',4',5,5,5',5'-八甲基-2,2'-雙(1,3,2-二氧雜環戊硼烷)（3.03 g，11.92 mmol，1當量）在1,4-二㗁𠮿（50 mL）中的攪拌溶液中添加Pd(dppf)Cl₂（0.87 g，1.19 mmol，0.1當量）和AcOK（3.51 g，35.77 mmol，3當量），並將所得混合物在80°C攪拌2 h。將混合物用水淬滅並用EtOAc萃取。將合併的有機層用水和鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮，以得到呈黃色固體的標題化合物。Example6 Synthesis of (S)-1-(6-(1-(2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Tributyl (1-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of tributyl (1-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (5 g, 11.92 mmol, 1 eq) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (3.03 g, 11.92 mmol, 1 eq) in 1,4-dioxaborolan (50 mL) at room temperature under a nitrogen atmosphere were added Pd(dppf)Cl₂ (0.87 g, 1.19 mmol, 0.1 eq) and AcOK (3.51 g, 35.77 mmol, 3 eq), and the resulting mixture was stirred at 80° C. for 2 h. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with water and brine, and dried over anhydrous Na₂ SO₄ . After filtration, the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid.

步驟2：(1-((3-羥基苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在室溫向(1-((3-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-苯基)磺醯基)哌啶-4-基) 胺基甲酸三級丁酯（9 g，19.3 mmol，1當量）在ACN（90 mL）中的攪拌溶液中添加H₂O₂（30%，45 mL）。將所得混合物在室溫攪拌10 min。將混合物在0°C用飽和Na₂SO₃溶液淬滅，並將所得混合物用EtOAc萃取。將合併的有機層用水和鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EtOAc/PE（0-50%）洗脫）純化，以得到呈白色固體的標題化合物。Step 2: (1-((3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamic acid tert-butyl ester To a stirred solution of tributyl (1-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)sulfonyl)piperidin-4-yl)carbamate (9 g, 19.3 mmol, 1 equivalent) in_{ACN (90 mL) was added H₂O₂(} 30%, 45 mL) at room temperature. The resulting mixture was stirred at room temperature for 10 min. The mixture was quenched with saturated_Na₂SO₃ solution at 0°C_and extracted with EtOAc. The combined organic layers were washed with water and brine,_and dried over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc/PE (0-50%) to give the title compound as a white solid.

步驟3：(S)-2-(3-((4-((三級丁氧基羰基)胺基)哌啶-1-基)磺醯基)苯氧基)-丙酸甲酯在0°C在氮氣氣氛下向(1-((3-羥基苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（2 g，5.6 mmol，1.0當量）、PPh₃（2.2 g，8.4 mmol，1.5當量）和(2S)-2-羥基丙酸甲酯（600 mg，5.78 mmol，1.03當量）在THF（20 mL）中的攪拌混合物中逐滴添加DIAD（1.36 g，6.73 mmol，1.20當量）。將混合物在室溫攪拌2 h。將混合物用水淬滅，並將所得混合物用EtOAc萃取。將合併的有機層用水和鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EtOAc/PE（0-25%）洗脫）純化，以得到呈白色固體的標題化合物。Step 3: (S)-2-(3-((4-((tert-butyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenoxy)-propionic acid methyl ester To a stirred mixture of tributyl (1-((3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamate (2 g, 5.6 mmol, 1.0 equiv),_PPh₃ (2.2 g, 8.4 mmol, 1.5 equiv), and methyl (2S)-2-hydroxypropanoate (600 mg, 5.78 mmol, 1.03 equiv) in THF (20 mL) at 0°C under a nitrogen atmosphere was added DIAD (1.36 g, 6.73 mmol, 1.20 equiv) dropwise. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water, and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, and dried over_{anhydrousNa₂SO₄} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc/PE (0-25%) to give the title compound as a white solid.

步驟4：(S)-(1-((3-((1-羥基丙-2-基)氧基)苯基)磺醯基)哌啶-4-基)-胺基甲酸三級丁酯在0°C向(S)-2-(3-((4-((三級丁氧基羰基)胺基)哌啶-1-基)磺醯基)苯氧基)丙酸甲酯（1.6 g，3.62 mmol，1.0當量）在THF（16 mL）中的攪拌溶液中逐滴添加THF中的2 M LiAlH₄（3.6 mL，7.2 mmol，2當量）。將所得混合物在0°C攪拌2 h。將混合物用水和15% NaOH（水性）淬滅，將所得混合物用EtOAc稀釋並過濾。將濾液在減壓下濃縮，以給出呈黃色固體的標題化合物。Step 4: (S)-(1-((3-((1-hydroxypropan-2-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)-carbamic acid tert-butyl ester To a stirred solution of (S)-methyl 2-(3-((4-((tert-butyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenoxy)propanoate (1.6 g, 3.62 mmol, 1.0 equiv) in THF (16 mL) at 0°C was added 2 M_LiAlH₄ in THF (3.6 mL, 7.2 mmol, 2 equiv) dropwise. The resulting mixture was stirred at 0°C for 2 h. The mixture was quenched with water and 15% NaOH (aq), diluted with EtOAc, and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow solid.

步驟5：(S)-2-(3-((4-胺基哌啶-1-基)磺醯基)苯氧基)丙-1-醇鹽酸鹽在室溫向(S)-(1-((3-((1-羥基丙-2-基)氧基)苯基)磺醯基)-哌啶-4-基)胺基甲酸三級丁酯（1 g，2.4 mmol，1.0當量）在DCM（10 mL）中的攪拌溶液中逐滴添加1,4-二㗁𠮿中的4 M HCl（5 mL）。將所得混合物攪拌2 h。將混合物在減壓下濃縮，以得到呈淡黃色固體的標題化合物。Step 5: (S)-2-(3-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)propan-1-ol hydrochloride To a stirred solution of (S)-tributyl(1-((3-((1-hydroxypropan-2-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (1 g, 2.4 mmol, 1.0 equiv) in DCM (10 mL) was added 4 M HCl in 1,4-dioxane (5 mL) dropwise at room temperature. The resulting mixture was stirred for 2 h. The mixture was concentrated under reduced pressure to give the title compound as a pale yellow solid.

步驟6：(S)-2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯氧基)丙-1-醇向(S)-2-(3-((4-胺基哌啶-1-基)磺醯基)苯氧基)丙-1-醇鹽酸鹽（760 mg，2.16 mmol，1.0當量）和2-氯-5-(二氟甲氧基)嘧啶（391 mg，2.16 mmol，1.0當量）在DMSO（7 mL）中的攪拌溶液中添加DIEA（560 mg，4.32 mmol，2.0當量），並將混合物在90°C攪拌16 h。將混合物用水淬滅，並將混合物用EtOAc萃取。將合併的有機層用水、鹽水洗滌，並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EtOAc/PE（0-50%）洗脫）純化，以得到呈淡黃色固體的標題化合物。Step 6: (S)-2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-phenoxy)propan-1-ol To a stirred solution of (S)-2-(3-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)propan-1-ol hydrochloride (760 mg, 2.16 mmol, 1.0 equiv) and 2-chloro-5-(difluoromethoxy)pyrimidine (391 mg, 2.16 mmol, 1.0 equiv) in DMSO (7 mL) was added DIEA (560 mg, 4.32 mmol, 2.0 equiv), and the mixture was stirred at 90°C for 16 h. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with water, brine, and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc/PE (0-50%) to give the title compound as a pale yellow solid.

步驟7：(S)-2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯氧基)丙醛在-5°C-0°C在氮氣氣氛下向(S)-2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)丙-1-醇（200 mg，0.44 mmol，1.0當量）和DIEA（338 mg，2.62 mmol，6.0當量）在DCM（1 mL）中的攪拌溶液中逐滴添加DMSO（1 mL）中的SO₃-吡啶（278 mg，1.74 mmol，4.0當量），並將混合物在0^oC攪拌10 min。將混合物藉由添加水淬滅，並將混合物用EtOAc萃取。將合併的有機層用水、鹽水洗滌，並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EtOAc/PE（0-30%）洗脫）純化，以得到呈淡黃色固體的標題化合物。Step 7: (S)-2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-phenoxy)propanal To a stirred solution of (S)-2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propan-1-ol (200 mg, 0.44 mmol, 1.0 equiv) and DIEA (338 mg, 2.62 mmol, 6.0 equiv) in DCM (1 mL) was added_SO₃ -pyridine (278 mg, 1.74 mmol, 4.0 equiv) in DMSO (1 mL) dropwise at -5°C to 0°C under a nitrogen atmosphere, and the mixture was stirred at 0^° C for 10 min_. The mixture was quenched by the addition of water and extracted with EtOAc. The combined organic layers were washed with water, brine, and dried over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc/PE (0-30%)) to give the title compound as a pale yellow solid.

步驟8：(S)-1-(6-(1-(2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)苯氧基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮在0°C向1-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽（80 mg，0.22 mmol，1.0當量）和TEA（44 mg，0.44 mmol，2.0當量）在DMAc（1 mL）中的攪拌混合物中分批添加(S)-2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)苯氧基)丙醛（100 mg，0.22 mmol，1.0當量）。將所得混合物在室溫攪拌30 min，隨後在0°C分批添加NaBH(OAc)₃（104 mg，0.49 mmol，2.25當量）。將所得混合物在室溫攪拌2 h。將混合物濃縮並將殘餘物藉由製備型HPLC純化，以得到呈灰白色固體的標題化合物。MS (ES, m/z): [M+H]⁺= 768.2。Step 8: (S)-1-(6-(1-(2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione To a stirred mixture of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (80 mg, 0.22 mmol, 1.0 equiv) and TEA (44 mg, 0.44 mmol, 2.0 equiv) in DMAc (1 mL) was added (S)-2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)phenoxy)propanal (100 mg, 0.22 mmol, 1.0 equiv) portionwise at 0°C. The resulting mixture was stirred at room temperature for 30 min, followed by the addition of NaBH(OAc)₃ (104 mg, 0.49 mmol, 2.25 equiv) portionwise at 0°C. The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated and the residue was purified by preparative HPLC to afford the title compound as an off-white solid. MS (ES, m/z): [M+H]⁺ = 768.2.

藉由與實例6中所述類似的方式進行來合成以下化合物。實例#結構實例 7實例8實例9The following compounds were synthesized in a similar manner to that described in Example 6.Example#structure Example 7 Example 8 Example 9

實例101-(6-(1-(3-(3-((4-((5-溴嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)二酮的合成步驟1：(1-((3-(2-甲基-3-側氧基丙基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在100°C在氮氣氣氛下將(1-((3-溴苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（5.1 g，12.2 mmol，1.0當量）、Pd(AcO)₂（0.27 g，1.2 mmol，0.1當量）、2-甲基丙-2-烯-1-醇（2.6 g，36.5 mmol，3.0當量）、NaHCO₃（2 g，24.3 mmol，2.0當量）和四丁基溴化銨（19.6 g，60.8 mmol，5.0當量）在DMF（51 mL）中的溶液攪拌3 h。將所得混合物用EtOAc稀釋，並將有機層用水和鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EtOAc/PE（0-25%）洗脫）純化，以得到呈淡黃色固體的標題化合物。Example10 Synthesis of 1-(6-(1-(3-(3-((4-((5-bromopyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)dione Step 1: Tributyl (1-((3-(2-methyl-3-hydroxypropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate A solution of tributyl (1-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (5.1 g, 12.2 mmol, 1.0 equiv), Pd(AcO)₂ (0.27 g, 1.2 mmol, 0.1 equiv), 2-methylprop-2-en-1-ol (2.6 g, 36.5 mmol, 3.0 equiv), NaHCO₃ (2 g, 24.3 mmol, 2.0 equiv), and tetrabutylammonium bromide (19.6 g, 60.8 mmol, 5.0 equiv) in DMF (51 mL) was stirred at 100°C under a nitrogen atmosphere for 3 h. The resulting mixture was diluted with EtOAc, and the organic layer was washed with water and brine, and dried over anhydrous Na₂ SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc/PE (0-25%)) to give the title compound as a pale yellow solid.

步驟2：(1-((3-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在0°C向1-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽（4.06 g，11.2 mmol，1.0當量）在DMAc（46 mL）中的攪拌溶液中添加TEA（5.7 g，56 mmol，5.0當量）。將所得混合物在室溫攪拌5 min。向上述混合物中添加(1-((3-(2-甲基-3-側氧基丙基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（4.6 g，11.2 mmol，1.0當量）。將所得混合物在室溫攪拌1 h。然後在0°C分批添加NaBH(AcO)₃（5.3 g，25.2 mmol，2.25當量）並在室溫攪拌2 h。將混合物用H₂O稀釋並用EtOAc萃取。將合併的有機層用鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EtOAc/PE（0-100%）洗脫）純化，以得到呈白色固體的標題化合物。Step 2: Tributyl (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (4.06 g, 11.2 mmol, 1.0 equiv) in DMAc (46 mL) at 0°C was added TEA (5.7 g, 56 mmol, 5.0 equiv). The resulting mixture was stirred at room temperature for 5 min. To this mixture was added tributyl (1-((3-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (4.6 g, 11.2 mmol, 1.0 equiv). The resulting mixture was stirred at room temperature for 1 h. NaBH(AcO)_₃ (5.3 g, 25.2 mmol, 2.25 equiv) was then added portionwise at 0°C and stirred at room temperature for 2 h. The mixture was diluted with_H₂O and extracted with EtOAc. The combined organic layers were washed with brine and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc/PE (0-100%) to afford the title compound as a white solid.

步驟3：1-(6-(1-(3-(3-((4-胺基哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽在0°C向(1-((3-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯基)磺醯基)哌啶-4-基)-胺基甲酸三級丁酯（3.7 g，5.1 mmol，1.0當量）在DCM（37 mL）中的攪拌溶液中逐滴添加1,4-二㗁𠮿中的4M HCl（18 mL）。將所得混合物在室溫攪拌1 h。將混合物在減壓下濃縮，以給出呈淡黃色固體的標題化合物。Step 3: 1-(6-(1-(3-(3-((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride To a stirred solution of tributyl (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)-carbamate (3.7 g, 5.1 mmol, 1.0 equiv) in DCM (37 mL) was added 4 M HCl in 1,4-dioxathiocarbamate (18 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give the title compound as a pale yellow solid.

步驟4：1-(6-(1-(3-(3-((4-((5-溴嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基) 哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H) 二酮在室溫向1-(6-(1-(3-(3-((4-胺基哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽（100 mg，0.15 mmol，1.0當量）在DMSO（1 mL）中的攪拌溶液中添加DIEA（120 mg，0.91 mmol，6.0當量），並將混合物攪拌5 min。向上述混合物中添加5-溴-2-氯嘧啶（45 mg，0.23 mmol，1.5當量），並將混合物在120°C攪拌16 h。將混合物濃縮並將殘餘物藉由製備型HPLC純化，以得到呈白色固體的標題化合物。MS (ES, m/z): [M+H]⁺=778.3。Step 4: 1-(6-(1-(3-(3-((4-((5-bromopyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)dione To a stirred solution of 1-(6-(1-(3-(3-((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (100 mg, 0.15 mmol, 1.0 equiv) in DMSO (1 mL) was added DIEA (120 mg, 0.91 mmol, 6.0 equiv) at room temperature, and the mixture was stirred for 5 min. To this mixture was added 5-bromo-2-chloropyrimidine (45 mg, 0.23 mmol, 1.5 equiv), and the mixture was stirred at 120°C for 16 h. The mixture was concentrated and the residue was purified by preparative HPLC to give the title compound as a white solid. MS (ES, m/z): [M+H]⁺ = 778.3.

藉由與實例10中所述類似的方式進行來合成以下化合物。實例#結構實例11實例12實例13實例14實例15*實例16*實例17*實例18**藉由外消旋材料的手性分離製備單一鏡像異構物。The following compounds were synthesized in a similar manner to that described in Example 10.Example#structure Example 11 Example 12 Example 13 Example 14 Example 15* Example 16* Example 17* Example 18* *Preparation of single mirror image isomers by chiral separation of racemic materials.

實例191-(6-(1-(2-((3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)苯基) 胺基) 丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮的合成步驟1：(3-((4-((三級丁氧基羰基)胺基)哌啶-1-基)磺醯基)苯基)(1-羥基-丙-2-基)胺基甲酸三級丁酯在80°C在氮氣氣氛下將(1-((3-氟苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（5 g，13.95 mmol，1.0當量）和2-胺基丙-1-醇（4.19 g，55.8 mmol，4.0當量）、NaOH（2.79 g，69.75 mmol，5.0當量）在DMSO（50 mL）中的溶液攪拌2 h。將混合物用水稀釋並將混合物用EtOAc萃取。將合併的有機層用水和鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。向上述殘餘物中添加MeOH（45 mL）中的Boc₂O（6.5 g，28 mmol，2.0當量），並將混合物在室溫攪拌16 h。將混合物用水稀釋並將所得混合物用EtOAc萃取。將合併的有機層用水和鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EtOAc/PE（0-25%）洗脫）純化，以得到呈黃色固體的標題化合物。Example19 Synthesis of 1-(6-(1-(2-((3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)amino)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: (3-((4-((tert-butyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenyl)(1-hydroxy-propan-2-yl)carbamic acid tert-butyl ester A solution of tributyl (1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)carbamate (5 g, 13.95 mmol, 1.0 equiv), 2-aminopropan-1-ol (4.19 g, 55.8 mmol, 4.0 equiv), and NaOH (2.79 g, 69.75 mmol, 5.0 equiv) in DMSO (50 mL) was stirred at 80°C under a nitrogen atmosphere for 2 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. To the residue was added_Boc₂O (6.5 g, 28 mmol, 2.0 equiv) in MeOH (45 mL), and the mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc/PE (0-25%), to afford the title compound as a yellow solid.

步驟2：1-(6-(1-(2-((3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯基)胺基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮藉由與實例6的步驟5-8中所述類似的方式進行來合成標題化合物。MS (ES, m/z): [M+H]⁺= 767.4。Step 2: 1-(6-(1-(2-((3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-phenyl)amino)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione The title compound was synthesized in a manner similar to that described in Steps 5-8 of Example 6. MS (ES, m/z): [M+H]⁺ = 767.4.

實例201-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮的合成步驟1：(1-((3-(2-甲基烯丙基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在65°C在氮氣氣氛下將(1-((3-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯基)-磺醯基)哌啶-4-基)胺基甲酸三級丁酯（3.3 g，7.1 mmol，1.0當量）、3-溴-2-甲基丙-1-烯（1.91 g，14.2 mmol，2.0當量）、Pd(PPh₃)₂Cl₂（497 mg，0.7 mmol，0.1當量）和Na₂CO₃（2.25 g，21.2 mmol，3.0當量）在THF（30 mL）和H₂O（3 mL）中的混合物攪拌4 h。將所得混合物用水稀釋並用DCM萃取。將合併的有機層用水和鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EtOAc/PE（0-30%）洗脫）純化，以得到呈黃色固體的標題化合物。Example20 Synthesis of 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Tributyl (1-((3-(2-methylallyl)phenyl)sulfonyl)piperidin-4-yl)carbamate A mixture of tributyl (1-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-sulfonyl)piperidin-4-yl)carbamate (3.3 g, 7.1 mmol, 1.0 equiv), 3-bromo-2-methylprop-1-ene (1.91 g, 14.2 mmol, 2.0 equiv), Pd(PPh₃ )₂ Cl₂ (497 mg, 0.7 mmol, 0.1 equiv), and Na₂ CO₃ (2.25 g, 21.2 mmol, 3.0 equiv) in THF (30 mL) and H₂ O (3 mL) was stirred at 65° C. under a nitrogen atmosphere for 4 h. The resulting mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, and dried over anhydrous Na₂ SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc/PE (0-30%)) to give the title compound as a yellow solid.

步驟2：(1-((3-((2-甲基氧雜丙環烷-2-基)甲基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在0°C向(1-((3-(2-甲基烯丙基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（810 mg，2.1 mmol，1.0當量）在DCM（10 mL）中的攪拌溶液中分批添加m-CPBA（834 mg，4.1 mmol，2.0當量，85%）。將所得混合物在室溫攪拌4 h。將反應在0°C用水性NaHCO₃淬滅，並將所得混合物用EtOAc萃取。將合併的有機層用水和鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EtOAc/PE（0-100%）洗脫）純化，以得到呈淡黃色固體的標題化合物。Step 2: Tributyl (1-((3-((2-methyloxopropylcycloalkan-2-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of tributyl (1-((3-(2-methylallyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (810 mg, 2.1 mmol, 1.0 equiv) in DCM (10 mL) was added portionwise m-CPBA (834 mg, 4.1 mmol, 2.0 equiv, 85%) at 0°C. The resulting mixture was stirred at room temperature for 4 h. The reaction was quenched with aqueous_NaHCO₃ at 0°C, and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc/PE (0-100%) to give the title compound as a pale yellow solid.

步驟3：(1-((3-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-羥基-2-甲基丙基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯向(1-((3-((2-甲基氧雜丙環烷-2-基)甲基)苯基)磺醯基)-哌啶-4-基)胺基甲酸三級丁酯（650 mg，1.6 mmol，1.0當量）和1-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽（634 mg，1.76 mmol，1.1當量）在EtOH（6 mL）中的攪拌溶液中添加TEA（240 mg，2.4 mmol，1.5當量），並將混合物在80°C攪拌24 h。將混合物用水稀釋並用EtOAc萃取。將合併的有機層用水和鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由與EtOAc/PE（1 : 3）一起研磨來純化，以得到呈白色固體的標題化合物。Step 3: (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-hydroxy-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamic acid tributyl ester To a stirred solution of tributyl (1-((3-((2-methyloxopropan-2-yl)methyl)phenyl)sulfonyl)-piperidin-4-yl)carbamate (650 mg, 1.6 mmol, 1.0 equiv) and 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (634 mg, 1.76 mmol, 1.1 equiv) in EtOH (6 mL) was added TEA (240 mg, 2.4 mmol, 1.5 equiv), and the mixture was stirred at 80°C for 24 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, and the organic layer was dried over_{anhydrousNa2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with EtOAc/PE (1:3) to give the title compound as a white solid.

步驟4：1-(6-(1-(3-(3-((4-胺基哌啶-1-基)磺醯基)苯基)-2-羥基-2-甲基丙基)-哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽向(1-((3-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-羥基-2-甲基丙基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（700 mg，1 mmol，1.0當量）在DCM（3 mL）中的攪拌溶液中逐滴添加1,4-二㗁𠮿中的4 M HCl（3 mL），並將混合物攪拌2 h。將所得混合物在真空下濃縮，以得到呈淡黃色固體的標題化合物。Step 4: 1-(6-(1-(3-(3-((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)-piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride To a stirred solution of tributyl (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-hydroxy-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (700 mg, 1 mmol, 1.0 equiv) in DCM (3 mL) was added 4 M HCl in 1,4-dioxathiocarbamate (3 mL) dropwise, and the mixture was stirred for 2 h. The resulting mixture was concentrated under vacuum to give the title compound as a pale yellow solid.

步驟5：1-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮向1-(6-(1-(3-(3-((4-胺基哌啶-1-基)磺醯基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽（90 mg，0.14 mmol，1.0當量）和2-氯-5-(二氟甲氧基)嘧啶（38 mg，0.2 mmol，1.5當量）在DMSO（0.45 mL）中的攪拌混合物中添加DIEA（0.45 mL），並將所得混合物在100°C在氮氣氣氛下攪拌16 h。將混合物用水稀釋並用EtOAc萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由製備型HPLC純化，以得到呈淡黃色固體的標題化合物。MS (ES, m/z): [M+H]⁺= 782.4。Step 5: 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione To a stirred mixture of 1-(6-(1-(3-(3-((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (90 mg, 0.14 mmol, 1.0 equiv) and 2-chloro-5-(difluoromethoxy)pyrimidine (38 mg, 0.2 mmol, 1.5 equiv) in DMSO (0.45 mL) was added DIEA (0.45 mL), and the resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, and then dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to yield the title compound as a pale yellow solid. MS (ES, m/z): [M+H]^⁺ = 782.4.

藉由與實例20中所述類似的方式進行來合成以下化合物。實例#結構實例 21實例 22The following compounds were synthesized in a similar manner to that described in Example 20.Example#structure Example 21 Example 22

實例231-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基) 磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮的合成步驟1：(1-((4-溴苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在0°C向4-溴苯磺醯氯（10.0 g，39.14 mmol，1.00當量）在DCM（20.0 mL）中的攪拌溶液中添加哌啶-4-基胺基甲酸三級丁酯（9.41 g，46.96 mmol，1.20當量）和TEA（7.92 g，78.27 mmol，2.00當量），並將混合物在室溫攪拌2 h。將混合物用水稀釋並用DCM萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮並將殘餘物藉由矽膠柱層析法（用PE:EtOAc = 4:1洗脫）純化，以得到呈白色固體的標題化合物。Example23 Synthesis of 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Tributyl (1-((4-bromophenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of 4-bromobenzenesulfonyl chloride (10.0 g, 39.14 mmol, 1.00 equiv) in DCM (20.0 mL) at 0°C was added tributyl piperidin-4-ylcarbamate (9.41 g, 46.96 mmol, 1.20 equiv) and TEA (7.92 g, 78.27 mmol, 2.00 equiv), and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, and the organic layer was dried over_{anhydrousNa₂SO₄} . After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluted with PE:EtOAc = 4:1) to give the title compound as a white solid.

步驟2：(1-((4-(2-甲基-3-側氧基丙基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯將(1-((4-溴苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（500 mg，1.20 mmol，1.00當量）、NaHCO₃（201 mg，2.39 mmol，2.00當量）、四丁基溴化銨（77.1 mg，0.239 mmol，0.2當量）、2-甲基丙-2-烯-1-醇（172.4 mg，2.39 mmol，2.00當量）和Pd(OAc)₂（6 mg，0.0239 mmol，0.02當量）在DMF（10.0 mL）中的混合物在100°C在N₂下攪拌12 h。將混合物倒入水中，用EtOAc萃取。將合併的有機層用水和鹽水洗滌，經Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由急速層析法純化，以給出呈白色固體的標題化合物。Step 2: Tributyl (1-((4-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate A mixture of tributyl (1-((4-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (500 mg, 1.20 mmol, 1.00 equiv), NaHCO₃ (201 mg, 2.39 mmol, 2.00 equiv), tetrabutylammonium bromide (77.1 mg, 0.239 mmol, 0.2 equiv), 2-methylprop-2-en-1-ol (172.4 mg, 2.39 mmol, 2.00 equiv), and Pd(OAc)₂ (6 mg, 0.0239 mmol, 0.02 equiv) in DMF (10.0 mL) was stirred at 100° C. under N₂ for 12 h. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with water and brine, and dried over Na₂ SO₄ . After filtration, the filtrate was concentrated and the residue was purified by flash chromatography to give the title compound as a white solid.

步驟3：(1-((4-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在0°C向(1-((4-(2-甲基-3-側氧基丙基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（150 mg，0.366 mmol，1.00當量）、1-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽（133 mg，0.366 mmol，1.00當量）和TEA（110.9 mg，1.1 mmol，3.00當量）在DMA（2.0 ml）中的攪拌溶液中添加NaBH(OAc)₃（187.7 mg，0.886 mmol，2.5當量），並將混合物在0°C攪拌2 h。將混合物倒入水中，用EtOAc萃取。將合併的有機層用水和鹽水洗滌，經Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由急速層析法純化，以給出呈白色固體的標題化合物。Step 3: Tributyl (1-((4-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of tributyl (1-((4-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (150 mg, 0.366 mmol, 1.00 equiv), 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (133 mg, 0.366 mmol, 1.00 equiv), and TEA (110.9 mg, 1.1 mmol, 3.00 equiv) in DMA (2.0 ml) was added NaBH(OAc)₃ (187.7 mg, 0.886 mmol, 2.5 equiv) at 0°C, and the mixture was stirred at 0°C for 2 h. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with water and brine, and dried over Na₂ SO₄ . After filtration, the filtrate was concentrated and the residue was purified by flash chromatography to give the title compound as a white solid.

步驟4：1-(6-(1-(3-(4-((4-胺基哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽將EtOAc中的HCl（2 M，2.0 mL）添加至(1-((4-(3-(4-(3-(2,4-二側氧基四氫-嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯基)磺醯基)-哌啶-4-基)胺基甲酸三級丁酯（110 mg，0.15 mmol，1.00當量）中，並將混合物在室溫攪拌2 h。將混合物在減壓下濃縮，以給出呈棕色油狀物的標題化合物。Step 4: 1-(6-(1-(3-(4-((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride To tributyl (1-((4-(3-(4-(3-(2,4-dioxotetrahydro-pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)phenyl)sulfonyl)-piperidin-4-yl)carbamate (110 mg, 0.15 mmol, 1.00 equiv) was added HCl in EtOAc (2 M, 2.0 mL), and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give the title compound as a brown oil.

步驟5：1-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基) 磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮將1-(6-(1-(3-(4-((4-胺基哌啶-1-基)磺醯基)苯基)-2-甲基丙基)-哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽（94.8 mg，0.15 mmol，1.00當量）、CsF（151.9 mg，0.76 mmol，5.00當量）、DIEA（98 mg，0.76 mmol，5.00當量）和2-氯-5-(二氟甲氧基) 嘧啶（27.4 mg，0.152 mmol，1.00當量）在DMSO（2.0 mL）中的混合物在50°C在N₂下攪拌12 h。將混合物用水稀釋並用EtOAc萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由急速層析法純化，以得到呈白色固體的標題化合物。MS (ES, m/z): [M+1]⁺= 766.3。Step 5: 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of 1-(6-(1-(3-(4-((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)-piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (94.8 mg, 0.15 mmol, 1.00 equiv), CsF (151.9 mg, 0.76 mmol, 5.00 equiv), DIEA (98 mg, 0.76 mmol, 5.00 equiv), and 2-chloro-5-(difluoromethoxy)pyrimidine (27.4 mg, 0.152 mmol, 1.00 equiv) in DMSO (2.0 mL) was stirred at 50° C. under N₂ for 12 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated, and the residue was purified by flash chromatography to afford the title compound as a white solid. MS (ES, m/z): [M+1]⁺ = 766.3.

藉由與實例23中所述類似的方式進行來合成以下化合物。實例#結構實例 24The following compounds were synthesized in a similar manner to that described in Example 23.Example#structure Example 24

實例251-(6-(1-(2-(5-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟甲基)苯氧基)乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮的合成步驟1：5-((4-(三級丁基)苄基)硫代)-2-(三氟甲基)苯酚向5-溴-2-(三氟甲基)苯酚（1.00 g，4.15 mmol，1.00當量）在1,4-二㗁𠮿（10.0 mL）中的攪拌溶液中添加(4-(三級丁基)苯基)甲硫醇（972 mg，5.40 mmol，1.30當量）、Pd₂(dba)₃（385 mg，0.42 mmol，0.10當量）、DIEA（1.61 g，12.45 mmol，3.00當量）和XantPhos（486 mg，0.84 mmol，0.20當量），並將混合物在100°C攪拌12 h。將混合物用水稀釋並用DCM萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用PE/EtOAc = 20:1洗脫）純化，以得到呈黃色固體的標題化合物。Example25 Synthesis of 1-(6-(1-(2-(5-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: 5-((4-(tert-butyl)benzyl)thio)-2-(trifluoromethyl)phenol To a stirred solution of 5-bromo-2-(trifluoromethyl)phenol (1.00 g, 4.15 mmol, 1.00 equiv) in 1,4-dioxane (10.0 mL) were added (4-(tert-butyl)phenyl)methanethiol (972 mg, 5.40 mmol, 1.30 equiv), Pd₂ (dba)₃ (385 mg, 0.42 mmol, 0.10 equiv), DIEA (1.61 g, 12.45 mmol, 3.00 equiv) and XantPhos (486 mg, 0.84 mmol, 0.20 equiv), and the mixture was stirred at 100° C. for 12 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, and dried over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE/EtOAc = 20:₁ ) to obtain the title compound as a yellow solid.

步驟2：三級丁基(2-(5-((4-(三級丁基)苄基)硫代)-2-(三氟甲基)苯氧基)乙氧基)二甲基-矽烷向5-((4-(三級丁基)苄基)硫代)-2-(三氟甲基)苯酚（801 mg，2.36 mmol，1.00當量）、2-((三級丁基二甲基甲矽烷基)氧基)乙-1-醇（415 mg，2.36 mmol，1.00當量）在THF（10.0 mL）中的攪拌溶液中添加三苯膦（1.24 g，4.72 mmol，2.00當量）並在0°C攪拌15 min。然後在0°C添加DIAD（953 mg，4.72 mmol，2.00當量）並將混合物攪拌3 h。將混合物用水稀釋並用DCM萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用PE/EtOAc = 20:1洗脫）純化，以得到呈黃色固體的標題化合物。Step 2: Tert-butyl (2-(5-((4-(tert-butyl)benzyl)thio)-2-(trifluoromethyl)phenoxy)ethoxy)dimethyl-silane To a stirred solution of 5-((4-(tributyl)benzyl)thio)-2-(trifluoromethyl)phenol (801 mg, 2.36 mmol, 1.00 equiv) and 2-((tributyldimethylsilyl)oxy)ethan-1-ol (415 mg, 2.36 mmol, 1.00 equiv) in THF (10.0 mL) was added triphenylphosphine (1.24 g, 4.72 mmol, 2.00 equiv) and stirred at 0°C for 15 min. DIAD (953 mg, 4.72 mmol, 2.00 equiv) was then added at 0°C, and the mixture was stirred for 3 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, and the organic layer was dried over_{anhydrousNa₂SO₄} . After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE/EtOAc = 20:1) to give the title compound as a yellow solid.

步驟3：3-(2-((三級丁基二甲基甲矽烷基)氧基)乙氧基)-4-(三氟甲基)苯磺醯氯在室溫向三級丁基(2-(5-((4-(三級丁基)苄基)硫代)-2-(三氟甲基)-苯氧基)乙氧基)二甲基矽烷（637 mg，1.28 mmol，1.00當量）在AcOH（1.0 mL）和ACN/H₂O（3.0 mL/0.4 mL）中的攪拌溶液中添加1,3-二氯-5,5-二甲基咪唑烷-2,4-二酮（504 mg，2.56 mmol，2.00當量），並將混合物攪拌12 h。將混合物用水稀釋並用DCM萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮，以得到呈白色固體的標題化合物。Step 3: 3-(2-((tributyldimethylsilyl)oxy)ethoxy)-4-(trifluoromethyl)benzenesulfonyl chloride To a stirred solution of tert-butyl(2-(5-((4-(tert-butyl)benzyl)thio)-2-(trifluoromethyl)-phenoxy)ethoxy)dimethylsilane (637 mg, 1.28 mmol, 1.00 equiv) in AcOH (1.0 mL) and ACN/_H₂O (3.0 mL/0.4 mL) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (504 mg, 2.56 mmol, 2.00 equiv) at room temperature, and the mixture was stirred for 12 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, and the organic layer was dried over_{anhydrousNa₂SO₄} . After filtration, the filtrate was concentrated under reduced pressure to give the title compound as a white solid.

步驟4：N-(1-((3-(2-((三級丁基二甲基甲矽烷基)氧基)乙氧基)-4-(三氟甲基)苯基)-磺醯基)-哌啶-4-基)-5-氯嘧啶-2-胺在室溫向5-氯-N-(哌啶-4-基)嘧啶-2-胺（349 mg，1.41 mmol，1.10當量）和TEA（388 mg，3.84 mmol，3.00當量）在DCM（5.0 mL）中的攪拌溶液中添加3-(2-((三級丁基二甲基甲矽烷基)氧基)乙氧基)-4-(三氟甲基)苯磺醯氯（535 mg，1.28 mmol，1.00當量），並將混合物攪拌12 h。將混合物用水稀釋並用DCM萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EtOAc:PE（0至100%）洗脫）純化，以得到呈白色固體的標題化合物。Step 4: N-(1-((3-(2-((tributyldimethylsilyl)oxy)ethoxy)-4-(trifluoromethyl)phenyl)-sulfonyl)-piperidin-4-yl)-5-chloropyrimidin-2-amine To a stirred solution of 5-chloro-N-(piperidin-4-yl)pyrimidin-2-amine (349 mg, 1.41 mmol, 1.10 equiv) and TEA (388 mg, 3.84 mmol, 3.00 equiv) in DCM (5.0 mL) was added 3-(2-((tributyldimethylsilyl)oxy)ethoxy)-4-(trifluoromethyl)benzenesulfonyl chloride (535 mg, 1.28 mmol, 1.00 equiv) at room temperature, and the mixture was stirred for 12 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, and the organic layer was dried over_{anhydrousNa₂SO₄} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc:PE (0-100%) to give the title compound as a white solid.

步驟5：2-(5-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟甲基)-苯氧基)乙-1-醇在室溫將TBAF（1.0 M在THF中，2.00 mL）添加至N-(1-((3-(2-((三級丁基二甲基甲矽烷基)氧基)乙氧基)-4-(三氟甲基)苯基)磺醯基)哌啶-4-基)-5-氯嘧啶-2-胺（120 mg，0.20 mmol，1.00當量）的攪拌溶液中，並將混合物攪拌3 h。將混合物用水稀釋並用DCM萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮，以得到呈白色固體的標題化合物。Step 5: 2-(5-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)-phenoxy)ethan-1-ol TBAF (1.0 M in THF, 2.00 mL) was added to a stirred solution of N-(1-((3-(2-((tributyldimethylsilyl)oxy)ethoxy)-4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4-yl)-5-chloropyrimidin-2-amine (120 mg, 0.20 mmol, 1.00 equiv) at room temperature, and the mixture was stirred for 3 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, and the organic layer was dried over_{anhydrousNa₂SO₄} . After filtration, the filtrate was concentrated under reduced pressure to give the title compound as a white solid.

步驟6：2-(5-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟甲基)-苯氧基)乙醛在室溫向2-(5-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟甲基)苯氧基)乙-1-醇（100 mg，0.21 mmol，1.00當量）在DCM（5.0 mL）中的攪拌溶液中添加戴斯-馬丁過碘烷（134 mg，0.32 mmol，1.50當量），並將混合物攪拌5 h。將混合物用水稀釋並用DCM萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮，以得到呈黃色油狀物的標題化合物。Step 6: 2-(5-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)-phenoxy)acetaldehyde To a stirred solution of 2-(5-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)phenoxy)ethan-1-ol (100 mg, 0.21 mmol, 1.00 equiv) in DCM (5.0 mL) was added Dess-Martin periodinane (134 mg, 0.32 mmol, 1.50 equiv) at room temperature, and the mixture was stirred for 5 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, and the organic layer was dried over_{anhydrousNa₂SO₄} . After filtration, the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil.

步驟7：1-(6-(1-(2-(5-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟-甲基)苯氧基)乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮在0°C向2-(5-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟甲基)苯氧基)乙醛（100 mg，0.21 mmol，1.00當量）在DMA（2.0 mL）中的攪拌混合物中添加1-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽（83 mg，0.23 mmol，1.10當量）、TEA（64 mg，0.63 mmol，3.00當量）、NaBH(OAc)₃（108 mg，0.51 mmol，2.5當量），並將所得混合物攪拌12 h。將混合物用水稀釋並用DCM萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用DCM/MeOH（20:1）洗脫）純化，以得到呈白色固體的標題化合物。MS (ES, m/z): [M+1]⁺= 790.2。Step 7: 1-(6-(1-(2-(5-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoro-methyl)phenoxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione To a stirred mixture of 2-(5-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)phenoxy)acetaldehyde (100 mg, 0.21 mmol, 1.00 equiv) in DMA (2.0 mL) was added 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (83 mg, 0.23 mmol, 1.10 equiv), TEA (64 mg, 0.63 mmol, 3.00 equiv), and NaBH(OAc)₃ (108 mg, 0.51 mmol, 2.5 equiv) at 0°C, and the resulting mixture was stirred for 12 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM/MeOH (20:1)) to afford the title compound as a white solid. MS (ES, m/z): [M+1]⁺ = 790.2.

實例264-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙氧基)苯甲腈的合成步驟1：4-((4-(三級丁基)苄基)硫代)-2-羥基苯甲腈將4-溴-2-羥基苯甲腈（3.10 g，15.7 mmol，1.00當量）、(4-三級丁基苯基)甲硫醇（3.11 g，17.2 mmol，1.10當量）、Pd₂(dba)₃（1.44 g，1.57 mmol，0.10當量）和XantPhos（1.82 g，3.14 mmol，0.20當量）、DIEA（6.09 g，47.1 mmol，3.00當量）在1,4-二㗁𠮿（40.0 mL）中的混合物在100°C在N₂下攪拌16 h。將混合物過濾，並且將濾液濃縮。將殘餘物藉由矽膠柱層析法（PE:EtOAc = 30 : 1）純化，以給出呈黃色固體的標題化合物。Example26 Synthesis of 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethoxy)benzonitrile Step 1: 4-((4-(tert-butyl)benzyl)thio)-2-hydroxybenzonitrile A mixture of 4-bromo-2-hydroxybenzonitrile (3.10 g, 15.7 mmol, 1.00 equiv), (4-tert-butylphenyl)methanethiol (3.11 g, 17.2 mmol, 1.10 equiv), Pd₂ (dba)₃ (1.44 g, 1.57 mmol, 0.10 equiv), XantPhos (1.82 g, 3.14 mmol, 0.20 equiv), and DIEA (6.09 g, 47.1 mmol, 3.00 equiv) in 1,4-dioxane (40.0 mL) was stirred at 100° C. under N₂ for 16 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc = 30:1) to give the title compound as a yellow solid.

步驟2：4-((4-(三級丁基)苄基)硫代)-2-(2-((三級丁基二甲基甲矽烷基)氧基)乙氧基)苯甲腈在0°C向4-((4-(三級丁基)苄基)硫代)-2-羥基苯甲腈（1.00 g，3.4 mmol，1.00當量）、2-[(三級丁基二甲基甲矽烷基)氧基]乙醇（0.66 g，3.7 mmol，1.10當量）和三苯膦（1.78 g，6.8 mmol，2.00當量）在THF（25.0 mL）中的攪拌溶液中緩慢添加偶氮二甲酸二異丙酯（1.38 g，6.8 mmol，2.00當量）。將混合物在室溫在N₂下攪拌3 h。將混合物用水稀釋並用EtOAc萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由矽膠柱層析法（PE:EtOAc = 20 : 1）純化，以給出呈淡黃色油狀物的標題化合物。Step 2: 4-((4-(tert-butyl)benzyl)thio)-2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzonitrile To a stirred solution of 4-((4-(tert-butyl)benzyl)thio)-2-hydroxybenzonitrile (1.00 g, 3.4 mmol, 1.00 equiv), 2-[(tert-butyldimethylsilyl)oxy]ethanol (0.66 g, 3.7 mmol, 1.10 equiv), and triphenylphosphine (1.78 g, 6.8 mmol, 2.00 equiv) in THF (25.0 mL) at 0°C was slowly added diisopropyl azodicarboxylate (1.38 g, 6.8 mmol, 2.00 equiv). The mixture was stirred at room temperature under_N₂ for 3 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (PE:EtOAc = 20:1) to give the title compound as a pale yellow oil.

步驟3：3-(2-((三級丁基二甲基甲矽烷基)氧基)乙氧基)-4-氰基苯磺醯氯向4-((4-(三級丁基)苄基)硫代)-2-(2-((三級丁基二甲基甲矽烷基)-氧基)乙氧基)苯甲腈（910 mg，2.00 mmol，1.00當量）在ACN（15.0 mL）/水（2.0 mL）中的攪拌溶液中添加AcOH（5.0 mL）。然後在0°C添加1,3-二氯-5,5-二甲基咪唑烷-2,4-二酮（786.8 mg，3.99 mmol，2.00當量），並將混合物在室溫攪拌3 h。將混合物用水稀釋並用EtOAc萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液濃縮以給出呈黃色油狀物的標題化合物。Step 3: 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-cyanobenzenesulfonyl chloride To a stirred solution of 4-((4-(tributyl)benzyl)thio)-2-(2-((tributyldimethylsilyl)oxy)ethoxy)benzonitrile (910 mg, 2.00 mmol, 1.00 equiv) in ACN (15.0 mL)/water (2.0 mL) was added AcOH (5.0 mL). 1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (786.8 mg, 3.99 mmol, 2.00 equiv) was then added at 0°C, and the mixture was stirred at room temperature for 3 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over_{anhydrousNa₂SO₄} . After filtration, the filtrate was concentrated to give the title compound as a yellow oil.

步驟4：4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-羥基乙氧基)-苯甲腈藉由與實例25的步驟4-5中所述類似的方式進行來合成標題化合物。Step 4: 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-hydroxyethoxy)-benzonitrile The title compound was synthesized by proceeding in a similar manner to that described in Steps 4-5 of Example 25.

步驟5：2-(2-溴乙氧基)-4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯甲腈在室溫向4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-羥基乙氧基)苯甲腈（100 mg，0.23 mmol，1.00當量）和四溴甲烷（90.9 mg，0.27 mmol，1.20當量）在DCM（5.0 mL）中的攪拌溶液中添加三苯膦（95.9 mg，0.37 mmol，1.60當量），並將混合物攪拌3 h。將混合物用水稀釋並用DCM萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（DCM:MeOH = 20:1）純化，以給出呈白色固體的標題化合物。Step 5: 2-(2-bromoethoxy)-4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzonitrile To a stirred solution of 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-hydroxyethoxy)benzonitrile (100 mg, 0.23 mmol, 1.00 equiv) and tetrabromomethane (90.9 mg, 0.27 mmol, 1.20 equiv) in DCM (5.0 mL) was added triphenylphosphine (95.9 mg, 0.37 mmol, 1.60 equiv) at room temperature, and the mixture was stirred for 3 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give the title compound as a white solid.

步驟6：4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-(4-(3-(2,4-二側氧基-四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙氧基)苯甲腈在室溫向1-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氫-嘧啶-2,4(1H,3H)-二酮鹽酸鹽（20 mg，0.06 mmol，1.00當量）和2-(2-溴-乙氧基)-4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈（27.5 mg，0.06 mmol，1.00當量）在DMSO（1.0 mL）中的攪拌溶液中添加K₂CO₃（22.8 mg，0.17 mmol，3.00當量）和KI（18.3 mg，0.11 mmol，2.00當量），並將混合物在70°C在N₂下攪拌16 h。將混合物用水稀釋並用EtOAc萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由製備型TLC（DCM:MeOH = 15:1）純化，以給出呈白色固體的標題化合物。MS (ES, m/z): [M+1]⁺= 747.2。Step 6: 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-(4-(3-(2,4-dioxo-tetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethoxy)benzonitrile To a stirred solution of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydro-pyrimidine-2,4(1H,3H)-dione hydrochloride (20 mg, 0.06 mmol, 1.00 equiv) and 2-(2-bromo-ethoxy)-4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile (27.5 mg, 0.06 mmol, 1.00 equiv) in DMSO (1.0 mL₎ was added_K2CO3 (22.8 mg, 0.17 mmol, 3.00 equiv) and KI (18.3 mg, 0.11 mmol, 2.00 equiv) at room temperature, and the mixture was stirred at 70°C under_N2 for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 15:1) to afford the title compound as a white solid. MS (ES, m/z): [M₊ 1]⁺ = 747.2.

實例272-((3-(4-(1-(2,6-二側氧基哌啶-3-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]-咪唑-4-基)哌啶-1-基)丙基)(甲基)胺基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈2,2,2-三氟乙酸鹽的合成步驟1：4-氰基-3-氟苯磺醯氯4-胺基-2-氟苯甲腈（4.80 g，35.29 mmol，1.00當量）在濃HCl（60.0 mL）和H₂O（20.0 mL）中的混合物在80^oC加熱後變澄清，然後將混合物冷卻至0°C。在0°C將NaNO₂（2.64 g，38.11 mmol，1.08當量）在H₂O（60.0 mL）中的溶液緩慢添加至上述混合物中，並將混合物攪拌15 min。然後緩慢添加CuCl（280 mg，2.82 mmol，0.08當量）在H₂O（60.0 mL）中的溶液，隨後在0^oC添加SOCl₂（10.0 mL）。將混合物在0°C攪拌30 min。將混合物用水稀釋並用EtOAc萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將有機層在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用（PE:EtOAc = 2:1）洗脫）純化，以得到呈黃色固體的標題化合物。Example27 Synthesis of 2-((3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]-imidazol-4-yl)piperidin-1-yl)propyl)(methyl)amino)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 2,2,2-trifluoroacetate Step 1: 4-cyano-3-fluorobenzenesulfonyl chloride A mixture of 4-amino-2-fluorobenzonitrile (4.80 g, 35.29 mmol, 1.00 equiv) in concentrated HCl (60.0 mL) and_H₂O (20.0 mL) became clear upon heating at 80^° C, and the mixture was then cooled to 0°C. A solution of_NaNO₂ (2.64 g, 38.11 mmol, 1.08 equiv) in_H₂O (60.0 mL) was slowly added to the mixture at 0°C, and the mixture was stirred for 15 min. A solution of CuCl₂ (280 mg, 2.82 mmol, 0.08 equiv) in_H₂O (60.0 mL) was then slowly added, followed by_SOCl₂ (10.0 mL) at 0^° C. The mixture was stirred at 0°C for 30 min. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, and dried over anhydrous_Na₂SO₄ . After filtration, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EtOAc = 2:₁ ) to afford the title compound as a yellow solid.

步驟2：2-氟-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯甲腈在0°C向N-(哌啶-4-基)-5-(三氟甲基)嘧啶-2-胺鹽酸鹽（1.28 g，4.56 mmol，1.00當量）在DCM（15.0 mL）中的攪拌溶液中添加TEA（1.38 g，13.68 mmol，3.00當量）和3-溴-4-氰基苯磺醯氯（1.00 g，4.56 mmol，1.00當量），並將混合物攪拌3 h。將混合物用水稀釋並用EtOAc萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將有機層在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用（DCM:MeOH = 40:1）洗脫）純化，以得到呈黃色固體的標題化合物。Step 2: 2-Fluoro-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzonitrile To a stirred solution of N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride (1.28 g, 4.56 mmol, 1.00 equiv) in DCM (15.0 mL) at 0°C was added TEA (1.38 g, 13.68 mmol, 3.00 equiv) and 3-bromo-4-cyanobenzenesulfonyl chloride (1.00 g, 4.56 mmol, 1.00 equiv), and the mixture was stirred for 3 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, and the organic layer was dried over_{anhydrousNa₂SO₄} . After filtration, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with (DCM:MeOH = 40:1)) to give the title compound as a yellow solid.

步驟3：2-((3-羥基丙基)(甲基)胺基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)苯甲腈向2-氟-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)苯甲腈（500 mg，1.17 mmol，1.00當量）在DMSO（8.0 mL）中的攪拌溶液中添加3-(甲基胺基)丙-1-醇（312 mg，3.51 mmol，3.00當量）和碳酸鉀（484 mg，3.51 mmol，3.00當量），並將混合物在100°C攪拌3 h。將混合物用水稀釋並用EtOAc萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將有機層在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用（DCM:MeOH = 50:1）洗脫）純化，以得到呈黃色固體的標題化合物。Step 3: 2-((3-Hydroxypropyl)(methyl)amino)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)benzonitrile To a stirred solution of 2-fluoro-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)benzonitrile (500 mg, 1.17 mmol, 1.00 equiv) in DMSO (8.0 mL) were added 3-(methylamino)propan-1-ol (312 mg, 3.51 mmol, 3.00 equiv) and potassium carbonate (484 mg, 3.51 mmol, 3.00 equiv), and the mixture was stirred at 100°C for 3 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, and the organic layer was dried over anhydrous_Na₂SO₄. After filtration, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with (DCM:MeOH = 50:1)) to give the title compound as a yellow solid.

步驟4：2-(甲基(3-側氧基丙基)胺基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈在0°C向2-((3-羥基丙基)(甲基)胺基)-4-((4-((5-(三氟甲基)-嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈（130 mg，0.26 mmol，1.00當量）在DCM（3.0 mL）中的攪拌溶液中添加戴斯-馬丁過碘烷（165 mg，0.39 mmol，1.50當量），並將混合物攪拌2 h。將混合物用水稀釋並用EtOAc萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將有機層在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用（PE:EtOAc = 5:1）洗脫）純化，以得到呈黃色油狀物的標題化合物。Step 4: 2-(Methyl(3-hydroxypropyl)amino)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile To a stirred solution of 2-((3-hydroxypropyl)(methyl)amino)-4-((4-((5-(trifluoromethyl)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile (130 mg, 0.26 mmol, 1.00 equiv) in DCM (3.0 mL) was added Dess-Martin periodinane (165 mg, 0.39 mmol, 1.50 equiv) at 0°C, and the mixture was stirred for 2 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, and the organic layer was dried over_{anhydrousNa₂SO₄} . After filtration, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with (PE:EtOAc = 5:1)) to give the title compound as a yellow oil.

步驟5：2-((3-(4-(1-(2,6-二側氧基哌啶-3-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-4-基)哌啶-1-基)丙基)(甲基)胺基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)苯甲腈2,2,2-三氟乙酸鹽在0°C向2-(甲基(3-側氧基丙基)胺基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈（150 mg，0.30 mmol，1.00當量）和3-(3-甲基-2-側氧基-4-(哌啶-4-基)-2,3-二氫-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮鹽酸鹽（113.4 mg，0.30 mmol，1.00當量）在DCM（5.0 mL）中的混合物中添加NaBH(OAc)₃（154 mg，0.73 mmol，2.50當量）和TEA（91 mg，0.90 mmol，3.00當量），並將混合物在室溫攪拌12 h。將混合物用水稀釋並用EtOAc萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮並將殘餘物藉由製備型HPLC純化，以得到呈白色固體的標題化合物作為其TFA鹽。MS (ES, m/z): [M+1]⁺= 823.3Step 5: 2-((3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)propyl)(methyl)amino)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)benzonitrile 2,2,2-trifluoroacetate To a mixture of 2-(methyl(3-oxopropyl)amino)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile (150 mg, 0.30 mmol, 1.00 equiv) and 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride (113.4 mg, 0.30 mmol, 1.00 equiv) in DCM (5.0 mL) at 0 °C was added NaBH(OAc)₃ (154 mg, 0.73 mmol, 2.50 equiv) and TEA (91 mg, 0.90 mmol, 3.00 equiv) and the mixture was stirred at room temperature for 12 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na₂ SO_4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC to give the title compound as a white solid as its TFA salt. MS (ES, m/z): [M+1]⁺ = 823.3

實例28(S)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈的合成步驟1：(S)-3-(5-((4-((三級丁氧基羰基)胺基)哌啶-1-基)磺醯基)-2-氰基苯基)-2-甲基丙酸甲酯在氮氣氣氛下向N-[1-(3-溴-4-氰基苯磺醯基)哌啶-4-基]胺基甲酸三級丁酯（1 g，2.25 mmol，1.00當量）、吡啶-2-甲脒鹽酸鹽（40 mg，0.23 mmol，0.1當量）、NaI（84 mg，0.56 mmol，0.25當量）、NiCl₂(dme)（50 mg，0.23 mmol，0.1當量）在DMA（10 mL）和(2R)-3-溴-2-甲基丙酸甲酯（610 mg，3.38 mmol，1.5當量）中的溶液中添加Mn粉（250 mg，4.5 mmol，2.0當量）。將所得混合物在40°C在氮氣氣氛下攪拌3 h。將反應用水淬滅。將所得混合物用EtOAc萃取。將合併的有機層用水和鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EtOAc/PE（0-100%）洗脫）純化，以得到呈淡黃色固體的標題化合物。Example28 Synthesis of (S)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile Step 1: (S)-3-(5-((4-((tert-butyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)-2-cyanophenyl)-2-methylpropanoic acid methyl ester To a solution of tributyl N-[1-(3-bromo-4-cyanobenzenesulfonyl)piperidin-4-yl]carbamate (1 g, 2.25 mmol, 1.00 equiv), pyridine-2-carboximidamide hydrochloride (40 mg, 0.23 mmol, 0.1 equiv), NaI (84 mg, 0.56 mmol, 0.25 equiv),_NiCl₂ (dme) (50 mg, 0.23 mmol, 0.1 equiv) in DMA (10 mL), and methyl (2R)-3-bromo-2-methylpropanoate (610 mg, 3.38 mmol, 1.5 equiv) was added Mn powder (250 mg, 4.5 mmol, 2.0 equiv) under a nitrogen atmosphere. The resulting mixture was stirred at 40°C under a nitrogen atmosphere for 3 h. The reaction was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc/PE (0-100%) to afford the title compound as a pale yellow solid.

步驟2：(S)-(1-((4-氰基-3-(3-羥基-2-甲基丙基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在-60°C在氮氣氣氛下向(S)-3-(5-((4-((三級丁氧基羰基)胺基)哌啶-1-基)磺醯基)-2-氰基苯基)-2-甲基丙酸甲酯（800 mg，1.72 mmol，1.0當量）在THF（8 mL）中的攪拌溶液中逐滴添加THF中的1 M LiAlH₄（2.4 mL，2.4 mmol，1.40當量）。將所得混合物在-60°C - -40°C在氮氣氣氛下攪拌30 min。將反應在0°C用水、15% NaOH（水性）和水淬滅。將所得混合物經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮，以得到呈淡黃色固體的標題化合物。Step 2: (S)-tert-butyl (1-((4-cyano-3-(3-hydroxy-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of (S)-methyl 3-(5-((4-((tert-butyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)-2-cyanophenyl)-2-methylpropanoate (800 mg, 1.72 mmol, 1.0 equiv) in THF (8 mL) was added dropwise 1 M_LiAlH₄ in THF (2.4 mL, 2.4 mmol, 1.40 equiv) at -60°C under a nitrogen atmosphere. The resulting mixture was stirred at -60°C to -40°C under a nitrogen atmosphere for 30 min. The reaction was quenched at 0°C with water, 15% NaOH (aq.), and water. The resulting mixture was dried over_{anhydrousNa₂SO₄} . After filtration, the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid.

步驟3：(S)-4-((4-胺基哌啶-1-基)磺醯基)-2-(3-羥基-2-甲基丙基)苯甲腈鹽酸鹽向(S)-(1-((4-氰基-3-(3-羥基-2-甲基丙基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（500 mg，1.14 mmol，1.0當量）在DCM（3 mL）中的攪拌溶液中添加1,4-二㗁𠮿中的4M HCl（3 mL）。將所得混合物在室溫攪拌1 h。將所得混合物在減壓下濃縮，以得到呈淡黃色固體的標題化合物。Step 3: (S)-4-((4-aminopiperidin-1-yl)sulfonyl)-2-(3-hydroxy-2-methylpropyl)benzonitrile hydrochloride To a stirred solution of (S)-tributyl(1-((4-cyano-3-(3-hydroxy-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (500 mg, 1.14 mmol, 1.0 equiv) in DCM (3 mL) was added 4 M HCl in 1,4-dioxane (3 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give the title compound as a light yellow solid.

步驟4：(S)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-羥基-2-甲基 丙基)苯甲腈在室溫向(S)-4-((4-胺基哌啶-1-基)磺醯基)-2-(3-羥基-2-甲基丙基)苯甲腈鹽酸鹽（500 mg，1.48 mmol，1當量）和DIEA（580 mg，4.49 mmol，3.03當量）在DMSO（5 mL）中的攪拌混合物中添加2-氯-5-(二氟甲氧基)嘧啶（400 mg，2.22 mmol，1.50當量）。將所得混合物在100°C在氮氣氣氛下攪拌過夜。將混合物藉由添加水淬滅。將所得混合物用EtOAc萃取。將合併的有機層用水和鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EtOAc/PE（0-30%）洗脫）純化，以得到呈灰白色固體的標題化合物。Step 4: (S)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-hydroxy-2-methylpropyl)benzonitrile To a mixture of (S)-4-((4-aminopiperidin-1-yl)sulfonyl)-2-(3-hydroxy-2-methylpropyl)benzonitrile hydrochloride (500 mg, 1.48 mmol, 1 equiv) and DIEA (580 mg, 4.49 mmol, 3.03 equiv) in DMSO (5 mL) was added 2-chloro-5-(difluoromethoxy)pyrimidine (400 mg, 2.22 mmol, 1.50 equiv) at room temperature. The resulting mixture was stirred at 100°C under a nitrogen atmosphere overnight. The mixture was quenched by the addition of water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and brine and dried_over anhydrous_NaSO . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc/PE (0-30%) to give the title compound as an off-white solid.

步驟5：(S)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-甲基-3-側氧基丙基)苯甲腈在-5°C-0°C在氮氣氣氛下向(S)-4-((4-((5-(二氟甲氧基) 嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-羥基-2-甲基丙基) 苯甲腈（170 mg，0.35 mmol，1.0當量）和DIEA（274 mg，2.12 mmol，6.0當量）在DCM（2 mL）中的攪拌溶液中逐滴添加DMSO（2 mL）中的SO₃-吡啶（225 mg，1.4 mmol，4.0當量）。將所得混合物在0°C在氮氣氣氛下攪拌10 min。將混合物用水淬滅。將所得混合物用EtOAc萃取。將合併的有機層用水和鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EtOAc/PE（0-30%）洗脫）純化，以得到呈淡黃色油狀物的標題化合物。Step 5: (S)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-methyl-3-oxopropyl)benzonitrile To a stirred solution of (S)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-hydroxy-2-methylpropyl)benzonitrile (170 mg, 0.35 mmol, 1.0 equiv) and DIEA (274 mg, 2.12 mmol, 6.0 equiv) in DCM (2 mL) was added SO₃ -pyridine (225 mg, 1.4 mmol, 4.0 equiv) in DMSO (2 mL) dropwise at -5°C to 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C under a nitrogen atmosphere for 10 min. The mixture was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, and dried over anhydrous Na₂ SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc/PE (0-30%)) to give the title compound as a pale yellow oil.

步驟6：(S)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈在0°C在氮氣氣氛下向1-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氫-嘧啶-2,4(1H,3H)-二酮（76 mg，0.23 mmol，1.0當量）和TEA（47 mg，0.46 mmol，2.0當量）在DMAc（1 mL）中的攪拌混合物中分批添加(S)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-甲基-3-側氧基丙基)苯甲腈（110 mg，0.23 mmol，1當量）。將所得混合物在室溫攪拌30 min。在0°C-5°C在氮氣氣氛下向上述混合物中分批添加NaBH(OAc)₃（110 mg，0.52 mmol，2.25當量）。將所得混合物在0°C-5°C攪拌2 h。將反應用水淬滅。將所得混合物用EtOAc萃取。將合併的有機層用水和鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由製備型HPLC純化，以得到呈灰白色固體的標題化合物。MS (ES, m/z): [M+H]⁺= 791.2。Step 6: (S)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile To a stirred mixture of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydro-pyrimidine-2,4(1H,3H)-dione (76 mg, 0.23 mmol, 1.0 equiv) and TEA (47 mg, 0.46 mmol, 2.0 equiv) in DMAc (1 mL) at 0°C under a nitrogen atmosphere was added (S)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-methyl-3-oxopropyl)benzonitrile (110 mg, 0.23 mmol, 1 equiv) portionwise. The resulting mixture was stirred at room temperature for 30 min. To the above mixture was added NaBH(OAc)_₃ (110 mg, 0.52 mmol, 2.25 equiv) portionwise at 0°C-5°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C-5°C for 2 h. The reaction was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to yield the title compound as an off-white solid. MS (ES, m/z): [M+H]^⁺ = 791.2.

實例291-(6-(1-(1-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)-2-(二氟甲基)苯氧基)丙-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮的合成步驟1：(3-溴-4-(二氟甲基)苯基)(4-(三級丁基)苄基)硫烷在0°C向(4-(三級丁基)苯基)甲硫醇（3.00 g，16.67 mmol，1.50當量）在DMF（50.0 mL）中的攪拌溶液中分批添加NaH（60%在油中，667 mg，16.67 mmol，1.50當量）。將混合物在室溫在氮氣下攪拌1 h。將2-溴-1-(二氟甲基)-4-氟苯（2.50 g，11.11 mmol，1.00當量）添加至該混合物中，並將所得混合物在室溫攪拌2 h。將反應混合物用水淬滅並用EA萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾和濃縮後，將殘餘物藉由矽膠柱層析法（PE）純化，以給出呈黃色油狀物的標題化合物。Example29 Synthesis of 1-(6-(1-(1-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenoxy)propan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: (3-Bromo-4-(difluoromethyl)phenyl)(4-(tert-butyl)benzyl)sulfane To a stirred solution of (4-(tert-butyl)phenyl)methanethiol (3.00 g, 16.67 mmol, 1.50 equiv) in DMF (50.0 mL) was added portionwise NaH (60% in oil, 667 mg, 16.67 mmol, 1.50 equiv) at 0°C. The mixture was stirred at room temperature under nitrogen for 1 h. 2-Bromo-1-(difluoromethyl)-4-fluorobenzene (2.50 g, 11.11 mmol, 1.00 equiv) was added to the mixture, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA. The combined organic layers were washed with brine and dried over_{anhydrousNa₂SO₄} . After filtration and concentration, the residue was purified by silica gel column chromatography (PE) to give the title compound as a yellow oil.

步驟2：3-溴-4-(二氟甲基)苯磺醯氯在0°C向(3-溴-4-(二氟甲基)苯基)(4-(三級丁基)苄基)硫烷（4.20 g，10.90 mmol，1.00當量）在ACN（40.0 mL）中的攪拌溶液中分批添加AcOH（3.27 g，54.50 mmol，5.00當量）、H₂O（981 mg，54.50 mmol，5.00當量）和NCS（7.27 g，54.50 mmol，5.00當量）。將反應混合物在室溫攪拌2 h，用水淬滅並用EA萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥，濃縮，以給出呈白色固體的粗標題化合物。Step 2: 3-Bromo-4-(difluoromethyl)benzenesulfonyl chloride To a stirred solution of (3-bromo-4-(difluoromethyl)phenyl)(4-(tert-butyl)benzyl)sulfane (4.20 g, 10.90 mmol, 1.00 equiv) in ACN (40.0 mL) were added AcOH (3.27 g, 54.50 mmol, 5.00 equiv),_H₂O (981 mg, 54.50 mmol, 5.00 equiv) and NCS (7.27 g, 54.50 mmol, 5.00 equiv) portionwise at 0°C. The reaction mixture was stirred at room temperature for 2 h, quenched with water and extracted with EA. The combined organic layers were washed with brine, dried over_{anhydrousNa₂SO₄} and concentrated to give the crude title compound as a white solid.

步驟3：(1-((3-溴-4-(二氟甲基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯向哌啶-4-基胺基甲酸三級丁酯（2.20 g，10.98 mmol，1.00當量）在DCM（20.0 mL）中的攪拌混合物中添加TEA（3.33 g，32.94 mmol，3.00當量），然後在0°C緩慢添加3-溴-4-(二氟甲基)苯磺醯氯（3.35 g，10.98 mmol，1.00當量）在DCM（30.0 mL）中的溶液。將反應混合物在室溫攪拌3 h，用水淬滅並用DCM萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾和濃縮後，將殘餘物藉由矽膠柱層析法（PE:EA = 6:1）純化，以給出呈黃色固體的標題化合物。Step 3: Tributyl (1-((3-bromo-4-(difluoromethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a mixture of tributyl piperidin-4-ylcarbamate (2.20 g, 10.98 mmol, 1.00 equiv) in DCM (20.0 mL) was added TEA (3.33 g, 32.94 mmol, 3.00 equiv), followed by the slow addition of a solution of 3-bromo-4-(difluoromethyl)benzenesulfonyl chloride (3.35 g, 10.98 mmol, 1.00 equiv) in DCM (30.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 3 h, quenched with water, and extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous_Na₂SO₄. After filtration and concentration, the residue was purified by silica gel column chromatography (PE:EA = 6:1) to give the title compound as a yellow solid.

步驟4：(1-((4-(二氟甲基)-3-羥基苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯向(1-((3-溴-4-(二氟甲基)苯基)磺醯基)-哌啶-4-基)胺基甲酸三級丁酯（2.34 g，4.99 mmol，1.00當量）在二㗁𠮿（30.0 mL）中的攪拌混合物中添加4,4,4',4',5,5,5',5'-八甲基-2,2'-雙(1,3,2-二氧雜環戊硼烷)（1.90 g，7.49 mmol，1.50當量）、Pd(dppf)Cl₂（366 mg，0.50 mmol，0.10當量）和KOAc（1.47 g，14.97 mmol，3.00當量）。將反應混合物在100°C在N₂下攪拌3 h，冷卻，然後在室溫添加H₂O₂（30%，1.70 g，15.0 mmol，3.00當量）。攪拌2 h後，將反應混合物用水淬滅並用EA萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。將殘餘物藉由矽膠柱層析法（DCM : MeOH = 120:1）純化，以給出呈黃色油狀物的標題化合物。Step 4: Tributyl (1-((4-(difluoromethyl)-3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred mixture of tributyl (1-((3-bromo-4-(difluoromethyl)phenyl)sulfonyl)-piperidin-4-yl)carbamate (2.34 g, 4.99 mmol, 1.00 equiv) in dioxane (30.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (1.90 g, 7.49 mmol, 1.50 equiv), Pd(dppf)_Cl2 (366 mg, 0.50 mmol, 0.10 equiv) and KOAc (1.47 g, 14.97 mmol, 3.00 equiv). The reaction mixture was stirred at 100°C under_N2 for 3 h, cooled, and then_H2O2( 30%, 1.70 g, 15.0 mmol, 3.00 equiv) was added at room temperature. After stirring for 2 h, the reaction mixture was quenched with water and extracted with EA. The combined organic layers were washed with brine and dried over anhydrous_Na2SO4 . The residue was purified by silica gel column chromatography (DCM:MeOH = 120:₁ ) to afford the title compound as a yellow oil.

步驟5：(1-((4-(二氟甲基)-3-(2-側氧基丙氧基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯向(1-((4-(二氟甲基)-3-羥基苯基)磺醯基)-哌啶-4-基)胺基甲酸三級丁酯（244 mg，0.60 mmol，1.00當量）在DMF（5.0 mL）中的攪拌溶液中添加1-氯丙-2-酮（110 mg，1.20 mmol，2.00當量）、K₂CO₃（248 mg，1.80 mmol，3.00當量）和KI（100 mg，0.60 mmol，1.00當量）。將反應混合物在80°C在N₂下攪拌5 h，冷卻，用水淬滅並用EA萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾和濃縮後，將殘餘物藉由矽膠柱層析法（DCM : MeOH = 30:1）純化，以給出呈黃色固體的標題化合物。Step 5: Tributyl (1-((4-(difluoromethyl)-3-(2-hydroxypropyloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of tributyl (1-((4-(difluoromethyl)-3-hydroxyphenyl)sulfonyl)-piperidin-4-yl)carbamate (244 mg, 0.60 mmol, 1.00 equiv) in DMF (5.0 mL) were added 1-chloropropan-2-one (110 mg, 1.20 mmol, 2.00 equiv),_K₂CO₃ (248 mg, 1.80 mmol, 3.00 equiv)_, and KI (100 mg, 0.60 mmol, 1.00 equiv). The reaction mixture was stirred at 80°C under_N₂ for 5 h, cooled, quenched with water, and extracted with EA. The combined organic layers were washed with brine and dried_over anhydrous_Na₂SO₄ . After filtration and concentration, the residue was purified by silica gel column chromatography (DCM:MeOH = 30:1) to give the title compound as a yellow solid.

步驟6：(1-((4-(二氟甲基)-3-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙氧基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯向(1-((4-(二氟甲基)-3-(2-側氧基丙氧基)苯基)-磺醯基)哌啶-4-基)胺基甲酸三級丁酯（50 mg，0.10 mmol，1.00當量）在MeOH/THF（1.0 mL/1.0 mL）中的攪拌溶液中添加1-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮（33 mg，0.10 mmol，1.00當量）、三甲氧基甲烷（11 mg，0.10 mmol，1.00當量）、TEA（20 mg，0.20 mmol，2.00當量）和NaBH₃CN（13 mg，0.20 mmol，2.00當量）。將反應混合物在70°C在N₂下攪拌16 h，冷卻，用水淬滅並用EA萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾和濃縮後，將殘餘物藉由矽膠柱層析法（DCM : MeOH = 20:1）純化，以給出呈黃色固體的標題化合物。Step 6: Tributyl (1-((4-(difluoromethyl)-3-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propyloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of tributyl (1-((4-(difluoromethyl)-3-(2-oxopropyloxy)phenyl)-sulfonyl)piperidin-4-yl)carbamate (50 mg, 0.10 mmol, 1.00 equiv) in MeOH/THF (1.0 mL/1.0 mL) was added 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (33 mg, 0.10 mmol, 1.00 equiv), trimethoxymethane (11 mg, 0.10 mmol, 1.00 equiv), TEA (20 mg, 0.20 mmol, 2.00 equiv) and_NaBH3CN (13 mg, 0.20 mmol, 2.00 equiv). The reaction mixture was stirred at 70°C under_N₂ for 16 h, cooled, quenched with water, and extracted with EA. The combined organic layers were washed with brine and dried over_{anhydrousNa₂SO₄} . After filtration and concentration, the residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to afford the title compound as a yellow solid.

步驟7：1-(6-(1-(1-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(二氟甲基)苯氧基)丙-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫-嘧啶-2,4(1H,3H)-二酮藉由與實例23的步驟4-5中所述類似的方式進行來合成標題化合物，以得到呈黃色固體的標題化合物。MS (ES, m/z): [M+1]⁺= 818.1。Step 7: 1-(6-(1-(1-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenoxy)propan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydro-pyrimidine-2,4(1H,3H)-dione The title compound was synthesized in a manner similar to that described in Steps 4-5 of Example 23 to give the title compound as a yellow solid. MS (ES, m/z): [M+1]⁺ = 818.1.

實例301-(1-甲基-6-(1-(2-甲基-3-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)-1H-吡唑-1-基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮的合成步驟1：甲磺酸3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙酯在室溫向3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙-1-醇（8.10 g，24.70 mmol，1.00當量）在DCM（90.0 mL）中的攪拌溶液中添加TEA（5.00 g，49.40 mmol，2.00當量）和MsCl（4.22 g，37.05 mmol，1.50當量），並將所得混合物攪拌16 h。將反應混合物用水稀釋並用EA萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮並藉由柱層析法（PE: EA= 10: 1）純化，以得到呈無色油狀物的標題化合物。Example30 Synthesis of 1-(1-methyl-6-(1-(2-methyl-3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: 3-((tert-butyldiphenylsilyl)oxy)-2-methylpropyl methanesulfonate To a stirred solution of 3-((tributyldiphenylsilyl)oxy)-2-methylpropan-1-ol (8.10 g, 24.70 mmol, 1.00 equiv) in DCM (90.0 mL) was added TEA (5.00 g, 49.40 mmol, 2.00 equiv) and MsCl (4.22 g, 37.05 mmol, 1.50 equiv) at room temperature, and the resulting mixture was stirred for₁₆ h. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with brine and dried over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 10:1) to give the title compound as a colorless oil.

步驟3：1H-吡唑-3-磺醯氯在0°C在N₂下向1H-吡唑-3-胺（1.00 g，12.04 mmol，1.00當量）在濃HCl（10.0 mL）中的攪拌溶液中添加NaNO₂（2.49 g，36.12 mmol，3.00當量）在水（10.0 mL）中的溶液，並將所得混合物在0°C攪拌15 min，然後在0°C向混合物中添加CuSO₄·5H₂O（300 mg，1.20 mmol，0.10當量）在濃HCl（2.0 mL）中的溶液，然後係NaHSO₃（12.53 g，120.40 mmol，10.00當量）在水（10.0 mL）中的溶液。在0°C攪拌30 min後，將反應混合物用水稀釋並用EA萃取。將合併的有機層用水、鹽水洗滌，然後經無水Na₂SO₄乾燥。過濾後，將濾液濃縮，以得到呈棕色油狀物的標題化合物。Step 3: 1H-pyrazole-3-sulfonyl chloride To a stirred solution of 1H-pyrazol-3-amine (1.00 g, 12.04 mmol, 1.00 equiv) in concentrated HCl (10.0 mL) at 0°C under_N2 was added a solution of_NaNO2 (2.49 g, 36.12 mmol, 3.00 equiv) in water (10.0 mL), and the resulting mixture was stirred at 0°C for 15 min. Then, a solution of_CuSO4 ·_5H2O (300 mg, 1.20 mmol, 0.10 equiv) in concentrated HCl (2.0 mL) was added to the mixture at 0°C, followed by a solution of_NaHSO3 (12.53 g, 120.40 mmol, 10.00 equiv) in water (10.0 mL). After stirring at 0°C for 30 min, the reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with water, brine, and then dried over anhydrous Na₂ SO_4. After filtration, the filtrate was concentrated to give the title compound as a brown oil.

步驟4：(1-((1H-吡唑-3-基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在0°C向哌啶-4-基胺基甲酸三級丁酯（1.14 g，5.67 mmol，1.50當量）和TEA（1.15 g，11.34 mmol，3.00當量）在DCM（5.0 ml）中的攪拌溶液中添加1H-吡唑-3-磺醯氯（630 mg，3.78 mmol，1.00當量）在DCM（5.0 mL）中的溶液，並將所得混合物攪拌2 h。將反應混合物用水稀釋並用EA萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮並藉由製備型HPLC純化，以得到呈白色固體的標題化合物。Step 4: Tributyl (1-((1H-pyrazol-3-yl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of tributyl piperidin-4-ylcarbamate (1.14 g, 5.67 mmol, 1.50 equiv) and TEA (1.15 g, 11.34 mmol, 3.00 equiv) in DCM (5.0 mL) at 0°C was added a solution of 1H-pyrazole-3-sulfonyl chloride (630 mg, 3.78 mmol, 1.00 equiv) in DCM (5.0 mL), and the resulting mixture was stirred for 2 h. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with water and brine, and the organic layer was dried over_{anhydrousNa₂SO₄} . After filtration, the filtrate was concentrated under reduced pressure and purified by preparative HPLC to yield the title compound as a white solid.

步驟5：(1-((1-(3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙基)-1H-吡唑-3-基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在50°C向(1-((1H-吡唑-3-基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（200 mg，0.61 mmol，1.00當量）在DMF（6.0 mL）中的攪拌溶液中添加甲磺酸3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙酯（246 mg，0.61 mmol，1.00當量）和Cs₂CO₃（395 mg，1.22 mmol，2.00當量），並將所得混合物攪拌16 h。將反應混合物用水稀釋並用EA萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮並藉由柱層析法（PE: EA= 1: 1）純化，以得到呈白色固體的標題化合物。Step 5: Tributyl (1-((1-(3-((tributyldiphenylsilyl)oxy)-2-methylpropyl)-1H-pyrazol-3-yl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of tert-butyl (1-((1H-pyrazol-3-yl)sulfonyl)piperidin-4-yl)carbamate (200 mg, 0.61 mmol, 1.00 equiv) in DMF (6.0 mL) was added 3-((tert-butyldiphenylsilyl)oxy)-2-methylpropyl methanesulfonate (246 mg, 0.61 mmol, 1.00 equiv) and Cs₂ CO₃ (395 mg, 1.22 mmol, 2.00 equiv) at 50° C., and the resulting mixture was stirred for 16 h. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with water and brine, and the organic layer was dried over anhydrous Na₂ SO₄ . After filtration, the filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 1:1) to obtain the title compound as a white solid.

步驟6：1-((1-(3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙基)-1H-吡唑-3-基)磺醯基)-哌啶-4-胺鹽酸鹽在40°C向(1-((1-(3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙基)-1H-吡唑-3-基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（130 mg，0.20 mmol，1.00當量）在EA（2.0 mL）中的攪拌溶液中添加EA/HCl（2.0 mL），並將所得混合物攪拌2 h。將反應混合物在減壓下濃縮，以得到呈白色固體的標題化合物（117 mg，粗品）。Step 6: 1-((1-(3-((tert-butyldiphenylsilyl)oxy)-2-methylpropyl)-1H-pyrazol-3-yl)sulfonyl)-piperidin-4-amine hydrochloride To a stirred solution of tributyl (1-((1-(3-(tributyldiphenylsilyl)oxy)-2-methylpropyl)-1H-pyrazol-3-yl)sulfonyl)piperidin-4-yl)carbamate (130 mg, 0.20 mmol, 1.00 equiv) in EA (2.0 mL) was added EA/HCl (2.0 mL) at 40°C, and the resulting mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (117 mg, crude) as a white solid.

步驟7：2-甲基-3-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丙-1-醇在50°C向1-((1-(3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙基)-1H-吡唑-3-基)磺醯基)哌啶-4-胺鹽酸鹽（60 mg，0.10 mmol，1.00當量）在DMSO（2.0 mL）中的攪拌溶液中添加2-氯-5-(三氟甲基)嘧啶（36 mg，0.20 mol，2.00當量）、DIEA（65 mg，0.50 mmol，5.00當量）和CsF（76 mg，0.50 mmol，5.00當量），並將所得混合物攪拌16 h。將反應混合物用水稀釋並用EA萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮並藉由製備型TLC（DCM: MeOH = 20 : 1）純化，以得到呈白色固體的標題化合物。Step 7: 2-Methyl-3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propan-1-ol To a stirred solution of 1-((1-(3-((tributyldiphenylsilyl)oxy)-2-methylpropyl)-1H-pyrazol-3-yl)sulfonyl)piperidin-4-amine hydrochloride (60 mg, 0.10 mmol, 1.00 equiv) in DMSO (2.0 mL) was added 2-chloro-5-(trifluoromethyl)pyrimidine (36 mg, 0.20 mol, 2.00 equiv), DIEA (65 mg, 0.50 mmol, 5.00 equiv), and CsF (76 mg, 0.50 mmol, 5.00 equiv) at 50°C, and the resulting mixture was stirred for 16 h. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with water and brine, and the organic layer was dried over_{anhydrousNaSO} . After filtration, the filtrate was concentrated under reduced pressure and purified by preparative TLC (DCM:MeOH = 20:1) to give the title compound as a white solid.

步驟8：2-甲基-3-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丙醛在室溫向2-甲基-3-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)-1H-吡唑-1-基)丙-1-醇（40 mg，0.090 mmol，1.00當量）在DCM（2.0 mL）中的攪拌溶液中添加戴斯-馬丁過碘烷（57 mg，0.13 mmol，1.44當量），並將所得混合物攪拌2 h。將反應混合物藉由柱層析法（DCM: MeOH = 10: 1）純化，以得到呈白色固體的標題化合物。Step 8: 2-Methyl-3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propanal To a stirred solution of 2-methyl-3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propan-1-ol (40 mg, 0.090 mmol, 1.00 equiv) in DCM (2.0 mL) was added Dess-Martin periodinane (57 mg, 0.13 mmol, 1.44 equiv) at room temperature, and the resulting mixture was stirred for 2 h. The reaction mixture was purified by column chromatography (DCM:MeOH = 10:1) to give the title compound as a white solid.

步驟9：1-(1-甲基-6-(1-(2-甲基-3-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮在室溫向1-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮（35 mg，0.11 mmol，1.22當量）在DMA（2.0 mL）中的攪拌溶液中添加2-甲基-3-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丙醛（40 mg，0.090 mmol，1.00當量）、TEA（27 mg，0.27 mmol，3.00當量）和NaBH(OAc)₃（46 mg，0.22 mmol，2.44當量），並將所得混合物攪拌3 h。將反應混合物用水稀釋並用EA萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮並將殘餘物藉由柱層析法（DCM : MeOH = 15 : 1）純化，以得到呈白色固體的標題化合物。MS (ES, m/z): [M+1]⁺= 758.1Step 9: 1-(1-methyl-6-(1-(2-methyl-3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione To a stirred solution of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (35 mg, 0.11 mmol, 1.22 equiv) in DMA (2.0 mL) was added 2-methyl-3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propanal (40 mg, 0.090 mmol, 1.00 equiv), TEA (27 mg, 0.27 mmol, 3.00 equiv), and NaBH(OAc)₃ (46 mg, 0.22 mmol, 2.44 equiv) at room temperature, and the resulting mixture was stirred for 3 h. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with water and brine, and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 15:1) to obtain the title compound as a white solid. MS (ES, m/z): [M+1]⁺ = 758.1

藉由與實例30中所述類似的方式進行來合成以下實例。實例#結構程序31在步驟4中，將1H-吡唑-3-磺醯氯替代為3-甲基-1H-吡唑-4-磺醯氯。32在步驟4中，將1H-吡唑-3-磺醯氯替代為5-甲基-1H-吡唑-4-磺醯氯。The following examples were synthesized in a manner similar to that described in Example 30.Example#structureprogram 31 In step 4, 1H-pyrazole-3-sulfonyl chloride was replaced by 3-methyl-1H-pyrazole-4-sulfonyl chloride. 32 In step 4, 1H-pyrazole-3-sulfonyl chloride was replaced by 5-methyl-1H-pyrazole-4-sulfonyl chloride.

實例331-(1-甲基-6-(1-(2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-咪唑-1-基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮的合成步驟1：N-[1-(1H-咪唑-4-磺醯基)哌啶-4-基]胺基甲酸三級丁酯向1H-咪唑-4-磺醯氯（250 mg，1.50 mmol,1.00當量）在DCM（10.0 mL）中的攪拌混合物中添加N-(哌啶-4-基)胺基甲酸三級丁酯（300 mg，1.50 mmol，1.00當量）和TEA（455 mg，4.50 mmol，3.00當量），並將所得混合物在25°C在N₂下攪拌1 h。將反應混合物用水稀釋並用EA萃取。將合併的有機層用水、鹽水洗滌，經無水Na₂SO₄乾燥、過濾並濃縮，以給出呈黃色固體的標題化合物。Example33 Synthesis of 1-(1-methyl-6-(1-(2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-imidazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: N-[1-(1H-imidazole-4-sulfonyl)piperidin-4-yl]carbamic acid tert-butyl ester To a stirred mixture of 1H-imidazole-4-sulfonyl chloride (250 mg, 1.50 mmol, 1.00 equiv) in DCM (10.0 mL) were added tributyl N-(piperidin-4-yl)carbamate (300 mg, 1.50 mmol, 1.00 equiv) and TEA (455 mg, 4.50 mmol, 3.00 equiv), and the resulting mixture was stirred at 25 ° C under N₂ for 1 h. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with water, brine, dried over anhydrous Na₂ SO₄ , filtered, and concentrated to give the title compound as a yellow solid.

步驟2：N-{1-[1-(3-羥基-2-甲基丙基)咪唑-4-磺醯基]哌啶-4-基}胺基甲酸三級丁酯向3-溴-2-甲基丙-1-醇（344 mg，2.25 mmol，1.50當量）在MeCN（10.0 mL）中的攪拌混合物中添加N-[1-(1H-咪唑-4-磺醯基)哌啶-4-基]胺基甲酸三級丁酯（495 mg，1.50 mmol，1.00當量）、KI（498 mg，3.00 mmol，2.00當量）和K₂CO₃（622 mg，4.50 mmol，3.00當量），並將所得混合物在70°C在N₂下攪拌2天。將反應混合物用水稀釋並用EA萃取。將合併的有機層用水、鹽水洗滌，經無水Na₂SO₄乾燥並濃縮，以給出呈黃色固體的標題化合物。Step 2: N-{1-[1-(3-hydroxy-2-methylpropyl)imidazol-4-sulfonyl]piperidin-4-yl}carbamic acid tert-butyl ester To a stirred mixture of 3-bromo-2-methylpropan-1-ol (344 mg, 2.25 mmol, 1.50 equiv) in MeCN (10.0 mL) were added tributyl N-[1-(1H-imidazole-4-sulfonyl)piperidin-4-yl]carbamate (495 mg, 1.50 mmol, 1.00 equiv), KI (498 mg, 3.00 mmol, 2.00 equiv₎ , and_KCO (622 mg, 4.50 mmol, 3.00 equiv), and the resulting mixture was stirred at 70 ° C under_N for 2 days. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with water, brine, dried over anhydrous_NaSO, and concentrated to give the title compound as a yellow solid.

步驟3：N-{1-[1-(2-甲基-3-側氧基丙基)咪唑-4-磺醯基]哌啶-4-基}胺基甲酸三級丁酯向N-{1-[1-(3-羥基-2-甲基丙基)咪唑-4-磺醯基]哌啶-4-基}胺基甲酸三級丁酯（600 mg，1.49 mmol，1.00當量）在DCM（15.0 mL）中的攪拌混合物中添加戴斯-馬丁過碘烷（948 mg，2.34 mmol，1.50當量），並將所得混合物在25°C攪拌1 h。將反應混合物用水稀釋並用EA萃取。將合併的有機層用水、鹽水洗滌，經無水Na₂SO₄乾燥並濃縮，以給出呈黃色油狀物的標題化合物。Step 3: N-{1-[1-(2-methyl-3-hydroxypropyl)imidazol-4-sulfonyl]piperidin-4-yl}carbamic acid tert-butyl ester To a mixture of tert-butyl N-{1-[1-(3-hydroxy-2-methylpropyl)imidazol-4-sulfonyl]piperidin-4-yl}carbamate (600 mg, 1.49 mmol, 1.00 equiv) in DCM (15.0 mL) was added Dess-Martin periodinane (948 mg, 2.34 mmol, 1.50 equiv), and the resulting mixture was stirred at 25°C for 1 h. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with water, brine, dried over anhydrous_Na₂SO₄, and concentrated to afford the title compound as a yellow oil.

步驟4：N-(1-{1-[2-({4-[3-(2,4-二側氧基-1,3-二氮雜己環烷-1-基)-1-甲基吲唑-6-基]哌啶-1-基}甲基)丙基]咪唑-4-磺醯基}哌啶-4-基)胺基甲酸三級丁酯向1-[1-甲基-6-(哌啶-4-基)吲唑-3-基]-1,3-二氮雜己環烷-2,4-二酮（1226 mg，3.75 mmol，2.50當量）在DCM（10.0 mL）中的攪拌混合物中添加N-{1-[1-(2-甲基-3-側氧基丙基)咪唑-4-磺醯基]哌啶-4-基}胺基甲酸三級丁酯（600 mg，1.50 mmol，1.00當量）、TEA（455 mg，4.49 mmol，3.00當量）和NaBH(OAc)₃（794 mg，3.75 mmol，2.50當量），並將所得混合物在40°C攪拌3 h。將反應混合物用水稀釋並用EA萃取。將合併的有機層用水、鹽水洗滌，經無水Na₂SO₄乾燥並濃縮。將殘餘物藉由快速柱層析法（EA:PE = 0-100%）純化，以給出呈黃色固體的標題化合物。Step 4: N-(1-{1-[2-({4-[3-(2,4-dioxo-1,3-diazohexylcycloalkan-1-yl)-1-methylindazol-6-yl]piperidin-1-yl}methyl)propyl]imidazol-4-sulfonyl}piperidin-4-yl)carbamic acid tert-butyl ester To a stirred mixture of 1-[1-methyl-6-(piperidin-4-yl)indazol-3-yl]-1,3-diazohexanedione-2,4-dione (1226 mg, 3.75 mmol, 2.50 equiv) in DCM (10.0 mL) was added tributyl N-{1-[1-(2-methyl-3-oxopropyl)imidazol-4-sulfonyl]piperidin-4-yl}carbamate (600 mg, 1.50 mmol, 1.00 equiv), TEA (455 mg, 4.49 mmol, 3.00 equiv), and NaBH(OAc)₃ (794 mg, 3.75 mmol, 2.50 equiv), and the resulting mixture was stirred at 40° C. for 3 h. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with water and brine, dried over anhydrous Na₂ SO₄ and concentrated. The residue was purified by flash column chromatography (EA:PE = 0-100%) to give the title compound as a yellow solid.

步驟5：1-(6-(1-(3-(4-((4-胺基哌啶-1-基)磺醯基)-1H-咪唑-1-基)-2-甲基丙基)-哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮氯化氫將(1-((1-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)-1H-咪唑-4-基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（230 mg，0.32 mmol，1.00當量）在EA/HCl（5.0 mL）中的混合物在40°C攪拌2 h。將反應混合物濃縮，以給出呈灰白色固體的標題化合物。Step 5: 1-(6-(1-(3-(4-((4-aminopiperidin-1-yl)sulfonyl)-1H-imidazol-1-yl)-2-methylpropyl)-piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride A mixture of tributyl (1-((1-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)carbamate (230 mg, 0.32 mmol, 1.00 equiv) in EA/HCl (5.0 mL) was stirred at 40 °C for 2 h. The reaction mixture was concentrated to give the title compound as an off-white solid.

步驟6：1-(1-甲基-6-(1-(2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-咪唑-1-基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮向2-氯-5-(三氟甲基)嘧啶（28 mg，0.154 mmol，1.00當量）在DMSO（3.0 mL）中的攪拌混合物中添加1-(6-(1-(3-(4-((4-胺基哌啶-1-基)磺醯基)-1H-咪唑-1-基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮氯化氫（100 mg，0.154 mmol，1.00當量）、CsF（117 mg，0.77 mmol，5.00當量）和DIEA（99 mg，0.77 mmol，5.00當量），並將所得混合物在50°C攪拌12 h。將反應混合物用水稀釋並用EA萃取。將合併的有機層用水、鹽水洗滌，經無水Na₂SO₄乾燥並濃縮。將殘餘物藉由快速柱層析法（DCM:MeOH=0-100%）純化，以給出呈白色固體的標題化合物。MS (ES, m/z): [M+1]⁺= 758.3。Step 6: 1-(1-methyl-6-(1-(2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-imidazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione To a stirred mixture of 2-chloro-5-(trifluoromethyl)pyrimidine (28 mg, 0.154 mmol, 1.00 equiv) in DMSO (3.0 mL) was added 1-(6-(1-(3-(4-((4-aminopiperidin-1-yl)sulfonyl)-1H-imidazol-1-yl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (100 mg, 0.154 mmol, 1.00 equiv), CsF (117 mg, 0.77 mmol, 5.00 equiv), and DIEA (99 mg, 0.77 mmol, 5.00 equiv), and the resulting mixture was stirred at 50°C for 12 h. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with water and brine, dried over_{anhydrousNa₂SO₄} , and concentrated. The residue was purified by flash column chromatography (DCM:MeOH = 0-100%) to afford the title compound as a white solid. MS (ES, m/z): [M+1]⁺ = 758.3.

實例344-((4-((5-(2,2-二氟環丙基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈的合成步驟1：(1-((4-氰基-3-(2-甲基-3-側氧基丙基)苯基)磺醯基)哌啶-4-基)-胺基甲酸三級丁酯向(1-((3-溴-4-氰基苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（600 mg，1.35 mmol，1.00當量）在DMF（6.0 mL）中的攪拌溶液中添加1-羥基丙-2-酮（588 mg，8.10 mmol，6.00當量）、Pd₂(dba)₃（27 mg，0.029 mmol，0.021當量）、2-(二-三級丁基膦醯基)-1-苯基-1H-吲哚（27 mg，0.080 mmol，0.059當量）和N-環己基-N-甲基環己胺（291 mg，1.49 mmol，1.10當量），並將所得混合物在100°C在N₂下攪拌7 h。將反應混合物冷卻，用水稀釋並用EA萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用（DCM:MeOH=120:1）洗脫）純化，以得到呈黃色油狀物的標題化合物。Example34 Synthesis of 4-((4-((5-(2,2-difluorocyclopropyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile Step 1: (1-((4-cyano-3-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)-carbamic acid tert-butyl ester To a stirred solution of tert-butyl (1-((3-bromo-4-cyanophenyl)sulfonyl)piperidin-4-yl)carbamate (600 mg, 1.35 mmol, 1.00 equiv) in DMF (6.0 mL) were added 1-hydroxypropan-2-one (588 mg, 8.10 mmol, 6.00 equiv),_Pd2 (dba)₃ (27 mg, 0.029 mmol, 0.021 equiv), 2-(di-tert-butylphosphinoyl)-1-phenyl-1H-indole (27 mg, 0.080 mmol, 0.059 equiv) and N-cyclohexyl-N-methylcyclohexylamine (291 mg, 1.49 mmol, 1.10 equiv), and the resulting mixture was stirred at 100 °C under_N2 for 7 h. The reaction mixture was cooled, diluted with water, and extracted with EA. The combined organic layers were washed with water and brine, and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with (DCM:MeOH = 120:1)) to yield the title compound as a yellow oil.

步驟2：(1-((4-氰基-3-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在0°C向1-[1-甲基-6-(哌啶-4-基)吲唑-3-基]-1,3-二氮雜己環烷-2,4-二酮鹽酸鹽（546 mg，1.50 mmol，1.00當量）在DMA（10.0 mL）中的攪拌溶液中添加TEA（455 mg，4.50 mmol，3.00當量）、(1-((4-氰基-3-(2-甲基-3-側氧基丙基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（980 mg，2.25 mmol，1.50當量）和三乙醯氧基硼氫化鈉（769 mg，3.63 mmol，2.42當量）。將反應混合物在0°C至25°C在氮氣下攪拌4 h。將反應混合物用水淬滅並用EA萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。將殘餘物藉由矽膠柱層析法（DCM:MeOH = 50 : 1）純化，以給出呈黃色固體的標題化合物。Step 2: Tributyl (1-((4-cyano-3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of 1-[1-methyl-6-(piperidin-4-yl)indazol-3-yl]-1,3-diazahexanedione hydrochloride (546 mg, 1.50 mmol, 1.00 equiv) in DMA (10.0 mL) at 0°C was added TEA (455 mg, 4.50 mmol, 3.00 equiv), tributyl (1-((4-cyano-3-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (980 mg, 2.25 mmol, 1.50 equiv), and sodium triacetoxyborohydride (769 mg, 3.63 mmol, 2.42 equiv). The reaction mixture was stirred at 0°C to 25°C under nitrogen for 4 h. The reaction mixture was quenched with water and extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na₂ SO₄ . The residue was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give the title compound as a yellow solid.

步驟3：4-((4-胺基哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈氯化氫向(1-((4-氰基-3-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（100 mg，0.13 mmol，1.00當量）在EA（1.0 mL）中的攪拌混合物中添加EA/HCl（1.0 mL），並將所得混合物在室溫攪拌2 h。將反應混合物濃縮，以給出呈白色固體的標題化合物。Step 3: 4-((4-aminopiperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile hydrochloride To a stirred mixture of tributyl (1-((4-cyano-3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (100 mg, 0.13 mmol, 1.00 equiv) in EA (1.0 mL) was added EA/HCl (1.0 mL), and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give the title compound as a white solid.

步驟4：三級丁基2-氯-5-(2,2-二氟環丙基)嘧啶.向2-氯-5-乙烯基嘧啶（100 mg，0.71 mmol，1.00當量）在甲苯（2.0 mL）中的攪拌溶液中添加(溴二氟甲基)三甲基矽烷（432 mg，2.13 mmol，3.00當量）和TBAB（14 mg，0.043 mmol，0.061當量），並將所得混合物在110°C攪拌2 h。將反應混合物冷卻，用水稀釋並用EA萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮並藉由柱層析法（PE : EA= 10 : 1）純化，以得到呈白色固體的標題化合物。Step 4: Tertiary butyl 2-chloro-5-(2,2-difluorocyclopropyl)pyrimidine. To a stirred solution of 2-chloro-5-vinylpyrimidine (100 mg, 0.71 mmol, 1.00 equiv) in toluene (2.0 mL) was added (bromodifluoromethyl)trimethylsilane (432 mg, 2.13 mmol, 3.00 equiv) and TBAB (14 mg, 0.043 mmol, 0.061 equiv), and the resulting mixture was stirred at 110°C for 2 h. The reaction mixture was cooled, diluted with water, and extracted with EA. The combined organic layers were washed with brine and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 10:1) to yield the title compound as a white solid.

步驟5：4-((4-((5-(2,2-二氟環丙基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈向4-((4-胺基哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基-四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)-苯甲腈氯化氫（61 mg，0.089 mmol，1.00當量）在DMSO（2.0 mL）中的攪拌溶液中添加三級丁基2-氯-5-(2,2-二氟環丙基)嘧啶（51 mg，0.27 mol，3.00當量）、DIEA（58 mg，0.45 mmol，5.00當量）和CsF（68 mg，0.45 mmol，5.00當量），並將所得混合物在50°C攪拌16 h。將反應混合物用水稀釋並用EA萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮並藉由製備型TLC（DCM : MeOH = 15 : 1）純化，以得到呈白色固體的標題化合物。MS (ES, m/z): [M+1]⁺= 801.4。Step 5: 4-((4-((5-(2,2-difluorocyclopropyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile To a stirred solution of 4-((4-aminopiperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxo-tetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)-benzonitrile hydrochloride (61 mg, 0.089 mmol, 1.00 equiv) in DMSO (2.0 mL) were added tert-butyl 2-chloro-5-(2,2-difluorocyclopropyl)pyrimidine (51 mg, 0.27 mol, 3.00 equiv), DIEA (58 mg, 0.45 mmol, 5.00 equiv) and CsF (68 mg, 0.45 mmol, 5.00 equiv), and the resulting mixture was stirred at 50°C for 16 h. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with water and brine, and then dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure and purified by preparative TLC (DCM:MeOH = 15:1) to yield the title compound as a white solid. MS (ES, m/z): [M+1]⁺ = 801.4.

實例35(R)-4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)苯甲腈的合成步驟1：(R)-2-(5-((4-((三級丁氧基羰基)胺基)哌啶-1-基)磺醯基)-2-氰基-苯氧基)丙酸甲酯在0°C在氮氣氣氛下向(1-((4-氰基-3-羥基苯基)磺醯基)哌啶-4-基)-胺基甲酸三級丁酯（2.0 g，5.24 mmol，1.00當量）、(S)-2-羥基丙酸甲酯（0.55 g，5.24 mmol，1.00當量）和PPh₃（2.06 g，7.87 mmol，1.50當量）在THF（20 mL）中的攪拌溶液中逐滴添加DIAD（1.27 g，6.29 mmol，1.20當量）。將所得混合物在室溫攪拌2 h。將反應混合物用EA稀釋並用水和鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由逆相急速層析法純化，以獲得呈淡黃色固體的標題化合物。Example35 Synthesis of (R)-4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)benzonitrile Step 1: (R)-2-(5-((4-((tert-butyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)-2-cyano-phenoxy)propionic acid methyl ester To a stirred solution of (1-((4-cyano-3-hydroxyphenyl)sulfonyl)piperidin-4-yl)-carbamic acid tributyl ester (2.0 g, 5.24 mmol, 1.00 equiv), (S)-methyl 2-hydroxypropanoate (0.55 g, 5.24 mmol, 1.00 equiv), and_PPh₃ (2.06 g, 7.87 mmol, 1.50 equiv) in THF (20 mL) at 0°C under a nitrogen atmosphere was added DIAD (1.27 g, 6.29 mmol, 1.20 equiv) dropwise. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EA and washed with water and brine,_and dried over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase flash chromatography to obtain the title compound as a pale yellow solid.

步驟2：(R)-(1-((4-氰基-3-((1-羥基丙-2-基)氧基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在0°C在氮氣氣氛下向(R)-2-(5-((4-((三級丁氧基羰基)胺基)哌啶-1-基)-磺醯基)-2-氰基苯氧基)丙酸甲酯（660 mg，1.41 mmol，1.00當量）在MeOH（6.6 mL）中的攪拌溶液中分批添加NaBH₄（160 mg，4.24 mmol，3.00當量）。將所得混合物在室溫在氮氣氣氛下攪拌1 h。將反應混合物在室溫用飽和NH₄Cl（水性）淬滅。將所得混合物用EA萃取。將合併的有機層用水和鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EA/PE（0-70%）洗脫）純化，以得到呈白色固體的標題化合物。Step 2: (R)-tert-butyl(1-((4-cyano-3-((1-hydroxypropan-2-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of (R)-methyl 2-(5-((4-((tert-butyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)-2-cyanophenoxy)propanoate (660 mg, 1.41 mmol, 1.00 equiv) in MeOH (6.6 mL) was added_NaBH₄ (160 mg, 4.24 mmol, 3.00 equiv) portionwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was quenched with saturated_NH₄Cl (aqueous) at room temperature. The resulting mixture was extracted with EA. The combined organic layers were washed with water and brine, and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EA/PE (0-70%) to give the title compound as a white solid.

步驟3：甲磺酸(R)-2-(5-((4-((三級丁氧基羰基)胺基)哌啶-1-基)磺醯基)-2-氰基苯氧基)丙酯在0°C在氮氣氣氛下向(R)-(1-((4-氰基-3-((1-羥基丙-2-基)氧基)-苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（500 mg，1.14 mmol，1.00當量）和TEA（345 mg，3.41 mmol，3.00當量）在DCM（5 mL）中的攪拌溶液中分批添加MsCl（170 mg，1.48 mmol，1.30當量）。將所得混合物在室溫攪拌2 h。將反應混合物在室溫用水淬滅並用DCM萃取。將合併的有機層用鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮，以獲得呈棕色固體的粗標題化合物。Step 3: (R)-2-(5-((4-((tert-butyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)-2-cyanophenoxy)propyl methanesulfonate To a stirred solution of (R)-tributyl(1-((4-cyano-3-((1-hydroxypropan-2-yl)oxy)-phenyl)sulfonyl)piperidin-4-yl)carbamate (500 mg, 1.14 mmol, 1.00 equiv) and TEA (345 mg, 3.41 mmol, 3.00 equiv) in DCM (5 mL) at 0°C under a nitrogen atmosphere was added MsCl (170 mg, 1.48 mmol, 1.30 equiv) portionwise. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water at room temperature and extracted with DCM. The combined organic layers were washed with brine and dried over_{anhydrousNa2SO4} . After filtration, the filtrate was concentrated under reduced pressure to obtain the crude title compound as a brown solid.

步驟4：(R)-(1-((4-氰基-3-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯將甲磺酸(R)-2-(5-((4-((三級丁氧基羰基)胺基)哌啶-1-基)磺醯基)-2-氰基苯氧基)丙酯（477 mg，0.92 mmol，1.00當量）、1-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽（0.40 g，1.11 mmol，1.20當量）、KI（0.31 g，1.84 mmol，2.00當量）和DIEA（0.60 g，4.61 mmol，5.00當量）在CH₃CN（5.0 mL）中的混合物在80°C攪拌過夜。將反應混合物冷卻，用水稀釋並用EA萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。將混合物過濾並在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用THF/PE（0-50%）洗脫）純化，以得到呈白色固體的標題化合物。Step 4: (R)-(1-((4-cyano-3-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamic acid tributyl ester A mixture of (R)-2-(5-((4-((tert-butyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)-2-cyanophenoxy)propyl methanesulfonate (477 mg, 0.92 mmol, 1.00 equiv), 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (0.40 g, 1.11 mmol, 1.20 equiv), KI (0.31 g, 1.84 mmol, 2.00 equiv), and DIEA (0.60 g, 4.61 mmol, 5.00 equiv) in CH₃ CN (5.0 mL) was stirred at 80° C. overnight. The reaction mixture was cooled, diluted with water, and extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na₂ SO₄ . The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with THF/PE (0-50%) to give the title compound as a white solid.

步驟5：(R)-4-((4-胺基哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)苯甲腈氯化氫在室溫向(R)-(1-((4-氰基-3-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（270 mg，0.36 mmol，1.00當量）在DCM（2.0 mL）中的攪拌溶液中逐滴添加二㗁𠮿中的4.0 M HCl（1.0 mL）。攪拌3 h後，將所得混合物濃縮以得到標題化合物。Step 5: (R)-4-((4-aminopiperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)benzonitrile hydrochloride To a stirred solution of (R)-tributyl(1-((4-cyano-3-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (270 mg, 0.36 mmol, 1.00 equiv) in DCM (2.0 mL) was added 4.0 M HCl in dioxane (1.0 mL) dropwise at room temperature. After stirring for 3 h, the resulting mixture was concentrated to give the title compound.

步驟6：(R)-4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)苯甲腈將((R)-4-((4-胺基哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基-四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)-苯甲腈鹽酸鹽（100 mg，0.154 mmol，1.00當量）、2,5-二氯嘧啶（0.03 g，0.231 mmol，1.50當量）、CsF（0.05 g，0.308 mmol，2.00當量）和DIEA（0.06 g，0.462 mmol，3.00當量）在DMSO（1.0 mL）中的混合物在80^oC攪拌16 h。將所得混合物冷卻，過濾，並將濾餅用DMSO洗滌。將濾液濃縮並將殘餘物藉由製備型HPLC純化，以得到呈白色固體的標題化合物。MS (ES,m/z): [M+H]⁺=761.4。Step 6: (R)-4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)benzonitrile A mixture of ((R)-4-((4-aminopiperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxo-tetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)-benzonitrile hydrochloride (100 mg, 0.154 mmol, 1.00 equiv), 2,5-dichloropyrimidine (0.03 g, 0.231 mmol, 1.50 equiv), CsF (0.05 g, 0.308 mmol, 2.00 equiv) and DIEA (0.06 g, 0.462 mmol, 3.00 equiv) in DMSO (1.0 mL) was stirred at 80^° C for 16 min. h. The resulting mixture was cooled, filtered, and the filter cake was washed with DMSO. The filtrate was concentrated, and the residue was purified by preparative HPLC to afford the title compound as a white solid. MS (ES,m/z ): [M+H]⁺ = 761.4.

藉由與實例35中所述類似的方式進行來合成以下化合物。實例#結構程序36在步驟6中，將2,5-二氯嘧啶替代為2-氯-5-(三氟甲基)-嘧啶。The following compounds were synthesized in a similar manner to that described in Example 35.Example#structureprogram 36 In step 6, 2,5-dichloropyrimidine was replaced by 2-chloro-5-(trifluoromethyl)-pyrimidine.

實例37(R)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-哌啶-1-基)丙-2-基)胺基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈三氟乙酸鹽的合成步驟1：(R)-(1-((4-氰基-3-((1-羥基丙-2-基)胺基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯將(1-((3-溴-4-氰基苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（5.0 g，11.25 mmol，1.00當量）、(2R)-2-胺基丙-1-醇（1.27 g，16.91 mmol，1.50當量）、XantPhos（1.30 g，2.25 mmol，0.20當量）、Pd₂(dba)₃（1.03 g，1.125 mmol，0.10當量）和Cs₂CO₃（11.0 g，33.76 mmol，3.00當量）在1, 4-二㗁𠮿（50 mL）中的溶液在100°C在氮氣氣氛下攪拌3 h。將反應混合物冷卻，用水稀釋並用EA萃取。將合併的有機層用水和鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EA/PE（0-50%）洗脫）純化，以得到呈黃色固體的標題化合物。Example37 Synthesis of (R)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-piperidin-1-yl)propan-2-yl)amino)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile trifluoroacetate Step 1: (R)-tert-butyl(1-((4-cyano-3-((1-hydroxypropan-2-yl)amino)phenyl)sulfonyl)piperidin-4-yl)carbamate A solution of tributyl (1-((3-bromo-4-cyanophenyl)sulfonyl)piperidin-4-yl)carbamate (5.0 g, 11.25 mmol, 1.00 equiv), (2R)-2-aminopropan-1-ol (1.27 g, 16.91 mmol, 1.50 equiv), XantPhos (1.30 g, 2.25 mmol, 0.20 equiv), Pd₂ (dba)₃ (1.03 g, 1.125 mmol, 0.10 equiv), and Cs₂ CO₃ (11.0 g, 33.76 mmol, 3.00 equiv) in 1,4-dioxane (50 mL) was stirred at 100° C. under a nitrogen atmosphere for 3 h. The reaction mixture was cooled, diluted with water, and extracted with EA. The combined organic layers were washed with water and brine, and dried over anhydrous Na₂ SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EA/PE (0-50%)) to give the title compound as a yellow solid.

步驟2：(R)-4-((4-胺基哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)胺基)苯甲腈鹽酸鹽藉由與實例35的步驟3-5中所述類似的方式進行來合成標題化合物。Step 2: (R)-4-((4-aminopiperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)amino)benzonitrile hydrochloride The title compound was synthesized by proceeding in a similar manner to that described in Steps 3-5 of Example 35.

步驟3：(R)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-哌啶-1-基)丙-2-基)胺基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈三氟乙酸鹽在室溫在氮氣氣氛下向(R)-4-((4-胺基哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基-四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)胺基)-苯甲腈鹽酸鹽（100 mg，0.15 mmol，1當量）和DIEA（113 mg，0.88 mmol，6當量）以及CsF（44 mg，0.29 mmol，2當量）在DMSO（1 mL）中的攪拌溶液中分批添加2-氯-5-(三氟甲基)-嘧啶（40 mg，0.22 mmol，1.5當量）。將所得混合物在80°C再攪拌16 h。將粗產物藉由製備型HPLC純化以得到標題化合物。MS (ES, m/z): [M+H]⁺= 794.4。Step 3: (R)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-piperidin-1-yl)propan-2-yl)amino)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile trifluoroacetate To a stirred solution of (R)-4-((4-aminopiperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxo-tetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)amino)-benzonitrile hydrochloride (100 mg, 0.15 mmol, 1 eq), DIEA (113 mg, 0.88 mmol, 6 eq), and CsF (44 mg, 0.29 mmol, 2 eq) in DMSO (1 mL) was added 2-chloro-5-(trifluoromethyl)-pyrimidine (40 mg, 0.22 mmol, 1.5 eq) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for an additional 16 h. The crude product was purified by preparative HPLC to afford the title compound. MS (ES, m/z): [M+H]⁺ = 794.4.

藉由與實例37中所述類似的方式進行來合成以下實例。實例#結構程序38在步驟3中，將2-氯-5-(三氟甲基)嘧啶替代為2,5-二氯嘧啶。The following examples were synthesized in a manner similar to that described in Example 37.Example#structureprogram 38 In step 3, 2-chloro-5-(trifluoromethyl)pyrimidine was replaced with 2,5-dichloropyrimidine.

實例392-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-哌啶-1-基)丙-2-基)硫代)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈的合成步驟1：2-((5-((4-((三級丁氧基羰基)胺基)哌啶-1-基)磺醯基)-2-氰基苯基)-硫代)丙酸甲酯將(1-((3-溴-4-氰基苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（5.0 g，11.25 mmol，1.00當量）、2-氫硫基丙酸甲酯（1.49 g，12.37 mmol，1.10當量）、Pd₂(dba)₃·CHCl₃（1.16 g，1.125 mmol，0.10當量）、XantPhos（0.65 g，1.125 mmol，0.10當量）和DIEA（4.36 g，33.76 mmol，3.00當量）在二㗁𠮿（50 mL）中的溶液在100°C在氮氣氣氛下攪拌4 h。將反應混合物在真空下濃縮。將殘餘物藉由矽膠柱層析法（用EA/PE（0-40%）洗脫）純化，以得到呈黃色固體的標題化合物。Example39 Synthesis of 2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-piperidin-1-yl)propan-2-yl)thio)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile Step 1: Methyl 2-((5-((4-((tert-butyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)-2-cyanophenyl)-thio)propanoate A solution of tert-butyl (1-((3-bromo-4-cyanophenyl)sulfonyl)piperidin-4-yl)carbamate (5.0 g, 11.25 mmol, 1.00 equiv), methyl 2-mercaptopropanoate (1.49 g, 12.37 mmol, 1.10 equiv), Pd₂ (dba)₃ ·CHCl₃ (1.16 g, 1.125 mmol, 0.10 equiv), XantPhos (0.65 g, 1.125 mmol, 0.10 equiv), and DIEA (4.36 g, 33.76 mmol, 3.00 equiv) in dihydrogen hydride (50 mL) was stirred at 100° C. under a nitrogen atmosphere for 4 h. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with EA/PE (0-40%) to give the title compound as a yellow solid.

步驟2：(1-((4-氰基-3-((1-羥基丙-2-基)硫代)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在0°C在氮氣氣氛下向2-((5-((4-((三級丁氧基羰基)胺基)哌啶-1-基)磺醯基)-2-氰基苯基)硫代)丙酸甲酯（3.6 g，7.44 mmol，1.00當量）在THF（10 mL）和MeOH（10 mL）中的攪拌混合物中添加NaBH₄（1.4 g，37.01 mmol，4.97當量）和CaCl₂（2.05 g，18.47 mmol，2.48當量）。將所得混合物在室溫在氮氣氣氛下攪拌4 h。將反應混合物在0°C用飽和NH₄Cl（水性）淬滅並用EA萃取。將合併的有機層用水和鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EA/PE（0-50%）洗脫）純化，以得到呈淡黃色固體的標題化合物。Step 2: Tributyl (1-((4-cyano-3-((1-hydroxypropan-2-yl)thio)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred mixture of methyl 2-((5-((4-((tert-butyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)-2-cyanophenyl)thio)propanoate (3.6 g, 7.44 mmol, 1.00 equiv) in THF (10 mL) and MeOH (10 mL) at 0°C under a nitrogen atmosphere were added_NaBH₄ (1.4 g, 37.01 mmol, 4.97 equiv) and_CaCl₂ (2.05 g, 18.47 mmol, 2.48 equiv). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 h. The reaction mixture was quenched with saturated_NH₄Cl (aq.) at 0°C and extracted with EA. The combined organic layers were washed with water and brine and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EA/PE (0-50%)) to give the title compound as a pale yellow solid.

步驟3：4-((4-胺基哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)硫代)苯甲腈鹽酸鹽藉由與實例35的步驟3-5中所述類似的方式進行來合成標題化合物。Step 3: 4-((4-aminopiperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)thio)benzonitrile hydrochloride The title compound was synthesized by proceeding in a similar manner to that described in Steps 3-5 of Example 35.

步驟4：2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)硫代)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈在室溫在氮氣氣氛下向4-((4-胺基哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基-四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)硫代)-苯甲腈（150 mg，0.214 mmol，1當量）和DIEA（165 mg，1.284 mmol，6當量）以及CsF（65 mg，0.428 mmol，2當量）在DMSO（1.5 mL）中的攪拌溶液中分批添加2-氯-5-(三氟甲基)-嘧啶（77 mg，0.428 mmol，2當量）。將所得混合物在80°C再攪拌16 h。將混合物濃縮並將殘餘物藉由製備型HPLC純化，以得到標題化合物。MS (ES, m/z): [M+H]⁺= 811.3。Step 4: 2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)thio)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile To a stirred solution of 4-((4-aminopiperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxo-tetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)thio)-benzonitrile (150 mg, 0.214 mmol, 1 eq) and DIEA (165 mg, 1.284 mmol, 6 eq) and CsF (65 mg, 0.428 mmol, 2 eq) in DMSO (1.5 mL) was added 2-chloro-5-(trifluoromethyl)-pyrimidine (77 mg, 0.428 mmol, 2 eq) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. for an additional 16 h. The mixture was concentrated and the residue was purified by preparative HPLC to afford the title compound. MS (ES, m/z): [M+H]⁺ = 811.3.

藉由與實例39中所述類似的方式進行來合成以下實例。實例#結構程序40在步驟4中，將2-氯-5-(三氟甲基)嘧啶替代為2,5-二氯嘧啶。The following examples were synthesized in a manner similar to that described in Example 39.Example#structureprogram 40 In step 4, 2-chloro-5-(trifluoromethyl)pyrimidine was replaced by 2,5-dichloropyrimidine.

實例412-(4-氰基-2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)丁基)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈的合成步驟1：5-羥基-4-(羥基甲基)戊腈在0°C向2-(2-氰基乙基)丙二酸二乙酯（4.26 g，20.00 mmol，1.00當量）在無水甲醇（100 mL）中的攪拌溶液中分批添加NaBH₄（3.8 g，100.45 mmol，5.00當量）。將該所得混合物在25°C攪拌16 h。將反應混合物用6 M水性氯化氫淬滅，然後在減壓下濃縮。將殘餘物藉由矽膠墊過濾並用乙酸乙酯/甲醇=10/1洗滌該墊。將濾液經無水Na₂SO₄乾燥，過濾，並將濾液在減壓下濃縮，以得到呈黃色油狀物的粗標題化合物。Example41 Synthesis of 2-(4-cyano-2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)butyl)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile Step 1: 5-Hydroxy-4-(hydroxymethyl)valeronitrile To a stirred solution of diethyl 2-(2-cyanoethyl)malonate (4.26 g, 20.00 mmol, 1.00 equiv) in anhydrous methanol (100 mL) was added_NaBH₄ (3.8 g, 100.45 mmol, 5.00 equiv) portionwise at 0°C. The resulting mixture was stirred at 25°C for 16 h. The reaction mixture was quenched with 6 M aqueous hydrogen chloride and then concentrated under reduced pressure. The residue was filtered through a silica gel pad_and the pad was washed with ethyl acetate/methanol = 10/1. The filtrate was dried over anhydrous_Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound as a yellow oil.

步驟2：5-((三級丁基二甲基甲矽烷基)氧基)-4-(羥基甲基)戊腈在0°C向5-羥基-4-(羥基甲基)戊腈（517 mg，4.00 mmol，1.25當量）在無水THF（8.0 mL）中的攪拌溶液中分批添加氫化鈉（60%在油中，160 mg，4.00 mmol，1.25當量）。將所得混合物在0°C在氬氣氣氛下攪拌10 min，然後逐滴添加TBSCl（480 mg，3.20 mmol，1.00當量）在無水THF（5.0 mL）中的溶液。將反應混合物在室溫攪拌16 h。將反應混合物用飽和NH₄Cl溶液淬滅，用水稀釋並用EA萃取。將合併的有機層用鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EA/PE（0-30%）洗脫）純化，以得到呈黃色油狀物的標題化合物。Step 2: 5-((tert-butyldimethylsilyl)oxy)-4-(hydroxymethyl)valeronitrile To a stirred solution of 5-hydroxy-4-(hydroxymethyl)pentanenitrile (517 mg, 4.00 mmol, 1.25 equiv) in anhydrous THF (8.0 mL) at 0°C was added sodium hydroxide (60% in oil, 160 mg, 4.00 mmol, 1.25 equiv) portionwise. The resulting mixture was stirred at 0°C under an atmosphere of hydrogen for 10 min, followed by the dropwise addition of a solution of TBSCl (480 mg, 3.20 mmol, 1.00 equiv) in anhydrous THF (5.0 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated_NH₄Cl solution, diluted with water, and extracted with EA. The combined organic layers were washed with brine and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EA/PE (0-30%)) to give the title compound as a yellow oil.

步驟3：5-((三級丁基二甲基甲矽烷基)氧基)-4-(碘甲基)戊腈在0°C在氬氣氣氛下向三苯膦（1.22 g，4.65 mmol，1.30當量）和咪唑（341 mg，5.01 mmol，1.40當量）在無水DCM（20 mL）中的攪拌溶液中添加碘（1.09 mg，4.29 mmol，1.20當量）。在室溫攪拌10 min後，添加5-((三級丁基二甲基甲矽烷基)氧基)-4-(羥基甲基)戊腈（870 mg，3.57 mmol，1.00當量）在無水DCM（10 mL）中的溶液。將所得混合物在室溫攪拌2 h，過濾，用水淬滅並用DCM萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EA/PE（0-10%）洗脫）純化，以得到呈黃色油狀物的標題化合物。Step 3: 5-((tert-butyldimethylsilyl)oxy)-4-(iodomethyl)valeronitrile To a stirred solution of triphenylphosphine (1.22 g, 4.65 mmol, 1.30 equiv) and imidazole (341 mg, 5.01 mmol, 1.40 equiv) in anhydrous DCM (20 mL) at 0°C under an atmosphere of hydrogen was added iodine (1.09 mg, 4.29 mmol, 1.20 equiv). After stirring at room temperature for 10 minutes, a solution of 5-((tributyldimethylsilyl)oxy)-4-(hydroxymethyl)pentanenitrile (870 mg, 3.57 mmol, 1.00 equiv) in anhydrous DCM (10 mL) was added. The resulting mixture was stirred at room temperature for 2 hours, filtered, quenched with water, and extracted with DCM. The combined organic layers were washed with brine and dried over_{anhydrousNa₂SO₄} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EA/PE (0-10%)) to give the title compound as a yellow oil.

步驟4：(1-((3-(2-(((三級丁基二甲基甲矽烷基)氧基)甲基)-4-氰基丁基)-4-氰基苯基)-磺醯基)哌啶-4-基)胺基甲酸三級丁酯向5-((三級丁基二甲基甲矽烷基)氧基)-4-(碘甲基)戊腈（348 mg，0.99 mmol，1.46當量）在無水DMAc（5.0 mL）中的攪拌溶液中添加Mn（148 mg，2.69 mmol，3.96當量）、N-[1-(3-溴-4-氰基-苯基)磺醯基-4-哌啶基]胺基甲酸三級丁酯（300 mg，0.68 mmol，1.00當量）和NiCl₂(DME)（30 mg，0.14 mmol，0.21當量）、吡啶-2-甲脒鹽酸鹽（21 mg，0.14 mmol，0.21當量）和NaI（25 mg，0.17 mmol，0.25當量）。將所得混合物在45°C在氬氣氣氛下在密封管中攪拌16 h，用水淬滅並用EA萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EA/PE（0-25%）洗脫）純化，以得到呈白色固體的標題化合物。Step 4: Tributyl (1-((3-(2-(((tributyldimethylsilyl)oxy)methyl)-4-cyanobutyl)-4-cyanophenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of 5-((tributyldimethylsilyl)oxy)-4-(iodomethyl)pentanenitrile (348 mg, 0.99 mmol, 1.46 equiv) in anhydrous DMAc (5.0 mL) were added Mn (148 mg, 2.69 mmol, 3.96 equiv), tert-butyl N-[1-(3-bromo-4-cyano-phenyl)sulfonyl-4-piperidinyl]carbamate (300 mg, 0.68 mmol, 1.00 equiv) and_NiCl2 (DME) (30 mg, 0.14 mmol, 0.21 equiv), pyridine-2-carboximidamide hydrochloride (21 mg, 0.14 mmol, 0.21 equiv) and NaI (25 mg, 0.17 mmol, 0.25 equiv). The resulting mixture was stirred at 45°C under an atmosphere of argon in a sealed tube for 16 h, quenched with water, and extracted with EA. The combined organic layers were washed with brine and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA/PE (0-25%), to afford the title compound as a white solid.

步驟5：(1-((4-氰基-3-(4-氰基-2-(羥基甲基)丁基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯向(1-((3-(2-(((三級丁基二甲基甲矽烷基)氧基)甲基)-4-氰基丁基)-4-氰基苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（120 mg，0.20 mmol，1.00當量）在無水THF（10 mL）中的攪拌溶液中添加TABF（0.41 mL，0.41 mmol，2.05當量）。在25°C攪拌16 h後，將反應混合物在減壓下濃縮。將殘餘物用水稀釋並用EA萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EA/PE（0-50%）洗脫）純化，以得到呈白色固體的標題化合物。Step 5: Tributyl (1-((4-cyano-3-(4-cyano-2-(hydroxymethyl)butyl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of tributyl (1-((3-(2-(((tributyldimethylsilyl)oxy)methyl)-4-cyanobutyl)-4-cyanophenyl)sulfonyl)piperidin-4-yl)carbamate (120 mg, 0.20 mmol, 1.00 equiv) in anhydrous THF (10 mL) was added TABF (0.41 mL, 0.41 mmol, 2.05 equiv). After stirring at 25°C for 16 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with EA. The combined organic layers were washed with brine and dried over_{anhydrousNa₂SO₄} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EA/PE (0-50%) to give the title compound as a white solid.

步驟6：甲磺酸2-(5-((4-((三級丁氧基羰基)胺基)哌啶-1-基)磺醯基)-2-氰基苄基)-4-氰基丁酯在0°C向(1-((4-氰基-3-(4-氰基-2-(羥基甲基)丁基) 苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（70 mg，0.15 mmol，1.00當量）和TEA（65 mg，0.59 mmol，3.93當量）在無水DCM（10.0 mL）中的攪拌溶液中分批添加甲磺酸酐（51 mg，0.29 mmol，1.93當量）。在25°C攪拌2 h後，將反應混合物用水淬滅並用DCM萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用MeOH/DCM（0-3%）洗脫）純化，以得到呈白色固體的標題化合物。Step 6: 2-(5-((4-((tert-butyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)-2-cyanobenzyl)-4-cyanobutyl methanesulfonate To a stirred solution of tributyl (1-((4-cyano-3-(4-cyano-2-(hydroxymethyl)butyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (70 mg, 0.15 mmol, 1.00 equiv) and TEA (65 mg, 0.59 mmol, 3.93 equiv) in anhydrous DCM (10.0 mL) at 0°C was added methanesulfonic anhydride (51 mg, 0.29 mmol, 1.93 equiv) portionwise. After stirring at 25°C for 2 h, the reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine and dried_over anhydrous_Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH/DCM (0-3%) to give the title compound as a white solid.

步驟7：(1-((4-氰基-3-(4-氰基-2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)丁基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯向1-[1-甲基-6-(4-哌啶基)吲唑-3-基]六氫嘧啶-2,4-二酮鹽酸鹽（46 mg，0.13 mmol，1.00當量）、甲磺酸2-(5-((4-((三級丁氧基羰基) 胺基)哌啶-1-基)磺醯基)-2-氰基苄基)-4-氰基丁酯（70 mg，0.13 mmol，1.00當量）和NaI（38 mg，0.25 mmol，1.92當量）在無水MeCN（7.0 mL）中的攪拌溶液中添加DIPEA（56 mg，0.50 mmol，3.85當量）。在100°C攪拌16 h後，將反應混合物冷卻，用水稀釋並用EA萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用MeOH/DCM（0-3%）洗脫）純化，以得到呈白色固體的標題化合物。Step 7: Tributyl (1-((4-cyano-3-(4-cyano-2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)butyl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of 1-[1-methyl-6-(4-piperidinyl)indazol-3-yl]hexahydropyrimidine-2,4-dione hydrochloride (46 mg, 0.13 mmol, 1.00 equiv), 2-(5-((4-((tributyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)-2-cyanobenzyl)-4-cyanobutyl methanesulfonate (70 mg, 0.13 mmol, 1.00 equiv), and NaI (38 mg, 0.25 mmol, 1.92 equiv) in anhydrous MeCN (7.0 mL) was added DIPEA (56 mg, 0.50 mmol, 3.85 equiv). After stirring at 100°C for 16 h, the reaction mixture was cooled, diluted with water, and extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na₂ SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH/DCM (0-3%) to give the title compound as a white solid.

步驟8：4-((4-胺基哌啶-1-基)磺醯基)-2-(4-氰基-2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)丁基)苯甲腈鹽酸鹽在0°C向(1-((4-氰基-3-(4-氰基-2-((4-(3-(2,4-二側氧基四氫-嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)丁基)苯基)磺醯基)-哌啶-4-基)胺基甲酸三級丁酯（15 mg，0.02 mmol）在無水DCM（5 mL）中的溶液中逐滴添加4 M HCl/1,4-二㗁𠮿（0.5 mL，2 mmol）。將該混合物在25°C攪拌2 h。將所得混合物在減壓下濃縮，以得到呈黃色固體的標題化合物。Step 8: 4-((4-aminopiperidin-1-yl)sulfonyl)-2-(4-cyano-2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)butyl)benzonitrile hydrochloride To a solution of tributyl (1-((4-cyano-3-(4-cyano-2-((4-(3-(2,4-dioxotetrahydro-pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)butyl)phenyl)sulfonyl)-piperidin-4-yl)carbamate (15 mg, 0.02 mmol) in anhydrous DCM (5 mL) at 0°C was added 4 M HCl/1,4-dioxathiol (0.5 mL, 2 mmol) dropwise. The mixture was stirred at 25°C for 2 h. The resulting mixture was concentrated under reduced pressure to give the title compound as a yellow solid.

步驟9：2-(4-氰基-2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)丁基)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈向2-氯-5-(二氟甲氧基)嘧啶（7 mg，0.04 mmol）、4-((4-胺基哌啶-1-基)磺醯基)-2-(4-氰基-2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)丁基)苯甲腈鹽酸鹽（13 mg，0.018 mmol）和CsF（6 mg，0.04 mmol）在DMSO（2 mL）中的溶液中添加DIPEA（10 mg，0.07 mmol）。將混合物在90°C攪拌6 h。將所得混合物藉由C18柱層析法（用MeCN/水（0-50%，0.05% NH₄HCO₃）洗脫）純化，以得到呈灰白色固體的標題化合物。MS (ES, m/z): [M+H]+ = 830.5。Step 9: 2-(4-cyano-2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)butyl)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile To a solution of 2-chloro-5-(difluoromethoxy)pyrimidine (7 mg, 0.04 mmol), 4-((4-aminopiperidin-1-yl)sulfonyl)-2-(4-cyano-2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)butyl)benzonitrile hydrochloride (13 mg, 0.018 mmol), and CsF (6 mg, 0.04 mmol) in DMSO (2 mL) was added DIPEA (10 mg, 0.07 mmol). The mixture was stirred at 90°C for 6 h. The resulting mixture was purified by C18 column chromatography, eluting with MeCN/water (0-50%, 0.05% NH₄ HCO₃ ), to give the title compound as an off-white solid. MS (ES, m/z): [M+H] + = 830.5.

藉由與實例41中所述類似的方式進行來合成以下實例。實例#結構程序42在步驟9中，將2-氯-5-(二氟甲氧基)-嘧啶替代為2-氯-5-(三氟甲基)-嘧啶。The following examples were synthesized in a manner similar to that described in Example 41.Example#structureprogram 42 In step 9, 2-chloro-5-(difluoromethoxy)-pyrimidine was replaced by 2-chloro-5-(trifluoromethyl)-pyrimidine.

實例434-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)-4-甲氧基丁基)苯甲腈的合成步驟1：2-甲醯基-4-甲氧基丁酸甲酯在-78°C向N-異丙基丙-2-胺（2.43 g，24.01 mmol，1.20當量）在無水THF（40 mL）中的攪拌溶液中添加nBuLi（2.5 M，9.6 mL，24.00 mmol，1.20當量）。在-78°C在氬氣氣氛下攪拌30 min後，添加4-甲氧基丁酸甲酯（2.64 g，20.00 mmol，1.00當量）。將所得混合物在-78°C攪拌1 h並添加甲酸乙酯（1.78 g，24.00 mmol，1.20當量）。在-78°C攪拌3 h後，將反應混合物緩慢加溫至室溫，然後在室溫攪拌16 h。將反應混合物用飽和NH₄Cl溶液淬滅並用EA萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EA/PE（0-40%）洗脫）純化，以得到呈黃色油狀物的標題化合物。Example43 Synthesis of 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)-4-methoxybutyl)benzonitrile Step 1: Methyl 2-methyl-4-methoxybutyrate To a stirred solution of N-isopropylpropan-2-amine (2.43 g, 24.01 mmol, 1.20 equiv) in anhydrous THF (40 mL) at -78°C was added nBuLi (2.5 M, 9.6 mL, 24.00 mmol, 1.20 equiv). After stirring at -78°C under an hydrogen atmosphere for 30 min, methyl 4-methoxybutyrate (2.64 g, 20.00 mmol, 1.00 equiv) was added. The resulting mixture was stirred at -78°C for 1 h, and ethyl formate (1.78 g, 24.00 mmol, 1.20 equiv) was added. After stirring at -78°C for 3 h, the reaction mixture was slowly warmed to room temperature and then stirred at room temperature for 16 h. The reaction mixture was quenched with saturated_NH₄Cl solution and extracted with EA. The combined organic layers were washed with brine and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with EA/PE (0-40%)) to give the title compound as a yellow oil.

步驟2：2-(羥基甲基)-4-甲氧基丁酸甲酯在0°C向2-甲醯基-4-甲氧基-丁酸甲酯（800 mg，4.99 mmol，1.00當量）在無水甲醇（10 mL）和THF（10 mL）中的攪拌溶液中分批添加NaBH₄（190 mg，4.99 mmol，1.00當量）。在0°C攪拌1 h後，將反應混合物用水淬滅並用EA萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EA/PE（0-40%）洗脫）純化，以得到呈黃色油狀物的標題化合物。Step 2: Methyl 2-(hydroxymethyl)-4-methoxybutyrate To a stirred solution of methyl 2-formyl-4-methoxy-butyrate (800 mg, 4.99 mmol, 1.00 equiv) in anhydrous methanol (10 mL) and THF (10 mL) at 0°C was added_NaBH₄ (190 mg, 4.99 mmol, 1.00 equiv) portionwise. After stirring at 0°C for 1 h, the reaction mixture was quenched with water and extracted with EA. The combined organic layers were washed with brine and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA/PE (0-40%) to afford the title compound as a yellow oil.

步驟3：2-(碘甲基)-4-甲氧基丁酸甲酯在0°C在氬氣氣氛下向三苯膦（776 mg，2.96 mmol，1.20當量）和咪唑（210 mg，3.08 mmol，1.25當量）在無水DCM（20 mL）中的攪拌溶液中添加碘（689 mg，2.71 mmol，1.10當量）。將所得混合物在室溫在氬氣氣氛下攪拌10 min，並添加2-(羥基甲基)-4-甲氧基丁酸甲酯（400 mg，2.47 mmol，1.00當量）在無水DCM（10 mL）中的溶液。在室溫攪拌2 h後，將反應混合物過濾，用水淬滅，然後用DCM萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EA/PE（0-5%）洗脫）純化，以得到呈黃色油狀物的標題化合物。Step 3: Methyl 2-(iodomethyl)-4-methoxybutyrate To a stirred solution of triphenylphosphine (776 mg, 2.96 mmol, 1.20 equiv) and imidazole (210 mg, 3.08 mmol, 1.25 equiv) in anhydrous DCM (20 mL) at 0°C under an atmosphere of hydrogen was added iodine (689 mg, 2.71 mmol, 1.10 equiv). The resulting mixture was stirred at room temperature under an atmosphere of hydrogen for 10 min, and a solution of methyl 2-(hydroxymethyl)-4-methoxybutanoate (400 mg, 2.47 mmol, 1.00 equiv) in anhydrous DCM (10 mL) was added. After stirring at room temperature for 2 h, the reaction mixture was filtered, quenched with water, and extracted with DCM. The combined organic layers were washed with brine and dried over_{anhydrousNa₂SO₄} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EA/PE (0-5%)) to give the title compound as a yellow oil.

步驟4：2-(5-((4-((三級丁氧基羰基)胺基)哌啶-1-基)磺醯基)-2-氰基苄基)-4-甲氧基丁酸甲酯在25°C向2-(碘甲基)-4-甲氧基丁酸甲酯（460 mg，1.69 mmol，1.64當量）在無水DMAc（7.5 mL）中的攪拌溶液中添加Mn（227 mg，4.12 mmol，4.00當量）、N-[1-(3-溴-4-氰基-苯基)磺醯基-4-哌啶基]胺基甲酸三級丁酯（458 mg，1.03 mmol，1.00當量）、NiCl₂(DME)（45 mg，0.21 mmol，0.20當量）、NaI（39 mg，0.26 mmol，0.25當量）和吡啶-2-甲脒鹽酸鹽（33 mg，0.21 mmol，0.20當量）。將所得混合物在45°C在氬氣氣氛下在密封管中攪拌16 h。將反應混合物用水淬滅並用EA萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EA/PE（0-20%）洗脫）純化，以得到呈白色固體的標題化合物。Step 4: Methyl 2-(5-((4-((tert-butyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)-2-cyanobenzyl)-4-methoxybutanoate To a stirred solution of methyl 2-(iodomethyl)-4-methoxybutanoate (460 mg, 1.69 mmol, 1.64 equiv) in anhydrous DMAc (7.5 mL) at 25 °C were added Mn (227 mg, 4.12 mmol, 4.00 equiv), tert-butyl N-[1-(3-bromo-4-cyano-phenyl)sulfonyl-4-piperidinyl]carbamate (458 mg, 1.03 mmol, 1.00 equiv),_NiCl2 (DME) (45 mg, 0.21 mmol, 0.20 equiv), NaI (39 mg, 0.26 mmol, 0.25 equiv) and pyridine-2-carboximidamide hydrochloride (33 mg, 0.21 mmol, 0.20 equiv). The resulting mixture was stirred at 45°C under an atmosphere of argon in a sealed tube for 16 h. The reaction mixture was quenched with water and extracted with EA. The combined organic layers were washed with brine and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA/PE (0-20%), to afford the title compound as a white solid.

步驟5：(1-((4-氰基-3-(2-(羥基甲基)-4-甲氧基丁基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在0°C向2-[[5-[[4-(三級丁氧基羰基胺基)-1-哌啶基]磺醯基]-2-氰基-苯基]甲基]-4-甲氧基-丁酸甲酯（340 mg，0.67 mmol，1.00當量）和CaCl₂（222 mg，2.00 mmol，3.00當量）在無水乙醇（3.0 mL）和THF（9.0 mL）中的攪拌溶液中分批添加NaBH₄（254 mg，6.67 mmol，10.00當量）。在25°C攪拌16 h後，將反應混合物用水淬滅並用EA萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用MeOH/DCM（0-2%）洗脫）純化，以得到呈白色固體的標題化合物。Step 5: Tributyl (1-((4-cyano-3-(2-(hydroxymethyl)-4-methoxybutyl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of 2-[[5-[[4-(tributyloxycarbonylamino)-1-piperidinyl]sulfonyl]-2-cyano-phenyl]methyl]-4-methoxy-butyric acid methyl ester (340 mg, 0.67 mmol, 1.00 equiv) and_CaCl₂ (222 mg, 2.00 mmol, 3.00 equiv) in anhydrous ethanol (3.0 mL) and THF (9.0 mL) at 0°C was added_NaBH₄ (254 mg, 6.67 mmol, 10.00 equiv) portionwise. After stirring at 25°C for 16 h, the reaction mixture was quenched with water and extracted with EA. The combined organic layers were washed with brine and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH/DCM (0-2%) to give the title compound as a white solid.

步驟6：甲磺酸2-(5-((4-((三級丁氧基羰基)胺基)哌啶-1-基)磺醯基)-2-氰基苄基)-4-甲氧基丁酯在0°C向(1-((4-氰基-3-(2-(羥基甲基)-4-甲氧基丁基)-苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（240 mg，0.50 mmol，1.00當量）和TEA（166 mg，1.49 mmol，2.98當量）在無水DCM（20 mL）中的攪拌溶液中添加甲磺酸酐（139 mg，0.80 mmol，1.20當量）。在25°C攪拌1 h後，將反應混合物用水淬滅並用DCM萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮，以得到呈白色固體的粗標題化合物。Step 6: 2-(5-((4-((tert-butyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)-2-cyanobenzyl)-4-methoxybutyl methanesulfonate To a stirred solution of tributyl (1-((4-cyano-3-(2-(hydroxymethyl)-4-methoxybutyl)-phenyl)sulfonyl)piperidin-4-yl)carbamate (240 mg, 0.50 mmol, 1.00 equiv) and TEA (166 mg, 1.49 mmol, 2.98 equiv) in anhydrous DCM (20 mL) at 0°C was added methanesulfonic anhydride (139 mg, 0.80 mmol, 1.20 equiv). After stirring at 25°C for 1 h, the reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine and dried_over anhydrous_Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure to give the crude title compound as a white solid.

步驟7：(1-((4-氰基-3-(2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)-4-甲氧基丁基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在25°C向1-[1-甲基-6-(4-哌啶基)吲唑-3-基]六氫嘧啶-2,4-二酮鹽酸鹽（130 mg，0.36 mmol，1.00當量）、甲磺酸2-(5-((4-((三級丁氧基羰基)胺基)-哌啶-1-基)磺醯基)-2-氰基苄基)-4-甲氧基丁酯（250 mg，0.45 mmol，1.25當量）和NaI（134 mg，0.89 mmol，2.47當量）在無水MeCN（20 mL）中的攪拌溶液中添加DIPEA（248 mg，2.23 mmol，6.19當量）。在90°C攪拌24 h後，將反應混合物冷卻，用水稀釋並用EA萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用MeOH/DCM（0-3%）洗脫）純化，以得到呈黃色油狀物的標題化合物。Step 7: Tributyl (1-((4-cyano-3-(2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)-4-methoxybutyl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of 1-[1-methyl-6-(4-piperidinyl)indazol-3-yl]hexahydropyrimidine-2,4-dione hydrochloride (130 mg, 0.36 mmol, 1.00 equiv), 2-(5-((4-((tributyloxycarbonyl)amino)-piperidin-1-yl)sulfonyl)-2-cyanobenzyl)-4-methoxybutyl methanesulfonate (250 mg, 0.45 mmol, 1.25 equiv), and NaI (134 mg, 0.89 mmol, 2.47 equiv) in anhydrous MeCN (20 mL) was added DIPEA (248 mg, 2.23 mmol, 6.19 equiv) at 25°C. After stirring at 90°C for 24 h, the reaction mixture was cooled, diluted with water, and extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na₂ SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH/DCM (0-3%) to give the title compound as a yellow oil.

步驟8：4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)-4-甲氧基丁基)苯甲腈藉由與實例23的步驟4-5中所述類似的方式進行來合成標題化合物，以得到呈白色固體的標題化合物。(ES, m/z): [M+H]⁺= 835.5。Step 8: 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-((4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)-4-methoxybutyl)benzonitrile The title compound was synthesized in a manner similar to that described in Steps 4-5 of Example 23 to give the title compound as a white solid. (ES, m/z): [M+H]⁺ = 835.5.

實例444-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-(氧環丁烷-3-基)丙基)苯甲腈的合成步驟1：2-(氧環丁烷-3-基)乙酸乙酯在25°C向2-(氧環丁烷-3-亞基)乙酸乙酯（5 g，35.17 mmol，1.00當量）在無水乙醇（150 mL）中的攪拌溶液中添加10% Pd/C（500 mg）。將所得混合物在25°C在1 atm氫氣氣氛下攪拌24 h。將反應混合物藉由矽藻土過濾並將濾液在減壓下濃縮，以得到呈黃色油狀物的粗標題化合物。Example44 Synthesis of 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-(oxobutan-3-yl)propyl)benzonitrile Step 1: Ethyl 2-(cyclohexane-3-yl)acetate To a stirred solution of ethyl 2-(oxocyclobutane-3-ylidene)acetate (5 g, 35.17 mmol, 1.00 equiv) in anhydrous ethanol (150 mL) was added 10% Pd/C (500 mg) at 25°C. The resulting mixture was stirred at 25°C under a 1 atm hydrogen atmosphere for 24 h. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the crude title compound as a yellow oil.

步驟2：2-(氧環丁烷-3-基)-3-側氧基丙酸乙酯在-78°C向N-異丙基丙-2-胺（2.43 g，24.01 mmol，1.20當量）在無水THF（80 mL）中的攪拌溶液中逐滴添加n-BuLi（2.5 M，9.6 mL，24.00 mmol，1.20當量）。將所得混合物在-78°C在氬氣氣氛下攪拌30 min，然後添加2-(氧環丁烷-3-基)乙酸乙酯（2.88 g，20.00 mmol，1.00當量）在無水THF（2.0 mL）中的溶液。在-78°C攪拌1 h後，添加甲酸乙酯（2.22 g，30.00 mmol，1.50當量）。將該反應混合物在-78°C攪拌3 h，緩慢加溫至25°C，然後在25°C攪拌16 h。將反應混合物用EtOH淬滅，然後用乙酸調節至pH = 6。將所得混合物用水稀釋並用EA萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EA/PE（0-40%）洗脫）純化，以得到呈黃色油狀物的標題化合物。Step 2: Ethyl 2-(cyclohexane-3-yl)-3-oxopropionate To a stirred solution of N-isopropylpropan-2-amine (2.43 g, 24.01 mmol, 1.20 equiv) in anhydrous THF (80 mL) at -78°C was added n-BuLi (2.5 M, 9.6 mL, 24.00 mmol, 1.20 equiv) dropwise. The resulting mixture was stirred at -78°C under an hydrogen atmosphere for 30 min, followed by the addition of a solution of ethyl 2-(oxocyclobutan-3-yl)acetate (2.88 g, 20.00 mmol, 1.00 equiv) in anhydrous THF (2.0 mL). After stirring at -78°C for 1 h, ethyl formate (2.22 g, 30.00 mmol, 1.50 equiv) was added. The reaction mixture was stirred at -78°C for 3 h, slowly warmed to 25°C, and then stirred at 25°C for 16 h. The reaction mixture was quenched with EtOH and then adjusted to pH = 6 with acetic acid. The resulting mixture was diluted with water and extracted with EA. The combined organic layers were washed with brine and dried_over anhydrous_Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EA/PE (0-40%)) to obtain the title compound as a yellow oil.

步驟3：3-羥基-2-(氧環丁烷-3-基)丙酸乙酯在0°C向2-(氧環丁烷-3-基)-3-側氧基丙酸乙酯（260 mg，1.51 mmol，1.00當量）在無水乙醇（5.0 mL）和THF（5.0 mL）中的攪拌溶液中分批添加NaBH₄（115 mg，3.02 mmol，2.00當量）。將反應混合物在0°C攪拌1 h，然後在減壓下濃縮。將殘餘物用水處理並用乙酸調節至pH = 6。將所得混合物用EA萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮，以得到呈黃色油狀物的標題化合物。Step 3: Ethyl 3-hydroxy-2-(cyclohexane-3-yl)propionate To a stirred solution of ethyl 2-(oxocyclobutan-3-yl)-3-oxopropanoate (260 mg, 1.51 mmol, 1.00 equiv) in anhydrous ethanol (5.0 mL) and THF (5.0 mL) was added_NaBH₄ (115 mg, 3.02 mmol, 2.00 equiv) portionwise at 0°C. The reaction mixture was stirred at 0°C for 1 h and then concentrated under reduced pressure. The residue was treated with water and adjusted to pH = 6 with acetic acid. The resulting mixture was extracted with EA. The combined organic layers were washed with brine and dried over_{anhydrousNa₂SO₄} . After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound as a yellow oil.

步驟4：2-(碘甲基)-4-甲氧基丁酸乙酯在0°C在氬氣氣氛下向三苯膦（199 mg，0.76 mmol）和咪唑（54 mg，0.79 mmol，1.14當量）在無水DCM（20 mL）中的攪拌溶液中添加碘（192 mg，0.76 mmol，1.10當量）。將所得混合物在室溫在氬氣氣氛下攪拌10 min，然後添加3-羥基-2-(氧環丁烷-3-基)丙酸乙酯（120 mg，0.69 mmol，1.00當量）在無水DCM（10 mL）中的溶液。在室溫攪拌2 h後，將反應混合物過濾，用水淬滅並用DCM萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EA/PE（0-20%）洗脫）純化，以得到呈黃色油狀物的標題化合物。Step 4: Ethyl 2-(iodomethyl)-4-methoxybutyrate To a stirred solution of triphenylphosphine (199 mg, 0.76 mmol) and imidazole (54 mg, 0.79 mmol, 1.14 equiv) in anhydrous DCM (20 mL) at 0°C under an atmosphere of hydrogen was added iodine (192 mg, 0.76 mmol, 1.10 equiv). The resulting mixture was stirred at room temperature under an atmosphere of hydrogen for 10 minutes, followed by the addition of a solution of ethyl 3-hydroxy-2-(oxetan-3-yl)propanoate (120 mg, 0.69 mmol, 1.00 equiv) in anhydrous DCM (10 mL). After stirring at room temperature for 2 hours, the reaction mixture was filtered, quenched with water, and extracted with DCM. The combined organic layers were washed with brine and dried over_{anhydrousNa₂SO₄} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EA/PE (0-20%)) to give the title compound as a yellow oil.

步驟5：4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-(氧環丁烷-3-基)-丙基)苯甲腈藉由與實例43的步驟4-8中所述類似的方式進行來合成標題化合物，以得到呈黃色固體的標題化合物。MS (ES, m/z): [M+H]⁺= 833.5。Step 5: 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-(oxobutan-3-yl)propyl)benzonitrile The title compound was synthesized in a manner similar to that described in Steps 4-8 of Example 43 to give the title compound as a yellow solid. MS (ES, m/z): [M+H]⁺ = 833.5.

實例454-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-((4-(3-(2,6-二側氧基哌啶-3-基)-1-甲基-1H-吲唑-6-基)環己基)氧基)乙基)苯甲腈的合成步驟1：4-((4-胺基哌啶-1-基)磺醯基)-2-溴苯甲腈鹽酸鹽在0°C向N-[1-(3-溴-4-氰基-苯基)磺醯基-4-哌啶基]-胺基甲酸三級丁酯（400 mg，0.90 mmol，1.00當量）在無水DCM（10.0 mL）和甲醇（5.0 mL）中的攪拌溶液中逐滴添加4.0 M HCl/1,4-二㗁𠮿（5.0 mL，20.0 mmol，22.2當量）。將所得混合物在25°C攪拌4 h。將反應混合物在減壓下濃縮，以得到呈白色固體的粗標題化合物。Example45 Synthesis of 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-((4-(3-(2,6-difluorooxypiperidin-3-yl)-1-methyl-1H-indazol-6-yl)cyclohexyl)oxy)ethyl)benzonitrile Step 1: 4-((4-aminopiperidin-1-yl)sulfonyl)-2-bromobenzonitrile hydrochloride To a stirred solution of N-[1-(3-bromo-4-cyano-phenyl)sulfonyl-4-piperidinyl]-carbamic acid tributyl ester (400 mg, 0.90 mmol, 1.00 equiv) in anhydrous DCM (10.0 mL) and methanol (5.0 mL) at 0°C was added 4.0 M HCl/1,4-dioxathiol (5.0 mL, 20.0 mmol, 22.2 equiv) dropwise. The resulting mixture was stirred at 25°C for 4 h. The reaction mixture was concentrated under reduced pressure to give the crude title compound as a white solid.

步驟2：(1-((3-溴-4-氰基苯基)磺醯基)哌啶-4-基)胺基甲酸苄酯在0°C向4-((4-胺基哌啶-1-基)磺醯基)-2-溴苯甲腈（340 mg，0.89 mmol，1.00當量）和NaHCO₃（662 mg，7.88 mmol，8.85當量）在THF（20 mL）和水（10 mL）中的攪拌混合物中逐滴添加CbzCl（0.18 mL，1.26 mmol，1.42當量）。將所得混合物在25°C攪拌2 h。將反應混合物用水稀釋並用DCM萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用MeOH/DCM（0-3%）洗脫）純化，以得到呈白色固體的標題化合物。Step 2: Benzyl (1-((3-bromo-4-cyanophenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred mixture of 4-((4-aminopiperidin-1-yl)sulfonyl)-2-bromobenzonitrile (340 mg, 0.89 mmol, 1.00 equiv) and_NaHCO₃ (662 mg, 7.88 mmol, 8.85 equiv) in THF (20 mL) and water (10 mL) at 0°C was added CbzCl (0.18 mL, 1.26 mmol, 1.42 equiv) dropwise. The resulting mixture was stirred at 25°C for 2 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH/DCM (0-3%) to give the title compound as a white solid.

步驟3：(1-((4-氰基-3-(2-羥基乙基)苯基)磺醯基)哌啶-4-基)胺基甲酸苄酯在25°C向(1-((3-溴-4-氰基苯基)磺醯基)哌啶-4-基)-胺基甲酸苄酯（350 mg，0.73 mmol，1.00當量）在無水DMAc（5.0 mL）中的攪拌溶液中添加Mn（161 mg，2.93 mmol，4.01當量）、2-碘乙醇（377 mg，2.19 mmol，3.00當量）、NiCl₂(DME)（32 mg，0.15 mmol，0.21當量）、吡啶-2-甲脒鹽酸鹽（23 mg，0.15 mmol，0.21當量）和NaI（27 mg，0.18 mmol，0.25當量）。將所得混合物在45°C在氬氣氣氛下在密封管中攪拌16 h。將反應混合物用水處理並用EA萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用EA/PE（0-40%）洗脫）純化，以得到呈白色固體的標題化合物。Step 3: Benzyl (1-((4-cyano-3-(2-hydroxyethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of benzyl (1-((3-bromo-4-cyanophenyl)sulfonyl)piperidin-4-yl)-carbamate (350 mg, 0.73 mmol, 1.00 equiv) in anhydrous DMAc (5.0 mL) was added Mn (161 mg, 2.93 mmol, 4.01 equiv), 2-iodoethanol (377 mg, 2.19 mmol, 3.00 equiv),_NiCl2 (DME) (32 mg, 0.15 mmol, 0.21 equiv), pyridine-2-carboximidamide hydrochloride (23 mg, 0.15 mmol, 0.21 equiv), and NaI (27 mg, 0.18 mmol, 0.25 equiv) at 25° C. The resulting mixture was stirred at 45° C. under an atmosphere of hydrogen in a sealed tube for 16 h. The reaction mixture was treated with water and extracted with EA. The combined organic layers were washed with brine and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with EA/PE (0-40%)) to yield the title compound as a white solid.

步驟4：4-((4-胺基哌啶-1-基)磺醯基)-2-(2-((4-(3-(2,6-二側氧基哌啶-3-基)-1-甲基-1H-吲唑-6-基)環己基)氧基)乙基)苯甲腈在25°C在氬氣氣氛下向3-[1-甲基-6-(4-側氧基環己基)吲唑-3-基]哌啶-2,6-二酮（105 mg，0.31 mmol，1.15當量）、(1-((4-氰基-3-(2-羥基乙基)苯基)磺醯基) 哌啶-4-基)胺基甲酸苄酯（120 mg，0.27 mmol，1.00當量）和苯基矽烷（100 mg，0.93 mmol，3.44當量）在MeCN（10 mL）中的攪拌溶液中添加TMSOTf（26 mg，0.12 mmol，0.44當量）。將所得混合物在25°C攪拌16 h。將反應混合物用飽和水性碳酸氫鈉淬滅並用EA萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用MeOH/DCM（0-5%）洗脫）純化，以得到呈黃色油狀物的標題化合物。Step 4: 4-((4-aminopiperidin-1-yl)sulfonyl)-2-(2-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)cyclohexyl)oxy)ethyl)benzonitrile To a stirred solution of 3-[1-methyl-6-(4-oxocyclohexyl)indazol-3-yl]piperidine-2,6-dione (105 mg, 0.31 mmol, 1.15 equiv), benzyl (1-((4-cyano-3-(2-hydroxyethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (120 mg, 0.27 mmol, 1.00 equiv), and phenylsilane (100 mg, 0.93 mmol, 3.44 equiv) in MeCN (10 mL) at 25°C under an atmosphere of hydrogen was added TMSOTf (26 mg, 0.12 mmol, 0.44 equiv). The resulting mixture was stirred at 25°C for 16 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na₂ SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH/DCM (0-5%) to give the title compound as a yellow oil.

步驟5：4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-((4-(3-(2,6-二側氧基哌啶-3-基)-1-甲基-1H-吲唑-6-基)環己基)氧基)乙基)苯甲腈向4-((4-胺基哌啶-1-基)磺醯基)-2-(2-((4-(3-(2,6-二側氧基哌啶-3-基)-1-甲基-1H-吲唑-6-基)環己基)氧基)乙基)苯甲腈（50 mg，0.056 mmol，1.00當量）、2-氯-5-(二氟甲氧基)嘧啶（20 mg，0.11 mmol，1.96當量）和CsF（17 mg，0.11 mmol，1.96當量）在DMSO（2.0 mL）中的攪拌溶液中添加DIPEA（29 mg，0.22 mmol，3.93當量）。將所得混合物在90°C攪拌3 h。將反應混合物藉由C18柱層析法（用MeCN/水（0-50%，0.05% NH₄HCO₃）洗脫）純化，以得到呈白色固體的標題化合物。MS (ES, m/z): [M+H]⁺= 777.5。Step 5: 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-((4-(3-(2,6-difluorooxypiperidin-3-yl)-1-methyl-1H-indazol-6-yl)cyclohexyl)oxy)ethyl)benzonitrile To a stirred solution of 4-((4-aminopiperidin-1-yl)sulfonyl)-2-(2-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)cyclohexyl)oxy)ethyl)benzonitrile (50 mg, 0.056 mmol, 1.00 equiv), 2-chloro-5-(difluoromethoxy)pyrimidine (20 mg, 0.11 mmol, 1.96 equiv), and CsF (17 mg, 0.11 mmol, 1.96 equiv) in DMSO (2.0 mL) was added DIPEA (29 mg, 0.22 mmol, 3.93 equiv). The resulting mixture was stirred at 90°C for 3 h. The reaction mixture was purified by C18 column chromatography, eluting with MeCN/water (0-50%, 0.05% NH₄ HCO₃ ), to give the title compound as a white solid. MS (ES, m/z): [M+H]⁺ = 777.5.

實例462-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丁基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈的合成步驟1：(E)-(1-((4-氰基-3-(2-甲基-3-側氧基丁-1-烯-1-基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯將3-甲基丁-3-烯-2-酮（2.84 g，33.75 mmol，3.00當量）、三鄰甲苯基膦（1.38 g，4.53 mmol，0.40當量）、NaOAc（2.77 g，33.75 mmol，3.00當量）和Pd(OAc)₂（1.26 g，5.63 mmol，0.50當量）相繼添加至N-{1-[(3-溴-4-氰基苯)-磺醯基]哌啶-4-基}胺基甲酸三級丁酯（5.00 g，11.25 mmol，1.00當量）在DMF（20.0 mL）中的溶液中。將反應混合物在100°C在微波照射下攪拌3 h。將混合物過濾，用水稀釋並用EA萃取。將合併的有機層經Na₂SO₄乾燥，過濾並濃縮。將殘餘物藉由二氧化矽柱（PE/EA = 3/1）純化，以給出呈黃色固體的標題化合物。Example46 Synthesis of 2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylbutyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile Step 1: (E)-tert-butyl (1-((4-cyano-3-(2-methyl-3-oxobut-1-en-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate 3-Methylbut-3-en-2-one (2.84 g, 33.75 mmol, 3.00 equiv), tri-(2-tolylphosphine) (1.38 g, 4.53 mmol, 0.40 equiv), NaOAc (2.77 g, 33.75 mmol, 3.00 equiv), and Pd(OAc)₂ (1.26 g, 5.63 mmol, 0.50 equiv) were added sequentially to a solution of tert-butyl N-{1-[(3-bromo-4-cyanophenyl)-sulfonyl]piperidin-4-yl}carbamate (5.00 g, 11.25 mmol, 1.00 equiv) in DMF (20.0 mL). The reaction mixture was stirred at 100°C under microwave irradiation for 3 h. The mixture was filtered, diluted with water, and extracted with EA. The combined organic layers were dried over Na₂ SO₄ , filtered and concentrated. The residue was purified by silica column (PE/EA = 3/1) to give the title compound as a yellow solid.

步驟2：(1-((4-氰基-3-(2-甲基-3-側氧基丁基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯將N-[1-({4-氰基-3-[(1E)-2-甲基-3-側氧基丁-1-烯-1-基]苯}-磺醯基)哌啶-4-基]胺基甲酸三級丁酯（1.40 g，3.13 mmol，1.00當量）和10% Pd/C（400 mg）在MeOH（10.0 mL）中的混合物在室溫在H₂（15 psi）下攪拌12 h。將反應混合物過濾並濃縮，以給出呈黃色固體的標題化合物。Step 2: Tributyl (1-((4-cyano-3-(2-methyl-3-oxobutyl)phenyl)sulfonyl)piperidin-4-yl)carbamate A mixture of tert-butyl N-[1-({4-cyano-3-[(1E)-2-methyl-3-oxobut-1-en-1-yl]phenyl}-sulfonyl)piperidin-4-yl]carbamate (1.40 g, 3.13 mmol, 1.00 equiv) and 10% Pd/C (400 mg) in MeOH (10.0 mL) was stirred at room temperature under_H2 (15 psi) for 12 h. The reaction mixture was filtered and concentrated to give the title compound as a yellow solid.

步驟3：(1-((4-氰基-3-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丁基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯向N-(1-{[4-氰基-3-(2-甲基-3-側氧基丁基)苯]-磺醯基}哌啶-4-基)胺基甲酸三級丁酯（1.40 g，3.13 mmol，1.00當量）在DMA（10.0 mL）中的攪拌溶液中添加1-[1-甲基-6-(哌啶-4-基)吲唑-3-基]-1,3-二氮雜己環烷-2,4-二酮（1.0 g，3.05 mmol，1.00當量）、AcOH（0.3 mL）和NaBH₃CN（590 mg，9.39 mmol，3.00當量）。將所得混合物在70°C攪拌4天。將反應混合物用DCM稀釋，並將有機層用鹽水洗滌，然後濃縮。將殘餘物藉由二氧化矽快速柱（DCM/MeOH = 20/1）純化，以給出呈黃色固體的標題化合物。Step 3: Tributyl (1-((4-cyano-3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylbutyl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of tert-butyl N-(1-{[4-cyano-3-(2-methyl-3-oxobutyl)phenyl]-sulfonyl}piperidin-4-yl)carbamate (1.40 g, 3.13 mmol, 1.00 equiv) in DMA (10.0 mL) was added 1-[1-methyl-6-(piperidin-4-yl)indazol-3-yl]-1,3-diazohexanedione-2,4-dione (1.0 g, 3.05 mmol, 1.00 equiv), AcOH (0.3 mL), and_NaBH₃CN (590 mg, 9.39 mmol, 3.00 equiv). The resulting mixture was stirred at 70°C for 4 days. The reaction mixture was diluted with DCM, and the organic layer was washed with brine and then concentrated. The residue was purified by silica flash column (DCM/MeOH = 20/1) to give the title compound as a yellow solid.

步驟4：4-((4-胺基哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丁基)苯甲腈鹽酸鹽將N-(1-{[4-氰基-3-(3-{4-[3-(2,4-二側氧基-1,3-二氮雜己環烷-1-基)-1-甲基吲唑-6-基]哌啶-1-基}-2-甲基丁基)苯]磺醯基}哌啶-4-基)胺基甲酸三級丁酯（130 mg，0.17 mmol，1.00當量）和EA/HCl（2.0 mL）在EA（2.0 mL）中的混合物在室溫攪拌3 h。將反應混合物濃縮，以給出呈黃色固體的標題化合物。Step 4: 4-((4-aminopiperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylbutyl)benzonitrile hydrochloride A mixture of tert-butyl N-(1-{[4-cyano-3-(3-{4-[3-(2,4-dioxo-1,3-diazolidin-1-yl)-1-methylindazol-6-yl]piperidin-1-yl}-2-methylbutyl)phenyl]sulfonyl}piperidin-4-yl)carbamate (130 mg, 0.17 mmol, 1.00 equiv) and EA/HCl (2.0 mL) in EA (2.0 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated to give the title compound as a yellow solid.

步驟5：2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丁基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯甲腈將4-(4-胺基哌啶-1-磺醯基)-2-(3-{4-[3-(2,4-二側氧基-1,3-二氮雜己環烷-1-基)-1-甲基吲唑-6-基]哌啶-1-基}-2-甲基丁基)苯甲腈鹽酸鹽（30 mg，0.043 mmol，1.00當量）、2,5-二氯嘧啶（37 mg，0.20 mmol，4.65當量）、CsF（30 mg，0.20 mmol，4.65當量）和DIEA（26 mg，0.20 mmol，4.65當量）在DMSO（1.5 mL）中的混合物在65°C在N₂下攪拌過夜。將反應混合物冷卻，用DCM稀釋並用水洗滌。將有機層經Na₂SO₄乾燥，過濾並濃縮。將殘餘物藉由製備型HPLC純化以給出呈白色固體的標題化合物並分離為兩種非鏡像異構物。MS (ES, m/z): [M+1]⁺=807.2。Step 5: 2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylbutyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzonitrile A mixture of 4-(4-aminopiperidin-1-sulfonyl)-2-(3-{4-[3-(2,4-dioxo-1,3-diazohexanedan-1-yl)-1-methylindazol-6-yl]piperidin-1-yl}-2-methylbutyl)benzonitrile hydrochloride (30 mg, 0.043 mmol, 1.00 equiv), 2,5-dichloropyrimidine (37 mg, 0.20 mmol, 4.65 equiv), CsF (30 mg, 0.20 mmol, 4.65 equiv), and DIEA (26 mg, 0.20 mmol, 4.65 equiv) in DMSO (1.5 mL) was stirred at 65° C. under N₂ overnight. The reaction mixture was cooled, diluted with DCM, and washed with water. The organic layer was dried over Na₂ SO₄ , filtered, and concentrated. The residue was purified by preparative HPLC to afford the title compound as a white solid, which was separated into two non-mirror isomers. MS (ES, m/z): [M+1]⁺ = 807.2.

實例47(S)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈的合成步驟1：(S)-4-((4-胺基哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)苯甲腈鹽酸鹽藉由與實例35的步驟1-5中所述類似的方式進行、用步驟1中的(R)-2-羥基丙酸甲酯代替(S)-2-羥基丙酸甲酯來合成標題化合物。Example47 Synthesis of (S)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile Step 1: (S)-4-((4-aminopiperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)benzonitrile hydrochloride The title compound was synthesized by proceeding in a similar manner to that described in steps 1-5 of Example 35, substituting (R)-methyl 2-hydroxypropionate for (S)-methyl 2-hydroxypropionate in step 1.

步驟2：(S)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈將(S)-4-((4-胺基哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基-四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)-苯甲腈鹽酸鹽（40 mg，0.06 mmol，1當量）、2-氯-5-(三氟甲基)嘧啶（16 mg，0.09 mmol，1.5當量）和DIEA（23 mg，0.18 mmol，3當量）在DMSO（1 mL）中的混合物在80°C攪拌16 h。將混合物藉由製備型HPLC純化，以得到呈白色固體的標題化合物。Step 2: (S)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile A mixture of (S)-4-((4-aminopiperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxo-tetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)-benzonitrile hydrochloride (40 mg, 0.06 mmol, 1 equiv), 2-chloro-5-(trifluoromethyl)pyrimidine (16 mg, 0.09 mmol, 1.5 equiv), and DIEA (23 mg, 0.18 mmol, 3 equiv) in DMSO (1 mL) was stirred at 80° C. for 16 h. The mixture was purified by preparative HPLC to give the title compound as a white solid.

藉由與實例47中所述類似的方式進行來合成以下化合物。實例結構程序48在步驟2中，2,5-二氯嘧啶替代2-氯-5-(三氟甲基)嘧啶。The following compounds were synthesized in a similar manner to that described in Example 47. Example structure program 48 In step 2, 2,5-dichloropyrimidine replaces 2-chloro-5-(trifluoromethyl)pyrimidine.

實例492-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁氧基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈和2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁-2-基)氧基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈的合成步驟1：1-(6-(1-(1-羥基丁-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫-嘧啶-2,4(1H,3H)-二酮（A）和1-(6-(1-(2-羥基丁基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮（B）在室溫在氮氣氣氛下向1-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽（500 mg，1.4 mmol，1當量）、AcOH（99 mg，1.6 mmol，1.2當量）、MgSO₄（827 mg，6.9 mmol，5當量）和1-羥基丁-2-酮（605 mg，6.9 mmol，5當量）在DMF（5 mL）中的攪拌溶液中分批添加NaBH(OAc)₃（2.3 g，11 mmol，8當量）。將所得混合物在室溫再攪拌16 h。將混合物用H₂O稀釋並用NH₃·H₂O鹼化至pH 10-11。將所得混合物用DCM萃取。將合併的有機層用水和鹽水洗滌，經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（用PE/THF（0-100%）洗脫）純化，以得到呈白色固體的標題化合物。Example49 Synthesis of 2-(2-(4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butoxy)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile and 2-((1-(4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)but-2-yl)oxy)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile Step 1: 1-(6-(1-(1-hydroxybutyl-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydro-pyrimidine-2,4(1H,3H)-dione(A) and 1-(6-(1-(2-hydroxybutyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydro-pyrimidine-2,4(1H,3H)-dione(B) To a stirred solution of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (500 mg, 1.4 mmol, 1 equiv), AcOH (99 mg, 1.6 mmol, 1.2 equiv),_MgSO₄ (827 mg, 6.9 mmol, 5 equiv), and 1-hydroxybutan-2-one (605 mg, 6.9 mmol, 5 equiv) in DMF (5 mL) was added NaBH(OAc)_₃ (2.3 g, 11 mmol, 8 equiv) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 16 h. The mixture was diluted with_H₂O and basified to pH 10-11 with_NH₃ ·_H₂O . The resulting mixture was extracted with DCM. The combined organic layers were washed with water and brine, and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/THF (0-100%) to afford the title compound as a white solid.

步驟2：(1-((4-氰基-3-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁氧基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（A）和(1-((4-氰基-3-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁-2-基)氧基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（B）在室溫在氮氣氣氛下向(1-((4-氰基-3-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁氧基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯和(1-((4-氰基-3-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁-2-基)氧基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯的混合物（300 mg，0.75 mmol，1當量）、(1-((4-氰基-3-羥基苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（286 mg，0.75 mmol，1當量）和PPh₃（236.4 mg，0.9 mmol，1.2當量）在THF（3 mL）中的攪拌溶液中添加DIAD（304 mg，1.5 mmol，2當量）。將所得混合物在室溫再攪拌1 h。將所得混合物在真空下濃縮。將殘餘物藉由矽膠柱層析法（用EA/PE（0-100%）洗脫）純化，以得到呈黃色固體的標題化合物。Step 2: Tributyl (1-((4-cyano-3-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butoxy)phenyl)sulfonyl)piperidin-4-yl)carbamate(A) and tributyl (1-((4-cyano-3-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)but-2-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate(B) To a mixture of tert-butyl (1-((4-cyano-3-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butoxy)phenyl)sulfonyl)piperidin-4-yl)carbamate and tert-butyl (1-((4-cyano-3-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)but-2-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (300 mg, 0.75 mL) was added at room temperature under nitrogen atmosphere. To a stirred solution of 1-((4-cyano-3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamic acid tributyl ester (286 mg, 0.75 mmol, 1 equiv), and PPh₃ (236.4 mg, 0.9 mmol, 1.2 equiv) in THF (3 mL) was added DIAD (304 mg, 1.5 mmol, 2 equiv). The resulting mixture was stirred at room temperature for an additional 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with EA/PE (0-100%) to afford the title compound as a yellow solid.

步驟3：4-((4-胺基哌啶-1-基)磺醯基)-2-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁氧基)苯甲腈鹽酸鹽（A）和4-((4-胺基哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁-2-基)氧基)苯甲腈鹽酸鹽（B）在室溫在氮氣氣氛下向(1-((4-氰基-3-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁氧基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯和(1-((4-氰基-3-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁-2-基)氧基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯的混合物（420 mg，0.551 mmol，1當量）在DCM（1 mL）中的攪拌溶液中逐滴添加1,4-二㗁𠮿中的4 M HCl（1 mL）。將所得混合物在室溫再攪拌1 h。將混合物在真空下濃縮，以給出呈黃色固體的標題化合物。Step 3: 4-((4-aminopiperidin-1-yl)sulfonyl)-2-(2-(4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butoxy)benzonitrile hydrochloride(A) and 4-((4-aminopiperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)but-2-yl)oxy)benzonitrile hydrochloride(B) To a mixture of tert-butyl (1-((4-cyano-3-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butoxy)phenyl)sulfonyl)piperidin-4-yl)carbamate and tert-butyl (1-((4-cyano-3-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)but-2-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (420 mg, 0.551 mmol, 1 eq) in DCM (1 To a stirred solution of 4 mL of 1,4-dioxane was added 4 M HCl in 1,4-dioxane dropwise (1 mL). The resulting mixture was stirred at room temperature for another 1 h. The mixture was concentrated under vacuum to afford the title compound as a yellow solid.

步驟4：2-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁氧基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈（A）和2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁-2-基)氧基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈（B）在室溫在氮氣氣氛下向4-((4-胺基哌啶-1-基)磺醯基)-2-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁氧基)苯甲腈鹽酸鹽和4-((4-胺基哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁-2-基)氧基)苯甲腈鹽酸鹽的混合物（80 mg，0.114 mmol，1當量）和DIEA（88.7 mg，0.7 mmol，6當量）在DMSO（2 mL）中的攪拌溶液中添加2-氯-5-(三氟甲基)嘧啶（32 mg，0.2 mmol，1.5當量）。將所得混合物在室溫再攪拌16 h。將粗混合物藉由製備型HPLC純化，以得到呈白色固體的標題化合物A，MS (ES, m/z): [M+H]⁺= 809.4。以及得到呈白色固體的標題化合物B。MS (ES, m/z): [M+H]⁺= 809.4。Step 4: 2-(2-(4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butoxy)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile(A) and 2-((1-(4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)but-2-yl)oxy)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile(B) To a mixture of 4-((4-aminopiperidin-1-yl)sulfonyl)-2-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butoxy)benzonitrile hydrochloride and 4-((4-aminopiperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)but-2-yl)oxy)benzonitrile hydrochloride (80 mg, 0.114 mmol, 1 eq) and DIEA (88.7 mg, 0.7 To a stirred solution of 2-chloro-5-(trifluoromethyl)pyrimidine (32 mg, 0.2 mmol, 1.5 equiv) in DMSO (2 mL) was added 2-chloro-5-(trifluoromethyl)pyrimidine (32 mg, 0.2 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature for an additional 16 h. The crude mixture was purified by preparative HPLC to afford the title compound A as a white solid. MS (ES, m/z): [M+H]⁺ = 809.4. The title compound B was also obtained as a white solid. MS (ES, m/z): [M+H]⁺ = 809.4.

實例50(S)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)胺基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈的合成步驟1：(S)-4-((4-胺基哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)胺基)苯甲腈鹽酸鹽藉由與實例37的步驟1-2中所述類似的方式進行、用步驟1中的(2S)-2-胺基丙-1-醇代替(2R)-2-胺基丙-1-醇來合成標題化合物。Example50 Synthesis of (S)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)amino)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile Step 1: (S)-4-((4-aminopiperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)amino)benzonitrile hydrochloride The title compound was synthesized by proceeding in a similar manner to that described in Step 1-2 of Example 37, substituting (2S)-2-aminopropan-1-ol for (2R)-2-aminopropan-1-ol in Step 1.

步驟2：(S)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)胺基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈在室溫在氮氣氣氛下向(S)-4-((4-胺基哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)胺基)苯甲腈鹽酸鹽（100 mg，0.15 mmol，1當量）和DIEA（113 mg，0.9 mmol，6當量）在DMSO（1 mL）中的攪拌溶液中添加2-氯-5-(三氟甲基)嘧啶（40 mg，0.22 mmol，1.5當量）。將所得混合物在80°C再攪拌16 h。將粗混合物藉由製備型HPLC純化，以得到呈白色固體的標題化合物。MS (ES, m/z): [M+H]+ = 794.3。Step 2: (S)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)amino)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile To a stirred solution of (S)-4-((4-aminopiperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)amino)benzonitrile hydrochloride (100 mg, 0.15 mmol, 1 eq) and DIEA (113 mg, 0.9 mmol, 6 eq) in DMSO (1 mL) was added 2-chloro-5-(trifluoromethyl)pyrimidine (40 mg, 0.22 mmol, 1.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. for an additional 16 h. The crude mixture was purified by preparative HPLC to give the title compound as a white solid. MS (ES, m/z): [M+H]+ = 794.3.

藉由與實例50中所述類似的方式進行來合成以下化合物。實例結構程序51在步驟2中，2,5-二氯嘧啶替代2-氯-5-(三氟甲基)嘧啶。The following compounds were synthesized in a similar manner to that described in Example 50. Example structure program 51 In step 2, 2,5-dichloropyrimidine replaces 2-chloro-5-(trifluoromethyl)pyrimidine.

實例521-(1-甲基-6-(1-(4-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丁-2-基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮的合成步驟1：N-(1-((1H-吡唑-4-基)磺醯基)哌啶-4-基)-5-(三氟甲基)嘧啶-2-胺在0°C向N-(哌啶-4-基)-5-(三氟甲基)嘧啶-2-胺鹽酸鹽（424 mg，1.50 mmol，1.50當量）和TEA（303 mg，3.00 mmol，3.00當量）在DCM（10.0 mL）中的溶液中分批添加1H-吡唑-4-磺醯氯（166 mg，1.00 mmol，1.00當量）。將混合物在室溫攪拌2 h。然後將混合物用水淬滅並用DCM萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。將它過濾並將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（PE:EA = 5:1）純化，以給出呈黃色固體的標題化合物。Example52 Synthesis of 1-(1-methyl-6-(1-(4-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)butan-2-yl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: N-(1-((1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine To a solution of N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride (424 mg, 1.50 mmol, 1.50 equiv) and TEA (303 mg, 3.00 mmol, 3.00 equiv) in DCM (10.0 mL) at 0°C was added 1H-pyrazole-4-sulfonyl chloride (166 mg, 1.00 mmol, 1.00 equiv) portionwise. The mixture was stirred at room temperature for 2 h. The mixture was then quenched with water and extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous_Na₂SO₄. Filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to give the title compound as a yellow solid.

步驟2：4-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丁-2-醇在0°C向N-(1-((1H-吡唑-4-基)磺醯基)哌啶-4-基)-5-(三氟甲基)-嘧啶-2-胺（200 mg，0.53 mmol，1.00當量）在DMF（5.0 mL）中的溶液中添加NaH（60%在礦物油中，64 mg，1.60 mmol，3.00當量）並攪拌0.5 h。然後在0°C將4-溴丁-2-醇（121 mg，0.80 mmol，1.5當量）添加至混合物中。將混合物在室溫攪拌2 h。然後將混合物用水淬滅並用EA萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。將它過濾並將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（PE:EA = 3:1）純化，以給出呈黃色固體的標題化合物。Step 2: 4-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)butan-2-ol To a solution of N-(1-((1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)-pyrimidin-2-amine (200 mg, 0.53 mmol, 1.00 equiv) in DMF (5.0 mL) was added NaH (60% in mineral oil, 64 mg, 1.60 mmol, 3.00 equiv) at 0°C and stirred for 0.5 h. 4-Bromobutan-2-ol (121 mg, 0.80 mmol, 1.5 equiv) was then added to the mixture at 0°C. The mixture was stirred at room temperature for 2 h. The mixture was then quenched with water and extracted with EA. The combined organic layers were washed with brine and dried_over anhydrous_Na₂SO₄ . It was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 3:1) to give the title compound as a yellow solid.

步驟3：4-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丁-2-酮在0°C向4-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丁-2-醇（200 mg，0.45 mmol，1.00當量）在DCM（10.0 mL）中的混合物中添加戴斯-馬丁過碘烷（286 mg，0.68 mmol，1.50當量）。將混合物在25°C攪拌3 h。然後將混合物用水淬滅並用DCM萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。將它過濾並將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（PE:EA = 5:1）純化，以給出呈黃色固體的標題化合物。Step 3: 4-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)butan-2-one To a mixture of 4-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)butan-2-ol (200 mg, 0.45 mmol, 1.00 equiv) in DCM (10.0 mL) at 0°C was added Dess-Martin periodinane (286 mg, 0.68 mmol, 1.50 equiv). The mixture was stirred at 25°C for 3 h. The mixture was then quenched with water and extracted with DCM. The combined organic layers were washed with brine and dried_over anhydrous_Na₂SO₄ . It was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to give the title compound as a yellow solid.

步驟4：1-(1-甲基-6-(1-(4-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丁-2-基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮向4-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丁-2-酮（90 mg，0.20 mmol，1.00當量）、1-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮（198 mg，0.61 mmol，3.00當量）和AcOH（0.3 mL）在DMA（10.0 mL）中的混合物中添加NaBH₃CN（38 mg，0.61 mmol，3.00當量）。將反應混合物在90°C在N₂下攪拌16 h。然後將混合物用水淬滅並用EA萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。將它過濾並將濾液在減壓下濃縮。將殘餘物藉由製備型TLC（DCM : MeOH = 20:1）純化，以給出呈白色固體的標題化合物。MS (ES, m/z): [M+1]⁺= 758.1。Step 4: 1-(1-methyl-6-(1-(4-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)butan-2-yl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione To a mixture of 4-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)butan-2-one (90 mg, 0.20 mmol, 1.00 equiv), 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (198 mg, 0.61 mmol, 3.00 equiv), and AcOH (0.3 mL) in DMA (10.0 mL) was added NaBH₃ CN (38 mg, 0.61 mmol, 3.00 equiv). The reaction mixture was stirred at 90° C. under N₂ for 16 h. The mixture was then quenched with water and extracted with EA. The combined organic layers were washed with brine and dried over_{anhydrousNa₂SO₄} . The organic layer was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 20:1) to afford the title compound as a white solid. MS (ES, m/z): [M+1]⁺ = 758.1.

實例531-(6-(1-(1-(2-氯-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)丙-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮的合成步驟1：(1-((4-氯-3-羥基苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯向(1-((3-溴-4-氯苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（1.00 g，2.21 mmol，1.00當量）、雙(酉品合)二硼（842 mg，3.32 mmol，1.5當量）和KOAc（650 mg，6.63 mmol，3.00當量）在二㗁𠮿（20.0 mL）中的混合物中添加Pd(dppf)Cl₂（161 mg，0.22 mmol，0.10當量）。將混合物在100°C在N₂下攪拌3 h。在25°C向混合物中添加30% H₂O₂溶液（225 mg，6.63 mmol，3.00當量）。將混合物在25°C攪拌0.5 h。然後將混合物用水淬滅並用EA萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。將它過濾並將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（PE:EA = 5:1）純化，以給出呈黃色固體的標題化合物。Example53 Synthesis of 1-(6-(1-(1-(2-chloro-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Tributyl (1-((4-chloro-3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamate To a mixture of tributyl (1-((3-bromo-4-chlorophenyl)sulfonyl)piperidin-4-yl)carbamate (1.00 g, 2.21 mmol, 1.00 equiv), bis(phenyl)diboron (842 mg, 3.32 mmol, 1.5 equiv), and KOAc (650 mg, 6.63 mmol, 3.00 equiv) in dioxane (20.0 mL) was added Pd(dppf)_Cl₂ (161 mg, 0.22 mmol, 0.10 equiv). The mixture was stirred at 100 °C under_N₂ for 3 h._{To the mixture was added 30% H₂O₂solution} (225 mg, 6.63 mmol, 3.00 equiv) at 25 °C. The mixture was stirred at 25 °C for 0.5 h. The mixture was then quenched with water and extracted with EA. The combined organic layers were washed with brine and dried_over anhydrous_Na₂SO₄ . Filtered, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to afford the title compound as a yellow solid.

步驟2：(1-((3-(2-溴丙氧基)-4-氯苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在0°C在N₂下向(1-((4-氯-3-羥基苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（700 mg，1.79 mmol，1.00當量）、2-溴丙-1-醇（741 mg，5.37 mmol，3.00當量）和PPh₃（1.41 g，5.37 mmol，3.00當量）在THF（30.0 mL）中的混合物中添加DIAD（1.09 g，5.37 mmol，3.00當量）。將混合物在25°C在N₂下攪拌16 h。然後將混合物用水淬滅並用EA萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。將它過濾並將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（DCM : MeOH = 100:1）純化，以給出呈黃色固體的標題化合物。Step 2: Tributyl (1-((3-(2-bromopropyloxy)-4-chlorophenyl)sulfonyl)piperidin-4-yl)carbamate To_a mixture of tributyl (1-((4-chloro-3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamate (700 mg, 1.79 mmol, 1.00 equiv), 2-bromopropan-1-ol (741 mg, 5.37 mmol, 3.00 equiv), and_PPh₃ (1.41 g, 5.37 mmol, 3.00 equiv) in THF (30.0 mL) at 0°C under N₂ was added DIAD (1.09 g, 5.37 mmol, 3.00 equiv). The mixture was stirred at 25°C under_N₂ for 16 h. The mixture was then quenched with water and extracted with EA. The combined organic layers were washed with brine and dried over_{anhydrousNa₂SO₄} . It was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:1) to give the title compound as a yellow solid.

步驟3：(1-((4-氯-3-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙氧基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯向(1-((3-(2-溴丙氧基)-4-氯苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（200 mg，0.39 mmol，1.00當量）、1-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮（128 mg，0.39 mmol，1.00當量）和KI（195 mg，1.18 mmol，3當量）在ACN（10.0 mL）中的混合物中添加K₂CO₃（163 mg，1.18 mmol，3.0當量）。將混合物在80°C攪拌16 h。然後將混合物用水淬滅並用EA萃取。將合併的有機層用鹽水洗滌並經無水Na₂SO₄乾燥。將它過濾並將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法（DCM : MeOH = 30:1）純化，以得到呈黃色固體的標題化合物。Step 3: Tributyl (1-((4-chloro-3-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propyloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate To a mixture of tributyl (1-((3-(2-bromopropoxy)-4-chlorophenyl)sulfonyl)piperidin-4-yl)carbamate (200 mg, 0.39 mmol, 1.00 equiv), 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (128 mg, 0.39 mmol, 1.00 equiv), and KI (195 mg, 1.18 mmol, 3 equiv) in ACN (10.0 mL) was added_K2CO3( 163 mg, 1.18 mmol, 3.0 equiv). The mixture was stirred at 80°C for 16 h. The mixture was then quenched with water and extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na₂ SO₄ . They were filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 30:1) to give the title compound as a yellow solid.

步驟4：1-(6-(1-(1-(5-((4-胺基哌啶-1-基)磺醯基)-2-氯苯氧基)丙-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽向(1-((4-氯-3-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙氧基)苯基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（20 mg，0.03 mmol，1.00當量）在EA（1.0 mL）中的混合物中添加EA中的4 M HCl（1.0 mL）。將混合物在25°C攪拌3 h。然後將混合物濃縮，以得到呈黃色固體的標題化合物。Step 4: 1-(6-(1-(1-(5-((4-aminopiperidin-1-yl)sulfonyl)-2-chlorophenoxy)propan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride To a mixture of tributyl (1-((4-chloro-3-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propyloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (20 mg, 0.03 mmol, 1.00 equiv) in EA (1.0 mL) was added 4 M HCl in EA (1.0 mL). The mixture was stirred at 25 °C for 3 h. The mixture was then concentrated to give the title compound as a yellow solid.

步驟5：1-(6-(1-(1-(2-氯-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)丙-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮向1-(6-(1-(1-(5-((4-胺基哌啶-1-基)磺醯基)-2-氯苯氧基)丙-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮鹽酸鹽（20 mg，0.03 mmol，1.00當量）在DMSO（2.0 mL）中的溶液中添加2-氯-5-(三氟甲基)嘧啶（17 mg，0.09 mmol，3.00當量）、DIEA（19 mg，0.15 mmol，5.00當量）和CsF（14 mg，0.15 mmol，5.00當量）。將混合物在50°C在N₂下攪拌16 h。然後將混合物用水淬滅並用EA萃取。將合併的有機層用鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。將它過濾並將濾液在減壓下濃縮。將殘餘物藉由製備型HPLC（ACN，在H₂O（0.1% FA）中）純化，以得到呈白色固體的標題化合物。MS (ES, m/z): [M+1]^-= 804.1。Step 5: 1-(6-(1-(1-(2-chloro-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione To a solution of 1-(6-(1-(1-(5-((4-aminopiperidin-1-yl)sulfonyl)-2-chlorophenoxy)propan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (20 mg, 0.03 mmol, 1.00 equiv) in DMSO (2.0 mL) was added 2-chloro-5-(trifluoromethyl)pyrimidine (17 mg, 0.09 mmol, 3.00 equiv), DIEA (19 mg, 0.15 mmol, 5.00 equiv), and CsF (14 mg, 0.15 mmol, 5.00 equiv). The mixture was stirred at 50 °C under_N2 for 16 h. The mixture was then quenched with water and extracted with EA. The combined organic layers were washed with brine and dried_over anhydrous_Na₂SO₄ . The organic layer was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (ACN in_H₂O (0.1% FA)) to yield the title compound as a white solid. MS (ES, m/z): [M+1]⁻ = 804.1.

實例541-(1-甲基-6-(1-(2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮的合成步驟1：(1-((1H-吡唑-4-基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在0°C向哌啶-4-基胺基甲酸三級丁酯（1.20 g，5.99 mmol，1.00當量）在DCM（40.0 mL）中的溶液中逐滴添加DCM（20.0 mL）中的TEA（1.82 g，17.97 mmol，3.00當量）和1H-吡唑-4-磺醯氯（998 mg，5.99 mmol，1.00當量）。將混合物在25°C在N₂下攪拌2 h。將混合物倒入水中並用EA萃取。將合併的有機層經Na₂SO₄乾燥並過濾。將濾液濃縮，以給出呈白色固體的標題化合物。Example54 Synthesis of 1-(1-methyl-6-(1-(2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: Tributyl (1-((1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)carbamate To a solution of tributyl piperidin-4-ylcarbamate (1.20 g, 5.99 mmol, 1.00 equiv) in DCM (40.0 mL) at 0°C was added TEA (1.82 g, 17.97 mmol, 3.00 equiv) and 1H-pyrazole-4-sulfonyl chloride (998 mg, 5.99 mmol, 1.00 equiv) in DCM (20.0 mL) dropwise. The mixture was stirred at 25°C under_N₂ for 2 h. The mixture was poured into water and extracted with EA. The combined organic layers were dried_{overNa₂SO₄} and filtered. The filtrate was concentrated to afford the title compound as a white solid.

步驟2：(1-((1-(3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙基)-1H-吡唑-4-基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯向甲磺酸3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙酯（406 mg，1.00 mmol，1.00當量）在DMF（10.0 mL）中的攪拌溶液中添加Cs₂CO₃（652 mg，2.00 mmol，2.00當量）和(1-((1H-吡唑-4-基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（330 mg，1.00 mmol，1.00當量），將混合物在50°C攪拌16 h。將混合物用水稀釋並用EA萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由急速層析法（PE:EA=3:1）純化，以得到呈白色固體的標題化合物。Step 2: Tributyl (1-((1-(3-((tributyldiphenylsilyl)oxy)-2-methylpropyl)-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of 3-((tri-butyldiphenylsilyl)oxy)-2-methylpropyl methanesulfonate (406 mg, 1.00 mmol, 1.00 equiv) in DMF (10.0 mL) were added Cs₂ CO₃ (652 mg, 2.00 mmol, 2.00 equiv) and tri-butyl (1-((1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)carbamate (330 mg, 1.00 mmol, 1.00 equiv), and the mixture was stirred at 50°C for 16 h. The mixture was diluted with water and extracted with EA. The combined organic layers were washed with water and brine, and the organic layer was dried over anhydrous Na₂ SO_4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (PE:EA=3:1) to give the title compound as a white solid.

步驟3：1-((1-(3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙基)-1H-吡唑-4-基)磺醯基)-哌啶-4-胺鹽酸鹽將(1-((1-(3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙基)-1H-吡唑-4-基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（120 mg，0.19 mmol，1.00當量）和EA中的4 M HCl（2.0 mL）的混合物在室溫在N₂下攪拌2 h。將混合物濃縮，以給出呈灰白色固體的標題化合物。Step 3: 1-((1-(3-((tert-butyldiphenylsilyl)oxy)-2-methylpropyl)-1H-pyrazol-4-yl)sulfonyl)-piperidin-4-amine hydrochloride A mixture of tributyl (1-((1-(3-(tributyldiphenylsilyl)oxy)-2-methylpropyl)-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)carbamate (120 mg, 0.19 mmol, 1.00 equiv) and 4 M HCl in EA (2.0 mL) was stirred at room temperature under_N2 for 2 h. The mixture was concentrated to give the title compound as an off-white solid.

步驟4：2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丙-1-醇向1-((1-(3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙基)-1H-吡唑-4-基)磺醯基)哌啶-4-胺鹽酸鹽（110 mg，0.19 mmol，1.00當量）在DMSO（6.0 mL）中的溶液中添加DIEA（123 mg，0.94 mmol，5.00當量）、CsF（143 mg，0.94 mmol，5.00當量）和2-氯-5-(三氟甲基)嘧啶（35 mg，0.19 mmol，1.00當量）。將混合物在50°C在N₂下攪拌12 h。將混合物倒入水中並用EA萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物濃縮並藉由急速層析法（PE:EA=1:1）純化，以得到呈白色固體的標題化合物。Step 4: 2-Methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propan-1-ol To a solution of 1-((1-(3-((tributyldiphenylsilyl)oxy)-2-methylpropyl)-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine hydrochloride (110 mg, 0.19 mmol, 1.00 equiv) in DMSO (6.0 mL) was added DIEA (123 mg, 0.94 mmol, 5.00 equiv), CsF (143 mg, 0.94 mmol, 5.00 equiv), and 2-chloro-5-(trifluoromethyl)pyrimidine (35 mg, 0.19 mmol, 1.00 equiv). The mixture was stirred at 50 °C under_N2 for 12 h. The mixture was poured into water and extracted with EA. The combined organic layers were washed with water and brine, and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was concentrated and purified by flash chromatography (PE:EA = 1:1) to afford the title compound as a white solid.

步驟5：2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丙醛在0°C向2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丙-1-醇（40 mg，0.09 mmol，1.00當量）在DCM（5.0 mL）中的攪拌溶液中添加戴斯-馬丁過碘烷（76 mg，0.18 mmol，2.00當量），將混合物在室溫在N₂下攪拌2 h。將混合物過濾並濃縮，以給出呈灰白色固體的標題化合物。Step 5: 2-Methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propanal To a stirred solution of 2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propan-1-ol (40 mg, 0.09 mmol, 1.00 equiv) in DCM (5.0 mL) at 0° C. was added Dess-Martin periodinane (76 mg, 0.18 mmol, 2.00 equiv) and the mixture was stirred at room temperature under N₂ for 2 h. The mixture was filtered and concentrated to give the title compound as an off-white solid.

步驟6：1-(1-甲基-6-(1-(2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮向1-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮（28 mg，0.09 mmol，1.00當量）在DMA（3.0 mL）中的混合物中添加2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丙醛（39 mg，0.09 mmol，1.00當量）、TEA（27 mg，0.27 mmol，3.00當量）、NaBH(OAc)₃（47 mg，0.22 mmol，2.40當量），並將混合物在室溫在N₂下攪拌1 h。將混合物倒入水中並用EA萃取。將合併的有機層用水、鹽水洗滌，並將有機層經無水Na₂SO₄乾燥。過濾後，將濾液在減壓下濃縮。將殘餘物藉由快速柱層析法（DCM:MeOH=0-100%）純化，以給出呈白色固體的標題化合物。MS (ES, m/z): [M+1]⁺= 758.3。Step 6: 1-(1-methyl-6-(1-(2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione To a mixture of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (28 mg, 0.09 mmol, 1.00 equiv) in DMA (3.0 mL) were added 2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propanal (39 mg, 0.09 mmol, 1.00 equiv), TEA (27 mg, 0.27 mmol, 3.00 equiv), and NaBH(OAc)₃ (47 mg, 0.22 mmol, 2.40 equiv), and the mixture was stirred at room temperature under N₂ for 1 h. The mixture was poured into water and extracted with EA. The combined organic layers were washed with water and brine, and dried_over anhydrous_Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM:MeOH = 0-100%) to afford the title compound as a white solid. MS (ES, m/z): [M+1]⁺ = 758.3.

實例551-(1-甲基-6-(1-(2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-1,2,3-三唑-1-基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮的合成步驟1：4-(苄硫基)-1H-1,2,3-三唑在室溫向1H-1,2,3-三唑-5-硫醇鈉（1.00 g，8.12 mmol，1.00當量）在DCM（10.0 mL）中的攪拌溶液中添加(溴甲基)苯（1.39 g，8.12 mmol，1.00當量）。將所得混合物在室溫攪拌過夜。將混合物用DCM稀釋並將混合物用水和鹽水洗滌。將有機層經Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由矽膠柱層析法（PE:EA = 8 : 1）純化，以給出呈白色固體的標題化合物。Example55 Synthesis of 1-(1-methyl-6-(1-(2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-1,2,3-triazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: 4-(Benzylthio)-1H-1,2,3-triazole To a stirred solution of sodium 1H-1,2,3-triazole-5-thiol (1.00 g, 8.12 mmol, 1.00 equiv) in DCM (10.0 mL) at room temperature was added (bromomethyl)benzene (1.39 g, 8.12 mmol, 1.00 equiv). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed with water and brine. The organic layer was dried over_Na₂SO₄. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (PE:EA = 8:1) to afford the title compound as a white solid.

步驟2：4-(苄硫基)-1-(3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙基)-1H-1,2,3-三唑向4-(苄硫基)-1H-1,2,3-三唑（200 mg，1.05 mmol，1.00當量）在DMF（5.0 mL）中的攪拌溶液中添加Cs₂CO₃（681 mg，2.10 mmol，2.00當量）和甲磺酸3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙酯（425 mg，1.05 mmol，1.00當量）。將所得混合物在50°C攪拌16 h。將混合物用EA稀釋並將混合物用水和鹽水洗滌。將有機層經Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由矽膠柱層析法（PE:EA = 5 : 1）純化，以給出呈白色固體的標題化合物。Step 2: 4-(Benzylthio)-1-(3-((tert-butyldiphenylsilyl)oxy)-2-methylpropyl)-1H-1,2,3-triazole To a stirred solution of 4-(benzylthio)-1H-1,2,3-triazole (200 mg, 1.05 mmol, 1.00 equiv) in DMF (5.0 mL) was added_CsCO( 681 mg, 2.10 mmol, 2.00 equiv) and 3-((tributyldiphenylsilyl)oxy)-2-methylpropyl methanesulfonate (425 mg, 1.05 mmol, 1.00 equiv). The resulting mixture was stirred at 50°C for 16 h. The mixture was diluted with EA and washed with water and brine. The organic layer_was dried over_NaSO . After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (PE:EA = 5:1) to give the title compound as a white solid.

步驟3：1-(3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙基)-1H-1,2,3-三唑-4-磺醯氯在0°C向4-(苄硫基)-1-(3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙基)-1H-1,2,3-三唑（100 mg，0.20 mmol，1.00當量）在CAN（3.0 mL）、AcOH（0.5 mL）和H₂O（0.5 mL）中的溶液中添加DCDMH（79 mg，0.40 mmol，2.00當量），並將混合物在室溫在N₂下攪拌2 h。將混合物用EA稀釋並將混合物用水和鹽水洗滌。將有機層經Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由矽膠柱層析法（PE:EA = 6 : 1）純化，以給出呈無色油狀物的標題化合物。Step 3: 1-(3-((tert-butyldiphenylsilyl)oxy)-2-methylpropyl)-1H-1,2,3-triazole-4-sulfonyl chloride To a solution of 4-(benzylthio)-1-(3-((tributyldiphenylsilyl)oxy)-2-methylpropyl)-1H-1,2,3-triazole (100 mg, 0.20 mmol, 1.00 equiv) in ACN (3.0 mL), AcOH (0.5 mL), and_H₂O (0.5 mL) was added DCDMH (79 mg, 0.40 mmol, 2.00 equiv) at 0°C, and the mixture was stirred at room temperature under_N₂ for 2 h. The mixture was diluted with EA and washed_with water and brine. The organic layer was dried over_Na₂SO₄ . After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (PE:EA = 6:1) to give the title compound as a colorless oil.

步驟4：(1-((1-(3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙基)-1H-1,2,3-三唑-4-基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯在0°C向1-(3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙基)-1H-1,2,3-三唑-4-磺醯氯（95 mg，0.20 mmol，1.00當量）在DCM（3.0 mL）中的混合物中添加哌啶-4-基胺基甲酸三級丁酯（50 mg，0.24 mmol，1.20當量）和TEA（40 mg，0.40 mmol，2.00當量）。將混合物在室溫在N₂下攪拌2 h。將混合物用DCM稀釋並將有機層用水和鹽水洗滌。將有機層經Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由矽膠柱層析法（PE:EA = 10 : 1）純化，以給出呈白色固體的標題化合物。Step 4: Tributyl (1-((1-(3-((tributyldiphenylsilyl)oxy)-2-methylpropyl)-1H-1,2,3-triazol-4-yl)sulfonyl)piperidin-4-yl)carbamate To a mixture of 1-(3-((tributyldiphenylsilyl)oxy)-2-methylpropyl)-1H-1,2,3-triazole-4-sulfonyl chloride (95 mg, 0.20 mmol, 1.00 equiv) in DCM (3.0 mL) at 0°C was added tributyl piperidin-4-ylcarbamate (50 mg, 0.24 mmol, 1.20 equiv) and TEA (40 mg, 0.40 mmol, 2.00 equiv). The mixture was stirred at room temperature under_N₂ for 2 h. The mixture was diluted with DCM, and the organic layer was washed_with water and brine. The organic layer was dried over_Na₂SO₄ . After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (PE:EA = 10:1) to give the title compound as a white solid.

步驟5：1-((1-(3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙基)-1H-1,2,3-三唑-4-基)磺醯基)-哌啶-4-胺鹽酸鹽向(1-((1-(3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙基)-1H-1,2,3-三唑-4-基)磺醯基)哌啶-4-基)胺基甲酸三級丁酯（300 mg，0.47 mmol，1.00當量）在EA（2.0 mL）中的混合物中添加EA中的4 M HCl（2.0 mL）。將混合物在室溫攪拌2 h並將混合物濃縮，以給出呈白色固體的標題化合物。Step 5: 1-((1-(3-((tributyldiphenylsilyl)oxy)-2-methylpropyl)-1H-1,2,3-triazol-4-yl)sulfonyl)-piperidin-4-amine hydrochloride To a mixture of tributyl (1-((1-(3-(tributyldiphenylsilyl)oxy)-2-methylpropyl)-1H-1,2,3-triazol-4-yl)sulfonyl)piperidin-4-yl)carbamate (300 mg, 0.47 mmol, 1.00 equiv) in EA (2.0 mL) was added 4 M HCl in EA (2.0 mL). The mixture was stirred at room temperature for 2 h and the mixture was concentrated to give the title compound as a white solid.

步驟6：2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-1,2,3-三唑-1-基)丙-1-醇在室溫向1-((1-(3-((三級丁基二苯基甲矽烷基)氧基)-2-甲基丙基)-1H-1,2,3-三唑-4-基)磺醯基)哌啶-4-胺鹽酸鹽（330 mg，0.57 mmol，1.00當量）在DMSO（3.0 mL）中的混合物中添加2-氯-5-(三氟甲基)嘧啶（152 mg，0.86 mmol，1.50當量）、DIEA（357 mg，2.85 mmol，5.00當量）和CsF（421 mg，2.85 mmol，5.00當量）。將混合物在60°C在N₂下攪拌16 h。將混合物用EA稀釋並將有機層用水和鹽水洗滌。將有機層經Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由矽膠柱層析法（PE:EA = 2 : 1）純化，以給出呈白色固體的標題化合物。Step 6: 2-Methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-1,2,3-triazol-1-yl)propan-1-ol To a mixture of 1-((1-(3-((tributyldiphenylsilyl)oxy)-2-methylpropyl)-1H-1,2,3-triazol-4-yl)sulfonyl)piperidin-4-amine hydrochloride (330 mg, 0.57 mmol, 1.00 equiv) in DMSO (3.0 mL) was added 2-chloro-5-(trifluoromethyl)pyrimidine (152 mg, 0.86 mmol, 1.50 equiv), DIEA (357 mg, 2.85 mmol, 5.00 equiv), and CsF (421 mg, 2.85 mmol, 5.00 equiv) at room temperature. The mixture was stirred at 60°C under_N2 for 16 h. The mixture was diluted with EA, and the organic layer was washed_with water and brine. The organic layer was dried over_Na2SO4 . After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (PE:EA = 2:1) to give the title compound as a white solid.

步驟7：2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-1,2,3-三唑-1-基)丙醛將2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-1,2,3-三唑-1-基)丙-1-醇（110 mg，0.24 mmol，1.00當量）、戴斯-馬丁過碘烷（204 mg，0.48 mmol，2.00當量）在DCM（8.0 mL）中的混合物在室溫攪拌3 h。將混合物過濾，並且將濾液濃縮並藉由矽膠柱層析法（DCM:MeOH = 30 : 1）純化，以給出呈白色固體的標題化合物。Step 7: 2-Methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-1,2,3-triazol-1-yl)propanal A mixture of 2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-1,2,3-triazol-1-yl)propan-1-ol (110 mg, 0.24 mmol, 1.00 equiv) and Dess-Martin periodinane (204 mg, 0.48 mmol, 2.00 equiv) in DCM (8.0 mL) was stirred at room temperature for 3 h. The mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (DCM:MeOH = 30:1) to give the title compound as a white solid.

步驟8：1-(1-甲基-6-(1-(2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-1,2,3-三唑-1-基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮在0°C向1-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮（124 mg，0.38 mmol，2.00當量）、2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-1,2,3-三唑-1-基)丙醛（87 mg，0.19 mmol，1.00當量）和TEA（58 mg，0.57 mmol，3.00當量）在DMA（5.0 mL）中的攪拌溶液中添加NaBH(OAc)₃（102 mg，0.48 mmol，2.50當量），並將混合物在室溫攪拌16 h。將混合物倒入水中，用EA萃取。將合併的有機層經Na₂SO₄乾燥。過濾後，將濾液濃縮並將殘餘物藉由製備型HPLC純化，以給出呈白色固體的標題產物。MS (ES, m/z): [M+1]⁺= 759.1。生物學實例Step 8: 1-(1-methyl-6-(1-(2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-1,2,3-triazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione To a stirred solution of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (124 mg, 0.38 mmol, 2.00 equiv), 2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-1,2,3-triazol-1-yl)propanal (87 mg, 0.19 mmol, 1.00 equiv) and TEA (58 mg, 0.57 mmol, 3.00 equiv) in DMA (5.0 mL) was added NaBH(OAc)₃ (102 mg, 0.48 mmol, 2.50 equiv) at 0°C and the mixture was stirred at room temperature for 16 h. The mixture was poured into water and extracted with EA. The combined organic layers were dried over Na₂ SO₄ . After filtration, the filtrate was concentrated and the residue was purified by preparative HPLC to give the title product as a white solid. MS (ES, m/z): [M+1]⁺ = 759.1.Biological Examples

生物學實例1細胞中的磷酸化Rb測量 使用來自浠思公司（Cisbio）的HTRF磷酸化RB細胞套組（目錄號64RBS807PEG）測量S807/811處的RB蛋白磷酸化。Biological Example1 Measurement of Phospho-Rb in Cells RB protein phosphorylation at S807/811 was measured using the HTRF Phospho-RB Cell Kit (Catalog No. 64RBS807PEG) from Cisbio.

第1天，將黏附細胞（如OVCAR3（CDK2依賴性細胞系）和T47D（CDK4依賴性））以200 µL以20,000個細胞/孔接種到96孔組織培養物處理的平板中，並且在37°C在CO₂氣氛中孵育過夜。第2天，使用HP D300數位分配器，用濃度為0.3至3,000 nM的測試化合物處理細胞。化合物處理之後二十四小時，藉由輕彈平板並用潔淨紙巾輕拍平板去除黏附細胞的細胞培養基。從套組中補充30 µL 1X裂解緩衝液，將其添加到黏附細胞的每個孔中。對於懸浮細胞，將13.3 µL 1X裂解緩衝液直接添加至384孔板中的40 µL細胞中。然後將平板在振盪器上在室溫孵育30 min。藉由上下移液進行均質化後，將8 µL細胞裂解物從細胞培養板轉移到384孔小容量白色檢測板中。添加2 µL預混合的檢測溶液，並且用封閉劑覆蓋平板。為了製備檢測溶液，根據製造商的說明書，將d2綴合的磷酸化RB抗體和Eu-穴狀化合物綴合的磷酸化RB抗體稀釋到檢測緩衝液中。將檢測板在室溫孵育4 h，並且在ClarioStar（BMG實驗室技術公司（BMG Labtech））上以TR-FRET模式（665 nM和620 nM）讀數。將TR-FRET比（665 nM/620 nM）相對化合物濃度作圖，並且相對於DMSO對照歸一化。半最大抑制濃度（IC₅₀）值使用GraphPad Prism（9版；拉荷雅，加利福尼亞州）用四參數邏輯擬合來計算。On day 1, adherent cells, such as OVCAR3 (a CDK2-dependent cell line) and T47D (CDK4-dependent), were seeded at 20,000 cells/well in 200 µL of lysis buffer in 96-well tissue culture-treated plates and incubated overnight at 37°C in a_CO₂ atmosphere. On day 2, cells were treated with test compounds at concentrations ranging from 0.3 to 3,000 nM using an HP D300 digital dispenser. Twenty-four hours after compound treatment, the cell culture medium was removed from adherent cells by flicking the plates and tapping them with a clean paper towel. 30 µL of 1X lysis buffer from the kit was added to each well of adherent cells. For suspended cells, add 13.3 µL of 1X lysis buffer directly to 40 µL of cells in a 384-well plate. Incubate the plate on a shaker at room temperature for 30 minutes. After homogenization by pipetting up and down, transfer 8 µL of cell lysate from the cell culture plate to a 384-well small-volume white assay plate. Add 2 µL of premixed assay solution and cover the plate with blocking agent. To prepare assay solution, dilute the d2-conjugated phospho-RB antibody and the Eu-cryptate-conjugated phospho-RB antibody into assay buffer according to the manufacturer's instructions. The assay plate was incubated at room temperature for 4 hours and read on a ClarioStar (BMG Labtech) in TR-FRET mode (665 nM and 620 nM). The TR-FRET ratio (665 nM/620 nM) was plotted against compound concentration and normalized to a DMSO control. Half-maximal inhibitory concentration (_IC50 ) values were calculated using a four-parameter logic fit using GraphPad Prism (version 9; La Jolla, CA).

在下表中，AA表示小於1 nM的IC₅₀；A表示IC₅₀大於或等於1 nM但小於或等於100 nM；B表示IC₅₀大於100 nM但小於或等於500 nM；C表示IC₅₀大於500 nM但小於或等於2.5 µM；D表示IC₅₀大於2.5 µM但小於或等於5.0 µM；E表示IC₅₀大於3 µM。化合物#pRB_OVCAR3_24h（nM）pRb_ T47D_ 24h（nM）化合物#pRB_OVCAR3_24h（nM）pRb_ T47D_ 24h（nM）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＞1 µM＞1 µM206AAA211AAA230AAA212AAA231AA213AAA232AA214BA233AAA215AAA234AA216AA235CA217AA236＞1 µM＞1 µM218AA237C＞1 µM219AA238AAA220BA239AA221AA240＞3 µM＞3 µM222BA241CC223BA242CA224AA243BA225AA244AB226AA245BA227AA246AA228BC247BA229AA248AAIn the table below, AA indicates an_IC50 less than 1 nM; A indicates an_IC50 greater than or equal to 1 nM but less than or equal to 100 nM; B indicates an_IC50 greater than 100 nM but less than or equal to 500 nM; C indicates an_IC50 greater than 500 nM but less than or equal to 2.5 µM; D indicates an_IC50 greater than 2.5 µM but less than or equal to 5.0 µM; and E indicates an_IC50 greater than 3 µM.Compound#pRB_OVCAR3_24h(nM)​​pRb_T47D_24h(nM)Compound#pRB_OVCAR3_24h(nM)​​pRb_T47D_24h(nM) 1 A A 54 A A 2 A NT 55 A A 4 A NT 56 B A 7 C NT 57 A A 9 A NT 58 A A 10 A NT 59 A AA 11 A NT 60 A AA 12 A NT 61 A A 13 A NT 62 A A 14 A A 63 A A 15 A A 64 A A 16 A A 65 A A 17 A A 66 A AA 18 A A 67 A A 19 A A 68 A A 20 A A 69 A AA twenty one A A 70 A A twenty two B B 71 A AA twenty three A A 72 A A twenty four A A 73 A A 25 A A 74 A A 26 B A 75 B A 27 B B 76 A A 28 A A 77 C B 29 A A 78 B A 30 A A 79 A A 31 B C 80 A A 32 B A 81 A A 33 A A 82 A A 34 A A 83 A A 35 A A 84 A A 36 A A 85 A A 37 C B 86 A AA 38 A A 87 A AA 39 A B 88 A AA 40 A AA 89 B A 41 A B 90 A A 42 A A 91 A A 43 A A 92 B A 44 A A 93 B A 45 A A 94 A AA 46 A A 95 A AA 47 A A 96 A AA 48 A A 97 B A 49 A A 98 B A 50 A A 99 B B 51 A A 100 B A 52 A A 101 A A 53 B NT 102 A A 107 A A 103 A A 109 A A 104 A AA 111 C B 105 A A 113 A A 106 A B 115 A A 108 A A 117 A A 110 A C 119 A A 112 A AA 121 A A 114 A A 123 A A 116 A A 125 B A 118 C D 127 B A 120 A A 129 B A 122 A A 131 B A 124 C C 133 A A 126 A A 135 A A 128 A A 137 B AA 130 B A 139 A AA 132 B A 141 C B 134 B A 143 B A 136 B A 145 A AA 138 B A 147 E A 140 E E 149 A A 142 B A 151 A A 144 A A 153 A A 146 A AA 155 B A 148 E E 157 B A 150 B A 159 C E 152 A A 161 A A 154 C B 163 C B 156 A A 165 A A 158 B A 167 A AA 160 A AA 169 A AA 162 B C 171 A AA 164 B B 173 A A 166 C A 175 A A 168 C B 177 E E 170 A AA 179 A AA 172 A AA 181 A AA 174 A A 183 B A 176 A AA 185 A A 178 A A 187 A A 180 B A 189 A A 182 A AA 191 A AA 184 A A 193 A A 186 A A 195 C D 188 A A 197 B A 190 B A 199 A AA 192 A A 201 A AA 194 C B 203 A AA 196 A A 205 A AA 198 C C 207 A AA 200 A A 208 A A 202 E E 209 A A 204 A A 210 >1 µM >1 µM 206 A AA 211 A AA 230 A AA 212 A AA 231 A A 213 A AA 232 A A 214 B A 233 A AA 215 A AA 234 A A 216 A A 235 C A 217 A A 236 >1 µM >1 µM 218 A A 237 C >1 µM 219 A A 238 A AA 220 B A 239 A A 221 A A 240 >3 µM >3 µM 222 B A 241 C C 223 B A 242 C A 224 A A 243 B A 225 A A 244 A B 226 A A 245 B A 227 A A 246 A A 228 B C 247 B A 229 A A 248 A A

生物學實例2細胞內源性CDK1/2/4/6的高通量測量 藉由高通量HTRF測定來監測化合物對細胞CDK水平的影響。Biological Example2: High-throughput measurement of endogenous CDK1/2/4/6 in cells. The effects of compounds on cellular CDK levels were monitored using a high-throughput HTRF assay.

為了確定化合物的半最大降解濃度（DC₅₀）值和最大降解水平（Dmax）值，使用來自浠思公司/瑞孚迪公司（Revvity）的HTRF總CDK細胞套組（CDK1，目錄號64CDK1TPEG；CDK2，目錄號64CDK2TPEG；CDK4，目錄號64CDK4TPEG；CDK6，目錄號64CDK6TPEG）以96孔格式測量細胞CDK水平。To determine the half-maximal degradation concentration (_DC50 ) and maximum degradation level (Dmax) values of the compounds, cellular CDK levels were measured in a 96-well format using the HTRF Total CDK Cell Panel from Revvity (CDK1, Catalog No. 64CDK1TPEG; CDK2, Catalog No. 64CDK2TPEG; CDK4, Catalog No. 64CDK4TPEG; CDK6, Catalog No. 64CDK6TPEG).

第1天，將細胞以200 µL以20,000個細胞/孔接種到96孔組織培養物處理的平板中，並且在37°C在CO₂氣氛中孵育過夜。第2天，使用HP D300數位分配器，用濃度範圍為0.1至1,000 nM的化合物處理細胞。化合物處理之後6或24小時，藉由輕彈平板並用潔淨紙巾輕拍平板去除細胞培養基。立即從套組中補充30 µL 1X裂解緩衝液並添加至每個孔中，並且將平板在振盪器上在室溫孵育30 min。藉由上下移液進行均質化後，將8 µL細胞裂解物從96孔細胞培養板轉移到384孔小容量白色檢測板中。添加2 µL預混合的檢測溶液，並且用封閉劑覆蓋平板。為了製備檢測溶液，根據製造商的說明書，將d2綴合的CDK抗體和Eu-穴狀化合物綴合的CDK抗體稀釋到檢測緩衝液中。將檢測板在室溫孵育過夜，並且在ClarioStar（BMG實驗室技術公司）上以TR-FRET模式（665 nM和620 nM）讀數。將TR-FRET比（665 nM/620 nM）相對化合物濃度作圖，並且相對於DMSO對照（0%降解）和裂解緩衝液對照（100%降解）歸一化。半最大降解濃度（DC₅₀）（0%降解）值和裂解緩衝液對照（100%降解）值使用GraphPad Prism（9版；拉荷雅，加利福尼亞州）用四參數邏輯擬合來計算。On day 1, cells were seeded at 20,000 cells/well in 200 µL of lysate into 96-well tissue culture-treated plates and incubated overnight at 37°C in a_CO₂ atmosphere. On day 2, cells were treated with compounds at concentrations ranging from 0.1 to 1,000 nM using an HP D300 digital dispenser. Six or 24 hours after compound treatment, the cell culture medium was removed by flicking the plates and tapping them with a clean paper towel. Immediately, 30 µL of 1X lysis buffer from the kit was added to each well, and the plates were incubated at room temperature on a shaker for 30 minutes. After homogenization by pipetting up and down, 8 µL of cell lysate was transferred from a 96-well cell culture plate to a 384-well small-volume white assay plate. 2 µL of premixed assay solution was added, and the plate was covered with blocking agent. To prepare the assay solution, d2-conjugated CDK antibody and Eu-cryptate-conjugated CDK antibody were diluted into assay buffer according to the manufacturer's instructions. The assay plate was incubated overnight at room temperature and read on a ClarioStar (BMG Laboratory Technologies) in TR-FRET mode (665 nM and 620 nM). TR-FRET ratios (665 nM/620 nM) were plotted against compound concentration and normalized to DMSO control (0% degradation) and lysis buffer control (100% degradation). Half-maximal degradation concentration (_DC50 ) values (0% degradation) and lysis buffer control (100% degradation) were calculated using a four-parameter logic fit using GraphPad Prism (version 9; La Jolla, CA).

在下表中，A表示DC₅₀大於或等於0.1 nM但小於或等於10 nM；B表示DC₅₀大於10 nM但小於或等於100 nM；C表示DC₅₀大於100 nM但小於或等於1 µM；並且D表示DC₅₀大於1 µM nM但小於或等於5 µM。NT表示未測試。化合物#CDK2DC50_OVCAR3_6h（nM）1B2B3A4A9A10B11A12B13A14B15A16A17B18A19A20A21AIn the table below, A indicates a_DC50 greater than or equal to 0.1 nM but less than or equal to 10 nM; B indicates a_DC50 greater than 10 nM but less than or equal to 100 nM; C indicates a_DC50 greater than 100 nM but less than or equal to 1 µM; and D indicates a_DC50 greater than 1 µM but less than or equal to 5 µM. NT indicates not tested.Compound#CDK2DC50_OVCAR3_6h(nM)​​ 1 B 2 B 3 A 4 A 9 A 10 B 11 A 12 B 13 A 14 B 15 A 16 A 17 B 18 A 19 A 20 A twenty one A

配製物實例 以下係含有本揭露之化合物的代表性藥物配製物。Formulation ExamplesThe following are representative pharmaceutical formulations containing the compounds of the present disclosure.

片劑配製物 將以下成分緊密混合並且壓製成單槽片劑。成分量/片劑（mg）具有式 (I) 的化合物400玉米澱粉50交聯羧甲基纖維素鈉25乳糖120硬脂酸鎂5Tablet Formulation The following ingredients are intimately mixed and compressed into single-slot tablets. Element Amount/tablet (mg) Compounds having formula (I) 400 corn starch 50 Cross-linked sodium carboxymethyl cellulose 25 lactose 120 Magnesium stearate 5

膠囊配製物 將以下成分緊密混合並裝入硬殼的明膠膠囊中。成分量/膠囊（mg）具有式 (I) 的化合物200噴霧乾燥的乳糖148硬脂酸鎂2Capsule Formulation: Intensely mix the following ingredients and fill into hard-shell gelatin capsules. Element Amount/capsule (mg) Compounds having formula (I) 200 Spray dried lactose 148 Magnesium stearate 2

可注射配製物 在2% HPMC中的具有式 (I) 的化合物、在DI水中的1% Tween 80，用MSA使得pH 2.2，適量到至少20 mg/mLInjectable FormulationCompound of Formula (I) in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, qs to at least 20 mg/mL

吸入組成物 為了製備用於吸入遞送的藥物組成物，將20 mg具有式 (I) 的化合物與50 mg無水檸檬酸和100 mL 0.9%氯化鈉溶液混合。將混合物併入適用於吸入投與的吸入遞送單元（如噴霧器）中。Inhalation CompositionsTo prepare a pharmaceutical composition for inhalation delivery, mix 20 mg of the compound of formula (I) with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit (e.g., a nebulizer) suitable for administration by inhalation.

局部凝膠組成物 為了製備藥用局部凝膠組成物，將100 mg具有式 (I) 的化合物與1.75 g羥基丙基纖維素、10 mL丙二醇、10 mL豆蔻酸異丙酯以及100 mL純化醇（USP）混合。然後將所得凝膠混合物併入適用於局部投與的容器（如管）中。Topical Gel CompositionTo prepare a pharmaceutical topical gel composition, mix 100 mg of the compound of formula (I) with 1.75 g of hydroxypropylcellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate, and 100 mL of purified alcohol (USP). The resulting gel mixture is then placed into a container suitable for topical administration, such as a tube.

眼用溶液組成物 為了製備藥用眼用溶液組成物，將100 mg具有式 (I) 的化合物與在100 mL純化水中的0.9 g NaCl混合並且使用0.2微米過濾器過濾。然後將所得等滲溶液併入適用於眼科投與的眼用遞送單元（如眼藥水容器）中。Ophthalmic Solution CompositionTo prepare a pharmaceutical ophthalmic solution composition, mix 100 mg of the compound of formula (I) with 0.9 g of NaCl in 100 mL of purified water and filter using a 0.2 micron filter. The resulting isotonic solution is then incorporated into an ophthalmic delivery unit (e.g., an eye drop container) suitable for ophthalmic administration.

鼻腔噴霧溶液 為了製備藥用鼻腔噴霧溶液，將10 g具有式 (I) 的化合物與30 mL的0.05 M磷酸鹽緩衝溶液（pH 4.4）混合。將溶液置於鼻腔給藥器中，該給藥器設計為遞送100 µL噴霧用於每次給藥。Nasal Spray SolutionTo prepare a pharmaceutical nasal spray solution, mix 10 g of the compound of formula (I) with 30 mL of 0.05 M phosphate buffer (pH 4.4). Place the solution in a nasal dispenser designed to deliver a 100 µL spray for each administration.

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Claims (52)

Translated fromChinese

一種具有式 (I) 的化合物：(I) 其中： R¹係烷基、烯基、炔基、環烷基、環烷基氧基（其中環烷基——單獨的或作為環烷氧基的一部分，被一至三個鹵代取代）、鹵代、鹵代烷基、鹵代烷氧基、烷氧基、芳基氧基、或氰基； R²和R^2a獨立地是氫或氘； Hy係環伸烷基、伸芳基、雜伸芳基、雜亞環基、雙環雜亞環基、螺雜亞環基、橋接雜亞環基或稠合雜亞環基，其中上述環中之每一個被獨立地選自氫、氘、烷基、鹵代、鹵代烷基、烷氧基、羥基和氰基的R^a、R^b和R^c取代； 降解決定子係選自以下的E3泛素連接酶配位基： (a)   具有式 (i) 的基團：(i)；    或者 (b)   具有式 (ii) 的基團：(ii)； Y^a係CH或N； Z^a係鍵、-CH₂-、-NH-、-O-或-NHC(O)-，其中-NHC(O)-的NH附接至Y^a； 環A係具有式 (a) 或 (b) 的基團：； 其中： R^aa、R^bb、R^cc和R^dd獨立地選自氫、烷基、烷氧基、鹵代、鹵代烷基、鹵代烷氧基和氰基； R⁴和R⁵獨立地是氫或烷基；或R⁴和R⁵與它們所附接的碳一起形成＞C=O； M係-O-或-NR⁶-； R⁶係氫或烷基； 環B係伸苯基、環亞胺基、5員或6員單環雜伸芳基、或9員或10員稠合雙環雜伸芳基，其中每個雜伸芳基環含有一至三個環原子，該等環原子係獨立地選自氮、氧或硫的雜原子，並且進一步地，其中該伸苯基、環亞胺基和每個雜伸芳基獨立地被獨立地選自氫、烷基、環烷基、烷氧基、鹵代、鹵代烷基、鹵代烷氧基和氰基的R^ee和R^ff取代；並且 Z係-O-、-NR³-（其中R³係氫或烷基）、伸炔基、環伸烷基、伸苯基、單環雜伸芳基、不飽和雜亞環基、雜亞環基、橋接雜亞環基或螺雜亞環基，並且其中每個環被獨立地選自氫、氘、烷基、烷氧基、鹵代、鹵代烷基、鹵代烷氧基和氰基的R^d和R^e取代； alk係被選自氫、氟和氰基的R^f取代的C₃至C₆伸烯基；C₃至C₆伸烷基或C₃至C₆雜伸烷基，其中該C₃至C₆伸烷基和C₃至C₆雜伸烷基被R^g、R^h和Rⁱ取代，其中R^g係氫、氘或鹵代，R^h係氫、氘、環烷基、環烷基氧基、橋接環烷基、鹵代、鹵代烷氧基、烷氧基、羥基、氰基、氰基烷基、氰基烷基氧基、胺基羰基、烷基胺基羰基、二烷基胺基羰基、烷基羰基胺基、苯基、雜芳基、雜環基、雜環基氧基、雜環基羰基、或橋接雜環基（其中環烷基——本身或作為環烷基氧基的一部分、橋接環烷基、苯基、雜芳基、雜環基——本身或作為雜環基氧基或雜環基羰基的一部分、和橋接雜環基被獨立地選自氫、氘、烷基、烷氧基、鹵代、鹵代烷基、鹵代烷氧基、羥基、烷基羰基、烷基氧基羰基、胺基、烷基胺基、二烷基胺基和氰基的R⁷和R⁸取代）；或者當R^g和R^h附接至該C₃至C₆伸烷基或C₃至C₆雜伸烷基的直鏈部分的相同碳或相鄰碳原子時，R^g和R^h可與它們所附接的碳原子一起形成環伸烷基或雜亞環基（其中由R^g和R^h形成的該環伸烷基和雜亞環基被獨立地選自氫、氘、烷基、烷氧基、鹵代、鹵代烷基、鹵代烷氧基、羥基、烷基羰基、烷基氧基羰基、胺基、烷基胺基、二烷基胺基和氰基的R⁹和R¹⁰取代），並且Rⁱ係氫或鹵代；並且附接Ar和Z的C₃至C₆伸烯基、C₃至C₆伸烷基和C₃至C₆雜伸烷基的直鏈部分含有至少三個原子；並且 Ar係伸苯基、單環雜伸芳基、雜亞環基、橋接雜亞環基或螺雜亞環基，其中上述環中之每一個被獨立地選自氫、氘、烷基、烷氧基、鹵代、鹵代烷基、鹵代烷氧基和氰基的R^j、R^k和R^m取代；或 其藥學上可接受的鹽。A compound having formula (I): (I) wherein: R¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy (wherein the cycloalkyl group, alone or as part of a cycloalkoxy group, is substituted with one to three halo groups), halo, haloalkyl, haloalkoxy, alkoxy, aryloxy, or cyano; R² and R^2a are independently hydrogen or deuterium; Hy is cycloalkylene, arylene, heteroarylene, heterocycloene, bicyclic heterocycloene, spiroheterocycloene, bridged heterocycloene, or fused heterocycloene, wherein each of the above rings is substituted with R a , R^b , and R^c , which are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy,^hydroxy , and cyano; The degradation determinant is selected from the following E3 ubiquitin ligase ligands: (a) a group having formula (i): (i); or (b) a group having formula (ii): (ii);^Ya is CH or N;^Za is a bond,_-CH2- , -NH-, -O-, or -NHC(O)-, wherein the NH of -NHC(O)- is attached to^Ya ; Ring A is a group having formula (a) or (b): wherein:^Raa ,^Rbb ,^Rcc , and^Rdd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano;^R4 and^R5 are independently hydrogen or alkyl; or^R4 and^R5 , together with the carbon to which they are attached, form >C=O; M is -O- or^-NR6- ;^R6 is hydrogen or alkyl; Ring B is phenylene, cycloimino, 5-membered or 6-membered monocyclic heteroaryl, or 9-membered or 10-membered fused bicyclic heteroaryl, wherein each heteroaryl ring contains one to three ring atoms, and the ring atoms are independently selected from nitrogen, oxygen or sulfur heteroatoms, and further, wherein the phenylene, cycloimino and each heteroaryl are independently substituted with R^ee and R^ff independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halogen, halogenated alkyl, halogenated alkoxy and cyano; and Z is -O-, -NR³ - (wherein R³ is hydrogen or alkyl), alkynyl, cycloalkylene, phenylene, monocyclic heteroaryl, unsaturated heterocycloene, heterocycloene, bridged heterocycloene or spiroheterocycloene, and wherein each ring is substituted by R d and R e independently selected from hydrogen, deuterium, alkyl, alkoxy, halogenated, halogenated alkyl, halogenated alkoxy and cyano; alk is C³ to C⁶ alkenyl substituted by R^f selected from hydrogen, fluorine and cyano; C₃ to C₆ alkylene or C₃ to C₆ heteroalkylene, wherein the C₃ to C₆ alkylene and C_{3toC 6heteroalkylene} are substituted by R^g , R^h and Rⁱ , wherein R^g is hydrogen, deuterium or halogenated, R^h is hydrogen, deuterium, cycloalkyl, cycloalkyloxy, bridged cycloalkyl, halogen, halogenated alkoxy, alkoxy, hydroxy, cyano, cyanoalkyl, cyanoalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, phenyl, heteroaryl, heterocyclic, heterocyclicoxy, heterocycliccarbonyl, or bridged heterocyclic (wherein cycloalkyl—itself or R as part of a cycloalkyloxy group, a bridged cycloalkyl group, a phenyl group, a heteroaryl group, a heterocyclo group, itself or as part of a heterocyclooxy group or a heterocyclocarbonyl group, and a bridged heterocyclo group independently selected from hydrogen, deuterium, an alkyl group, an alkoxy group, a halogenated group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, an alkylcarbonyl group, an alkyloxycarbonyl group, an amino group, an alkylamino group, a dialkylamino group, and a cyano group^{or when R g and R hareattached} to the same carbon or adjacent carbon atoms of the linear portion of the C₃ to C₆ alkylene or^C₃ to C₆ heteroalkylene, R^g and R^h may form together with the carbon atoms to which they are attached a cycloalkylene or heterocycloene group (wherein the cycloalkylene and heterocycloene group formed by R^g and R^h are substituted with R 9 and R 10 independently selected from hydrogen, deuterium, alkyl, alkoxy, halogenated, halogenated alkyl, halogenated alkoxy, hydroxy, alkylcarbonyl, alkyloxycarbonyl, amino, alkylamino, dialkylamino, and cyano groups), and Rⁱ is hydrogen or halogenated; and the C₃ to C⁶ alkenylene, C₃ to C₆ alkylene, and C 3 to C₆ heteroalkylene group attached to Ar and Z are substituted with R g and R^h_; wherein the straight chain portion of_{the 6} -heteroalkylene group contains at least three atoms; and Ar is a phenylene group, a monocyclic heteroaryl group, a heterocycloene group, a bridged heterocycloene group, or a spiroheterocycloene group, wherein each of the above rings is substituted with^Rj ,^Rk, and^Rm independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, halogenated alkyl, halogenated alkoxy, and cyano; or a pharmaceutically acceptable salt thereof.如請求項1所述之化合物或其藥學上可接受的鹽，其中R¹係鹵代。The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein R¹ is halogenated.如請求項1所述之化合物或其藥學上可接受的鹽，其中R¹係鹵代烷基。The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein R¹ is a halogenated alkyl group.如請求項1所述之化合物或其藥學上可接受的鹽，其中R¹係鹵代烷氧基。The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein R¹ is a halogenated alkoxy group.如請求項1至4中任一項所述之化合物或其藥學上可接受的鹽，其中R¹係氯、溴、二氟甲基、三氟甲基、二氟甲氧基或三氟甲氧基。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 4, wherein R¹ is chloro, bromo, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy.如請求項1至5中任一項所述之化合物或其藥學上可接受的鹽，其中R²和R^2a係氫。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein R² and R^2a are hydrogen.如請求項1至6中任一項所述之化合物或其藥學上可接受的鹽，其中Hy係被R^a、R^b和R^c取代的雜亞環基，其中R^a和R^b獨立地選自氫、氘、烷基、鹵代、鹵代烷基、烷氧基、羥基和氰基，並且R^c係氫。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 6, wherein Hy is a heterocycloene substituted by^Ra ,^Rb , and^Rc , wherein^Ra and^Rb are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxyl, and cyano, and^Rc is hydrogen.如請求項1至7中任一項所述之化合物或其藥學上可接受的鹽，其中Hy的雜亞環基係：其中哌啶-1,4-二基環的N原子附接至-SO₂-。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein the heterocyclic group of Hy is: wherein the N atom of the piperidine-1,4-diyl ring is attached to -SO₂ -.如請求項1至7中任一項所述之化合物或其藥學上可接受的鹽，其中Hy的伸苯基係根據結構的1,4-伸苯基，其中表示到NH的鍵且表示到-SO₂-的鍵，並且R^a係氫、氟、甲基或甲氧基，並且R^b係氫。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein the phenyl group of Hy is 1,4-phenylene, wherein Indicates the key to NH and represents a bond to -SO₂ -, and^Ra is hydrogen, fluorine, methyl or methoxy, and^Rb is hydrogen.如請求項1至9中任一項所述之化合物或其藥學上可接受的鹽，其中該降解決定子係具有式 (i) 的E3泛素連接酶配位基：(i)。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein the degron is an E3 ubiquitin ligase ligand having formula (i): (i).如請求項1至10中任一項所述之化合物或其藥學上可接受的鹽，其中該具有式 (i) 的E3泛素連接酶配位基的環A係：。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is: .如請求項1至11中任一項所述之化合物或其藥學上可接受的鹽，其中R^aa和R^bb、R^cc和R^dd獨立地選自氫、甲基、甲氧基、乙氧基、氟、三氟甲基、二氟甲基和三氟甲氧基。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 11, wherein^Raa ,^Rbb ,^Rcc and^Rdd are independently selected from hydrogen, methyl, methoxy, ethoxy, fluorine, trifluoromethyl, difluoromethyl and trifluoromethoxy.如請求項1至9中任一項所述之化合物或其藥學上可接受的鹽，其中該降解決定子係具有式 (ii) 的E3泛素連接酶配位基：(ii)。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein the degron is an E3 ubiquitin ligase ligand having formula (ii): (ii).如請求項1至9和13中任一項所述之化合物或其藥學上可接受的鹽，其中Y^a係CH。The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 9 and 13, wherein^Ya is CH.如請求項1至9和13中任一項所述之化合物或其藥學上可接受的鹽，其中Y^a係N。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 9 and 13, wherein^Ya is N.如請求項1至9和13至15中任一項所述之化合物或其藥學上可接受的鹽，其中Z^a係鍵、-NH-、-O-或-NHC(O)-。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 and 13 to 15, wherein^Za is a bond, -NH-, -O- or -NHC(O)-.如請求項1至9和13至16中任一項所述之化合物或其藥學上可接受的鹽，其中環B係5員或6員單環雜伸芳基或者9員或10員稠合雙環雜伸芳基，其中每個雜伸芳基環含有一至三個氮環原子，並且環B的每個環被R^ee和R^ff取代。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 9 and 13 to 16, wherein Ring B is a 5-membered or 6-membered monocyclic heteroaryl group or a 9-membered or 10-membered fused bicyclic heteroaryl group, wherein each heteroaryl ring contains one to three nitrogen ring atoms, and each ring of Ring B is substituted by R^ee and R^ff .如請求項1至9和13至17中任一項所述之化合物或其藥學上可接受的鹽，其中該具有式 (ii) 的E3泛素連接酶配位基係：、、、、、、、、、、、、、或其中環B係環亞胺基。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 and 13 to 17, wherein the E3 ubiquitin ligase ligand of formula (ii) is: 、 、 、 、 、 、 、 、 、 、 、 、 、 or Ring B is a cycloimino group.如請求項1至9和13至18中任一項所述之化合物或其藥學上可接受的鹽，其中該具有式 (ii) 的E3泛素連接酶配體係或。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 9 and 13 to 18, wherein the E3 ubiquitin ligase ligand of formula (ii) is or .如請求項1至9和13至19中任一項所述之化合物或其藥學上可接受的鹽，其中R^ee和R^ff獨立地選自氫、甲基、乙基、異丙基、環丙基、甲氧基、乙氧基、氟、氯、三氟甲基、2,2,2-三氟乙基、二氟甲基、二氟甲氧基、三氟甲氧基和氰基。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 and 13 to 19, wherein R^ee and R^ff are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy and cyano.如請求項1至20中任一項所述之化合物或其藥學上可接受的鹽，其中Ar係伸苯基、單環雜伸芳基、橋接雜亞環基或雜亞環基，其中Ar的每個環被R^j、R^k和R^m取代，其中R^m係氫。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 20, wherein Ar is a phenylene group, a monocyclic heteroarylene group, a bridged heterocycloene group or a heterocycloene group, wherein each ring of Ar is substituted by^Rj ,^Rk and^Rm , wherein^Rm is hydrogen.如請求項1至21中任一項所述之化合物或其藥學上可接受的鹽，其中-r-係被R^j、R^k和R^m取代的具有式或的伸苯基，其中R^j和R^k獨立地選自氫、烷基、烷氧基、鹵代、氰基、鹵代烷基和鹵代烷氧基，並且R^m係氫。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 21, wherein -r- is substituted by R^j , R^k and R^m and has the formula or phenylene, wherein^Rj and^Rk are independently selected from hydrogen, alkyl, alkoxy, halogen, cyano, halogenated alkyl and halogenated alkoxy, and^Rm is hydrogen.如請求項1至22中任一項所述之化合物或其藥學上可接受的鹽，其中Ar的伸苯基係。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, wherein the phenyl group of Ar is .如請求項1至22中任一項所述之化合物或其藥學上可接受的鹽，其中Ar的伸苯基係。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, wherein the phenyl group of Ar is .如請求項1至21中任一項所述之化合物或其藥學上可接受的鹽，其中Ar係被R^j、R^k和R^m取代的單環雜伸芳基，其中R^j和R^k獨立地選自氫、烷基、烷氧基、鹵代、鹵代烷基、氰基和鹵代烷氧基，並且R^m係氫。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 21, wherein Ar is a monocyclic heteroaryl substituted by^Rj ,^Rk and^Rm , wherein^Rj and^Rk are independently selected from hydrogen, alkyl, alkoxy, halogen, halogenated alkyl, cyano and halogenated alkoxy, and^Rm is hydrogen.如請求項1至21中任一項所述之化合物或其藥學上可接受的鹽，其中Ar係被R^j、R^k和R^m取代的雜亞環基，其中R^j和R^k獨立地選自氫、甲基、甲氧基、氟、氯、二氟甲基、三氟甲基、2,2,2-三氟乙基、二氟甲氧基和三氟甲氧基，並且R^m係氫。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 21, wherein Ar is a heterocycloalkylene substituted by^Rj ,^Rk and^Rm , wherein^Rj and^Rk are independently selected from hydrogen, methyl, methoxy, fluorine, chlorine, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy and trifluoromethoxy, and^Rm is hydrogen.如請求項1至26中任一項所述之化合物或其藥學上可接受的鹽，其中Z係雜亞環基、橋接雜亞環基或螺雜亞環基，其中Z的每個環被R^d和R^e取代。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 26, wherein Z is a heterocycloalkylene, a bridged heterocycloalkylene, or a spiroheterocycloalkylene, wherein each ring of Z is substituted by R^d and Re^.如請求項1至27中任一項所述之化合物或其藥學上可接受的鹽，其中Z的該雜亞環基、橋接雜亞環基和螺雜亞環基分別選自：，並且其中上述環中之每一個被獨立地選自氫、氘、烷基和鹵代的R^d和R^e取代。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 27, wherein the heterocyclic group, bridged heterocyclic group, and spiroheterocyclic group of Z are selected from: , and wherein each of the above rings is substituted with R^d and^Re independently selected from hydrogen, deuterium, alkyl and halogen.如請求項1至28中任一項所述之化合物或其藥學上可接受的鹽，其中Z的該雜亞環基、橋接雜亞環基和螺雜亞環基分別獨立地選自：。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 28, wherein the heterocyclic group, bridged heterocyclic group, and spiroheterocyclic group of Z are independently selected from: .如請求項1至22和27至29中任一項所述之化合物或其藥學上可接受的鹽，其中-Z-alk-Ar-SO₂-係：其中每個R^d、R^e和R^k獨立地選自氫、烷基、鹵代、鹵代烷基、鹵代烷氧基、烷氧基和氰基，並且R^j係氫。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 22 and 27 to 29, wherein -Z-alk-Ar-SO₂ - is: wherein each of R^d ,^Re and R^k is independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy and cyano, and R^j is hydrogen.如請求項1至22和27至30中任一項所述之化合物或其藥學上可接受的鹽，其中-Z-alk-Ar-SO₂-係：其中每個R^d、R^e和R^k獨立地選自氫、烷基、鹵代、鹵代烷基、鹵代烷氧基、烷氧基和氰基，並且R^j係氫。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 22 and 27 to 30, wherein -Z-alk-Ar-SO₂ - is: wherein each of R^d ,^Re and R^k is independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy and cyano, and R^j is hydrogen.如請求項1至22和27至31中任一項所述之化合物或其藥學上可接受的鹽，其中-Z-alk-Ar-SO₂-係：。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 22 and 27 to 31, wherein -Z-alk-Ar-SO₂ - is: .如請求項30、31和32中任一項所述之化合物或其藥學上可接受的鹽，其中係：。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 30, 31 and 32, wherein Department: .如請求項1至33中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆雜伸烷基。The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 33, wherein alk is a C₃ -C₆ heteroalkylene group substituted with R^g , R^h and Rⁱ .如請求項1至34中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^g、R^h和Rⁱ取代的C₃至C₆雜伸烷基，其中R^g、R^h和Rⁱ係氫。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 34, wherein alk is a C₃ -C₆ heteroalkylene substituted with R^g , R^h and Rⁱ , wherein R^g , R^h and Rⁱ are hydrogen.如請求項1至35中任一項所述之化合物或其藥學上可接受的鹽，其中alk的該C₃至C₆雜伸烷基係支鏈C₄至C₆雜伸烷基。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 35, wherein the C₃ to C₆ heteroalkylene group of alk is a branched C₄ to C₆ heteroalkylene group.如請求項1至36中任一項所述之化合物或其藥學上可接受的鹽，其中alk的該支鏈C₄至C₆雜伸烷基係-CH₂X^aCH(CH₃)CH₂-、-CH₂X^yCH₂CH(CH₃)X^a-、-CH₂CH₂CH(CH₃)X^a-、-X^aCH(CH₃)CH₂CH₂-、-X^yCH₂CH(CH₃)X^a-、-X^yCH(CH₃)CH₂X^a-、-CH₂CH₂CH₂CH(CH₃)X^a-、-X^aCH(CH₂R^h)CH₂-、-CH₂CH(CH₂R^h)X^a-、-X^aCH(CH₂CH₂R^h)CH₂-、-CH₂CH(CH₂CH₂R^h)X^a-、-CH₂C(CH₃)(CH₃)X^a-、-X^aC(CH₃)(CH₃)CH₂-、-CH(CH₃)CH(CH₃)X^a-、-CONR^zCH₂CH(CH₃)X^a-、-CH₂NR^qCOCH(CH₃)CH₂-、或-NR^qCOCH(CH₃)CH₂-，其中X^a係-NR^q-、-O-、-S-、-SO-、-SO₂-或-CO-。The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 36, wherein the branched C₄ to C₆ heteroaryl alkyl group of alk is -CH₂ X^a CH(CH₃ )CH₂ -, -CH₂ X^y CH₂ CH(CH₃ )X^a -, -CH₂ CH₂ CH(CH₃ )X^{a -} , -X^a CH(CH₃ )CH₂ CH₂ -, -X^y CH₂ CH(CH₃ )X^a -, -X^y CH(CH₃ )CH₂ X^a -, -CH_{2 CH 2CH2} CH(CH₃ )X^a -, -X^a CH(CH₂ R^h )CH₂ -, -CH₂ CH(CH₂ R^h )X^a -, -X^a CH(CH₂ CH₂ R^h )CH₂ -, -CH₂ CH(CH₂ CH₂ R^h )X^a -, -CH₂ C(CH₃ )(CH₃ )X^a -, -X^a C(CH₃ )(CH₃ )CH₂ -, -CH(CH₃ )CH(CH₃ )X^a -, -CONR^z CH₂ CH(CH₃ )X^a -, -CH₂ NR^q COCH(CH₃ )CH₂ -, or -NR^q COCH(CH₃ )CH₂ -, where^a is -NR^q -, -O-, -S-, -SO-, -SO₂ - or -CO-.如請求項1至37中任一項所述之化合物或其藥學上可接受的鹽，其中alk的該支鏈C₄至C₆雜伸烷基係-CH₂C(CH₃)(CH₃)X^a-、-CH(CH₃)(CHCH₃)X^a-、-X^aCH(CH₂CH₂R^h)CH₂-、-CH₂CH(CH₂CH₂R^h)X^a-、-X^aCH(CH₂R^h)CH₂-、或-CH₂CH(CH₂R^h)X^a-。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 37_,^wherein the branched_C4 -_C6 heteroalkylene group of_{alkis -CH2C(CH3)(CH3)Xa-, -CH(CH3)(CHCH3)Xa-, -XaCH(CH2CH2Rh)}^CH2-_,^-CH2CH_(CH2CH2Rh)^Xa-,-XaCH_(CH2Rh)CH2- , or^-CH2CH(_CH2Rh^)Xa- .如請求項36至38中任一項所述之化合物或其藥學上可接受的鹽，其中X^a係-NR^q-，其中R^q係氫或甲基。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 36 to 38, wherein X^a is -NR^q -, wherein R^q is hydrogen or methyl.如請求項36至38中任一項所述之化合物或其藥學上可接受的鹽，其中X^a係-O-。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 36 to 38, wherein X^a is -O-.如請求項36至38中任一項所述之化合物或其藥學上可接受的鹽，其中X^y係-O-或-NH-或-NCH₃-。The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 36 to 38, wherein^Xy is -O-, -NH-, or_-NCH3- .如請求項1至33中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^g、R^h和Rⁱ取代的直鏈C₃至C₆伸烷基，其中R^g、R^h和Rⁱ係氫。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 33, wherein alk is a linear C₃ to C₆ alkylene group substituted with R^g , R^h and Rⁱ , wherein R^g , R^h and Rⁱ are hydrogen.如請求項1至33中任一項所述之化合物或其藥學上可接受的鹽，其中alk係被R^g、R^h和Rⁱ取代的支鏈C₄至C₆伸烷基，其中R^g、R^h和Rⁱ係氫。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 33, wherein alk is a branched C₄ -C₆ alkylene group substituted with R^g , R^h and Rⁱ , wherein R^g , R^h and Rⁱ are hydrogen.如請求項1至33和43中任一項所述之化合物或其藥學上可接受的鹽，其中alk的該支鏈C₄至C₆伸烷基係-CH₂C(CH₃)(R^h)CH₂-、-CH₂C(C₂H₅)(R^h)CH₂-、-CH₂CH(CH₂R^h)CH₂-、-CH₂CH(CH₂CH₂R^h)CH₂-、-CH₂C(CH₃)(CH₂R^h)CH₂-、-CH₂C(C₂H₅)(CH₂R^h)CH₂-、-CH₂C(CH₃)(CH₂CH₂R^h)CH₂-、-CH₂CH(CH₃)CH(CH₂R^h)-、-CH₂CH₂C(CH₃)(CH₂R^h)-、-CH₂CH(CH₃)C(R^g)(R^h)-、-CH₂CH(C₂H₅)C(R^g)(R^h)-、-CH₂CH(C(R^g)(R^h)(Rⁱ))CH(CH₃)-、-CH₂C(CH₃)(C(R^g)(R^h)(Rⁱ))CH(CH₃)-、-CH₂CH(C(R^g)(R^h)(Rⁱ))CH₂-、-CH₂CH₂CH(C(R^g)(R^h)(Rⁱ))-、-CH₂CH₂CH(C(R^g)(R^h)(Rⁱ))CH₂-、或-CH₂CH₂CH₂CH(C(R^g)(R^h)(Rⁱ))-。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 33 and 43, wherein the side chain C₄ to C₆ alkylene group of alk is -CH₂ C(CH₃ )(R^h )CH₂ -, -CH₂ C(C₂ H₅ )(R^h )CH₂ -, -CH₂ CH(CH₂ R^h )CH₂ -, -CH₂ CH(CH₂ CH₂ R^h )CH₂ -, -CH₂ C(CH₃ )(CH₂ R^h )CH₂ -, -CH₂ C(C₂ H₅ )(CH₂ R^h )CH₂ -, -CH₂ C(CH₃ )(CH₂ CH₂ R^h )CH₂ -, -CH₂ CH(CH₃ )CH(CH₂ R^h )-, -CH₂ CH₂ C(CH₃ )(CH₂ R^h )-, -CH₂ CH(CH₃ )C(R^g )(R^h )-, -CH₂ CH(C₂ H₅ )C(R^g )(R^h )-, -CH₂ CH(C(R^g )(R^h )(Rⁱ ))CH(CH₃ )-, -CH₂ C(CH₃ )(C(R^g )(R^h )(Rⁱ ))CH(CH₃ )-, -CH₂ CH(C(R^g )(R^h )(Rⁱ ))CH₂ -, -CH₂ CH₂ CH(C(R^g )(R^h )(Rⁱ ))-, -CH₂ CH₂ CH(C(R^g )(R^h )(Rⁱ ))CH₂ -, or -CH₂ CH₂ CH₂ CH(C(R^g )(R^h )(Rⁱ ))-.如請求項1至33、43和44中任一項所述之化合物或其藥學上可接受的鹽，其中alk的該支鏈C₄至C₆伸烷基係-CH₂C(CH₃)(R^h)CH₂-、-CH₂CH(CH₂R^h)CH₂-、-CH₂CH(CH₂CH₂R^h)CH₂-、-CH₂CH(C(R^g)(R^h)(Rⁱ))CH₂-、-CH₂CH₂CH(C(R^g)(R^h)(Rⁱ))CH₂-、或-CH₂CH₂CH₂CH(C(R^g)(R^h)(Rⁱ))-。The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 33_, 43 and 44_, wherein the side chain_C4 to_C6^alkylene group of_alkis-CH2C (_CH3 )(_Rh )CH2-, -CH2CH(^CH2Rh )CH2-,_-CH2CH (CH2CH2Rh)_CH2- , -CH2CH(C(^Rg )(^Rh) (_Ri) )_CH2-^,_-CH2CH2CH (C(^Rg )(^Rh )₍^Ri )_)CH2-, or_-CH2CH2CH2CH (C(_Rg )(^Rh) (^Ri ))-.如請求項1至45中任一項所述之化合物或其藥學上可接受的鹽，其中alk係：The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 45, wherein alk is:如請求項1至46中任一項所述之化合物或其藥學上可接受的鹽，其中降解決定子係選自以下的E3泛素連接酶配位基：、、、、、、、、、、、和； 其中R^ee係氫、甲基、乙基、環丙基或2,2,2-三氟乙基，並且R^ff係氫、甲基、環丙基、氟、氰基、甲氧基、二氟甲氧基、三氟甲氧基或三氟甲基。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 46, wherein the degradation determinant is selected from the following E3 ubiquitin ligase ligands: 、 、 、 、 、 、 、 、 、 、 、 and wherein R^ee is hydrogen, methyl, ethyl, cyclopropyl or 2,2,2-trifluoroethyl, and R^ff is hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.一種化合物，其選自：(R)-1-(1-甲基-6-(1-(2-甲基-3-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮(S)-1-(1-甲基-6-(1-(2-甲基-3-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(1-甲基-6-(1-(3-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮3-(5-(4-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌𠯤-1-基)-6-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈1-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-7-氟-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(1-甲基-6-(1-(2-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)丁基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)丁基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮(R)-1-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮(S)-1-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈1-(1-甲基-6-(1-(2-甲基-3-(3-((4-((5-(三氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(3-((4-((5-溴嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(1-甲基-6-(1-(2-甲基-3-(3-((4-((5-乙烯基嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮2-((3-(4-(1-(2,6-二側氧基哌啶-3-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-4-基)哌啶-1-基)丙基)(甲基)胺基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈2,2,2-三氟乙酸鹽3-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)哌啶-2,6-二酮(S)-1-(6-(1-(2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮(R)-1-(6-(1-(2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(3-((4-((5-乙基嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氟苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮3-(3-甲基-4-(1-(3-(甲基(2-(三氟甲基)-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)胺基)丙基)哌啶-4-基)-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮2,2,2-三氟乙酸鹽4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙氧基)苯甲腈1-(6-(1-(3-(3-((4-((5-異丙基嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(2-((3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)胺基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(2-((3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)硫代)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮(S)-1-(6-(1-(2-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮(R)-1-(6-(1-(2-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈1-(6-(1-(2-(5-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氟苯氧基)乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,6-二側氧基哌啶-3-基)-1-甲基-1H-吲哚-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈4-((4-((5-(2,2-二氟乙氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈1-(6-(1-(2-((4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)胺基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,6-二側氧基哌啶-3-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈1-(6-(1-(2-(5-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟甲基)苯氧基)乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(2-((3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)(甲基)胺基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(2-羥基-2-甲基-3-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(3-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(2-((4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)(甲基)胺基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮3-(4-(1-(3-((2-氟-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)(甲基)胺基)丙基)哌啶-4-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮甲酸鹽1-(6-(1-((2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)環戊基)甲基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-((2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)環戊基)甲基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-((2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)環己基)甲基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮甲酸鹽1-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氟苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)-3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-N,N-二甲基丙醯胺4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-3,3-二氟哌啶-1-基)-2-甲基丙基)苯甲腈甲酸鹽4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-(2,2,2-三氟乙基)-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)-4-((4-((5-(三氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(4-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丁基)苯甲腈4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(1-(2,6-二側氧基哌啶-3-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-4-基)哌啶-1-基)-2-甲基丙基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙氧基)苯甲腈(S)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈(R)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈(E)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙-1-烯-1-基)苯甲腈1-(6-(1-(2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)烯丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-羥基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮2-(3-(4-(1-(2,6-二側氧基哌啶-3-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-4-基)哌啶-1-基)-2-甲基丙基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(1-(2,6-二側氧基哌啶-3-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-4-基)哌啶-1-基)-2-甲基丙基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-7-氟-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈1-(6-(1-(3-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氟苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(5-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氟苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(2-氟-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丁基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)-4-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁腈1-(6-(1-(3-(3-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-5-氟苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(3-氟-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-5-氟苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮5-(1-(3-(2-氰基-5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-N-(2,6-二側氧基哌啶-3-基)吡啶甲醯胺3-(4-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮5-(1-(3-(5-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氰基苯基)-2-甲基丙基)哌啶-4-基)-N-(2,6-二側氧基哌啶-3-基)吡啶甲醯胺4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)苯甲腈5-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈1-(6-(1-(3-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟甲基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氟苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(2-氟-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-羥基-2-甲基丙基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-羥基-2-甲基丙基)苯甲腈2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-羥基-2-甲基丙基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈1-(6-(1-(3-(4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氟苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氟苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(2-氟-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(2-羥基-2-甲基-3-(2-(三氟甲基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(2-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟甲基)苯氧基)乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟甲基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟甲基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(1-甲基-6-(1-(2-甲基-3-(2-(三氟甲基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(2-羥基-2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟甲基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(三氟甲基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮(E)-4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙-1-烯-1-基)苯甲腈4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)烯丙基)苯甲腈(E)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙-1-烯-1-基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈2-(2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)烯丙基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-((2R)-4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2-甲基哌啶-1-基)-2-甲基丙基)苯甲腈甲酸鹽4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(3-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-8-氮雜雙環[3.2.1]辛-8-基)-2-甲基丙基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁基)苯甲腈(E)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-1-烯-1-基)苯甲腈(E)-1-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基烯丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮(E)-1-(1-甲基-6-(1-(2-甲基-3-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)烯丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮(E)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁-1-烯-1-基)苯甲腈(E)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丁-1-烯-1-基)苯甲腈(E)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-3-甲基丁-1-烯-1-基)苯甲腈(E)-2-(3-(4-(3-(2,6-二側氧基哌啶-3-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙-1-烯-1-基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈(E)-1-(6-(1-(3-(2-(二氟甲基)-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)烯丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮(Z)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-1-烯-1-基)苯甲腈1-(6-(1-(3-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(二氟甲基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-((2S,6S)-4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2,6-二甲基哌啶-1-基)-2-甲基丙基)苯甲腈甲酸鹽4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙基)胺基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2-側氧基吡啶-1(2H)-基)-2-甲基丙基)苯甲腈1-(6-(1-(2-(2-氟-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮2,2,2-三氟乙酸鹽2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)-3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-N-甲基丙醯胺1-(6-(1-(2-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-氟苯氧基)乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮2-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙氧基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈1-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-(1-甲基-1H-吡唑-4-基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基-3-側氧基丙基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(4-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁-2-基)苯甲腈(R)-1-(1-甲基-6-(1-(2-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮(S)-1-(1-甲基-6-(1-(2-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-羥基丙基)苯甲腈2-(3-(3-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-8-氮雜雙環[3.2.1]辛-8-基)-2-甲基丙基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-((2S)-4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2-甲基哌啶-1-基)-2-甲基丙基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙基)(甲基)胺基)苯甲腈4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙基)(甲基)胺基)苯甲腈2-((2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙基)(甲基)胺基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙基)硫代)苯甲腈(R)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)苯甲腈(S)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)苯甲腈1-(6-(1-(3-(4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-3-氟苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-3-氟苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(3-氟-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-羥基-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)苯乙氧基)苯甲腈1-(6-(1-(2-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(2-(4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(1-甲基-6-(1-(2-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)乙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-((2R)-4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2-甲基哌啶-1-基)乙氧基)苯甲腈2-(3-((2R)-4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2-甲基哌啶-1-基)-2-甲基丙基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈2-(3-((2S)-4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2-甲基哌啶-1-基)-2-甲基丙基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(7-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-3-氧雜-9-氮雜雙環[3.3.1]壬-9-基)-2-甲基丙基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-3-甲基苯乙氧基)苯甲腈1-(6-(1-(3-(2-(二氟甲基)-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(5-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(二氟甲基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-((2S)-4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2-甲基哌啶-1-基)乙氧基)苯甲腈1-(6-(1-(3-(2-溴-5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(2-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(二氟甲基)苯氧基)乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(6-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-2-氮雜螺[3.3]庚-2-基)-2-甲基丙基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(3-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)四氫吖唉-1-基)-2-甲基丙基)苯甲腈2-(3-氰基-2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)丙基)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈1-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮甲酸鹽4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙氧基)苯甲腈1-(6-(1-((1-((3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯氧基)甲基)環丙基)甲基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(2-氯-5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-3,3-二氟丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮2-(4-氰基-3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁基)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌𠯤-1-基)-2-甲基丙基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(3-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-3,8-二氮雜雙環[3.2.1]辛-8-基)-2-甲基丙基)苯甲腈1-(6-(1-(4-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(二氟甲基)苯基)丁-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-3-甲氧基丙-2-基)氧基)苯甲腈3-(6-(1-(3-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(二氟甲基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)哌啶-2,6-二酮1-(6-(1-(2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)-3,3,3-三氟丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(3-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-側氧基吡啶-1(2H)-基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(1-(2,6-二側氧基哌啶-3-基)-1H-吲唑-5-基)哌啶-1-基)-2-甲基丙基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,6-二側氧基哌啶-3-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁基)苯甲腈1-(1-甲基-6-(1-(2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(4-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)丁-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙氧基)苯甲腈4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙氧基)苯甲腈2-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙氧基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈1-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1-甲基-1H-咪唑-2-基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(2-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)-4,4,4-三氟丁基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮3-(6-(1-(4-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(二氟甲基)苯基)丁-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)哌啶-2,6-二酮1-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-3,3-二氟-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-(4-(3-(2,6-二側氧基哌啶-3-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙氧基)苯甲腈2-(2-(4-(3-(2,6-二側氧基哌啶-3-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙氧基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈1-(6-(4-(((3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苄基)(甲基)胺基)甲基)環己基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮甲酸鹽4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-5-基)哌啶-1-基)丁基)苯甲腈1-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(二氟甲基)苯基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((2S)-3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丁基)苯甲腈1-(6-(1-(4-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2-甲基丁-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(1-(2,6-二側氧基哌啶-3-基)-3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-4-基)哌啶-1-基)丁基)苯甲腈1-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)-2-甲基丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(2-(2,6-二側氧基哌啶-3-基)-1,3-二側氧基異吲哚啉-5-基)哌啶-1-基)丁基)苯甲腈4-((4-((5-環丙基嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-(4-(1-(2,6-二側氧基哌啶-3-基)-1H-吲唑-5-基)哌啶-1-基)丙氧基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-3-甲基丁基)苯甲腈1-(6-(1-(3-(3-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯基)-2,2-二氟丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2,2-二氟丙基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)戊基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(4-((2,6-二側氧基哌啶-3-基)胺基)苯基)哌啶-1-基)-2-甲基丙基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-((2,6-二側氧基哌啶-3-基)胺基)苯基)哌啶-1-基)-2-甲基丙基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(1-(2,6-二側氧基哌啶-3-基)-3-甲基-1H-吲唑-5-基)哌啶-1-基)-2-甲基丙基)苯甲腈1-(6-(1-(4-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-側氧基吡啶-1(2H)-基)丁-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-(甲氧基甲基)丙基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-4,4,4-三氟丁基)苯甲腈4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,6-二側氧基哌啶-3-基)-1-(2,2,2-三氟乙基)-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈甲酸鹽4-((4-((5-((二氟甲基)硫代)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)苯甲腈1-(6-(1-(3-(4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-側氧基吡啶-1(2H)-基)-2-甲基丙基)-哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮2-(3-(4-(1-環丙基-3-(2,4-二側氧基-四氫嘧啶-1(2H)-基)-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)苯甲腈2-(3-(4-(1-(2,6-二側氧基哌啶-3-基)-1H-吲唑-5-基)哌啶-1-基)丁基)-4-((4-((5-(三氟-甲基)嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)苯甲腈4-((4-((5-(二氟甲氧基)-嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)-4-甲氧基丁基)苯甲腈4-((4-((5-環丙基嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-(4-(3-(2,4-二側氧基四氫-嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-丙氧基)苯甲腈4-((4-((5-(二氟甲氧基)-嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-(氧環丁烷-3-基)丙基)苯甲腈1-(1-甲基-6-(1-(4-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丁-2-基)-哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮2-(4-氰基-2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)丁基)-4-((4-((5-(二氟甲氧基)-嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈1-(1-甲基-6-(1-(2-甲基-3-(5-甲基-4-((4-((5-(三氟甲基)-嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(1-甲基-6-(1-(2-甲基-3-(3-甲基-4-((4-((5-(三氟甲基)-嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)-嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(3-(4-(1-(2,6-二側氧基哌啶-3-基)-1H-苯并-[d][1,2,3]三唑-5-基)-哌啶-1-基)-2-甲基丙基)-苯甲腈1-(1-甲基-6-(1-(2-甲基-3-(3-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-1H-吡唑-1-基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮1-(6-(1-(1-(2-氟-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯氧基)丙-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮(R)-4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫-嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)苯甲腈(R)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯甲腈(R)-4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)胺基)-苯甲腈2,2,2-三氟乙酸鹽(R)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)胺基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)苯甲腈2,2,2-三氟乙酸鹽4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)硫代)苯甲腈2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)硫代)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯甲腈(E)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁-1-烯-1-基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯甲腈1-(1-甲基-6-(1-(2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)-1H-咪唑-1-基)-丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-(二氟甲氧基)-嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(2-((4-(3-(2,6-二側氧基哌啶-3-基)-1-甲基-1H-吲唑-6-基)環己基)氧基)-乙基)苯甲腈1-(1-甲基-6-(1-(2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)-1H-1,2,3-三唑-1-基)丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮N-(2-氰基-5-((4-((5-(二氟-甲氧基)嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)苯基)-2-(4-(3-(2,4-二側氧基四氫-嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-乙醯胺2,2,2-三氟乙酸鹽4-((4-((5-(2,2-二氟環-丙基)嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)-苯甲腈2-(4-氰基-2-((4-(3-(2,4-二側氧基-四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)丁基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯甲腈4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-(4-氰基-2-((4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)甲基)丁基)-苯甲腈2-(2-環丙基-3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙基)-4-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯甲腈1-(1-甲基-6-(1-(2-甲基-3-(4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)-1H-吡唑-1-基)-丙基)哌啶-4-基)-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮2-(3-(4-(3-(2,4-二側氧基四氫-嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丁基)-4-((4-((5-(三氟-甲基)嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)苯甲腈2-(3-(4-(3-(2,4-二側氧基四氫-嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丁基)-4-((4-((5-(三氟-甲基)嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)苯甲腈(S)-2-((1-(4-(3-(2,4-二側氧基-四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯甲腈(S)-4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫-嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)氧基)苯甲腈(R)-4-((4-((5-環丙基嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)-苯甲腈(S)-4-((4-((5-環丙基嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)-2-(3-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)-2-甲基丙基)-苯甲腈(S)-4-((4-((5-氯嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)胺基)-苯甲腈(S)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丙-2-基)胺基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯甲腈1-(6-(1-(1-(2-氯-5-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)苯氧基)丙-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮4-((4-((5-環丙基嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁-2-基)氧基)苯甲腈4-((4-((5-環丙基嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-2-((2-(4-(3-(2,4-二側氧基四氫-嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙基)胺基)苯甲腈2-((1-(4-(3-(2,4-二側氧基四氫-嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁-2-基)氧基)-4-((4-((5-(三氟甲基)-嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈(S)-1-(6-(1-(3-(5-((4-((5-環丙基嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)-2-(二氟甲基)苯基)-2-甲基-丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫-嘧啶-2,4(1H,3H)-二酮1-(6-(1-(2-(2-氯-5-((4-((5-環丙基嘧啶-2-基)胺基)-哌啶-1-基)磺醯基)苯氧基)-丙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫-嘧啶-2,4(1H,3H)-二酮甲酸鹽1-(6-(1-(1-(2-氯-5-((4-((5-環丙基嘧啶-2-基)胺基)哌啶-1-基)磺醯基)-苯氧基)丙-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮甲酸鹽1-(6-(1-(1-(5-((4-((5-(二氟甲氧基)嘧啶-2-基)胺基)哌啶-1-基)-磺醯基)-2-(二氟甲基)苯氧基)丙-2-基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮2-(2-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁氧基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈和2-((1-(4-(3-(2,4-二側氧基四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)丁-2-基)氧基)-4-((4-((5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-基)磺醯基)苯甲腈或其藥學上可接受的鹽。A compound selected from: (R)-1-(1-methyl-6-(1-(2-methyl-3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (S)-1-(1-methyl-6-(1-(2-methyl-3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(1-methyl-6-(1-(3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 3-(5-(4-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-7-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(1-methyl-6-(1-(2-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)butyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)butyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (R)-1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (S)-1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 1-(1-methyl-6-(1-(2-methyl-3-(3-((4-((5-(trifluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(3-((4-((5-bromopyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(1-methyl-6-(1-(2-methyl-3-(3-((4-((5-vinylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2-((3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)propyl)(methyl)amino)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 2,2,2-trifluoroacetate 3-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (S)-1-(6-(1-(2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (R)-1-(6-(1-(2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(3-((4-((5-ethylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 3-(3-methyl-4-(1-(3-(methyl(2-(trifluoromethyl)-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)amino)propyl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 2,2,2-trifluoroacetate 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethoxy)benzonitrile 1-(6-(1-(3-(3-((4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(2-((3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)amino)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(2-((3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)thio)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (S)-1-(6-(1-(2-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (R)-1-(6-(1-(2-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 1-(6-(1-(2-(5-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenoxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,6-difluorooxypiperidin-3-yl)-1-methyl-1H-indol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 4-((4-((5-(2,2-difluoroethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 1-(6-(1-(2-((4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)amino)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,6-difluorooxypiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 1-(6-(1-(2-(5-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(2-((3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)(methyl)amino)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(2-hydroxy-2-methyl-3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(2-((4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)(methyl)amino)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 3-(4-(1-(3-((2-fluoro-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)(methyl)amino)propyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dionecarboxylate 1-(6-(1-((2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)cyclopentyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-((2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)cyclopentyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-((2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dionecarboxylate 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-N,N-dimethylpropionamide 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3-difluoropiperidin-1-yl)-2-methylpropyl)benzonitrile formate 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)-4-((4-((5-(trifluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylbutyl)benzonitrile 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethoxy)benzonitrile (S)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile (R)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile (E)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylprop-1-en-1-yl)benzonitrile 1-(6-(1-(2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)allyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-hydroxypropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2-(3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-2-methylpropyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7-fluoro-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 1-(6-(1-(3-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(5-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(2-fluoro-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)butyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butanenitrile 1-(6-(1-(3-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-5-fluorophenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(3-fluoro-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-5-fluorophenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 5-(1-(3-(2-cyano-5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-N-(2,6-difluorooxypiperidin-3-yl)picolinamide 3-(4-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 5-(1-(3-(5-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-cyanophenyl)-2-methylpropyl)piperidin-4-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)benzonitrile 5-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 1-(6-(1-(3-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(2-fluoro-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-hydroxy-2-methylpropyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-hydroxy-2-methylpropyl)benzonitrile 2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-hydroxy-2-methylpropyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 1-(6-(1-(3-(4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(2-fluoro-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(2-hydroxy-2-methyl-3-(2-(trifluoromethyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(2-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(1-methyl-6-(1-(2-methyl-3-(2-(trifluoromethyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(2-hydroxy-2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (E)-4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylprop-1-en-1-yl)benzonitrile 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)allyl)benzonitrile (E)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylprop-1-en-1-yl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 2-(2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)allyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-((2R)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2-methylpiperidin-1-yl)-2-methylpropyl)benzonitrile formate 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-methylpropyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butyl)benzonitrile (E)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)prop-1-en-1-yl)benzonitrile (E)-1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylallyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (E)-1-(1-methyl-6-(1-(2-methyl-3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)allyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (E)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)but-1-en-1-yl)benzonitrile (E)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylbut-1-en-1-yl)benzonitrile (E)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-3-methylbut-1-en-1-yl)benzonitrile (E)-2-(3-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylprop-1-en-1-yl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile (E)-1-(6-(1-(3-(2-(difluoromethyl)-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)allyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Z)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)prop-1-en-1-yl)benzonitrile 1-(6-(1-(3-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-((2S,6S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2,6-dimethylpiperidin-1-yl)-2-methylpropyl)benzonitrile formate 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((2-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethyl)amino)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2-oxopyridin-1(2H)-yl)-2-methylpropyl)benzonitrile 1-(6-(1-(2-(2-fluoro-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-trifluoroacetate 2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-N-methylpropionamide 1-(6-(1-(2-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenoxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethoxy)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-(1-methyl-1H-pyrazol-4-yl)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methyl-3-oxopropyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butan-2-yl)benzonitrile (R)-1-(1-methyl-6-(1-(2-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (S)-1-(1-methyl-6-(1-(2-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-hydroxypropyl)benzonitrile 2-(3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-methylpropyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-((2S)-4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2-methylpiperidin-1-yl)-2-methylpropyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethyl)(methyl)amino)benzonitrile 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethyl)(methyl)amino)benzonitrile 2-((2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethyl)(methyl)amino)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethyl)thio)benzonitrile (R)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)benzonitrile (S)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)benzonitrile 1-(6-(1-(3-(4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-3-fluorophenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-3-fluorophenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(3-fluoro-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)phenethoxy)benzonitrile 1-(6-(1-(2-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(2-(4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(1-methyl-6-(1-(2-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)ethyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-((2R)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2-methylpiperidin-1-yl)ethoxy)benzonitrile 2-(3-((2R)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2-methylpiperidin-1-yl)-2-methylpropyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 2-(3-((2S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2-methylpiperidin-1-yl)-2-methylpropyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(7-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3-oxahio-9-azabicyclo[3.3.1]nonan-9-yl)-2-methylpropyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3-methylphenethoxy)benzonitrile 1-(6-(1-(3-(2-(difluoromethyl)-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(5-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-((2S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2-methylpiperidin-1-yl)ethoxy)benzonitrile 1-(6-(1-(3-(2-bromo-5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(2-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenoxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(6-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2-azaspiro[3.3]hept-2-yl)-2-methylpropyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)tetrahydroazolidin-1-yl)-2-methylpropyl)benzonitrile 2-(3-cyano-2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)propyl)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dionecarboxylate 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propoxy)benzonitrile 1-(6-(1-((1-((3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(2-chloro-5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3,3-difluoropropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2-(4-cyano-3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butyl)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylpropyl)benzonitrile 1-(6-(1-(4-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenyl)butan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-3-methoxypropan-2-yl)oxy)benzonitrile 3-(6-(1-(3-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione 1-(6-(1-(2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-3,3,3-trifluoropropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(3-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-oxopyridin-1(2H)-yl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(1-(2,6-difluorooxypiperidin-3-yl)-1H-indazol-5-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,6-difluorooxypiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butyl)benzonitrile 1-(1-methyl-6-(1-(2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(4-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)butan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propoxy)benzonitrile 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propoxy)benzonitrile 2-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propoxy)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1-methyl-1H-imidazol-2-yl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(2-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-4,4,4-trifluorobutyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 3-(6-(1-(4-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenyl)butan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3,3-difluoro-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-(4-(3-(2,6-difluorooxypiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethoxy)benzonitrile 2-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethoxy)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 1-(6-(4-(((3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)(methyl)amino)methyl)cyclohexyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dionecarboxylate 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)butyl)benzonitrile 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((2S)-3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylbutyl)benzonitrile 1-(6-(1-(4-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylbutan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)butyl)benzonitrile 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-1-yl)butyl)benzonitrile 4-((4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-(4-(1-(2,6-difluorooxypiperidin-3-yl)-1H-indazol-5-yl)piperidin-1-yl)propoxy)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-3-methylbutyl)benzonitrile 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2,2-difluoropropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2,2-difluoropropyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)pentyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(4-((2,6-difluorooxypiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-methylpropyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-((2,6-difluorooxypiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-methylpropyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(1-(2,6-difluorooxypiperidin-3-yl)-3-methyl-1H-indazol-5-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 1-(6-(1-(4-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-oxopyridin-1(2H)-yl)butan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-difluorooxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-(methoxymethyl)propyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-4,4,4-trifluorobutyl)benzonitrile 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,6-dioxopiperidin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile formate 4-((4-((5-((difluoromethyl)thio)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile 1-(6-(1-(3-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-oxopyridin-1(2H)-yl)-2-methylpropyl)-piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2-(3-(4-(1-cyclopropyl-3-(2,4-dioxo-tetrahydropyrimidin-1(2H)-yl)-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 2-(3-(4-(1-(2,6-dioxopiperidin-3-yl)-1H-indazol-5-yl)piperidin-1-yl)butyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 4-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-((4-(3-(2,4-difluoromethoxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)-4-methoxybutyl)benzonitrile 4-((4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-(4-(3-(2,4-dioxotetrahydro-pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-propyloxy)benzonitrile 4-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-(oxobutan-3-yl)propyl)benzonitrile 1-(1-methyl-6-(1-(4-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)butan-2-yl)-piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2-(4-cyano-2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)butyl)-4-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 1-(1-methyl-6-(1-(2-methyl-3-(5-methyl-4-((4-((5-(trifluoromethyl)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(1-methyl-6-(1-(2-methyl-3-(3-methyl-4-((4-((5-(trifluoromethyl)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(1-(2,6-difluorooxypiperidin-3-yl)-1H-benzo-[d][1,2,3]triazol-5-yl)-piperidin-1-yl)-2-methylpropyl)-benzonitrile 1-(1-methyl-6-(1-(2-methyl-3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-(1-(1-(2-fluoro-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-phenoxy)propan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (R)-4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydro-pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)benzonitrile (R)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzonitrile (R)-4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)amino)benzonitrile 2,2,2-trifluoroacetate (R)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)amino)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 2,2,2-trifluoroacetate 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)thio)benzonitrile 2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)thio)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzonitrile (E)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)but-1-en-1-yl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzonitrile 1-(1-methyl-6-(1-(2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-imidazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-((4-(3-(2,6-difluorooxypiperidin-3-yl)-1-methyl-1H-indazol-6-yl)cyclohexyl)oxy)ethyl)benzonitrile 1-(1-methyl-6-(1-(2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-1,2,3-triazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione N-(2-cyano-5-((4-((5-(difluoro-methoxy)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)phenyl)-2-(4-(3-(2,4-dioxotetrahydro-pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-acetamide 2,2,2-trifluoroacetate 4-((4-((5-(2,2-difluorocyclopropyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)-benzonitrile 2-(4-cyano-2-((4-(3-(2,4-dioxo-tetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)butyl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzonitrile 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-cyano-2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)butyl)-benzonitrile 2-(2-Cyclopropyl-3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propyl)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzonitrile 1-(1-methyl-6-(1-(2-methyl-3-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2-(3-(4-(3-(2,4-dioxotetrahydro-pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylbutyl)-4-((4-((5-(trifluoro-methyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 2-(3-(4-(3-(2,4-dioxotetrahydro-pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylbutyl)-4-((4-((5-(trifluoro-methyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile (S)-2-((1-(4-(3-(2,4-dioxo-tetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzonitrile (S)-4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydro-pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)oxy)benzonitrile (R)-4-((4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)-benzonitrile (S)-4-((4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)-benzonitrile (S)-4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)amino)-benzonitrile (S)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propan-2-yl)amino)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzonitrile 1-(6-(1-(1-(2-chloro-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)propan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 4-((4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butan-2-yl)oxy)benzonitrile 4-((4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((2-(4-(3-(2,4-dioxotetrahydro-pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethyl)amino)benzonitrile 2-((1-(4-(3-(2,4-Dioxotetrahydro-pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butan-2-yl)oxy)-4-((4-((5-(trifluoromethyl)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile (S)-1-(6-(1-(3-(5-((4-((5-cyclopropylpyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenyl)-2-methyl-propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydro-pyrimidine-2,4(1H,3H)-dione 1-(6-(1-(2-(2-chloro-5-((4-((5-cyclopropylpyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)phenoxy)-propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydro-pyrimidine-2,4(1H,3H)-dionecarboxylate 1-(6-(1-(1-(2-chloro-5-((4-((5-cyclopropylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-phenoxy)propan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dionecarboxylate 1-(6-(1-(1-(5-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(difluoromethyl)phenoxy)propan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butoxy)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile and 2-((1-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butan-2-yl)oxy)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile or a pharmaceutically acceptable salt thereof.一種藥物組成物，該藥物組成物包含如請求項1至48中任一項所述之化合物或其藥學上可接受的鹽、以及藥學上可接受的賦形劑。A pharmaceutical composition comprising the compound according to any one of claims 1 to 48 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.一種治療患者的由CDK2介導的疾病的方法，該方法包括向公認有需要的患者投與治療有效量的如請求項1至48中任一項所述之化合物或如請求項49所述之藥物組成物。A method for treating a disease mediated by CDK2 in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 48 or a pharmaceutical composition according to claim 49.一種治療患者的癌症的方法，該方法包括向有需要的患者投與治療有效量的如請求項1至48中任一項所述之化合物或其藥學上可接受的鹽、或如請求項49所述之藥物組成物。A method for treating cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 48, or a pharmaceutical composition as described in claim 49.如請求項51所述之方法，其中將如請求項1至48中任一項所述之化合物或其藥學上可接受的鹽、或如請求項49所述之藥物組成物與至少一種其他抗癌劑組合投與。The method of claim 51, wherein the compound of any one of claims 1 to 48 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 49 is administered in combination with at least one other anticancer agent.