Bifunctional compounds containing pyrido [2, 3-d] pyrimidine-7 (8H)-one derivatives for degradation of cyclin-dependent kinase 2 via ubiquitin proteasome pathway

Abstract

The present disclosure provides certain bifunctional compounds that elicit degradation of cyclin dependent kinase 2 (CDK2) via the ubiquitin proteasome pathway, and thus are useful in the treatment of diseases mediated by CDK2. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This international application claims the benefit of U.S. Provisional Application No. 63 / 354,669, filed on June 22, 2022, the entire contents of which are incorporated herein for all purposes. Technical Field

[0003] The present disclosure provides certain bifunctional compounds containing pyrido[2,3-d]-pyrimidin-7(8H)-one derivatives, which cause degradation of cyclin-dependent kinase 2 (CDK2) via the ubiquitin proteasome pathway and are therefore useful for treating diseases mediated by CDK2. Pharmaceutical compositions containing such compounds and methods for preparing such compounds are also provided. Background Art

[0004] Cyclin-dependent kinases (CDKs) are cellular kinases that are critical for carefully arranging signal transduction events (such as DNA replication and protein synthesis) to ensure reliable eukaryotic cell division and proliferation. To date, at least 21 mammalian CDKs have been identified (Malumbres M. Genome Biol. [Genome Biology] (2014) 15: 122). Among these CDKs, at least CDK1 / cyclin B, CDK2 / cyclin E, CDK2 / cyclin A, CDK4 / cyclin D and CDK6 / cyclin D complexes are considered to be important regulators of cell cycle progression; and other CDKs are important in regulating gene transcription, DNA repair, differentiation and apoptosis (see Morgan, DO Annu. Rev. Cell. Dev. Biol. [Annual Review of Cell and Developmental Biology] (1997) 13: 261-291).

[0005] Due to their role in regulating the cell cycle and other essential cellular processes, it has been shown that increased activity or transient abnormal activation of CDKs leads to the development of various cancer types. The development of human tumors is often associated with changes in the CDK protein itself or its regulatory factors (Cordon-Cardo C. Am. J. Pathol. [American Journal of Pathology] (1995) 147: 545-560; Karp JE, Broder S. Nat. Med. [Natural Medicine] (1995) 1: 309-320; Hall M, Peters G. Adv. Cancer Res. [Advances in Cancer Research] (1996) 68: 67-108). For example, amplification of regulatory subunits of CDKs and cell cycle proteins, as well as mutations, gene deletions or transcriptional silencing of endogenous CDK inhibitory regulatory factors have been reported (Smalley et al. Cancer Res. [Cancer Research] (2008) 68: 5743-52). A large number of studies have determined the role of these changes in promoting tumor occurrence and development. Therefore, over the past two decades, there has been great interest in developing cyclin-dependent kinase (CDK) inhibitors for therapeutic purposes.

[0006] Selective CDK4 / 6 inhibitors have transformed the therapeutic management of hormone receptor-positive (HR+) metastatic breast cancer (MBC). Palbociclib, ribociclib, and abemaciclib are selective, reversible inhibitors of CDK4 and CDK6 that are approved for use in hormone receptor-positive (HR+) metastatic breast cancer in combination with endocrine therapy. Additional clinical trials using these CDK4 / 6 inhibitors are ongoing in breast cancer and other cancers, either as single agents or in combination with other therapeutic agents. (O'Leary et al. Nature Reviews (2016) 13:417-430). Although CDK4 / 6 inhibitors have shown significant clinical efficacy in ER-positive metastatic breast cancer, clinical benefit may be limited over time due to the development of primary or acquired resistance.

[0007] An important mechanism of CDK4 / 6 inhibitor resistance is the abnormal activation of CDK2. It is reported that high expression of cyclin E leads to over-activated CDK2 / cyclin E complex, which bypasses the need for CDK4 / 6 to re-enter the cell cycle (Asghar, U. et al. Clin. Cancer Res. [Clinical Cancer Research] (2017) 23: 5561). In addition, it has been found that when CDK4 / 6 is inhibited, there is a non-canonical CDK2 / cyclin D1 complex formation that promotes pRb phosphorylation recovery and drives cell cycle progression (Herrera-Abreu MT et al., Cancer Res. [Cancer Research] (2006) 15: 2301).

[0008] The CDK2 / cyclin E complex plays an important role in regulating the G1 / S transition, histone biosynthesis, and centrosome duplication. After Rb is initially phosphorylated by Cdk4 / 6 / cyclin D, Cdk2 / cyclin E further hyperphosphorylates p-RB, releasing E2F to transcribe genes required for entering the S phase. During the S phase, cyclin E is degraded, and CDK2 forms a complex with cyclin A to promote phosphorylation of substrates, thereby allowing DNA replication and inactivation of E2F to complete the S phase (Asghar et al. Nat. Rev. Drug. Discov. [Nature Review: Drug Discovery] (2015) 14: 130-146). In addition to cyclin binding, the activity of CDK2 is also tightly regulated by its interaction with negative regulators such as p21 and p27. In response to mitogenic stimuli that signal an optimal environment for the cell cycle, p21 and p27 are phosphorylated and degraded, thereby unblocking CDK2 / cyclin activation.

[0009] Cyclin E (regulatory cyclin of CDK2) is usually overexpressed in cancer, and its overexpression is associated with poor prognosis. For example, it has been shown that amplification or overexpression of cyclin E is associated with poor outcomes in breast cancer (Keyomarsi et al., NEngl J Med. [New England Journal of Medicine] (2002) 347: 1566-75). Cyclin E2 (CCNE2) overexpression is associated with endocrine resistance in breast cancer cells, and CDK2 inhibition has been reported to restore sensitivity to tamoxifen or CDK4 / 6 inhibitors in tamoxifen resistance and CCNE2 overexpressing cells. (Caldon et al., Mol Cancer Ther. [Molecular Cancer Therapeutics] (2012) 11: 1488-99; Herrera-Abreu et al., Cancer Res. [Cancer Research] (2016) 76: 2301-2313). It is reported that cyclin E amplification also contributes to trastuzumab resistance in HER2+ breast cancer. (Scaltriti et al. Proc Natl Acad Sci. (2011) 108:3761-6). Cyclin E overexpression has also been reported to play a role in basal-like and triple-negative breast cancer (TNBC) as well as inflammatory breast cancer (Elsawaf Z. et al. Breast Care (2011) 6:273-278; Alexander A. et al. Oncotarget (2017) 8:14897-14911).

[0010] Amplification or overexpression of cyclin E1 (CCNE1) is also frequently found in ovarian cancer, gastric cancer, endometrial cancer, uterine cancer, bladder cancer, esophageal cancer, prostate cancer, lung cancer, and other types of cancer (Nakayama et al. Cancer (2010) 116:2621-34; Etemadmoghadam et al. Clin Cancer Res (2013) 19:5960-71; Au-Yeung et al. Clin. Cancer Res. (2017) 23:1862-1874; Ayhan et al. Modern Pathology (2017) 30:297-303; Ooi et al. Hum ...19:5960-71; Au-Yeung et al. Clin. Cancer Res. (2017) 19:5960-71; Ayhan et al. Modern Pathology (2017) 19:5960-71; Ooi et al. Hum Cancer Res (2013) 19:5960-71; Au-Yeung et al. Clin. Cancer Res. (2017) 19:5960-71; Au-Yeung et al. Clin. Cancer Res. (2017) 19:5960-71; Au-Yeung et al. Clin. Cancer Res. Pathol. [Human Pathology] (2017) 61: 58-67; Noske et al. Oncotarget [Tumor Target] (2017) 8: 14794-14805) and is often associated with poor clinical outcomes.

[0011] In some cancers, FBXW7 (SCF responsible for cyclin E degradation)Fbw7 Loss-of-function mutations in cyclin E (a component of the ubiquitin E3 ligase) also lead to overexpression of cyclin E and activation of CDK2. Alternatively, some cancer cells express overactive, truncated forms of cyclin E. In addition, amplification and overexpression of cyclin A have also been reported in various cancers such as hepatocellular carcinoma, colorectal cancer, and breast cancer.

[0012] In contrast to the frequent upregulation of cyclin E, the inhibitory regulators of CDK2, p21, and p27, are often aberrantly downregulated in cancer. It is hypothesized that loss or reduction of these key endogenous inhibitors results in hyperactivation and / or transient aberrant activation of CDK2, thereby promoting tumor growth.

[0013] In addition, CDC25A and CDC25B, the protein phosphatases responsible for dephosphorylation that activates CDK2, are overexpressed in various tumors. These different mechanisms of CDK2 activation have been validated using mouse cancer models. Furthermore, CDK2 / cyclin E phosphorylates oncogenic Myc to counteract ras-induced senescence, highlighting the importance of CDK2 in myc / ras-induced tumorigenesis. It has been shown that inactivation of CDK2 is synthetically lethal to cancer cells that overexpress Myc.

[0014] Recently, it was also shown that pharmacological inhibition or genetic deletion of CDK2 preserves hearing function in animal models treated with cisplatin or noise (Teitz T et al. J Exp Med. 2018 Apr 2;215(4):1187-1203). Mechanistically, inhibition of CDK2 kinase activity reduces cisplatin-induced production of mitochondrial reactive oxygen species, thereby improving the survival of inner ear cells. Therefore, in addition to anti-tumor therapy, CDK2 inhibition may also be used as a promising preventive treatment for noise-, cisplatin-, or antibiotic-induced or age-related hearing loss, for which no Food and Drug Administration-approved drugs are currently available.

[0015] Currently, there are a few CDK2 inhibitors in early clinical trials. For example, Denacilib (MK-7965), which inhibits CDK1, CDK2, CDK5, and CDK9, is in clinical development for solid tumors and blood cancers in combination with other agents; CYC065 (which effectively inhibits CDK2, CDK3, CDK4, CDK9 and moderately inhibits CDK1, CDK5, and CDK7) is currently being studied for the treatment of refractory CLL and other cancers; and PF-06873600 (which is a CDK2 inhibitor with activity against other CDKs) is currently undergoing clinical trials for the treatment of breast cancer as a single agent or in combination with endocrine therapy.

[0016] As an alternative to inhibition, removal of CDK2 protein will eliminate CDK2 activity as well as any protein interactions or scaffolding functions of CDK2. Therefore, there is a need for bifunctional molecules that can recruit CDK2 to ubiquitin ligases and thereby lead to CDK2 ubiquitination and proteasomal degradation. The present disclosure meets this need and related needs. Summary of the invention

[0017] In a first aspect, there is provided a compound having formula (I) or a pharmaceutically acceptable salt thereof:

[0018]

[0019] in:

[0020] The degron is an E3 ligase ligand selected from the group consisting of:

[0021] (a) a group having the formula (i):

[0022]

[0023] (b) a group having the formula (ii):

[0024]

[0025]

[0026] (c) a group having the formula (iii):

[0027]

[0028] (d) a group having the formula (iv):

[0029]

[0030] (e) a group having the formula (v):

[0031]

[0032] (v); and (f) a group having the formula (vi):

[0033]

[0034] in:

[0035] R x is hydrogen, alkyl, cycloalkyl or alkylcarbonyloxy;

[0036] Y a is CH or N;

[0037] Z ais a bond, -CH2-, -NH-, O or -NHC(O)-, wherein the NH of -NHC(O)- is attached to Y a ;

[0038] Ring A of the E3 ligase ligand of formula (i) is a group of formula (a), (b) or (c):

[0039]

[0040] in:

[0041] R aa , R bb , R cc and R dd independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano;

[0042] R 4 and R 5 are independently hydrogen or alkyl; or R 4 and R 5 Together with the carbon to which they are attached, form >C=O; and

[0043] R 6 is hydrogen or alkyl;

[0044] The ring B of the E3 ligase ligand of formula (ii) is a phenylene, a cycloamine, a 5-membered or 6-membered monocyclic heteroarylene or a 9-membered or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three nitrogen ring atoms and further wherein the phenylene, cycloamine and each heteroarylene are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano R ee and R ff replace; and

[0045] X 1 , X 2 , X 3 and X 4 are independently a bond, alkylene, -O-, -(O-alkylene)-, -(alkylene-O)-, -(NR gg -alkylene)-, -(alkylene-NR hh )-、 -NH-, -N(alkyl)-, -C(=O)-, -NR jj C(=O)- or -C(=O)NR kk -, where R gg , R hh , R jj and R kk are independently hydrogen, alkyl or cycloalkyl, and each alkylene group is optionally substituted with one or two fluorines;

[0046] R y is alkyl, hydroxyalkyl, cycloalkyl or heterocyclic, wherein the cycloalkyl and heterocyclic are selected from hydrogen, halogen, cyano, alkylcarbonyl and alkylcarbonylamino. a replace; and

[0047] W a is a bond, O, S or alkylene;

[0048] Hy is a cycloalkylene, arylene, heterocyclylene, bicyclic heterocyclylene, spiro heterocyclylene, bridged heterocyclylene or fused heterocyclylene, wherein each of the above rings is independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxyl and cyano. b , R c and R d replace;

[0049] R 1 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkylalkyl or heterocyclylalkyl, wherein aryl, by itself or as part of aralkyl, heteroaryl, by itself or as part of heteroaralkyl, cycloalkyl of cycloalkylalkyl and heterocyclyl of heterocyclylalkyl are independently selected from hydrogen, deuterium, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, halogen and hydroxyl. e , R f and R g replace;

[0050] R 2 is hydrogen, alkyl or haloalkyl;

[0051] R 3 is hydrogen, cyano, halogen, NH2, alkyl or haloalkyl, wherein alkyl and haloalkyl are optionally substituted with hydroxy, cyano, alkoxy, haloalkoxy, C(O)NH2 and -C(O)OH; and

[0052] L is -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -,in:

[0053] Z 1 is a bond, alkylene, -C(O)NR-, -NR'(CO)-, -S(O)2NR-, -NR'S(O)2-, -(O-alkylene) a -, -(alkylene-O) a-, phenylene, monocyclic heteroarylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy R h and R i replace;

[0054] Z 2 is a bond, alkylene, alkynylene, -C(O)-, -C(O)N(R)-, -NR'(CO)-, -(O-alkylene) b -, -(alkylene-O) b -, -O(CH2)7-, -O(CH2)8-, cycloalkylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy R j and R k replace;

[0055] Z 3 is a bond, alkylene, alkynylene, -C(O)NR-, -NR'(CO)-, -O-, -NR"-, -(O-alkylene) c -, -(alkylene-O) c -, cycloalkylene, spirocycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, spiro heterocyclylene, or 11- to 13-membered spiro heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, and haloalkoxy R m and R n replace;

[0056] Z 4 is a bond, alkylene, alkynylene, -(alkylene-NR")-, -O-, -C(O)-, -NR"-, -(O-alkylene) d -, -(alkylene-O) d -, cycloalkylene, spirocycloalkylene, phenylene, heteroarylene, heterocyclylene, fused heterocyclylene, bridged heterocyclylene or spiro heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxyl, amino, alkylamino and dialkylamino R o and R p replace;

[0057] Z 5 is a bond, -alkylene, -NR"-, -O-, -C(O)-, -S(O)2-, -NR'(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. q and R rReplace, and

[0058] Z 6 is a bond, alkylene, -NR"-, -O-, -(alkylene-O)-, -C(O)-, -S(O)2-, -NR'(CO)-, or -C(O)NR-;

[0059] wherein each R, R' and R" is independently hydrogen or alkyl, each a, b, c and d is independently an integer selected from 1 to 6, and -Z 1 -、-Z 2 -、-Z 3 -、-Z 4 -、-Z 5 -and-Z 6 Each alkylene group in - is replaced by R s and R t Substitution, where R s is hydrogen or deuterium and R t is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl or monocyclic heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano; provided that -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -At least one of them is not a key.

[0060] Typically, compounds of formula (I) selectively inhibit CDK2 relative to CDK1. Thus, in a second aspect, a method of treating a disease mediated by CDK2 in a patient (preferably a patient in need of such treatment) is provided, the method comprising administering to the patient (preferably a patient in need of such treatment) a therapeutically effective amount of a compound of formula (I) (or any embodiment thereof as described herein) or a pharmaceutically acceptable salt thereof. In a first embodiment of the second aspect, the disease is cancer. In a second sub-embodiment of the second aspect, the disease is a cancer selected from the group consisting of lung cancer (e.g., adenocarcinoma, small cell lung cancer and / or non-small cell lung cancer, small cell carcinoma and non-small cell carcinoma, bronchial carcinoma, bronchial adenoma, 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 intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, stomach 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 cholangiocarcinoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., pancreatic exocrine cancer), gastric cancer, thyroid cancer and parathyroid cancer. In a third embodiment of the second aspect, the cancers are those that are resistant to CDK4 / 6 inhibitors through a CDK2-mediated mechanism. In a fourth embodiment of the second aspect, the therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition.

[0061] In a third aspect, a method of treating noise, cisplatin, or antibiotic-induced or age-related hearing loss is provided, the method 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 of its embodiments described herein) or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of hearing loss is reduced when compared to an age-matched control. In some embodiments, hearing loss is prevented when compared to an age-matched control.

[0062] In a fourth aspect, a pharmaceutical composition is provided, comprising a compound of formula (I) (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0063] In a fifth aspect, a compound of formula (I) (or any embodiment thereof as described herein) or a pharmaceutically acceptable salt thereof is provided for use as a medicine. In one embodiment, a compound of formula (I) (and any embodiment thereof as described herein) or a pharmaceutically acceptable salt thereof can be used to treat one or more diseases disclosed in the above-mentioned second aspect.

[0064] In a sixth aspect, there is provided a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof (and any embodiment thereof disclosed herein) in the manufacture of a medicament for treating a disease in a patient, wherein the activity of CDK2 contributes to the pathology and / or symptoms of the disease. In one embodiment, the disease is one or more of the diseases disclosed in the second aspect above.

[0065] In a seventh aspect, a method for degrading CDK2 via a ubiquitin proteasome pathway is provided, the method comprising contacting CDK2 with a compound of formula (I) (or any embodiment thereof as described herein) or a pharmaceutically acceptable salt thereof; or contacting CDK2 with a pharmaceutical composition comprising a compound of formula (I) (or any embodiment thereof as described herein) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In some or any embodiments, CDK2 is degraded in a cell or in a patient.

[0066] In the above aspects relating to the treatment of cancer, further embodiments are provided, including administering a compound of formula (I) or a pharmaceutically acceptable salt thereof (or any embodiment thereof disclosed herein) in combination with at least one additional anticancer agent. When a combination therapy is used, these agents may be administered simultaneously or sequentially. DETAILED DESCRIPTION

[0067] definition:

[0068] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this application and have the following meanings:

[0069] "Alkyl" means a straight chain saturated monovalent hydrocarbon group having one to six carbon atoms or a branched chain saturated monovalent hydrocarbon group having three to six carbon atoms, for example, methyl, ethyl, propyl, 2-propyl, butyl, pentyl and the like.

[0070] "Alkylcarbonyloxy" means -OR z Group, where R z is alkylcarbonyl as defined herein.

[0071] Unless otherwise specified, "alkylene" means a straight-chain saturated divalent hydrocarbon group having one to six carbon atoms or a branched-chain saturated divalent hydrocarbon group having three to six carbon atoms, for example, methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[0072] "Alkyne" means a straight-chain unsaturated divalent hydrocarbon group having two to six carbon atoms or a branched-chain saturated divalent hydrocarbon group having three to six carbon atoms containing a triple bond, for example, wait.

[0073] "Alkylsulfonyl" means -SO2R z Group (where R z is alkyl as defined above), for example methylsulfonyl, ethylsulfonyl, and the like.

[0074] "Alkylthio" means -SR z Group (where R z is alkyl as defined above), for example methylthio, ethylthio, and the like.

[0075] "Alkoxy" means -OR z Group (where R z is alkyl as defined above), for example, methoxy, ethoxy, propoxy or 2-propoxy, n-butoxy, isobutoxy or tert-butoxy, and the like.

[0076] "Alkoxyalkyl" means a straight chain monovalent hydrocarbon radical having one to six carbon atoms or a branched monovalent hydrocarbon radical having three to six carbon atoms substituted with at least one alkoxy radical as defined above (e.g., one or two alkoxy radicals), for example, 2-methoxyethyl, 1-, 2- or 3-methoxypropyl, 2-ethoxyethyl, and the like.

[0077] "Alkylcarbonyl" means -C(O)OR z Group (where R z is alkyl as defined above), for example, methoxycarbonyl, ethoxycarbonyl, and the like.

[0078] "Alkylcarbonylamino" means -NR z 'C(O)R z Group (where R z is an alkyl group as defined above, and R z ' is H or alkyl as defined above), for example, methylcarbonylamino, ethylcarbonylamino, and the like.

[0079] "Acyl" means -C(O)R z Group (where R z is alkyl, haloalkyl, cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl or optionally substituted heterocyclyl as defined herein, for example, methylcarbonyl, ethylcarbonyl, benzoyl, trifluoromethylcarbonyl, cyclopropylcarbonyl, etc. When R z When an alkyl group, an acyl group is also referred to herein as an "alkylcarbonyl group."

[0080] "Amino" means -NH2.

[0081] "Alkylamino" means -NHR z Group (where R z is alkyl as defined above), for example, methylamino, ethylamino, propylamino, and the like.

[0082] "Aminoalkyl" refers to z 'R z "substituted linear monovalent hydrocarbon radical having one to six carbon atoms or branched monovalent hydrocarbon radical having three to six carbon atoms, wherein R z ' and R z " is independently hydrogen, alkyl, deuterated alkyl, cycloalkyl, cycloalkylalkyl (wherein cycloalkyl and the cycloalkyl ring in cycloalkylalkyl are optionally substituted with one, two or three substituents independently selected from alkyl, hydroxyalkyl, haloalkyl, halogen, hydroxy, alkoxy, -NH2, alkylamino, dialkylamino and cyano), hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, alkylcarbonyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, each as defined herein, e.g., aminomethyl, aminoethyl, methylaminomethyl, and the like.

[0083] "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 ring atoms, for example, phenyl or naphthyl.

[0084] "Arylene" means a divalent aromatic radical (as defined above), for example, phenylene or naphthylene.

[0085] "Aralkyl" means -(alkylene)-R z Group, where R z is an aryl group as defined above. Examples include, but are not limited to, benzyl, phenethyl, and the like.

[0086] Unless otherwise specified, "bicyclic heterocyclylene" means a saturated or unsaturated divalent fused bicyclic radical having 9 to 12 ring atoms, wherein one, two or three of the ring atoms are independently selected from N, O and S(O). n (wherein n is an integer selected from 0 to 2 (including end values)) heteroatoms, and the remaining ring atoms are carbon. In addition, one or two ring carbon atoms of the bicyclic heterocyclylene ring can be optionally replaced by -CO-groups. More specifically, the term bicyclic heterocyclylene includes but is not limited to hexahydrofuran [3,2-b] furan -3,6- diyl etc. When the heterocyclylene ring is unsaturated, it can contain one or two ring double bonds, provided that the ring is not aromatic.

[0087] "Bridged heterocyclylene" means a saturated divalent bicyclic ring having 5 to 7 ring carbon atoms (not including the atoms in the bridging group) in which two non-adjacent ring atoms are connected by (CR z R z ') n A group (also referred to herein as a "bridging" group) is connected, wherein n is an integer selected from 1 to 3 (including the end value) and R z and R z' is independently H or methyl, and further, one or two of the ring carbon atoms (including atoms in the bridging group) are selected from N, O and S(O) n (wherein n is an integer selected from 0 to 2 (including end values)) heteroatom replacement. Unless otherwise indicated, the bridged heterocyclylene group is optionally substituted by one or two substituents independently selected from alkyl, halogen, alkoxy, hydroxyl and cyano. Examples include, but are not limited to, 3,8-diazabicyclo[3.2.1]octan-3,8-diyl, etc.

[0088] "Cycloalkyl" means a monocyclic saturated monovalent hydrocarbon group having three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0089] "Cycloalkylalkyl" means an -(alkylene)-R z Group, where R z is a cycloalkyl group as defined above. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

[0090] The "cycloalkylene group" means a divalent saturated hydrocarbon group having three to six carbon atoms, and further examples thereof include 1,1-cyclopropylene, 1,1-cyclobutylene, 1,4-cyclohexylene and the like.

[0091] "Cyanoalkyl" means a straight-chain monovalent hydrocarbon group having one to six carbon atoms or a branched monovalent hydrocarbon group having three to six carbon atoms substituted with a cyano group, for example, cyanomethyl, cyanoethyl, and the like.

[0092] "Carboxy" means -COOH.

[0093] "Cycloamino" means a saturated divalent monocyclic ring having 4 to 8 ring atoms, wherein one ring atom is nitrogen and the remaining ring atoms are carbon. More specifically, the term cycloamino includes, but is not limited to, pyrrolidinylene, piperidinylene, homopiperidinylene, and the like.

[0094] Deuterium means 2 H or D.

[0095] "Deuterated alkyl" means an alkyl group as defined above which is substituted with one, two or three deuteriums.

[0096] "Dialkylamino" means -NR z’ R z’ Group, where R z’ and R z” is an alkyl group as defined above, for example, dimethylamino, diethylamino, methylpropylamino and the like.

[0097] As used herein, "fused heterocyclylene" refers to a divalent bicyclic ring in which two adjacent ring atoms of a saturated monocyclic ring having 4 to 7 ring atoms, one or two heteroatoms independently selected from N, O and S(O)n (wherein n is 0, 1 or 2) and the remaining ring atoms are carbon are fused to two adjacent ring members of a phenyl or a five-membered or six-membered heteroaryl (each as defined herein), unless otherwise indicated. The nitrogen atom is optionally oxidized or quaternized. The fused heterocyclylene may be attached to any two atoms of the ring. Representative examples include, but are not limited to, 1,2,3,4-tetrahydroquinoline-1,4-diyl, 3,4-dihydro-2H-benzo[b][1,4]oxazine-5,8-diyl, etc.

[0098] "Halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0099] "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, for example, -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc. When an alkyl group is substituted only with fluorine, it may be referred to as a fluoroalkyl group in this application.

[0100] "Haloalkoxy" means -OR z Group (where R z is a haloalkyl group as defined above), for example, -OCF3, -OCHF2, etc. z When it is a haloalkyl group, wherein the alkyl group is substituted only with fluorine (in some instances, one or more fluorines), it is referred to herein as a fluoroalkoxy group.

[0101] "Haloalkoxyalkyl" means -(alkylene)OR z Group (where R z is a haloalkyl group as defined above), for example, trifluoromethoxyalkyl and the like.

[0102] "Hydroxyalkyl" means a linear monovalent hydrocarbon radical having one to six carbon atoms or a branched monovalent hydrocarbon radical having three to six carbon atoms substituted with one or two hydroxyl groups, provided that if two hydroxyl groups are present, they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-(hydroxymethyl)-2-hydroxyethyl.

[0103] 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) ring atoms are heteroatoms selected from N, 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, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 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 a monocyclic ring, it is also referred to herein as a 5-yuan or 6-yuan monocyclic heteroaryl or monocyclic heteroaryl. 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- or 10-membered fused bicyclic heteroaryl.

[0104] "Heteroarylene" means a divalent heteroaryl group as defined above, unless otherwise indicated. Representative examples include, but are not limited to, benzimidazole diyl, for example, benzimidazole-1,5-diyl, etc. When the heteroarylene ring contains 5 or 6 ring atoms and is a monocyclic ring, it is also referred to herein as a monocyclic heteroarylene or a 5-membered or 6-membered monocyclic heteroarylene, for example, pyrazolyl-1,4-diyl. When the heteroarylene 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 heteroarylene.

[0105] "Heteroaralkyl" refers to an -(alkylene)-R z Group (where R z is a heteroaryl as defined above), for example, pyridylmethyl, etc. When the heteroaryl ring in the heteroaralkyl contains 5 or 6 ring atoms, it is also referred to herein as a 5-membered or 6-membered heteroaralkyl or a monocyclic heteroaralkyl.

[0106] Unless otherwise specified, "heterocyclyl" means a saturated or unsaturated monovalent monocyclic group having 4 to 8 ring atoms, wherein one or two ring atoms are independently selected from N, O and S(O). n (wherein n is an integer selected from 0 to 2 (including end values)) heteroatoms, and the remaining ring atoms are C. In addition, one or two ring carbon atoms in the heterocyclic ring can be optionally replaced by-CO-groups. More particularly, the term heterocyclic includes but is not limited to pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl, piperazinyl, tetrahydro-pyranyl, thiomorpholinyl etc. When the heterocyclic ring is unsaturated, it can contain one or two ring double bonds, provided that the ring is not aromatic. When the heterocyclic group contains at least one nitrogen-atoms, it is also referred to as heterocyclic amino in this article and it is a subset of the heterocyclic group.

[0107] "Heterocyclylalkyl" or "heterocycloalkyl" refers to an -(alkylene)-R z Base (where R z is a heterocyclyl ring as defined above), for example tetrahydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.

[0108] Unless otherwise specified, "heterocyclylene" means a saturated divalent monocyclic radical having 4 to 6 ring atoms, wherein one or two of the ring atoms are independently selected from N, O and S(O). n (wherein n is an integer selected from 0 to 2 (including the end value)) heteroatom, and the remaining ring atoms are C. In addition, one or two ring carbon atoms of the heterocyclylene group may be optionally substituted by a -CO- group. More specifically, the term heterocyclylene includes but is not limited to Piperidine-1,4-diyl, azetidine-1,3-diyl, and the like.

[0109] "Phenylene" refers to a divalent phenyl group.

[0110] The term "oxo," as used herein, alone or in combination, refers to =(O).

[0111] "Optionally substituted aryl" means an aryl as defined above optionally substituted by one, two or three substituents, which are independently selected from alkyl, hydroxyl, cycloalkyl, carboxyl, alkoxycarbonyl, hydroxyl, alkoxy, alkylthio, alkylsulfonyl, amino, alkylamino, dialkylamino, halogen, haloalkyl, haloalkoxy and cyano. In some embodiments, the optionally substituted aryl is an optionally substituted phenyl.

[0112] "Optionally substituted heteroaryl" means a heteroaryl as defined above optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alkylthio, alkylsulfonyl, hydroxy, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino and cyano.

[0113] Unless otherwise indicated, "optionally substituted heterocyclyl" means a heterocyclyl as defined above optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alkylthio, alkylsulfonyl, alkylcarbonyl, hydroxy, cycloalkyl, cycloalkylalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, cyanoalkyl, halogen, haloalkyl, haloalkoxy and cyano.

[0114] 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 the event or circumstance does not occur. For example, the phrase "heteroaryl optionally substituted with alkyl" is intended to encompass heteroaryl groups that are not substituted with alkyl groups and heteroaryl groups that are substituted with alkyl groups.

[0115] "Spirocycloalkylene" means a saturated bicyclic divalent hydrocarbon ring with 6 to 12 ring atoms, wherein the rings are connected by only one atom, which is also called a spiro atom, most commonly a quaternary carbon ("spiro carbon"). Unless otherwise indicated, spirocycloalkylene is optionally substituted by one or two substituents independently selected from alkyl, halogen, alkoxy, hydroxyl and cyano. Representative examples include, but are not limited to, spiro [3,5] nonane diyl, for example, spiro [3.5] nonane-2,7-diyl, etc.

[0116] "Spiroheterocyclylene" means a saturated divalent bicyclic ring having 6 to 10 ring atoms, wherein one, two or three of the ring atoms are selected from N, O and S(O). n (wherein n is an integer selected from 0 to 2 (including end values)), 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 indicated, spiroheterocyclylene is optionally substituted by one or two substituents independently selected from alkyl, halogen, alkoxy, hydroxyl and cyano.

[0117] "11- to 13-membered spiroheterocyclylene" means a saturated divalent bicyclic ring having 11 to 13 ring atoms, wherein one, two or three of the ring atoms are selected from N, O and S(O). n (wherein n is an integer selected from 0 to 2 (including end values)) one or more heteroatoms, the remaining ring atoms are C, and these rings are connected by only one atom, the connecting atom is also called a spiro atom, most commonly a quaternary carbon ("spiro carbon"). Unless otherwise indicated, 11 to 13 yuan of spiro heterocyclyl groups are optionally substituted by one or two substituents independently selected from alkyl, halogen, alkoxy, hydroxyl and cyano. Representative examples include, but are not limited to, diazaspiro [5.5] undecane-diyl, 1-oxa-diazaspiro [5.5] undecane-diyl, etc.

[0118] The disclosure also includes protected derivatives of compounds with formula (I). For example, when compounds with formula (I) contain groups (such as hydroxyl, carboxyl or any group containing one or more nitrogen atoms), these groups may be protected by suitable protecting groups. A complete list of suitable protecting groups can be found in the following literature: TW Greene, Protective Groups in Organic Synthesis [protective groups in organic synthesis], 5th edition, John Wiley & Sons, Inc. [John Wiley & Sons Publishing Company] (2014), the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds disclosed herein can be prepared by methods well known in the art.

[0119] The present disclosure also includes polymorphic forms and deuterated forms of the compounds of Formula (I) or pharmaceutically acceptable salts thereof.

[0120] The term "prodrug" refers to a compound that becomes more active in vivo. Certain compounds of formula (I) may also exist as prodrugs, as described in the following literature: 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 compounds that readily undergo chemical changes under physiological conditions to provide active compounds. Prodrugs are often useful because they are easier to administer than the compound or parent drug in some cases. For example, they can be bioavailable by oral administration, while the parent drug cannot. Various prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example of a prodrug (without limitation) would be a compound that is administered as an ester ("prodrug"), but then metabolically hydrolyzed to a carboxylic acid (the active entity). Additional examples include peptidyl derivatives of the compounds.

[0121] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include:

[0122] Acid addition salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.); or acid addition salts formed 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-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptanoic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.); or

[0123] When the acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion); or a salt formed by coordination with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.). It should be understood that pharmaceutically acceptable salts are non-toxic. Additional information about suitable pharmaceutically acceptable salts can be found in the following literature: Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pennsylvania, 1985, which is incorporated herein by reference in its entirety.

[0124] Compounds with formula (I) may have asymmetric centers. Compounds with formula (I) containing asymmetrically substituted atoms may be separated in optically active forms or racemic forms. Individual stereoisomers of compounds may be prepared by synthesizing from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products and then separating (e.g., converting into a mixture of diastereoisomers and then separating or recrystallizing, chromatographic techniques, directly separating enantiomers on a chiral chromatographic column, or any other appropriate method known in the art). Unless specific stereochemical forms or isomeric forms are specifically indicated, all chiral forms, diastereomeric forms, all mixtures of chiral or diastereomeric forms, and racemic forms are within the scope of this disclosure. It will also be appreciated by those of ordinary skill in the art that when a compound is represented as a (R) stereoisomer, it may contain a corresponding (S) stereoisomer as an impurity, and vice versa.

[0125] Some compounds with formula (I) can exist as tautomers and / or geometric isomers. All possible tautomers and cis and trans isomers (as separate forms and mixtures thereof) are within the scope of this disclosure. In addition, as used herein, although only a few examples are listed, the term alkyl includes all possible isomeric forms of the alkyl group. In addition, when these cyclic groups (such as aryl) are substituted, although only a few examples are listed, it includes all positional isomers. In addition, all hydrates of compounds with formula (I) are within the scope of this disclosure.

[0126] Compounds of formula (I) may also contain unnatural amounts of isotopes on one or more atoms that make up such compounds. An unnatural amount of an isotope may be defined as an amount 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 may be incorporated into compounds of the present disclosure, such as compounds of formula (I) (and any of its embodiments disclosed herein, including specific compounds), include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as, respectively. 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 32 P. 33 P. 35 S. 18 F. 36 Cl, 123 I and 125 1. Isotope-labeled compounds (e.g., 3 H and 14 C-labeled compounds) can be used in compound or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful because of their ease of preparation and detectability. In addition, heavier isotopes such as deuterium (i.e., 2 H) substitution (or isotopic enrichment) 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 compounds of formula (I) (including those in Table 1 or Table 1a below), one or more hydrogen atoms are replaced by 2 H or 3 H is replaced, or one or more carbon atoms are 13 C- or 14C-enriched carbon substitution. Positron emitting isotopes (such as 15 O. 13 N. 11 C and 15 F) can be used in positron emission tomography (PET) studies to examine substrate 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.

[0127] "Pharmaceutically acceptable carrier or excipient" means a carrier or excipient useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes carriers or excipients that are acceptable for veterinary as well as human pharmaceutical use.

[0128] As used in the specification and claims, "pharmaceutically acceptable carrier / excipient" includes both one and more than one such excipient.

[0129] As used herein, the term "about" is intended to qualify the numerical value it modifies, indicating that this value is a variable within the error limit. 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 covering ±10%, preferably ±5%, including the listed values ​​and ranges.

[0130] In formula (I), X 1 , X 2 , X 3 and X 4 In the definition of , the phrase "alkylene optionally substituted by one or two fluorines" (and similar phrases used to define other groups in formula (I)) is intended to encompass unsubstituted alkylene as well as alkylene substituted by one or two fluorines.

[0131] Certain structures provided herein are drawn with one or more floating substituents. Unless otherwise provided or otherwise clear from the context, one or more substituents may be present on any atom of the ring to which they are attached, where chemically feasible and permitted by the rules of valence. For example, in the structure: R aa Substituent R aa , R bb and X 1 , and similarly R bb and X 1 A substituent may replace any hydrogen of a CH that has not been replaced by an R bb and X 1 , and relative to R bb and X 1 Similarly Raa and X 1 and R aa and X bb The substituents substituted a portion of the benzo portion of the bicyclic ring.

[0132] Additionally, as used throughout the 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 divalent group,

[0133]

[0134] (a), (b) and (c) on the left The key is attached to the following rings:

[0135]

[0136] And the right side of (a), (b) and (c) (i.e. X 1 , X 2 and X 3 ) is attached to Z of L having the following structure 1 :

[0137]

[0138] Similarly, for L, i.e. -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -, the left side of L (i.e. Z 1 ) attached to X 1 , X 2 , X 3 or X 4 And Z 6 Attached to the atom of Hy. For example, when L is a group having the formula:

[0139]

[0140] And the degron is a group having formula (a), namely When the left bond of L (i.e. -NH- group) is attached to X 1 And the right bond of L (i.e. -SO2-) is attached to Hy of atoms, as indicated below.

[0141] The term "disease" as used herein is intended to be generally synonymous and may be 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 or that impairs its normal functioning, typically manifests itself by distinctive signs and symptoms, and causes the human or animal to have a reduced life span or quality of life.

[0142] The term "combination therapy" means the administration of two or more therapeutic agents to treat the diseases or disorders described in the present disclosure. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as administration in a single capsule with a fixed ratio of active ingredients or administration 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.

[0143] 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.

[0144] “Treating” or “treatment” illnesses include:

[0145] (1) preventing the disease, that is, causing clinical symptoms of the disease to not develop in a mammal that may be exposed to or susceptible to the disease but does not yet experience or display symptoms of the disease;

[0146] (2) inhibit the disease, that is, delay, arrest or reduce the development or severity of the disease or its clinical symptoms; or

[0147] (3) Alleviate the disease, that is, cause the disease or its clinical symptoms to subside.

[0148] 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 alleviating the disease, i.e., causing regression of the disease or its clinical symptoms.

[0149] "Therapeutically effective amount" means the amount of the disclosed compound and / or its pharmaceutically acceptable salt that, when administered to a patient for treating a disease, is sufficient to affect such treatment of the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal to be treated.

[0150] The terms "inhibit" and "reduce" or any variants of these terms in relation to CDK2 and / or CDK1 include any measurable reduction or complete inhibition to achieve the desired result. For example, reduction can be compared to normal activity, CDK2 and / or CDK1 activity is reduced 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, or any range derivable therein.

[0151] The representative compounds prepared are disclosed in the following Compound Table 1:

[0152] Compound Table 1

[0153]

[0154] Contemplated compounds of formula (I) are disclosed in Table 1a below:

[0155] Table 1a

[0156]

[0157]

[0158]

[0159] Example:

[0160] In embodiments A1 to A152, the disclosure includes:

[0161] A1. In embodiment A1, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in the first aspect of the present invention is provided.

[0162] A2. In embodiment A2, the compound as described in embodiment A1 or a pharmaceutically acceptable salt thereof is wherein R 1 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl.

[0163] A3. In embodiment A3, the compound as described in embodiment A1 or a pharmaceutically acceptable salt thereof is wherein R 1 is aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkylalkyl or heterocyclylalkyl, wherein aryl, by itself or as part of aralkyl, heteroaryl, by itself or as part of heteroaralkyl, cycloalkyl of cycloalkylalkyl and heterocyclyl of heterocyclylalkyl are replaced by R e , R f and R g replace.

[0164] A4a. In Embodiment A4a, the compound or pharmaceutically acceptable salt thereof as described in Embodiment A1 or A2 is wherein R 1 It is an alkyl group.

[0165] A4. In embodiment A4, the compound or pharmaceutically acceptable salt thereof as described in embodiments A1, A2 and A4a is wherein R 1 It is methyl, ethyl, propyl (including isopropyl) or butyl.

[0166] A5a. In embodiment A5a, the compound as described in embodiment A1 or A2 or a pharmaceutically acceptable salt thereof is wherein R 1 It is a halogenated alkyl group.

[0167] A5. In Embodiment A5, the compound or pharmaceutically acceptable salt thereof as described in Embodiment A1, A2 or A5a is wherein R 1 It is 2,2-difluoroethyl or 2,2,2-trifluoroethyl.

[0168] A6a. In embodiment A6a, the compound as described in embodiment A1 or A2 or a pharmaceutically acceptable salt thereof is wherein R 1 It is a hydroxyalkyl group.

[0169] A6. In embodiment A6, the compound as described in embodiment A1 or A2 or a pharmaceutically acceptable salt thereof is wherein R 1 It is hydroxymethyl or hydroxyethyl.

[0170] A7a. In Embodiment A7a, the compound as described in Embodiment A1 or A2 or a pharmaceutically acceptable salt thereof is wherein R 1 It is an alkoxyalkyl group.

[0171] A7. In embodiment A7, the compound as described in embodiment A1 or A2 or a pharmaceutically acceptable salt thereof is wherein R 1 It is methoxymethyl or methoxyethyl.

[0172] A8. In embodiment A8, the compound as described in embodiment A1 or A2 or a pharmaceutically acceptable salt thereof is wherein R 1 It is an aminoalkyl group.

[0173] A9. In embodiment A9, the compound as described in embodiment A1 or A3 or a pharmaceutically acceptable salt thereof is wherein R 1 For R e , R f and R g Substituted phenyl.

[0174] A10. In embodiment A10, the compound or pharmaceutically acceptable salt thereof as described in embodiment A1 or A3 is wherein R 1 For R e , R f and R g Substituted heteroaryl.

[0175] A11. In embodiment A11, the compound or pharmaceutically acceptable salt thereof as described in embodiment A1 or A3 is wherein R 1 For R e , R f and R g Substituted pyridinyl.

[0176] A12a. In embodiment A12a, the compound as described in embodiment A1 or A3 or a pharmaceutically acceptable salt thereof is wherein R 1 For R e , R f and R g Substituted aralkyl.

[0177] A12. In embodiment A12, the compound or pharmaceutically acceptable salt thereof as described in embodiment A1 or A3 is wherein R 1 For R e , R f and R g Substituted benzyl.

[0178] A13. In embodiment A13, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1, A3 and A10 to A12 is wherein R 1 For R e , R f and R g Substituted heteroaralkyl.

[0179] A14. In embodiment A14, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 or A3 is wherein R 1 For R e , R f and R g Substituted cycloalkylalkyl.

[0180] A15a. In embodiment A15a, the compound or pharmaceutically acceptable salt thereof as described in embodiment A1 or A3 is wherein R 1 For R e , R f and R g Substituted heterocyclylalkyl.

[0181] A15. In embodiment A15, the compound or pharmaceutically acceptable salt thereof as described in embodiment A1 or A3 is wherein R 1 It is an oxetanylmethyl group.

[0182] A16. In embodiment A16, the compound as described in embodiment A1 or A2 or a pharmaceutically acceptable salt thereof is wherein R 1 It is methyl, ethyl, isopropyl or 2,2,2-trifluoroethyl.

[0183] A17. In embodiment A17, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A16 is wherein R 3 is hydrogen, cyano, halogen, haloalkyl or alkyl optionally substituted by hydroxy.

[0184] A18. In embodiment A18, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A17 is wherein R 3 It is hydrogen, cyano, fluorine, chlorine, difluoromethyl, trifluoromethyl, methyl or hydroxymethyl.

[0185] A19. In embodiment A19, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A18 is wherein R 3 For hydrogen.

[0186] A20a. In embodiment A20a, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A17 is wherein R 3 It is a halogenated alkyl group.

[0187] A20. In embodiment A20, the compound as described in embodiment A20a or a pharmaceutically acceptable salt thereof is wherein R 3 It is difluoromethyl.

[0188] A21. In embodiment A21, the compound as described in embodiment A17 or a pharmaceutically acceptable salt thereof is wherein R 3 It is an alkyl group.

[0189] A22a. In embodiment A22a, the compound as described in any one of embodiments A1 to A17 or a pharmaceutically acceptable salt thereof, wherein R 3 It is an alkyl group substituted by a hydroxy group.

[0190] A22. In embodiment A22, the compound as described in embodiment A22a or a pharmaceutically acceptable salt thereof is wherein R 3 It is hydroxymethyl.

[0191] A23a. In embodiment A23a, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A17 is wherein R 3 It is a halogen.

[0192] A23. In embodiment A23, the compound as described in embodiment A23a or a pharmaceutically acceptable salt thereof is wherein R 3 It is fluorine or chlorine.

[0193] A24. In embodiment A24, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A17, wherein R 3 It is cyano.

[0194] A25. In embodiment A25, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A24, wherein R 2 For hydrogen.

[0195] A26. In embodiment A26, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A25 is wherein Hy is heterocyclylene, phenylene or spiroheterocyclylene or cycloalkylene, wherein each of the above rings is replaced by R b , R c and R d Substitution, where R b and R c are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy and hydroxy, and R d For hydrogen.

[0196] A27. In embodiment A27, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A26 is wherein Hy is R b , R c and R d A substituted heterocyclylene group, wherein R b and R c are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy and hydroxy, and R d For hydrogen.

[0197] A28. In embodiment A28, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A27 is wherein Hy is R b , R c and R d Substituted pyrrolidine-1,3-diyl or piperidine-1,4-diyl, wherein R b and R c are independently hydrogen, deuterium, methyl, fluorine, methoxy or hydroxy, R dis hydrogen, and L is attached to the nitrogen atom of the piperidine-1,4-diyl or pyrrolidine-1,3-diyl ring of Hy.

[0198] A29. In embodiment A29, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A28, wherein Hy is:

[0199]

[0200] wherein the N atom of the pyrrolidine-1,3-diyl or piperidine-1,4-diyl ring is attached to L.

[0201] A30. In embodiment A30, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A29, wherein Hy is:

[0202]

[0203] wherein the N atom of the pyrrolidine-1,3-diyl or piperidine-1,4-diyl ring is attached to L.

[0204] A30a. In embodiment A30a, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A29, wherein Hy is:

[0205]

[0206] wherein the N atom of the piperidine-1,4-diyl ring is attached to L.

[0207] A31. In embodiment A31, the compound as described in any one of embodiments A1 to A25, or a pharmaceutically acceptable salt thereof, is wherein Hy is R independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxyl and cyano. b , R c and R d In a subembodiment of embodiment A31, the compound is wherein Hy is a ring having the formula:

[0208]

[0209] wherein X is CH or N and forms a bond with L; Y is CH, CMe or N; provided that at least one of X and Y is N; z is 0, 1 or 2; z' is 0 or 1; provided that at least one of z' and z is 1; and Hy is independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy and hydroxyl. b , R c and R d replace.

[0210] A32. In embodiment A32, the compound as described in embodiment A31, or a pharmaceutically acceptable salt thereof, is wherein X is N and Y is CH.

[0211] A33. In embodiment A33, the compound as described in embodiment A31, or a pharmaceutically acceptable salt thereof, is wherein Y is N and X is CH.

[0212] A34. In embodiment A34, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A26 is wherein Hy is R b , R c and R d Substituted cycloalkylene, wherein R b is deuterium, methyl, fluorine, methoxy or hydroxyl, and R c and R d For hydrogen.

[0213] A35. In embodiment A35, the compound as described in embodiment A34 or a pharmaceutically acceptable salt thereof is wherein Hy is cyclohexylene.

[0214] A36. In embodiment A36, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A26, A34 and A35 is wherein Hy is in represents a bond to NH and Indicates the key of L.

[0215] A37. In embodiment A37, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A26 is wherein Hy is R b , R c and R d Substituted phenylene, wherein R b and R c are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy and hydroxy, and R d For hydrogen.

[0216] A38. In embodiment A38, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A26 is wherein Hy is R b , R c and R d Substituted spiroheterocyclylene, wherein R b and R c are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy and hydroxy, and R d For hydrogen.

[0217] A39. In embodiment A39, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A25 is wherein Hy is R b , R c and R d A substituted bridged heterocyclylene group, wherein R b and R c are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy and hydroxy, and R d For hydrogen.

[0218] A39a1. In embodiment A39a1, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A25 is wherein Hy is R b , R c and R d A substituted fused heterocyclylene group, wherein R b and R c are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy and hydroxy, and R d For hydrogen.

[0219] A39a. In embodiment A39a, the compound of any one of embodiments A1 to A39a1, or a pharmaceutically acceptable salt thereof, is wherein the degron is an E3 ligase ligand of formula (i) or (ii).

[0220] A40. In embodiment A40, the compound of any one of embodiments A1 to A39a, or a pharmaceutically acceptable salt thereof, is wherein the degron is an E3 ligase ligand having formula (i):

[0221]

[0222] A41. In embodiment A41, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A40, wherein ring A of the E3 ligase ligand of formula (i) is a group of formula (a):

[0223]

[0224] A42. In embodiment A42, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A41 is wherein R 4 and R 5 are independently hydrogen or alkyl.

[0225] A43. In embodiment A43, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A42 is wherein R 4 and R 5 Each is hydrogen.

[0226] A44. In embodiment A44, the compound as described in any one of embodiments A1 to 42 or a pharmaceutically acceptable salt thereof is wherein R 4 is hydrogen and R 5 It is methyl.

[0227] A45. In embodiment A45, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A41 is wherein R 4 and R 5 Together with the carbon to which they are attached they form >C=O.

[0228] A46. In embodiment A46, the compound of any one of embodiments A1 to A40, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ligase ligand of formula (i) is a group of formula (b):

[0229]

[0230] A47. In embodiment A47, the compound as described in any one of embodiments A1 to A40 and A46, or a pharmaceutically acceptable salt thereof, is wherein R 6 For hydrogen.

[0231] A48. In embodiment A48, the compound as described in any one of embodiments A1 to A40 and A46, or a pharmaceutically acceptable salt thereof, is wherein R 6 It is an alkyl group.

[0232] A48a. In embodiment A48a, the compound as described in any one of embodiments A1 to A40, A46 and A48, or a pharmaceutically acceptable salt thereof, is wherein R 6 It is methyl.

[0233] A49. In embodiment A49, the compound of any one of embodiments A1 to A40, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ligase ligand of formula (i) is a group of formula (c):

[0234]

[0235] A50. In embodiment A50, the compound of any one of embodiments A1 to A48a, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ligase ligand of formula (i) is:

[0236]

[0237] A51. In embodiment A51, the compound of any one of embodiments A1 to A48a and A50, or a pharmaceutically acceptable salt thereof, is wherein Ring A of the E3 ligase ligand of formula (i) is:

[0238]

[0239] A52. In embodiment A52, the compound of any one of embodiments A1 to A48a, A50 and A51, or a pharmaceutically acceptable salt thereof, is wherein Ring A of the E3 ligase ligand of formula (i) is:

[0240]

[0241] That is, where R bb , R cc and R dd For hydrogen.

[0242] A52a. In embodiment A52a, the compound as described in any one of embodiments A1 to A41, A45 and A51 to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ligase ligand having formula (i) is:

[0243]

[0244] That is, where R bb For hydrogen.

[0245] A53. In embodiment A53, the compound of any one of embodiments A1 to A48a and A50 to A52, or a pharmaceutically acceptable salt thereof, is wherein Ring A of the E3 ligase ligand of formula (i) is:

[0246]

[0247] That is, where R bb For hydrogen.

[0248] A54. In embodiment A54, the compound of any one of embodiments A1 to A43 and A50 to A52, or a pharmaceutically acceptable salt thereof, is wherein Ring A of the E3 ligase ligand of formula (i) is:

[0249]

[0250] That is, where R bb For hydrogen.

[0251] A55. In embodiment A55, the compound of any one of embodiments A1 to A43 and A50 to A52, or a pharmaceutically acceptable salt thereof, is wherein Ring A of the E3 ligase ligand of formula (i) is:

[0252]

[0253] That is, where R aa and R bb For hydrogen.

[0254] A56. In embodiment A56, the compound of any one of embodiments A1 to A40, A46, A48, A48a, A50 to A52, or a pharmaceutically acceptable salt thereof, is wherein Ring A of the E3 ligase ligand of formula (i) is:

[0255]

[0256] That is, where R cc and R dd For hydrogen.

[0257] A57. In embodiment A57, the compound of any one of embodiments A1 to A40, or a pharmaceutically acceptable salt thereof, is wherein Ring A of the E3 ligase ligand of formula (i) is:

[0258]

[0259] That is, where R cc and R dd For hydrogen.

[0260] A58. In embodiment A58, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A54 is wherein R aa , R bb , R cc and R dd (when present) are independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy.

[0261] A59. In embodiment A59, the compound as described in any one of embodiments A1 to A54 or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc and R dd (when present) are independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl and cyano.

[0262] A60. In embodiment A60, the compound as described in any one of embodiments A1 to A54 or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc and R dd(when present) are independently selected from hydrogen, methyl, methoxy, ethoxy, fluoro, trifluoromethyl, difluoromethyl and trifluoromethoxy.

[0263] A61. In embodiment A61, the compound as described in any one of embodiments A1 to A54 or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc and R dd (when present) are independently selected from hydrogen and methyl.

[0264] A62. In embodiment A62, the compound as described in any one of embodiments A1 to A54 or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc and R dd (when present) are independently selected from hydrogen and methoxy.

[0265] A63. In embodiment A63, the compound as described in any one of embodiments A1 to A54 or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc and R dd (when present) are independently selected from hydrogen and fluorine.

[0266] A64. In embodiment A64, the compound as described in any one of embodiments A1 to A54 or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc and R dd (when present) is independently selected from hydrogen, trifluoromethyl and difluoromethyl.

[0267] A65. In embodiment A65, the compound as described in any one of embodiments A1 to A54 or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc and R dd (when present) is independently selected from hydrogen and trifluoromethoxy.

[0268] A66. In embodiment A66, the compound as described in any one of embodiments A1 to A54 or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc and R dd When present) is independently selected from hydrogen, fluoro and trifluoromethyl.

[0269] A67. In embodiment A67, the compound of any one of embodiments A1 to A39a, or a pharmaceutically acceptable salt thereof, is wherein the degron is an E3 ligase ligand having formula (ii):

[0270]

[0271] A68. In embodiment A68, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A39a and A67 is wherein Y a For CH.

[0272] A69. In embodiment A69, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A39a and A67 is wherein Y a is N.

[0273] A70. In embodiment A70, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A39a and A67-A69 is wherein Z a is a bond, -NH-, O or -NHC(O)-.

[0274] A71. In embodiment A71, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A39a and A67-A70 is wherein Z a is a bond, -NH- or -NHC(O)-.

[0275] A72. In embodiment A72, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A39a and A67-A69 is wherein Z a is the key.

[0276] A73. In embodiment A73, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A39a and A67-A68 and A71 is wherein Z a It is -NH- or -NHC(O)-.

[0277] A74. In embodiment A74, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A39a and A67-A68 and A71 is wherein Z a It is -NH-.

[0278] A74a. In embodiment A74a, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A39a and A67-A68 and A71 is wherein Z a It is -NHC(O)-.

[0279] A75. In embodiment A75, the compound as described in any one of embodiments A1 to A39a and A67-A74a, or a pharmaceutically acceptable salt thereof, is wherein Ring B is R independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano. ee and R ff Substituted phenylene.

[0280] A76. In embodiment A76, the compound as described in any one of embodiments A1 to A39a and A67-A74a, or a pharmaceutically acceptable salt thereof, is wherein Ring B is R independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano. ee and R ff Substituted cycloamine.

[0281] A77. In embodiment A77, the compound as described in any one of embodiments A1 to A39a and A67-A74a, or a pharmaceutically acceptable salt thereof, is wherein Ring B is a 5-membered or 6-membered monocyclic heteroarylene or a 9-membered or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three nitrogen ring atoms and each ring is independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano. ee and R ff replace.

[0282] A78. In embodiment A78, the compound as described in any one of embodiments A1 to A39a and A67-A74a, or a pharmaceutically acceptable salt thereof, is wherein Ring B is R containing one or two nitrogen ring atoms and independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano. ee and R ff Substituted 5-membered or 6-membered monocyclic heteroarylene.

[0283] A79. In embodiment A79, the compound as described in any one of embodiments A1 to A39a and A67-A74a, or a pharmaceutically acceptable salt thereof, is wherein Ring B is R containing one to three nitrogen ring atoms and independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano. ee and R ff Substituted 9- or 10-membered fused bicyclic heteroarylene.

[0284] A80. In embodiment A80, the compound as described in any one of embodiments A1 to A39a and A67 to A74a and A79, or a pharmaceutically acceptable salt thereof, is wherein Ring B is R containing two nitrogen ring atoms and independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano.ee and R ff Substituted 9- or 10-membered fused bicyclic heteroarylene.

[0285] A81. In embodiment A81, the compound of any one of embodiments A1 to A39a and A67 to A80, or a pharmaceutically acceptable salt thereof, is wherein the E3 ligase ligand of formula (ii) is:

[0286]

[0287]

[0288] A82. In embodiment A82, the compound of any one of embodiments A1 to A39a and A67 to A81, or a pharmaceutically acceptable salt thereof, is wherein the E3 ligase ligand of formula (ii) is:

[0289]

[0290] Wherein ring B is a cycloamine group.

[0291] A83. In embodiment A83, the compound of any one of embodiments A1 to A39a and A67 to A82, or a pharmaceutically acceptable salt thereof, is wherein the E3 ligase ligand of formula (ii) is:

[0292]

[0293]

[0294] A84. In embodiment A84, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A39a and A67 to A83 is wherein R ee and R ff Each of is independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halogen, cyano, haloalkyl and haloalkoxy.

[0295] A85. In embodiment A85, the compound as described in any one of embodiments A1 to A39a and A67 to A84, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff Each of is independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halogen, haloalkyl and cyano.

[0296] A86. In embodiment A86, the compound as described in any one of embodiments A1 to A39a and A67 to A85, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ffEach of is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy or cyano.

[0297] A87. In embodiment A87, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A39a and A67 to A86 is wherein R ee and R ff Each of is independently selected from hydrogen and methyl, ethyl or isopropyl.

[0298] A88. In embodiment A88, the compound as described in any one of embodiments A1 to A39a and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff Each of is independently selected from hydrogen and methoxy.

[0299] A89. In embodiment A89, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A39a and A67 to A86 is wherein R ee and R ff Each of is independently selected from hydrogen, methyl, ethyl, isopropyl, chlorine and fluorine.

[0300] A90 In embodiment A90, the compound as described in any one of embodiments A1 to A39a and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff is hydrogen or fluorine, and R ee and R ff The other of the two is selected from the group consisting of hydrogen, trifluoromethyl, 2,2,2-trifluoroethyl and difluoromethyl.

[0301] A91. In embodiment A91, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A39a and A67 to A86 is wherein R ee and R ff Each of is independently selected from hydrogen, difluoromethoxy and trifluoromethoxy.

[0302] A92. In embodiment A92, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A39a and A67 to A86 is wherein R ee and R ff Each of is independently selected from hydrogen, chlorine, fluorine and trifluoromethyl.

[0303] A93. In embodiment A93, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A39a and A67 to A86 is wherein Ree and R ff are independently hydrogen.

[0304] A94. In embodiment A94, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A39a and A67 to A86 is wherein R ee and R ff are independently chlorine.

[0305] A95. In embodiment A95, the compound as described in any one of embodiments A1 to A39a and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff are independently fluorine.

[0306] A96. In embodiment A96, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A39a and A67 to A86 is wherein R ee and R ff Each of is independently trifluoromethyl or 2,2,2-trifluoroethyl.

[0307] A96a. In embodiment A96a, the compound of any one of embodiments A1 to A39a, or a pharmaceutically acceptable salt thereof, is wherein the degron is an E3 ligase ligand of formula (iii), (iv), (v) or (vi).

[0308] A96b. In embodiment A96b, the compound as described in any one of embodiments A1 to A39a and A96a, or a pharmaceutically acceptable salt thereof, is wherein the degron is an E3 ligase ligand having formula (iii), (iv), (v) or (vi), wherein R y is 1-fluorocyclopropane-1-yl and W a is a bond, S or methylene.

[0309] A97. In embodiment A97, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96 is wherein X 1 , X 2 , X 3 and X 4 Independently key.

[0310] A98. In embodiment A98, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96 is wherein X 1 , X 2 , X 3 and X 4 are independently alkylene.

[0311] A98a. In embodiment A98a, the compound as described in any one of embodiments A1 to A96 and A98, or a pharmaceutically acceptable salt thereof, is wherein X 1 , X 2 , X 3 and X 4 Each is a methylene group.

[0312] A99. In embodiment A99, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96 is wherein X 1 , X 2 , X 3 and X 4 is independently -O-.

[0313] A100a. In embodiment A100a, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96 is wherein X 1 , X 2 , X 3 and X 4 is independently -(O-alkylene)-.

[0314] A100. In embodiment A100, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96 and A100a is wherein X 1 , X 2 , X 3 and X 4 are independently -(O-CH2)-, -O-(CH2)2- or -O-(CH2)3-.

[0315] A101a. In embodiment A101a, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96 is wherein X 1 , X 2 , X 3 and X 4 is independently -(alkylene-O)-.

[0316] A101. In embodiment A101, the compound as described in any one of embodiments A1 to A96 and A101, or a pharmaceutically acceptable salt thereof, is wherein X 1 , X 2 , X 3 and X 4 are independently -(CH2-O)-, -(CH2)2-O- or -(CH2)3-O-.

[0317] A102. In embodiment A102, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96 is wherein X 1 , X2 , X 3 and X 4 Independently -(NR gg -alkylene)-.

[0318] A103. In embodiment A103, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96 is wherein X 1 , X 2 , X 3 and X 4 are independently -(alkylene-NR hh )-.

[0319] A104. In embodiment A104, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96 is wherein X 1 , X 2 , X 3 and X 4 for

[0320] A105. In embodiment A105, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96 is wherein X 1 , X 2 , X 3 and X 4 It is -NH-.

[0321] A106. In embodiment A106, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96 is wherein X 1 , X 2 , X 3 and X 4 is independently -N(alkyl)-.

[0322] A107. In embodiment A107, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96 is wherein X 1 , X 2 , X 3 and X 4 It is -C(=O)-.

[0323] A108. In embodiment A108, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96 is wherein X 1 , X 2 , X 3 and X 4 Independently -NR jj C(=O)-.

[0324] A109. In embodiment A109, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96 is wherein X 1 , X 2 , X 3 and X 4 are independently -C(=O)NR kk -.

[0325] A110. In embodiment A110, the compound as described in any one of embodiments A1 to A96, A102, A103, A108 and A109, or a pharmaceutically acceptable salt thereof, is wherein R gg , R hh , R jj and R kk are independently hydrogen or alkyl.

[0326] A111. In embodiment A111, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A110 is wherein Z 6 It is -S(O)2-.

[0327] A112. In embodiment A112, the compound as described in any one of embodiments A1 to A96 or a pharmaceutically acceptable salt thereof is wherein L (when the degron is a group having formula (iii) to (vi)), -X 1 -L-, -X 2 -L-, -X 3 -L- and -X 4 -L- is independently selected from:

[0328]

[0329] A113. In embodiment A113, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111 is wherein Z 5 is the key.

[0330] A114. In embodiment A114, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96, A111 and A113 is wherein Z 5 is a key and Z 1 and X 1 One of them is a key, Z 1 and X 2 One of them is a key, Z 1 and X 3 One of them is a key, and Z 1 and X 4 One of them is the key.

[0331] A115. In embodiment A115, the compound of any one of embodiments A1 to A96b or a pharmaceutically acceptable salt thereof is wherein:

[0332] X 1 , X 2 , X 3 and X 4 are independently a bond, -(O-alkylene)-, -(NR gg -alkylene)-, -NH- or -N(alkyl)-, where R gg is hydrogen or alkyl, and each alkylene group is optionally substituted with one or two fluorine groups;

[0333] Z 1 is a bond, alkylene, -(CO)NR-, -(O-alkylene) a -, -(alkylene-O) a -, phenylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy R h and R i replace;

[0334] Z 2 is a bond, an alkylene group, -(O-alkylene group) b -, -(alkylene-O) b -, cycloalkylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy R j and R k replace;

[0335] Z 3 is a bond, an alkylene group, -C(O)NR-, -NR'(CO)-, -O-, -NR"-, a cycloalkylene group, a phenylene group, a monocyclic heteroarylene group, a heterocyclylene group, a fused heterocyclylene group, or a spiroheterocyclylene group, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, and haloalkoxy groups. m and R n replace;

[0336] Z 4 is a bond, -(alkylene-NR")-, -O-, -NR"-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene or spiroheterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. o and R p replace;

[0337] Z 5 is a key; and

[0338] Z 6 is -S(O)2-; and

[0339] Each alkylene group is R s and R t replace.

[0340] A116. In embodiment A116, the compound of any one of embodiments A1 to A96b or a pharmaceutically acceptable salt thereof is wherein:

[0341] X 1 , X 2 , X 3 , X 4 and Z 1 Each is a key;

[0342] Z 2 is a bond, alkylene, cycloalkylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. j and R k replace;

[0343] Z 3 is a bond, an alkylene group, -C(O)NR-, -NR'(CO)-, -O-, -NR"-, a cycloalkylene group, a phenylene group, a monocyclic heteroarylene group, a heterocyclylene group, a bicyclic heterocyclylene group, a bridged heterocyclylene group, a fused heterocyclylene group, or a spiroheterocyclylene group, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, and haloalkoxy groups. m and R n replace;

[0344] Z 4 is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene or spiroheterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. o and R p replace;

[0345] Z 5 is phenylene, monocyclic heteroarylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. q and R r replace; and

[0346] Z 6 is -S(O)2-; and

[0347] Each alkylene group is R s and R t replace.

[0348] A117. In embodiment A117, the compound as described in any one of embodiments A1 to A96b and A116, or a pharmaceutically acceptable salt thereof, is wherein:

[0349] X 1 , X 2 , X 3 , X 4 , Z 1 and Z 2 Each is a key;

[0350] Z 3 R is cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene or spiroheterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy m and R n replace;

[0351] Z 4 R is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene or spiroheterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxyl, amino, alkylamino and dialkylamino o and R p replace;

[0352] Z 5 is phenylene, monocyclic heteroarylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. q and R r replace; and

[0353] Z 6 is -S(O)2-; and

[0354] Where the alkylene group is R s and R t replace.

[0355] A117a. In embodiment A117a, the compound as described in any one of embodiments A1 to A96b and A117, or a pharmaceutically acceptable salt thereof, is wherein R o and R p are independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy.

[0356] A118. In embodiment A118, the compound as described in any one of embodiments A1 to A96b, A116 and A117a, or a pharmaceutically acceptable salt thereof, is wherein:

[0357] X 1 , X 2 , X 3 , X 4 , Z 1 and Z 2 Each is a key;

[0358] Z 3 R is a heterocyclylene, a bicyclic heterocyclylene, a bridged heterocyclylene, a fused heterocyclylene, or a spiro heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, and haloalkoxy. m and R n replace;

[0359] Z 4 R is alkylene, -O-, cycloalkylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene or spiroheterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxyl, amino, alkylamino and dialkylamino o and R p replace;

[0360] Z 5 is phenylene, monocyclic heteroarylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. q and R r replace; and

[0361] Z 6 is -S(O)2-; and

[0362] Where the alkylene group is R s and R t replace.

[0363] A118a. In embodiment A118a, the compound as described in any one of embodiments A1 to A96b, A116 and A118, or a pharmaceutically acceptable salt thereof, is wherein R o and R p are independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy.

[0364] A119. In embodiment A119, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96b and A116 to A118a, wherein:

[0365] X1 , X 2 , X 3 and X 4 , Z 1 and Z 2 Each is a key;

[0366] Z 3 is a heterocyclylene, a bridged heterocyclylene or a spiro heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. m and R n replace;

[0367] Z 4 R is alkylene, -O-, cycloalkylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino and dialkylamino o and R p replace;

[0368] Z 5 is phenylene, monocyclic heteroarylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. q and R r replace; and

[0369] Z 6 is -S(O)2-; and

[0370] Where the alkylene group is R s and R t replace.

[0371] A119a. In embodiment A119a, the compound as described in any one of embodiments A1 to A96b and A116 to A119, or a pharmaceutically acceptable salt thereof, is wherein R o and R p are independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy.

[0372] A120. In embodiment A120, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96b and A116 to A119a is wherein:

[0373] X 1 , X 2 , X 3 , X 4 , Z 1 and Z 2 Each is a key;

[0374] Z 3is a heterocyclylene, a bridged heterocyclylene or a spiro heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. m and R n replace;

[0375] Z 4 R is alkylene, -O-, cycloalkylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino and dialkylamino o and R p replace;

[0376] Z 5 is phenylene or a monocyclic heteroarylene, each ring being independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. q and R r replace; and

[0377] Z 6 is -S(O)2-; and

[0378] Where the alkylene group is R s and R t replace.

[0379] A120a. In embodiment A120a, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96b and A116 to A120 is wherein Z 4 It is alkylene or -O-.

[0380] A120b. In embodiment A120b, the compound as described in any one of embodiments A1 to A96b and A116 to A120, or a pharmaceutically acceptable salt thereof, is wherein R o and R p are independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy.

[0381] A121. In embodiment A121, the compound as described in any one of embodiments A1 to A96b and A116, or a pharmaceutically acceptable salt thereof, is wherein:

[0382] X 1 , X 2 , X 3 , X 4 and Z 1 Each is a key;

[0383] Z 2is a cycloalkylene or heterocyclylene group, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. j and R k replace;

[0384] Z 3 R is cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene or spiroheterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy m and R n replace;

[0385] Z 4 is a bond, an alkylene group or -O-;

[0386] Z 5 R is phenylene, monocyclic heteroarylene (e.g., pyridinediyl), or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, and haloalkoxy. q and R r ;and

[0387] Z 6 is -S(O)2-; and

[0388] Where the alkylene group is R s and R t replace.

[0389] A122. In embodiment A122, the compound of any one of embodiments A1 to A96b, A116 and A121, or a pharmaceutically acceptable salt thereof, is wherein:

[0390] X 1 , X 2 , X 3 , X 4 and Z 1 Each is a key;

[0391] Z 2 R is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy j and R k substituted heterocyclylene;

[0392] Z 3 R is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy m and R n substituted heterocyclylene;

[0393] Z 4 is a bond, an alkylene group or -O-;

[0394] Z 5 is phenylene or a monocyclic heteroarylene, each ring being independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. q and R r replace; and

[0395] Z 6 is -S(O)2-; and

[0396] wherein the alkylene group is optionally replaced by R s and R t replace.

[0397] A123. In embodiment A123, the compound as described in any one of embodiments A1 to A96b and A116, or a pharmaceutically acceptable salt thereof, is wherein:

[0398] X 1 , X 2 , X 3 , X 4 and Z 1 Each is a key;

[0399] Z 2 R is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy j and R k substituted heterocyclylene;

[0400] Z 3 is a bond, an alkylene group or -O-;

[0401] Z 4 is a heterocyclylene, a bridged heterocyclylene or a spiro heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. o and R p replace;

[0402] Z 5 is phenylene or a monocyclic heteroarylene, each ring being independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. q and R r replace; and

[0403] Z 6 It is -S(O)2-.

[0404] A123a. In embodiment A123, the compound as described in any one of embodiments A1 to A96b, or a pharmaceutically acceptable salt thereof, is wherein Z 4is a heterocyclylene or spiroheterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. o and R p replace.

[0405] A123b. In embodiment A123b, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96b and A116 to A120 is wherein:

[0406] X 1 , X 2 , X 3 , X 4 , Z 1 and Z 2 Each is a key;

[0407] Z 3 is a heterocyclylene group, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. m and R n replace;

[0408] Z 4 R is independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy o and R p Substituted cycloalkylene;

[0409] Z 5 is phenylene or a monocyclic heteroarylene, each ring being independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. q and R r replace; and

[0410] Z 6 It is -S(O)2-.

[0411] A124. In embodiment A124, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111 and A116 to A123b is wherein -Z 5 - is R independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy q and R r Replaced (i.e., Z 5 is phenylene, wherein Z 4 and Z 6 Attached to the meta position of the phenylene ring).

[0412] A125. In embodiment A125, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111 and A116 to A124 is wherein -Z 5 - is R independently selected from hydrogen, deuterium, methyl, methoxy, fluorine, chlorine, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy q and R r Replaced

[0413] A126. In embodiment A126, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111 and A116 to A125 is wherein -Z 5 - is R independently selected from hydrogen, deuterium, methyl, fluorine, trifluoromethyl and trifluoromethoxy q and R r Replaced

[0414] A127. In embodiment A127, the compound as described in any one of embodiments A1 to A111 and A116 to A123b, or a pharmaceutically acceptable salt thereof, is wherein -Z 5 - is imidazole-1,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl or pyridine-3,5-diyl, each ring being independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy q and R r replace.

[0415] A128. In embodiment A128, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111, A116 to A123b and A127 is wherein -Z 5 - is imidazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl or pyridine-3,5-diyl, each ring being independently selected from hydrogen, methyl, methoxy, fluorine, chlorine, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy and trifluoromethoxy q and R r replace.

[0416] A129. In embodiment A129, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A128 is wherein -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 - each alkylene group in itself and when present is each replaced by R s and R tSubstituted methylene, ethylene or propylene.

[0417] A130. In embodiment A130, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A128 is wherein -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 - each alkylene group in itself and, when present, is replaced by R s and R t Substituted methylene.

[0418] A131. In embodiment A131, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A130 is wherein -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -, each alkylene group as another group (e.g., -(O-alkylene) a 、-(alkylene-O) a -, -(alkylene-NR")-) and when present is ethylene or propylene.

[0419] A132. In embodiment A132, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A131 is wherein -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -, each alkylene group as another group (e.g., -(O-alkylene) a 、-(alkylene-O) a -, -(alkylene-NR")-) and when present is ethylene.

[0420] A133. In embodiment A133, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A132 is wherein -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 Each R, R' and R" in -, when present, is independently hydrogen or methyl.

[0421] A134. In embodiment A134, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A133 is wherein -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 Each R, R' and R" in -, when present, is hydrogen.

[0422] A135. In embodiment A135, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A133 is wherein -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 Each R, R' and R" in -, when present, is methyl.

[0423] A136. In embodiment A136, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A135 is wherein -Z 2 -Z 3 -Z 4 Each cycloalkylene in -, when present, is independently selected from cyclopropylene, cyclobutylene, cyclopentylene and cyclohexylene.

[0424] A137. In embodiment A137, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A136 is wherein -Z 2 -Z 3 -Z 4 Each cycloalkylene in -, when present, is independently selected from 1,3-cyclopentylene, 1,3-cyclohexylene and 1,4-cyclohexylene.

[0425] A138. In embodiment A138, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A137 is wherein the heteroarylene is a monocyclic heteroarylene, and -Z 1 -Z 3 -Z 4 -Z 5 Each monocyclic heteroarylene in -, when present, is independently selected from imidazolediyl, pyridinediyl and pyrimidinediyl, unless otherwise stated in any of the above Examples.

[0426] A139. In embodiment A139, the compound as described in any one of embodiments A1 to A138, or a pharmaceutically acceptable salt thereof, is wherein the heteroarylene is a monocyclic heteroarylene, and -Z 1 -Z 3 -Z4 -Z 5 Each monocyclic heteroarylene in -, when present, is independently selected from imidazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl and pyridine-3,5-diyl, unless otherwise stated in any of the above Examples.

[0427] A140. In embodiment A140, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A139 is wherein -Z 1 -Z 3 -Z 4 -Z 5 Each phenylene group in -, when present, is independently selected from 1,3-phenylene and 1,4-phenylene, unless otherwise stated in any of the above Examples.

[0428] A141. In embodiment A141, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A140 is wherein -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 Each heterocyclylene, bridged heterocyclylene and spiro heterocyclylene in -, when present, is independently selected from:

[0429]

[0430] wherein each ring is optionally substituted with 1, 2 or 3 fluorines.

[0431] A142. In embodiment A142, the compound as described in any one of embodiments A1 to A96b, or a pharmaceutically acceptable salt thereof, is wherein L (when the degron is a group having any one of formula (iii) to (iv)), -X 1 -L-, -X 2 -L-, -X 3 -L- and -X 4 -L- independently for:

[0432]

[0433]

[0434] A143. In embodiment A143, the compound as described in any one of embodiments A1 to A96b and A142, or a pharmaceutically acceptable salt thereof, is wherein L (when the degron is a group having any one of formula (iii) to (iv)), -X 1 -L-, -X 2 -L-, -X 3 -L- and -X4 -L- independently for:

[0435]

[0436] A144. In embodiment A144, the compound as described in any one of embodiments A1 to A110 and A120-A120b, or a pharmaceutically acceptable salt thereof, is wherein -Z 3 -Z 4 -Z 5 -Z 6 -for:

[0437]

[0438]

[0439] Where R q , R m and R n are independently selected from hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, haloalkoxy, alkoxy and cyano.

[0440] A144a. In embodiment A144a, the compound as described in any one of embodiments A1 to A110, A120-A120b and A144, or a pharmaceutically acceptable salt thereof, is wherein R q and R m are independently selected from hydrogen, methyl, fluoro, chloro, cyano, methoxy, difluoromethoxy, cyclopropyl, difluoromethyl and trifluoromethyl.

[0441] A145. In embodiment A145, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96b, A120-A120b and A144 is wherein -Z 3 -Z 4 -Z 5 -Z 6 -for:

[0442]

[0443] Where R m , R n and R q are independently selected from hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, haloalkoxy, alkoxy and cyano.

[0444] A145a1. In embodiment A145a1, the compound as described in any one of embodiments A1 to A96b, A120-A120b, A144 and A145, or a pharmaceutically acceptable salt thereof, is wherein R q and R mare independently selected from hydrogen, methyl, fluoro, chloro, cyano, methoxy, difluoromethoxy, cyclopropyl, difluoromethyl and trifluoromethyl.

[0445] A145a. In embodiment A145a, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A96b, A120-A120b, A144 to A145a1 is wherein R n For hydrogen.

[0446] A146. In embodiment A146, the compound as described in any one of embodiments A1 to A110, A116 and A123, or a pharmaceutically acceptable salt thereof, is -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -for:

[0447]

[0448] Where R j , R k , R m , R n and R q are independently selected from hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, haloalkoxy, alkoxy and cyano.

[0449] A146a1. In embodiment A146a1, the compound as described in any one of embodiments A1 to A110, A116, A123 and A146, or a pharmaceutically acceptable salt thereof, is wherein R q and R m are independently selected from hydrogen, methyl, fluoro, chloro, cyano, methoxy, difluoromethoxy, cyclopropyl, difluoromethyl and trifluoromethyl.

[0450] A146a. In embodiment A146a, the compound as described in any one of embodiments A1 to A110, A116, A123 and A146a1, or a pharmaceutically acceptable salt thereof, is wherein R n For hydrogen.

[0451] A147. In embodiment A147, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A135, A144 to A145a is wherein Z 4 For R s and R t Substituted alkylene, wherein R s and R t For hydrogen.

[0452] A148. In embodiment A148, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A135, A144 to A145a and A147 is wherein Z 4 The alkylene group is -CH2-, -(CH2)2-, -CH(CH3)-, -CH2CH(CH3)-CH2- or -C(CH3)2-.

[0453] A148a. In embodiment A148a, the compound as described in embodiment A148 or a pharmaceutically acceptable salt thereof is wherein Z 4 It is -CH2-, -(CH2)2-, -CH(CH3)- or -C(CH3)2-.

[0454] A149. In embodiment A149, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111, A113-A122, A124 to A128, A133-A135, A144 to A145a is wherein Z 4 For -O-.

[0455] A150. In embodiment A150, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A135, A144 to A145a is wherein Z 4 For R s and R t Substituted alkylene, wherein R s is hydrogen and deuterium and R t is hydrogen, deuterium, halogenated alkyl, hydroxy, alkoxy or cyano.

[0456] A151. In embodiment A151, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A135, A144 to A145a and A150 is wherein Z 4 For-CR s R t -, where R s is hydrogen or deuterium and R t is hydrogen or deuterium.

[0457] A152. In embodiment A152, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A135, A144 to A145a and A150 is wherein Z 4 For R s and R t Substituted alkylene, wherein R s is hydrogen and R t It is a halogenated alkyl group.

[0458] A153. In embodiment A153, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A135, A144 to A145a and A150 is wherein Z 4 For R s and R t Substituted alkylene, wherein R s is hydrogen and R t It is hydroxyl.

[0459] A154. In embodiment A154, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A135, A144 to A145a and A150 is wherein Z 4 For R s and R t Substituted alkylene, wherein R s is hydrogen and R t It is an alkoxy group.

[0460] A155. In embodiment A155, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A135, A144 to A145a, A150 and A152 to A154 is wherein Z 4 It is -CH(CHF2)-, -CH(CF3)-, -C(CH3)(CF3)-, -CH(CH2CF3)-, -CH(CH2CH2CF3)-, -CH(CH(CF3)2)-, -CH(CH2OH)-, -CH(CH2OCH3)-, -CH(CH2O-ethyl)- or -CH(CH2CN)-.

[0461] A156. In embodiment A156, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A135, A144 to A145a is wherein Z 4 For R s and R t Substituted alkylene, wherein R s is hydrogen and R t is a cycloalkyl group, a heterocyclyl group, an aryl group or a monocyclic heteroaryl group, wherein the cycloalkyl group, the heterocyclyl group, the aryl group or the monocyclic heteroaryl group is substituted by one or two substituents independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy or cyano.

[0462] A157. In embodiment A157, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A135, A144 to 145a and A156 is wherein Z 4 For R s and R t Substituted alkylene, wherein R s is hydrogen and deuterium and R t is cycloalkyl substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy or cyano.

[0463] A158. In embodiment A158, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A136, A144 to 145a and A156 is wherein Z 4 For R s and R t Substituted alkylene, wherein R s is hydrogen and R t is a heterocyclic group substituted by one or two substituents independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy or cyano.

[0464] A159. In embodiment A159, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A135, A144 to 145a and A156 is wherein Z 4 For R s and R t Substituted alkylene, wherein R sis hydrogen and R t is aryl substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy or cyano.

[0465] A160. In embodiment A160, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A135, A144 to 145a and A156 is wherein Z 4 For R s and R t Substituted alkylene, wherein R s is hydrogen and R t is a monocyclic heteroaryl substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy or cyano.

[0466] A161. In embodiment A161, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A135, A144 to A145a and A156 to 160 is wherein Z 4 is -CH(benzyl)-, -CH(phenyl)-, -CH(pyridin-4-yl)-, -CH(cyclopentyl)-, -CH(cyclohexyl)-, -CH(tetrahydropyran-4-yl)- or -CH(piperidin-4-yl)-, wherein phenyl-- itself or as part of benzyl, pyridin-4-yl, cyclopentyl, cyclohexyl, tetrahydropyran-4-yl and piperidin-4-yl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy or cyano.

[0467] A162. In embodiment A162, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A135, A144 to 145a and A156 to 160 is wherein Z 4 is -CH(benzyl)-, -CH(phenyl)-, -CH(pyrazol-4-yl)-, -CH(pyridin-4-yl)-, -CH(cyclopentyl)-, -CH(cyclohexyl)-, -CH(tetrahydropyran-4-yl)- or -CH(piperidin-4-yl)-, wherein phenyl-- itself or as part of benzyl, pyrazol-4-yl, pyridin-4-yl, cyclopentyl, cyclohexyl, tetrahydropyran-4-yl and piperidin-4-yl are substituted with one or two substituents independently selected from hydrogen, fluorine, chlorine, methyl, methoxy, difluoromethoxy, trifluoromethoxy or cyano.

[0468] A163. In embodiment A163, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111, A113-A120, A120b, A123b, A124 to A128, A133-A135, A144 to A145a, wherein Z 4 For R o and R p Substituted 1,1-cycloalkylene.

[0469] A164. In embodiment A164, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A111, A113-A120, A120b, A123b, A124 to A128, A133, A144 to A145a, wherein Z 4 For R o and R p Substituted heterocyclylene.

[0470] A165. In embodiment A165, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments A1 to A120, A120b, A123b, A124 to A128, A133, A144 to A145a and A163-A164 is wherein Z 4 for:

[0471]

[0472] A166. In embodiment A166, the compound of any one of embodiments A1 to A165, or a pharmaceutically acceptable salt thereof, is wherein the degron is an E3 ligase ligand selected from:

[0473]

[0474] A167. In embodiment A167, the compound of any one of embodiments A1 to A165, or a pharmaceutically acceptable salt thereof, is wherein the degron is an E3 ligase ligand selected from:

[0475]

[0476] Where R ee is hydrogen, methyl, ethyl, cyclopropyl or 2,2,2-trifluoroethyl, and R ff is hydrogen, methyl, cyclopropyl, fluorine, cyano, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.

[0477] A168. In embodiment A168, the compound of any one of embodiments A1 to A165, or a pharmaceutically acceptable salt thereof, is wherein the degron is an E3 ligase ligand selected from:

[0478]

[0479] Where R ee is hydrogen, methyl, cyclopropyl or 2,2,2-trifluoroethyl and R ff is hydrogen, methyl, fluorine or trifluoromethyl.

[0480] A169. In embodiment A169, the compound as described in any one of embodiments A1 to A165 is wherein R x For hydrogen.

[0481] A170. In embodiment A170, a pharmaceutical composition is provided, which comprises a compound as described in any one of embodiments A1 to A169 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0482] A171. In embodiment A171, a method for degrading CDK2 in a cell is provided, the method comprising contacting the cell with a compound as described in any one of embodiments A1 to A169 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in embodiment A170.

[0483] A172. In embodiment A172, a method for treating a disease mediated by CDK2 in a patient is provided, the method comprising administering to a patient in recognized need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound as described in any one of embodiments A1 to A169 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0484] A173. In embodiment A173, a method for treating cancer in a patient is provided, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound as described in any one of embodiments A1 to A169 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in A170.

[0485] A174. In embodiment A174, the method as described in embodiment A173 is wherein the compound as described in any one of embodiments A1 to A169 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as described in A170 is administered in combination with at least one other anticancer agent.

[0486] A175. In embodiment A175, the method as described in embodiment A173 or A174 is wherein the cancer is lung cancer, skin cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, stomach cancer, head and neck cancer, liver cancer, ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, stomach cancer, thyroid cancer or parathyroid cancer.

[0487] It should be understood that the embodiments and sub-embodiments described above include all combinations of the embodiments and sub-embodiments listed therein.

[0488] General synthetic scheme

[0489] Compounds having formula (I) can be prepared by the methods depicted in the reaction schemes shown below.

[0490] Starting materials and reagents used to prepare these compounds are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.), 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, 1989); Organic Reactions, Vols. 1-40 (John Wiley and Sons, 1991); Sons [John Wiley and Sons Publishing Company], 1991); March's Advanced Organic Chemistry [Ma Chi's Advanced Organic Chemistry] (John Wiley and Sons [John Wiley and Sons Publishing Company], 4th Edition) and Larock's Comprehensive Organic Transformations [La Rock's Comprehensive Organic Transformations] (VCH Publishers Inc. [VCH Publishing Company], 1989). These schemes are merely illustrative of some of the methods by which compounds of formula (I) can be synthesized, and various modifications to these schemes can be made and will be enlightening to those of ordinary skill in the art upon reading this disclosure. If desired, these starting materials and intermediates and the final products of the reactions can be separated 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.

[0491] Unless indicated to the contrary, the reactions described herein occur at atmospheric pressure, at a temperature range 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), for example about 20°C.

[0492] Compounds of formula (I) can be prepared as described in Scheme 1 below, wherein the degron is an E3 ligase ligand of formula (i), wherein ring A is a group of formula (a), (b) or (c), wherein X1 , X 2 and X 3 is -CONH-, L is attached to Hy through -NH-, and the other groups are as defined in the Summary of the Invention.

[0493] Solution 1

[0494]

[0495] The carboxylic acid group in 1-a and the compound of formula 1-b (wherein L' is a precursor group of L in the compound of formula (I) as defined in the Summary of the Invention) are coupled with a suitable coupling agent (such as HATU) to provide the corresponding amide of formula 1-c. The hydroxyl group in 1-c can be converted into a leaving group (such as mesylate, triflate, etc.) by methods well known in the art to provide a compound of formula 1-d. Under conditions well known in the art, in the presence of a suitable base, compound 1-d is reacted with a compound of formula 1-e to provide a compound of formula (I) (wherein X, X 1 , X 2 and X 3 is -CONH-, and L is attached to Hy via -NH-).

[0496] Compounds of formula (I) can be prepared as described in Scheme 2 below, wherein the degron is an E3 ligase ligand of formula (i), wherein ring A is a group of formula (a), (b) or (c), wherein X 1 , X 2 and X 3 is -NH-, L is attached to Hy via -O-,

[0497] And other groups are as defined in the Summary of the Invention.

[0498] Solution 2

[0499]

[0500] In the presence of a suitable base (such as NaH, etc.), LG in the compound of formula 2-a is replaced with an alcohol compound of formula 2-b (wherein PG is a suitable amino protecting group such as benzyl or CBz, and L' is a precursor group of L as defined in the Summary of the Invention): 1(leaving group, such as halogen, methylsulfonyl, etc.), provides a compound of formula 2-c (wherein -L'- is a precursor group of L in the compound of formula (I) as defined in the Summary of the Invention. Removal of the protecting group under appropriate conditions provides an amine compound of formula 2-d. Replacement of the leaving group (LG, such as halide, sulfonate, etc.) in the compound of formula 2-e (wherein ring A is as defined in the Summary of the Invention) with the amino group of formula 2-d provides a compound of formula 2-f. Removal of the Boc protecting group in compound 2-f using an acid (such as TFA) provides a compound of formula 2-g. Under appropriate conditions (such as acidic, basic or transition metal-catalyzed reaction conditions well known in the art), compound 2-g is reacted with a compound of formula 2-h (wherein LG 2 is a suitable leaving group, such as Cl or SO2Me, and R 1 , R 2 and R 3 as defined in the Summary of the Invention) to provide a compound of formula (I).

[0501] With the following structure A compound of formula 2-h (wherein R 2 and R 3 It's hydrogen, LG 2 is -SO2Me, and R 1 As defined in the Summary of the Invention) can be synthesized by the method shown in the following method (a) or method (b).

[0502] Method (a):

[0503]

[0504] Under basic conditions (such as TEA), the chlorine in compound 1 is replaced with an amine having formula 2 to provide a compound having formula 3. Compound 1 and amine 2 are commercially available, or they can be prepared by methods well known in the art. For example, methylamine, ethylamine and benzylamine are all commercially available.

[0505] Reduction of the ester group in 3 with a suitable reducing agent (such as LiAlH4) provides a hydroxy compound of formula 4, which can be converted to the corresponding aldehyde of formula 5 with an oxidizing agent (such as MnO2). 5 is reacted with 2-(triphenyl-λ 5 Olefination of ethyl acetate with ethyl acetate (phosphoranylidene) provides a compound of formula 6, which can be cyclized with ethyl acetate in the presence of a base (such as DBU) under heating conditions to provide a compound of formula 7. Compound 7 can then be converted to a compound of formula 2-h (wherein LG 2 is -SO2Me).

[0506] Method (b):

[0507]

[0508] The compound of formula 12 can be synthesized by a method similar to the synthesis of compound 7 in method (a). Under alkaline conditions (such as in the presence of NaH, Cs2CO3), a compound of formula 13 (wherein R 1 As defined in the Summary of the Invention and LG 4 Treatment of pyridone 12 with a suitable leaving group such as halogen, triflate, provides a compound of formula 14. Compound 14 can then be converted to a compound of formula 2-h (wherein LG 2 is -SO2Me).

[0509] Compounds of formula (I) can be prepared as described in Scheme 3 below, wherein the degron is an E3 ligase ligand of formula (i), wherein ring A is a group of formula (a), (b) or (c), X 1 , X 2 and X 3 is ethylene, L is attached to Hy through -NH-, and the other groups are as defined in the Summary of the Invention.

[0510] Solution 3

[0511]

[0512] In the presence of a palladium (0) catalyst, a copper (I) co-catalyst and a suitable base (such as triethylamine, etc.), a compound (X) having a formula 3-a is reacted with a The terminal alkynyl group of a compound of formula 3-b (wherein L' is a precursor group of L in a compound of formula (I) as defined in the Summary of the Invention) undergoes a sonogravure coupling, providing a compound of formula 3-c. The ternary bond is hydrogenated, providing a corresponding compound of formula 3-d. The Boc group in 3-d is removed using an acid (such as TFA), providing an amine compound of formula 3-e. 3-e is reacted with a compound of formula 2-a under suitable conditions, providing a compound of formula 3-g. The Boc group in compound 3-g is removed, and then the amine of formula 3-h obtained is reacted with a compound of formula 2-h as described above, providing a compound of formula (I).

[0513] Compounds of formula (I) can be prepared as described in Scheme 4 below, wherein the degron is an E3 ligase ligand of formula (ii), wherein X 4is a bond, L is attached to the E3 ligase ligand having formula (ii) through the piperidinyl ring and to Hy through -SO2-, and the other groups are as defined in the Summary of the Invention:

[0514] Solution 4

[0515]

[0516] In the presence of a suitable base (such as TEA, etc.), an amine compound having the formula 4-1 (wherein ring B, ring Hy, R x , Y a , Z a As defined in the Summary of the Invention, and L' is a precursor group of L as defined in the Summary of the Invention) replaces LG in the compound having formula 4-2 1 (leaving group, such as halogen, methylsulfonyl, etc.), provides a compound having formula 4-3. Use acid (such as TFA) to remove the Boc protecting group in compound 4-3, and provide an amine compound having formula 4-4. Under suitable conditions (such as acidic, alkaline or transition metal catalyzed reaction conditions well known in the art), compound 4-4 is reacted with a compound having formula 2-h (wherein LG 2 is a suitable leaving group, such as Cl or SO2Me, and R 1 , R 2 and R 3 as defined in the Summary of the Invention) to provide a compound of formula (I).

[0517] utility

[0518] Compounds of formula (I) may cause degradation of CDK2 protein via the ubiquitin proteasome pathway and are therefore useful for treating diseases mediated by CDK2. Increasing evidence suggests that overactivated CDK2 leads to abnormal cell cycle regulation and proliferation in cancer cells. Although CDK2 mutations are rarely found, the kinase activity of the CDK2 / cyclin E or CDK2 / cyclin A complexes is elevated in human cancers via several mechanisms. Cyclin E has been found to be frequently amplified in human malignancies, for example, in ovarian and breast cancers. In some cancer types, FBXW7 (SCF responsible for cyclin E degradation) is expressed in 1% of the 1% cyclin E complexes. Fbw7Functional loss mutations in cyclin E (a component of ubiquitin E3 ligase) can also lead to overexpression of cyclin E and activation of CDK2. Alternatively, some cancer cells express overactive truncated forms of cyclin E. In addition, amplification and overexpression of cyclin A have also been reported in various cancers such as hepatocellular carcinoma, colorectal cancer, and breast cancer. In some tumors, the catalytic activity of CDK2 increases after the expression loss or positional change of endogenous CDK2 inhibitors p27 or p21. In addition, CDC25A and CDC25B (protein phosphatases responsible for dephosphorylation of activated CDK2) are overexpressed in various tumors. These different mechanisms of CDK2 activation have been verified using mouse cancer models. In addition, CDK2 / cyclin E phosphorylates oncogenic Myc to counteract ras-induced senescence, highlighting the importance of CDK2 in myc / ras-induced tumorigenesis. It has been shown that inactivation of CDK2 is synthetically lethal to cancer cells overexpressing myc. Therefore, the compounds of the present invention are particularly useful for treating tumors characterized by: 1) overexpression of CDK2, 2) amplification of cyclin E or cyclin A, 3) loss-of-function mutations in FBXW7, 4) expression of truncated cyclin E, 5) dysregulation of p21 or p27, and 6) overactive MYC / RAS.

[0519] CDK2 activation due to cyclin E amplification or overexpression has also been identified as a key primary or acquired resistance pathway in tumors treated with CDK4 / 6 inhibitors or trastuzumab.

[0520] In some embodiments, the cancer is ovarian cancer, endometrial cancer, breast cancer (e.g., triple negative breast cancer), lung cancer (e.g., adenocarcinoma, small cell lung cancer and 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, cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, stomach 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 cholangiocarcinoma), prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), gastric cancer, thyroid cancer, brain cancer, fallopian tube cancer, peritoneal cancer, AML, and parathyroid cancer. In some embodiments, the cancer is ovarian cancer. In some such embodiments, ovarian cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2. In some embodiments, the cancer is hepatocellular carcinoma, colorectal cancer, and breast cancer. In some embodiments, the cancer is ovarian cancer. In some such embodiments, ovarian cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0521] 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, triple-negative breast cancer (TNBC), or inflammatory breast cancer. In some embodiments, the breast cancer is endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, 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 above, the breast cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0522] In other embodiments, compounds of formula (I) can also be used in autoimmune diseases (e.g., 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.

[0523] test

[0524] The CDK2 potency and CDK2 degradation activity of the compounds of the present disclosure can be tested using the in vitro assays described in the Biological Examples below.

[0525] Pharmaceutical composition

[0526] Typically, a compound of formula (I) (unless otherwise specified, reference to a compound of formula (I) herein includes any of its embodiments described herein or a pharmaceutically acceptable salt thereof) will be administered in a therapeutically effective amount by any of the acceptable modes of administration for medicaments for similar effects. The therapeutically effective amount of a compound of formula (I) may range from about 0.01 to about 500 mg / kg patient weight / day, which may be administered in a single dose or in multiple doses. Suitable dosage levels may be from about 0.1 to about 250 mg / kg / day, about 0.5 to about 100 mg / kg / day. Suitable dosage levels may be from 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 from 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 tablet form containing from about 1.0 to about 1000 mg of 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 active ingredient. The actual amount of the compound of formula (I) (i.e., active ingredient) will depend on many factors, such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.

[0527] Typically, the compound of formula (I) will be administered in the form of 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 mode of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of illness. The composition can take the form of a tablet, pill, capsule, semisolid, powder, sustained release formulation, solution, suspension, elixir, aerosol or any other suitable composition.

[0528] 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 are preferred, including enteric-coated or delayed-release tablets, pills or capsules) and the bioavailability of the drug substance.

[0529] These compositions are usually composed of a combination of a compound of formula (I) and at least one pharmaceutically acceptable excipient. Acceptable excipients are usually nontoxic, helpful for administration, and do not adversely affect the therapeutic benefits of the compound of formula (I). Such excipients can be any solid, liquid, semisolid or gaseous excipients commonly available to those of ordinary skill in the art in the case of aerosol compositions.

[0530] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, skim milk powder, etc. Liquid and semisolid excipients 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, particularly for injectable solutions, include water, saline, aqueous dextrose and glycols.

[0531] Compounds with formula (I) can be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Injectable preparations can be provided in unit dosage form, for example, in ampoules added with preservatives or in multi-dose containers. Compositions can take the form of suspensions, solutions or emulsions, for example, in oily or aqueous vehicles, and can contain formulations (such as suspending agents, stabilizers and / or dispersants). Formulations can be present in unit doses or multi-dose containers (e.g., sealed ampoules and vials), and can be stored in powder form or stored under freeze drying (lyophilization) conditions, requiring only the immediate addition of sterile liquid carriers (e.g., saline or sterile pyrogen-free water) before use. Temporary injection solutions and suspensions can be prepared by sterile powders, granules and tablets of the aforementioned types.

[0532] Preparations 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 make the preparation 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 dextran. Optionally, the suspension may also contain a suitable stabilizer or an agent that increases the solubility of the compound to allow the preparation of a highly concentrated solution.

[0533] In addition to the aforementioned preparations, compounds with formula (I) can also be formulated into depot preparations. Such long-acting preparations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Therefore, for example, these compounds can be formulated with suitable polymers or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or are formulated into slightly soluble derivatives, such as slightly soluble salts.

[0534] For buccal or sublingual administration, these compositions may take the form of tablets, lozenges, pastilles or gels in conventional manner.Such compositions may comprise the active ingredient in a flavored base such as sucrose and acacia or tragacanth.

[0535] The compounds of formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0536] Certain compounds of formula (I) can be administered topically, i.e., by non-systemic administration. This includes external application of compounds of formula (I) to the epidermis or oral cavity and instillation of such compounds into the ears, eyes, and nose, so that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0537] Preparations suitable for topical application 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, and drops suitable for application to the eye, ear or nose. The active ingredient for topical application can constitute, for example, from 0.001% to 10% w / w (by weight) of the preparation. In certain embodiments, the active ingredient can constitute up to 10% w / w. In other embodiments, it can constitute less than 5% w / w. In certain embodiments, the active ingredient can constitute from 2% w / w to 5% w / w. In other embodiments, it can constitute from 0.1% to 1% w / w of the preparation.

[0538] For administration by inhalation, compounds of formula (I) can be conveniently delivered from insufflators, nebulizer pressurized packs, or other convenient methods of delivering aerosol sprays. Pressurized packs can contain suitable propellants, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. In the case of pressurized aerosols, the dosage unit can be determined by providing a valve for delivering a metered amount. Alternatively, for administration by inhalation or insufflation, compounds of formula (I) can be in the form of dry powder compositions, such as a powder mixture of the compound and a suitable powder matrix (such as lactose or starch). Powder compositions can be presented in unit dosage form, such as capsules, cartridges, gelatin, or blister packs, from which the powder can be administered by means of an insufflator or insufflator. Other suitable pharmaceutical excipients and formulations thereof are described in Remington's Pharmaceutical Sciences edited by EW Martin (Mack Publishing Company, 20th edition, 2000).

[0539] The level of the compound of formula (I) can vary within the full range employed by those skilled in the art. Typically, the formulation will contain (based on weight percentage (wt.%)) from about 0.01 wt.% to 99.99 wt.% of the compound of formula (I) based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1-80 wt.%.

[0540] Combination and combination therapies

[0541] The compound with formula (I) can be used in combination with one or more other drugs for the treatment of diseases or conditions, for which the compound with formula (I) or other drugs can have utility. Such one or more other drugs can be administered simultaneously or sequentially with the compound with formula (I) by a route and its usual amount. When the compound with formula (I) is used simultaneously with one or more other drugs, a pharmaceutical composition containing such other drugs and a unit dosage form of the compound with formula (I) is preferred. However, combination therapy can also include the therapy in which the compound with formula (I) and one or more other drugs are administered with different overlapping schedules. It is also expected that when used in combination with one or more other active ingredients, the compound with formula (I) and other active ingredients can be used with a lower dosage than when each is used alone.

[0542] Therefore, the pharmaceutical compositions of the present disclosure also include those containing one or more additional drugs in addition to the compound having formula (I).

[0543] The above combination includes not only a combination of a compound with formula (I) and a kind of other drugs, but also a combination with two or more other active drugs. Similarly, the compound with formula (I) can be used in combination with other drugs for preventing, treating, controlling, improving diseases or illnesses (for which the compound with formula (I) is useful) or reducing its risk. Such other drugs can be administered simultaneously or sequentially with the compound with formula (I) by a route and its usual amount. When the compound with formula (I) is used simultaneously with one or more other drugs, a pharmaceutical composition containing such other drugs except the compound with formula (I) can be used. Therefore, the pharmaceutical composition of the present disclosure also includes those containing one or more other active ingredients except the compound with formula (I). The weight ratio of the compound of the present disclosure to the second active ingredient can vary, and will depend on the effective dose of each component. Usually, respective effective doses will be used.

[0544] In the case where a subject in need has cancer or is at risk of developing cancer, the subject may be treated with any combination of a compound of formula (I) 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, rametinib, cometinib (GDC-0973), AZD8330, BVD-523, LTT462, neratinib, AMG510 (sotolaciib), ARS853, adagraciib, opranolaciib, divarasib, LY3537982 (2-amino-4-[(4aS)-8-chloro-10-fluoro-2,3,4,4a,5,6-hexahydro-12-oxo-3- (1-oxo-2-propen-1-yl)-1H,12H-pyrazino[2,1-d][1,5]benzazecyclooctin-9-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile), MRTX1133 (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol), RMC-6291, RMC-9805, RMC0708, RMC-8839 and disclosed in PCT application WO 2016049565, WO2016164675, WO 2016168540, WO 2017015562, WO 2017058728, WO 2017058768, WO2017058792, WO 2017058805, WO 2017058807, WO 2017058902, WO 2017058915, WO2017070256, WO 2017087528, WO 2017100546, WO 2017172979, WO 2017201161, WO2018064510, WO 2018068017, WO 2018119183, WO Any RAS inhibitor of 2022 / 187528 and WO 2023 / 284730;

[0545] CSF1R inhibitors (PLX3397, LY3022855, etc.) and CSF1R antibodies (IMC-054, RG7155) TGFβ receptor kinase inhibitors such as LY2157299;

[0546] BTK inhibitors, such as ibrutinib; BCR-ABL inhibitors: imatinib Inilotinib hydrochloride; Nilotinib Dasatinib (BMS-345825); Bosutinib (SKI-606); Ponatinib (AP24534); Bafitinib (INNO406); Danusertib (PHA-739358), AT9283 (CAS1133385-83-7); 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);

[0547] ALK inhibitor: PF-2341066 ( Crizotinib); 5-chloro-N4-(2-(isopropyl-sulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine; GSK1838705 A; CH5424802; Ceritinib (ZYKADIA); TQ-B3139, TQ-B3101 PI3K inhibitor: 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (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);

[0548] Vascular endothelial growth factor (VEGF) receptor inhibitors: Bevacizumab (marketed by Genentech / Roche under the trademark 1H-indazol-6-yl]sulfanyl]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]triazin-6-yloxy)propan-2-yl) 2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, and described in PCT Publication No. WO 01 / 002369). 02 / 066470), pasireotide (also known as SOM230 and described in PCT Publication No. WO 02 / 010192), sorafenib (known under the trademark Sold); AL-2846 MET inhibitors, such as foreitinib, cabozantinib, or crizotinib;

[0549] FLT3 inhibitor - sunitinib malate (trademarked by Pfizer (sold); PKC412 (midostaurin); tanutinib, sorafenib, lestaurine, KW-2449, quizartinib (AC220), and crelanib;

[0550] Epidermal growth factor receptor (EGFR) inhibitors: Gefitinib (trade name: N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3"S")-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butyramide (sold by Boehringer Ingelheim under the trademark ), cetuximab (sold by Bristol-Myers Squibb under the trademark ), panitumumab (sold by Amgen under the trademark Sale);

[0551] HER2 receptor inhibitors: trastuzumab (developed by Genentech / Roche under the trademark ), 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 (marketed by GlaxoSmithKline under the trademark Trastuzumab emtansine (marketed in the United States as Ado-Trastuzumab emtansine, trade name Kadcyla) - an antibody-drug conjugate consisting of the monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent mertansine (DM1);

[0552] HER dimerization inhibitor: Pertuzumab (developed by Genentech under the trademark Sale);

[0553] CD20 antibody: Rituximab (developed by Genentech / Roche under the trademark and Tositumomab (sold by GlaxoSmithKline under the trademark ofatumumab (sold by GlaxoSmithKline under the trademark Sale);

[0554] Tyrosine kinase inhibitors: Erlotinib hydrochloride (manufactured by Genentech / Roche under the trademark ), 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 malate (sold by Pfizer under the trademark ), bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606 and described in U.S. Pat. No. 6,780,996), dasatinib (Bristol-Myers Squibb Company under the trademark ), Armala (also known as pazopanib, marketed by GlaxoSmithKline under the trademark imatinib and imatinib mesylate (sold by Novartis under the trademark and Sale);

[0555] DNA synthesis inhibitors: Capecitabine (available from Roche under the trademark Gemcitabine hydrochloride (sold by Eli Lilly and Company under the trademark Nelarabine ((2R3S,4R,5R)-2-(2-amino-6-methoxy-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol), sold by GlaxoSmithKline under the trademark and Sale);

[0556] Antineoplastic agent: Oxaliplatin (manufactured by Sanofi-Aventis under the trademark sold and described in U.S. Patent No. 4,169,846);

[0557] Human granulocyte colony-stimulating factor (G-CSF) regulators: Filgrastim (marketed by Amgen under the trademark Sale);

[0558] Immunomodulators: Afutuzumab (available from Pegfilgrastim (available from Amgen under the trademark ), lenalidomide (also known as CC-5013, marketed under the trademark Sold under the trademark Sale);

[0559] CD40 inhibitor: daclizumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc); Pro-apoptotic receptor agonist (PARA): duralamine (also known as AMG-951, available from Amgen / Genentech);

[0560] 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);

[0561] Phospholipase A2 inhibitors: Anagrelide (known as Sale);

[0562] BCL-2 inhibitor: 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-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);

[0563] MCl-1 inhibitors: MIK665, S64315, AMG 397, and AZD5991;

[0564] Aromatase inhibitors: Exemestane (marketed by Pfizer under the trademark Letrozole (sold by Novartis under the trademark Anastrozole (sold under the trademark Sale);

[0565] Topoisomerase I inhibitors: irinotecan (developed by Pfizer under the trademark Topotecan hydrochloride (sold by GlaxoSmithKline under the trademark Sale);

[0566] Topoisomerase II inhibitors: Etoposide (also known as VP-16 and etoposide phosphate, sold under the trade name and Teniposide (also known as VM-26, marketed under the trademark Sale);

[0567] mTOR inhibitors: Temsirolimus (developed by Pfizer under the trademark , marketed as lirolimus), lirolimus (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-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0 4'9]trihexatin-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl dimethylphosphinate, also known as AP23573 and MK8669 and described in PCT Publication No. WO 03 / 064383), irolimus (available from Novartis under the trademark Sale);

[0568] Proteasome inhibitors such as carfilzomib, MLN9708, dexamethasone, or bortezomib;

[0569] BET inhibitors, such as INCB054329, OTX015, and CPI-0610;

[0570] LSD1 inhibitors, such as GSK2979552 and INCB059872;

[0571] HIF-2α inhibitors, such as PT2977 and PT2385;

[0572] Osteoclast bone resorption inhibitor: 1-Hydroxy-2-imidazol-1-yl-phosphonoethyl)phosphonic acid monohydrate (available from Novartis under the trademark CD33 antibody-drug conjugate: Gemtuzumab ozogamicin (sold by Pfizer / Wyeth under the trademark Sale);

[0573] CD22 antibody-drug conjugate: inotuzumab (also known as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.);

[0574] CD20 antibody-drug conjugate: Ibritumomab (trademark Sale);

[0575] Somatostatin analogs: Octreotide (also known as octreotide acetate, under the trade name and Sandostatin down sales);

[0576] Synthetic interleukin 11 (IL-11): oprelvekin (developed by Pfizer / Wyeth under the trademark Sale);

[0577] Synthetic erythropoietin: Darbepoietin alfa (developed by Amgen under the trademark Sale);

[0578] Receptor activator of nuclear factor kappa B (RANK) inhibitors: Denosumab (marketed by Amgen under the trademark Sale);

[0579] Thrombopoietin mimetic peptide: Romiplostim (trademarked by Amgen Sale);

[0580] Cell growth stimulator: Parifelmin (developed by Amgen under the trademark Sale);

[0581] 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);

[0582] Anti-CS1 antibody: Elotuzumab (HuLuc63, CAS No. 915296-00-3);

[0583] CD52 antibody: Alemtuzumab (trade name: Sale);

[0584] Histone deacetylase inhibitors (HDIs): Voninostat (marketed by Merck under the trademark Sale);

[0585] Alkylating agents: Temozolomide (marketed by Schering-Plough / Merck under the trademark and Dactinomycin (also known as actinomycin D and marketed under the trademark ), melphalan (also known as L-PAM, L-sarcolyticin, and phenylalanine mustard, sold under the trademark Hexamethylmelamine (also known as hexamethylmelamine (HMM), sold under the trademark Carmustine (sold under the trademark Bendamustine (marketed under the trademark Sales), busulfan (under the trademark and Carboplatin (sold under the trademark CCNU, sold under the trademark Cisplatin (also known as CDDP, sold under the trademark

[0586] and -AQ), chlorambucil (sold under the trademark Cyclophosphamide (sold under the trademark and ), dacarbazine (also known as DTIC, DIC, and imidazole carboxamide, sold under the trademark DTIC- Hexamethylmelamine (also known as hexamethylmelamine (HMM), sold under the trademark Ifosfamide (sold under the trademark Procarbazine (sold under the trademark ), dichloromethyldiethylamine (also known as nitrogen mustard, mustine, and mechloroethamine hydrochloride, sold under the trademark Sold under the trademark ), thiotepa (also known as phosphorothioate amide, TESPA, and TSPA, sold under the trademark Sales; Biological response modifier: BCG (under the trademark and BCG), denileukin (sold under the trademark Sale);

[0587] Antitumor antibiotics: Doxorubicin (trade name: and Bleomycin (sold under the trademark daunomycin (also known as daunomycin hydrochloride, daunomycin, and daunorubicin hydrochloride, sold under the trademark daunomycin liposomes (daunomycin citrate liposomes, sold under the trademark ), mitoxantrone (also known as DHAD, sold under the trademark Sold under the trademark Ellence TM Sold), Idabixin (under the trademark Idamycin Mitomycin C (sold under the trademark Sale);

[0588] Antimicrotubule agents: Estramustine (known under the trade name Sale);

[0589] 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); Epothilone B analog: Ixabepilone (available from Bristol-Myers Squibb under the trademark Sale);

[0590] Heat shock protein (HSP) inhibitors: Tanespimycin (17-allylamino-17-demethoxygeldanamycin, also known as KOS-953 and 17-AAG, available from SIGMA and described in U.S. Pat. No. 4,261,989), NVP-HSP990, AUY922, AT13387, STA-9090, Debio 0932, KW-2478, XL888, CNF2024, TAS-116

[0591] TpoR agonists: Eltrombopag (developed by GlaxoSmithKline under the trade name and Sale);

[0592] Antimitotic agents: docetaxel (marketed by Sanofi under the trademark Adrenal steroid inhibitors: aminoglutethimide (marketed under the trademark Sale);

[0593] Antiandrogen: Nilutamide (trade name and Bicalutamide (sold under the trademark Flutamide (sold under the trademark Fulexin TM Sale);

[0594] Androgens: Fluoxymesterone (trade name Sale);

[0595] 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-1-methyl-4-piperidinyl]-4-chromenone, and described in U.S. Pat. No. 5,621,002);

[0596] CDK4 / 6 inhibitors such as palbociclib, ribociclib, abemaciclib, and tricaspecib; CDK9 inhibitors such as AZD 4573, P276-00, AT7519M, and TP-1287; CDK2 / 4 / 6 inhibitors such as PF-06873600;

[0597] SHP-2 inhibitors, such as TNO155;

[0598] MDM2 / MDMX, MDM2 / p53 and / or MDMX / p53 modulators;

[0599] Gonadotropin-releasing hormone (GnRH) receptor agonists: leuprolide or leuprolide acetate (marketed by Bayer AG under the trademark Sanofi-Aventis and by Abbott Lab Sale);

[0600] Taxane antitumor agents: Cabazitaxel (l-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-ene-2a,4,13a-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropionate), larotaxel ((2α,3ξ,4α,5β,7α,10β,13α)-4,10-bis(acetyloxy)-13-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropionyl}oxy)-l-hydroxy-9-oxo-5,20-epoxy-7,19-cyclotax-11-ene-2-yl benzoate);

[0601] 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. Pat. No. 5,266,573); HPC vaccine: marketed by GlaxoSmithKline Marketed by Merck Iron chelators: Deferasirox (available from Novartis under the trademark Sale);

[0602] Antimetabolites: Cladribine (2-chlorodeoxyadenosine, sold under the brand name 5-fluorouracil (sold under the trademark ), 6-thioguanine (sold under the trademark Pemetrexed (sold under the trademark Spore arabinoside (also known as cytosine arabinoside (Ara-C), sold under the trademark Cytosar- cytarabine liposomes (also known as liposome Ara-C, sold under the trademark DepoCyt TM Sold under the trademark Hydroxyurea (sold under the trademark Droxia TM and Mylocel TMFludarabine (sold under the trademark Fluuridine (sold under the trademark Cladribine (also known as 2-chlorodeoxyadenosine (2-CdA), marketed under the trademark Leustatin TM Sold under the trademark and Trexall TM Sold under the trademark Sale);

[0603] Bisphosphonates: Pamidronate (known under the trade name Zoledronic acid (sold under the trademark demethylating agent: 5-azacitidine (sold under the trademark Sold under the trademark Sale);

[0604] Plant alkaloids: Taxol protein-bound (trademark ), vinblastine (also known as vinblastine sulfate, vinblastine, and VLB, sold under the trademark Alkaban- and vincristine (also known as vincristine sulfate, LCR, and VCR, sold under the trademark and Vincasar Sales), Changchunruibin (trademark Taxol (marketed under the trademarks Taxol and Onxal TM Sale);

[0605] Retinoids: alitretinoin (known under the brand name Retinoic acid (all-trans retinoic acid, also known as ATRA, sold under the trademark Isotretinoin (13-cis-retinoic acid, sold under the trademark and Bexarotene (sold under the trademark Sale);

[0606] Glucocorticoids: Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and under the trademark Ala- Hydrocortisone phosphate, Solu- Hydrocort and ), dexamethasone ((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), prednisolone (sold under the trademark Delta- and Sold under the trademark Liquid and methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, and M- and Solu- Sale);

[0607] Cytokines: Interleukin-2 (also known as aldesleukin and IL-2, known by the trade name leukin-11 (also known as Oprelleukin, marketed under the trademark Interferon alpha (also known as IFN-α, marketed under the trademark A and Roferon-

[00209] Estrogen receptor down-regulator: Fulvestrant (trademark Sale);

[0608] Anti-estrogen: Tamoxifen (known under the brand name toremifene (sold under the trademark Sale);

[0609] Selective estrogen receptor modulators (SERMs): Raloxifene (trade name: Sale);

[0610] Leukocyte stimulating hormone-releasing hormone (LHRH) agonists: Goserelin (trade name Progesterone: megestrol acetate (also known as megestrol acetate, sold under the trademark Sale);

[0611] Miscellaneous cytotoxic agents: Arsenic trioxide (known under the trademark Asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the trademark and Sale);

[0612] 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 CD27, 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, arginase, 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.

[0613] In some embodiments, the inhibitor of the 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 or pembrolizumab or PDR001. In some embodiments, the anti-PD1 antibody is pembrolizumab.

[0614] In some embodiments, the inhibitor of the 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).

[0615] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, for example, an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, for example, an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of GITR, for example, an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or MK-4166, INCAGN01876 or MK-1248. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of OX40, for example, 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.

[0616] Compounds of formula (I) can also be used to increase or enhance immune responses, including increasing immune responses to antigens; improving immunization, including increasing vaccine efficacy; and increasing inflammation. In some embodiments, the compounds of the invention can be used to enhance immune responses to vaccines, including but not limited to Listeria vaccines, oncolytic virus vaccines, and cancer vaccines, such as (Tumor cell vaccines transfected with granulocyte-macrophage colony stimulating factor (GM-CF) gene). Anticancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses. Other immunomodulators also include those that block immune cell migration, such as antagonists of chemokine receptors (including CCR2 and CCR4); Sting agonists and Toll receptor agonists.

[0617] Other anticancer agents also include those that enhance the immune system, such as adjuvants or adoptive T cell transfers. The compounds of the present application may be effective in combination with CAR (chimeric antigen receptor) T cell therapy as a booster for T cell activation.

[0618] The compounds of formula (I) may also be used in combination with the following adjunctive treatments: Antinausea drugs: NK-1 receptor antagonists: Casopitant (available from GlaxoSmithKline under the trademark and sales); and

[0619] Cytoprotectants: Amifostine (trademark Sold), leucovorin (also known as calcium folinate, leucovorin factor and folinic acid).

[0620] Examples

[0621] The following preparations of intermediates (references) and compounds (examples) of formula (I) 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 intended to illustrate and represent it.

[0622] Synthesis Example

[0623] Reference 1

[0624] 4-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)

[0625] Synthesis of Isoindoline-1,3-dione 2,2,2-Trifluoroacetate

[0626]

[0627] Step 1: tert-Butyl (14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate

[0628]

[0629] A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (500.0 mg, 1.81 mmol, 1.00 equiv), tert-butyl (14-amino-3,6,9,12-tetraoxatetradecyl)carbamate (609.0 mg, 1.81 mmol, 1.00 equiv), DIPEA (467.9 mg, 3.62 mmol, 2.00 equiv) in DMF (6.0 mL) was stirred at 90 ° C under a nitrogen atmosphere for 16 h. The mixture was cooled, diluted with water, and then extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and then concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give the title compound as a yellow solid.

[0630] Step 2: 4-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, 2,2,2-trifluoroacetate

[0631]

[0632] TFA (0.3 mL, 3.92 mmol, 46.67 equiv) was added to a stirred solution of tert-butyl (14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate (50 mg, 0.084 mmol, 1.00 equiv) in DCM (1.0 mL) at 0° C. under nitrogen atmosphere. The mixture was stirred for 2 h and then concentrated to give the crude title compound as a light yellow oil.

[0633] Reference 2

[0634] Synthesis of 2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-acetamido)ethoxy)ethoxy)ethyl methanesulfonate

[0635]

[0636] Step 1: tert-Butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetate

[0637]

[0638] A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (1.5 g, 5.47 mmol, 1.00 equiv), tert-butyl 2-bromoacetate (1.3 g, 6.66 mmol, 1.22 equiv) and KCO (1.1 g, 7.96 mmol, 1.46 equiv) in DMF (20.0 mL) was stirred at room temperature for 2 h. The mixture was diluted with H0 and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over NaSO and concentrated to give the title compound as a white solid.

[0639] Step 2: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid

[0640]

[0641] A solution of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-acetic acid (1.0 g, 2.57 mmol, 1.00 equiv) and TFA (5.0 mL) in DCM (10.0 mL) was stirred at room temperature for 2 h. The mixture was concentrated and the residue was triturated with diethyl ether to give the title compound as a white solid.

[0642] Step 3: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)acetamide

[0643]

[0644] HATU (513 mg, 1.35 mmol, 1.5 eq) was added to a stirred solution of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (300 mg, 0.90 mmol, 1.00 eq), 2-(2-(2-aminoethoxy)ethoxy)ethanol (201 mg, 1.35 mmol, 1.50 eq) and DIPEA (348 mg, 2.69 mmol, 2.99 eq) in DMF (6.0 mL) at 0°C and the mixture was stirred at room temperature for 1 h. The mixture was diluted with H2O and extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to give the crude title compound as a yellow oil which was used in the next step without further purification.

[0645] Step 4: 2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy)ethoxy)ethyl methanesulfonate

[0646]

[0647] MsCl (298 mg, 2.60 mmol, 1.50 equiv) was added to a stirred solution of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)acetamide (800 mg, 1.73 mmol, 1.00 equiv) and TEA (524 mg, 5.18 mmol, 2.99 equiv) in DCM (8.0 mL) at 0°C, and the mixture was stirred at 0°C for 1 h. The mixture was diluted with H2O and extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4, concentrated and purified by flash silica gel chromatography (DCM:MeOH=50:1) to give the title compound as a white solid.

[0648] Reference 3

[0649] Synthesis of 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy)-ethyl methanesulfonate

[0650]

[0651] Step 1: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(2-(2-hydroxyethoxy)-ethyl)acetamide

[0652]

[0653] A mixture of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (180 mg, 0.54 mmol, 1.00 equiv), 2-(2-aminoethoxy)ethan-1-ol (85 mg, 0.81 mmol, 1.50 equiv), HATU (308 mg, 0.81 mmol, 1.50 equiv) and DIPEA (209 mg, 1.62 mmol, 3.00 equiv) in DMF (5.0 mL) was stirred at 0 °C for 1 h. The reaction mixture was diluted with H2O and extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to give the crude title compound as a yellow oil which was used in the next step without further purification.

[0654] Step 2: 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy)-ethyl methanesulfonate

[0655]

[0656] MsCl (162 mg, 1.41 mmol, 1.48 equiv) was slowly added to a stirred solution of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(2-(2-hydroxyethoxy)ethyl)acetamide (400 mg, 0.95 mmol, 1.00 equiv) and TEA (288 mg, 2.85 mmol, 3.00 equiv) in DCM (8.0 mL) at 0°C. The resulting mixture was stirred at 0°C for 1 h, diluted with H2O and extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4, concentrated, and the residue was purified by flash silica gel chromatography (DCM:MeOH=50:1) to give the title compound as a white solid.

[0657] Reference 4

[0658] Synthesis of 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12-trioxa-3-azatetradec-14-yl methanesulfonate

[0659]

[0660] Step 1: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)acetamide

[0661]

[0662] HATU (513 mg, 1.35 mmol, 1.50 equiv) and DIPEA (348 mg, 2.69 mmol, 3.00 equiv) were added to a mixture of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (300 mg, 0.90 mmol, 1.00 equiv) and 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethan-1-ol (259 mg, 1.34 mmol, 1.49 equiv) in DMF (5.0 mL) at 0°C. The mixture was stirred at 0°C for 1 h, diluted with H2O, and then extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude title compound as a yellow oil, which was used in the next step without further purification.

[0663] Step 2: 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12-trioxa-3-azatetradec-14-yl methanesulfonate

[0664]

[0665] MsCl (271 mg, 2.37 mmol, 1.50 equiv) was added slowly to a stirred solution of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(2-(2-(2-hydroxyethoxy)ethoxy)-ethoxy)ethyl)acetamide (800 mg, 1.58 mmol, 1.00 equiv) and TEA (479 mg, 4.73 mmol, 3.00 equiv) in DCM (8.0 mL) at 0°C. The mixture was stirred at 0°C for 1 h, diluted with H2O and extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4, concentrated and purified by flash silica gel chromatography (DCM:MeOH=50:1) to give the title compound as a white solid.

[0666] Reference 5

[0667] Synthesis of 2-(2-(2-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-acetamido)ethoxy)ethyl methanesulfonate

[0668]

[0669] Step 1: tert-Butyl 2-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetate

[0670]

[0671] Di-tert-butyl azodicarboxylate (897 mg, 3.90 mmol, 3.02 equiv) was slowly added to a stirred solution of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetate (500 mg, 1.29 mmol, 1.00 equiv), MeOH (125 mg, 3.90 mmol, 3.02 equiv) and PPh3 (681 mg, 2.60 mmol, 2.02 equiv) in THF (80.0 mL) at 0°C. The resulting mixture was stirred at room temperature overnight, diluted with H2O and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, concentrated and purified by flash silica gel chromatography (DCM:MeOH=100:1) to give the title compound as a yellow oil.

[0672] Step 2: 2-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid

[0673]

[0674] A solution of tert-butyl 2-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetate (400 mg, 0.99 mmol, 1.00 equiv) and TFA (2.0 mL) in DCM (4.0 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated and the residue was triturated with diethyl ether to give the title compound as a yellow solid.

[0675] Step 3: N-(2-(2-hydroxyethoxy)ethyl)-2-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide

[0676]

[0677] A solution of 2-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (350 mg, 1.01 mmol, 1.00 equiv), 2-(2-aminoethoxy)ethan-1-ol (158 mg, 1.50 mmol, 1.49 equiv), DIPEA (387 mg, 2.99 mmol, 2.96 equiv) and HATU (570 mg, 1.50 mmol, 1.49 equiv) in DMF (6.0 mL) was stirred at 0 °C for 1 h. The reaction mixture was diluted with H2O and extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to give the crude title compound as a brown oil.

[0678] Step 4: 2-(2-(2-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy)ethyl methanesulfonate

[0679]

[0680] MsCl (275 mg, 2.40 mmol, 1.48 equiv) was added to a stirred solution of N-(2-(2-hydroxy-ethoxy)ethyl)-2-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (700 mg, 1.62 mmol, 1.00 equiv) and TEA (485 mg, 4.79 mmol, 2.96 equiv) in DCM (8.0 mL) at 0°C. After stirring at 0°C for 1 h, the reaction mixture was diluted with H2O and extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4, concentrated and purified by flash silica gel chromatography (DCM:MeOH=30:1) to give the title compound as a white solid.

[0681] Reference 6

[0682] Synthesis of 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-17-yl methanesulfonate

[0683]

[0684] Step 1: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(14-hydroxy-3,6,9,12-tetraoxatetradecyl)acetamide

[0685]

[0686] A mixture of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (300 mg, 0.90 mmol, 1.00 equiv), 14-amino-3,6,9,12-tetraoxatetradecan-1-ol (320 mg, 1.35 mmol, 1.50 equiv), HATU (513 mg, 1.35 mmol, 1.50 equiv) and DIPEA (348 mg, 2.69 mmol, 2.99 equiv) in DMF (6.0 mL) was stirred at 0 °C for 1 h. The reaction mixture was diluted with H2O and extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to give the crude title compound as a yellow oil which was used in the next step without further purification.

[0687] Step 2: 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-17-yl methanesulfonate

[0688]

[0689] MsCl (271 mg, 2.37 mmol, 1.63 equiv) was slowly added to a stirred solution of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(14-hydroxy-3,6,9,12-tetraoxatetradecyl)acetamide (800 mg, 1.45 mmol, 1.00 equiv) and TEA (479 mg, 4.73 mmol, 326 equiv) in DCM (8.0 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 h, diluted with H2O and extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4, concentrated and purified by flash silica gel chromatography (DCM:MeOH=50:1) to give the title compound as a white solid.

[0690] Reference 7

[0691] Synthesis of 5-(3-(4-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-2-(2,6-dioxo-piperidin-3-yl)isoindoline-1,3-dione

[0692]

[0693] Step 1: tert-Butyl (1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)carbamate

[0694]

[0695] A solution of 4-fluorobenzenesulfonyl chloride (2.6 g, 13.36 mmol, 1.07 equiv) in DCM (10.0 mL) was added dropwise to a stirred solution of tert-butyl piperidin-4-ylcarbamate (2.5 g, 12.48 mmol, 1.00 equiv) in DCM (10.0 mL) and TEA (5.2 mL) at 0 ° C. The resulting mixture was stirred at room temperature overnight, concentrated and diluted with DCM. The mixture was stirred at room temperature for 1 h and filtered to give the title compound as a white solid.

[0696] Step 2: (1-((4-((1-Benzhydrylazetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)-carbamic acid tert-butyl ester

[0697]

[0698] To a stirred solution of 1-dibenzylazetidine-3-ol (1.0 g, 4.18 mmol, 1.00 equiv) in THF (5.0 mL) was added NaH (60%, 251 mg, 6.28 mmol, 1.50 equiv) at 0 ° C under N2. The resulting mixture was stirred at room temperature for 15 min, then a solution of tert-butyl (1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)carbamate (1.65 g, 4.60 mmol, 1.10 equiv) in THF (5.0 mL) was slowly added, and the mixture was stirred at room temperature overnight. The mixture was diluted with H2O and then extracted with DCM. The combined organic layers were washed with NaCl aqueous solution, dried over Na2SO4, filtered, and then concentrated. The residue was purified by silica gel flash column (PE:EA=3:1) to give the title compound as a white solid.

[0699] Step 3: tert-Butyl (1-((4-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0700]

[0701] A mixture of tert-butyl (1-((4-((1-benzhydrylazetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (500 mg, 0.87 mmol, 1.00 equiv), Pd(OH)2 (300 mg, 20% on carbon) in THF (20.0 mL) was stirred at 50° C. under H2 (50 psi) overnight. The mixture was cooled, filtered and concentrated. The residue was purified by silica gel flash column (DCM:MeOH=10:1) to give the title compound as a white solid.

[0702] Step 4: tert-Butyl (1-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0703]

[0704] A mixture of tert-butyl (1-((4-(-87-azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (100 mg, 0.24 mmol, 1.00 equiv), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (74 mg, 0.27 mmol, 1.13 equiv) and DIPEA (94 mg, 0.73 mmol, 3.04 equiv) in NMP (1.5 mL) was stirred at 140 ° C. under microwave irradiation for 2 h. The mixture was cooled, diluted with water, extracted with DCM, and then concentrated. The residue was purified by silica gel flash column (PE:EA=1:1) to give the title product as a yellow solid.

[0705] Step 5: 5-(3-(4-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0706]

[0707] A mixture of tert-butyl (1-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-isoindolin-5-yl)-88-azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (144 mg, 0.21 mmol, 1.00 equiv), TFA (1.0 mL) in DCM (4.0 mL) was stirred at rt for 2 h. The mixture was concentrated to give the title compound as a yellow oil which was used in the next step without further purification.

[0708] Reference 8

[0709] 5-((3-(4-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)methyl)-2-

[0710] Synthesis of (2,6-dioxo-piperidin-3-yl)isoindoline-1,3-dione

[0711]

[0712] Step 1: 5-(Bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0713]

[0714] NBS (196 mg, 1.10 mmol, 1.10 equiv) and AIBN (32.8 mg, 0.20 mmol, 0.20 equiv) were added to a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-methylisoindoline-1,3-dione (272 mg, 1.00 mmol, 1.00 equiv) in MeCN (15.0 mL), and the mixture was stirred at 80° C. under N2 overnight. The mixture was cooled and concentrated, and the residue was purified by flash column chromatography (EA:PE=0-100%) to give the title compound as a white solid.

[0715] Step 2: tert-Butyl (1-((4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0716]

[0717] A mixture of tert-butyl (1-((4-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (100 mg, 0.24 mmol, 1.00 equiv, from Ref. 7, Step 3), 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (111 mg, 0.32 mmol, 1.33 equiv) and KCO (67 mg, 0.48 mmol, 2.00 equiv) in MeCN (2.0 mL) was stirred overnight at 80° C. The reaction mixture was cooled, concentrated and purified by silica gel flash column (DCM:MeOH=20:1) to give the title compound as a white solid.

[0718] Step 3: 5-((3-(4-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)methyl)-2-(2,6-dioxo-piperidin-3-yl)isoindoline-1,3-dione

[0719]

[0720] A mixture of tert-butyl (1-((4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (33 mg, 0.048 mmol, 1.00 equiv) and TFA (1.0 mL) in DCM (4.0 mL) was stirred at rt for 3 h. The mixture was concentrated to give the title compound as a yellow solid.

[0721] Reference 9

[0722] Synthesis of 4-amino-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-ethoxy)ethoxy)ethyl)piperidine-1-sulfonamide

[0723]

[0724] Step 1: tert-Butyl (2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)-ethoxy)ethyl)carbamate

[0725]

[0726] A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (100 mg, 0.36 mmol, 1.10 equiv), tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (81.7 mg, 0.33 mmol, 1.00 equiv), DIPEA (127 mg, 0.98 mmol, 2.97 equiv) in NMP (1.5 mL) was stirred at 140 °C under microwave for 2 h. The mixture was cooled and diluted with ethyl acetate, and then washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (EA:PE=1:3) to give the title compound as a yellow oil.

[0727] Step 2: 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0728]

[0729] A mixture of tert-butyl (2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-isoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)carbamate (180 mg, 0.36 mmol, 1.00 equiv), TFA (0.5 mL) in DCM (2.0 mL) was stirred at rt for 2 h. The mixture was concentrated to give the title compound as a yellow oil which was used in the next step without further purification.

[0730] Step 3: tert-Butyl (1-(chlorosulfonyl)piperidin-4-yl)carbamate

[0731]

[0732] Thionyl chloride (81 mg, 0.60 mmol, 1.20 equiv) was added to a stirred solution of tert-butyl piperidin-4-ylcarbamate (100 mg, 0.50 mmol, 1.00 equiv) and TEA (76 mg, 0.75 mmol, 1.50 equiv) in DCM (2.0 mL) at 0 ° C and the mixture was stirred for 3 h at 0 ° C. The mixture was diluted with water and then extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and then concentrated to give the title compound as a white solid, which was used directly in the next step.

[0733] Step 4: tert-butyl (1-(N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-ethoxy)ethoxy)ethyl)sulfamoyl)piperidin-4-yl)carbamate

[0734]

[0735] To a stirred solution of 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxo-piperidin-3-yl)isoindoline-1,3-dione (70 mg, 0.17 mmol, 1.00 equiv) and tert-butyl (1-(chloro-sulfonyl)piperidin-4-yl)carbamate (51.9 mg, 0.17 mmol, 1.00 equiv) in DCM (2.0 mL) was added TEA (52.4 mg, 0.52 mmol, 3.00 equiv). The mixture was stirred at 35 °C overnight and then concentrated. The residue was purified by silica gel chromatography (DCM:MeOH=30:1) to give the title compound as a yellow oil.

[0736] Step 5: 4-amino-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-ethoxy)ethoxy)ethyl)piperidine-1-sulfonamide

[0737]

[0738] A mixture of tert-butyl (l-(N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)sulfamoyl)piperidin-4-yl)carbamate (60 mg, 0.090 mmol, 1.00 equiv) in DCM (2.0 mL) and TFA (0.5 mL) was stirred at rt for 2 h. The mixture was concentrated to give the title compound as a yellow oil.

[0739] Reference 10

[0740] Synthesis of 4-amino-N-(3-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)-propyl)-N-methylpiperidine-1-sulfonamide

[0741]

[0742] Step 1: 4-Bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0743]

[0744] A mixture of 4-bromoisobenzofuran-1,3-dione (22.8 g, 100.44 mmol, 1.00 equiv), 3-aminopiperidine-2,6-dione (18.0 g, 109.36 mmol, HCl, 1.09 equiv) and KOAc (29.4 g, 299.54 mmol, 2.98 equiv) in HOAc (200.0 mL) was stirred at 90° C. for 16 h. The reaction mixture was cooled, diluted with ice water, and then stirred at 0° C. for 1 h. The mixture was filtered, and the filter cake was dried in vacuo to give the title compound as a grey solid.

[0745] Step 2: tert-Butyl methyl(3-(prop-2-yn-1-yloxy)propyl)carbamate

[0746]

[0747] A mixture of tert-butyl (3-hydroxypropyl)(methyl)carbamate (3.0 g, 15.85 mmol, 1.00 equiv), 3-bromoprop-1-yne (3.0 g, 25.22 mmol, 1.59 equiv), 40% aqueous NaOH (30.0 mL) and tetrabutylammonium hydrogen sulfate (270 mg, 0.80 mmol, 0.050 equiv) in DCM (50.0 mL) was stirred overnight at room temperature under N2. The mixture was diluted with water and then extracted with DCM. The organic layer was washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography (EA:PE=0 to 100%) to give the title compound as a yellow oil.

[0748] Step 3: tert-Butyl (3-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)propyl)(methyl)carbamate

[0749]

[0750] A mixture of 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.38 g, 4.09 mmol, 1.00 equiv), tert-butyl methyl(3-(prop-2-yn-1-yloxy)-propyl)carbamate (1.4 g, 6.16 mmol, 1.51 equiv), CuI (78 mg, 0.41 mmol, 0.10 equiv), TEA (7.5 g, 74.12 mmol, 18.12 equiv) and Pd(PPh3)2Cl2 (288 mg, 0.41 mmol, 0.10 equiv) in DMF (15.0 mL) was stirred at 80°C under N2 for 2 h. The mixture was cooled, diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4, and concentrated. Purification by flash column chromatography (EA:PE = 0 to 100%) gave the title compound as a yellow oil.

[0751] Step 4: tert-butyl (3-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)propyl)-(methyl)carbamate

[0752]

[0753] A mixture of tert-butyl (3-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)propyl)(methyl)carbamate (1.86 g, 3.85 mmol, 1.00 equiv), Pd(OH)2 / C (0.93 g, 50% w / w) in THF (50.0 mL) was stirred at room temperature under H2 atmosphere overnight. The reaction mixture was filtered, concentrated and the residue was purified by flash chromatography (EA:PE=0 to 100%) to give the title compound as a yellow oil.

[0754] Step 5: 2-(2,6-dioxopiperidin-3-yl)-4-(3-(3-(methylamino)propoxy)propyl)isoindoline-1,3-dione

[0755]

[0756] A mixture of tert-butyl (3-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)propyl)(methyl)carbamate (1.45 g, 2.97 mmol, 1.00 equiv), TFA (1.0 mL) in DCM (10.0 mL) was stirred at room temperature under N for 2 h. The mixture was concentrated and the pH was adjusted to 9 using aqueous NaCO solution, and then the mixture was extracted with DCM. The organic layer was washed with water, brine, dried over NaSO, and then concentrated to give the title compound as a yellow oil.

[0757] Step 6: tert-butyl (1-(N-(3-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)-propyl)-N-methylsulfamoyl)piperidin-4-yl)carbamate

[0758]

[0759] A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-(3-(3-(methylamino)propoxy)-propyl)isoindoline-1,3-dione (150 mg, 0.39 mmol, 1.00 equiv), tert-butyl (1-(chlorosulfonyl)-piperidin-4-yl)carbamate (173 mg, 0.58 mmol, 1.49 equiv) and TEA (118 mg, 1.17 mmol, 3.00 equiv) in DCM (2.0 mL) was stirred at 40 °C under N2 overnight. The mixture was cooled, diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4, and concentrated to give the title compound as a yellow solid.

[0760] Step 7: 4-amino-N-(3-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)propyl)-N-methylpiperidine-1-sulfonamide

[0761]

[0762] To a stirred solution of tert-butyl (1-(N-(3-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)propyl)-N-methylsulfamoyl)piperidin-4-yl)carbamate (200 mg, 0.31 mmol, 1.00 equiv) in DCM (2.0 mL) was added TFA (0.5 mL). The resulting mixture was stirred at room temperature under N for 3 h, concentrated and the pH was adjusted to 9 using aqueous Na2CO3 solution, and then extracted with DCM. The organic layer was washed with water, brine, dried over Na2SO4, concentrated to give the title compound as a yellow oil, which was used in the next step without further purification.

[0763] Reference 11

[0764] Synthesis of 4-(3-(2-(2-aminoethoxy)ethoxy)propyl)-2-(2,6-dioxopiperidin-3-yl)-isoindoline-1,3-dione

[0765]

[0766] Step 1: tert-Butyl (2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate

[0767]

[0768] NaH (1.2 g, 60%, 30.00 mmol, 1.50 equiv) was added in batches to a stirred solution of tert-butyl (2-(2-hydroxyethoxy)ethyl)carbamate (4.1 g, 19.98 mmol, 1.00 equiv) in THF (50.0 mL) at 0°C, and the mixture was stirred for 1 h. 3-Bromoprop-1-yne (2.83 g, 23.79 mmol, 1.19 equiv) was then added at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 h, poured into water and extracted with DCM. The organic layer was washed with water, brine, dried over Na2SO4, concentrated and purified by flash column chromatography (EA:PE=0 to 100%) to give the title compound as a yellow oil.

[0769] Step 2: 4-amino-N-(2-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)ethoxy)ethyl)piperidine-1-sulfonamide

[0770]

[0771] Proceeding similarly as described above in steps 3-7 of reference 10, but using tert-butyl (2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate provided the title compound.

[0772] Reference 12

[0773] Synthesis of 5-(3-(3-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0774]

[0775] Step 1: Benzyl (1-((3-methoxyphenyl)sulfonyl)piperidin-4-yl)carbamate

[0776]

[0777] A solution of 3-methoxybenzene-1-sulfonyl chloride (3.24 g, 15.68 mmol, 1.05 equiv) in DCM (20.0 mL) was added dropwise to a stirred solution of piperidin-4-ylcarbamic acid benzyl ester (3.5 g, 14.94 mmol, 1.00 equiv) and TEA (4.52 g, 44.82 mmol, 3.00 equiv) in DCM (50.0 mL) at 0°C and the mixture was stirred at room temperature for 3 h. The mixture was diluted with DCM, and the organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (EA:PE=1:3) to give the title compound as a white solid.

[0778] Step 2: 3-((4-aminopiperidin-1-yl)sulfonyl)phenol

[0779]

[0780] A solution of benzyl (1-((3-methoxyphenyl)sulfonyl)piperidin-4-yl)carbamate (3.5 g, 8.66 mmol, 1.00 equiv) in CF3SO3H (20.0 mL) was stirred at 100° C. under N2 for 3 h. The reaction mixture was cooled and concentrated to give the title compound as a brown oil which was used in the next step without further purification.

[0781] Step 3: tert-Butyl (1-((3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamate

[0782]

[0783] A solution of (Boc)2O (852 mg, 3.91 mmol, 1.00 equiv) in DCM (5.0 mL) was added to a stirred solution of 3-((4-aminopiperidin-1-yl)sulfonyl)phenol (1.0 g, 3.91 mmol, 1.00 equiv) in DCM (20.0 mL) and TEA (1.18 g, 11.73 mmol, 3.00 equiv) at 0°C. The mixture was stirred at room temperature for 2 h, diluted with DCM and the organic layer was washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by flash silica gel chromatography (ACN / water = (35%-75%)) to give the title compound as a white solid.

[0784] Step 4: 1-Benzhydrylazetidin-3-yl methanesulfonate

[0785]

[0786] To a stirred solution of 1-benzhydrylazetidine-3-ol (500 mg, 2.09 mmol, 1.00 equiv) in DCM (10.0 mL) was added TEA (633 mg, 6.27 mmol, 3.00 equiv) and MsCl (479 mg, 4.18 mmol, 2.00 equiv) at 0°C. The mixture was stirred at room temperature overnight, diluted with DCM, and then washed with water. The organic layer was washed with brine, dried over Na2SO4, concentrated, and then purified by silica gel chromatography (EA:PE=1:3) to give the title compound as a white solid.

[0787] Step 5: (1-((3-((1-benzhydrylazetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)-carbamic acid tert-butyl ester

[0788]

[0789] A mixture of tert-butyl (1-((3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamate (533 mg, 1.49 mmol, 1.00 equiv), 1-benzhydrylazetidin-3-yl methanesulfonate (570 mg, 1.79 mmol, 1.20 equiv), CsCO (1.46 g, 4.49 mmol, 3.00 equiv) in DMSO (10.0 mL) was stirred at 90 ° C under N for 3 h. The mixture was cooled, diluted with EtOAc, and the organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by silica gel chromatography (EA:PE=1:3) to give the title compound as a light yellow solid.

[0790] Step 6: tert-Butyl (1-((3-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0791]

[0792] To a stirred solution of tert-butyl (1-((3-((1-benzhydrylazetidin-3-yl)oxy)phenyl)sulfonyl)-piperidin-4-yl)carbamate (400 mg, 0.69 mmol, 1.00 equiv) in MeOH (15.0 mL) was added Pd(OH)2 / C (20 wt.%, 250 mg) and AcOH (0.5 mL) at room temperature. The resulting mixture was stirred at 50 °C under H2 (50 psi) overnight. The reaction mixture was cooled and filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (MeOH:DCM=1:15) to give the title compound as a white solid.

[0793] Step 7: tert-Butyl (1-((3-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)-oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0794]

[0795] Proceeding similarly as described in step 4 of reference 7 above, but using tert-butyl (1-((3-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione provided the title compound.

[0796] Step 8: 5-(3-(3-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0797]

[0798] Proceeding similarly as described in step 5 of reference 7 above, but using tert-butyl (1-((3-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)oxy)phenyl)-sulfonyl)piperidin-4-yl)carbamate provided the title compound.

[0799] Reference 13

[0800] 3-(4-(3-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)piperidin-4-yl)-oxy)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine

[0801] Synthesis of -2,6-dione

[0802]

[0803] Step 1: tert-Butyl 4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate

[0804]

[0805] A mixture of 3-(3-methyl-2-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (300 mg, 0.76 mmol, 1.00 equiv, prepared by proceeding as described in steps 1 and 2 of reference 11 above), tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (421 mg, 1.51 mmol, 2.00 equiv), NaI (114 mg, 0.76 mmol, 1.00 equiv), KCO (634.8 mg, 4.59 mmol, 6.00 equiv) in ACN (5.0 mL) was stirred at 70° C. overnight. The reaction mixture was cooled, concentrated, and then purified by silica gel chromatography (DCM / MeOH=20 / 1) to give the title compound as a yellow solid.

[0806] Step 2: 3-(3-methyl-2-oxo-4-(3-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0807]

[0808] Proceeding similarly as described in step 5 of reference 10 above, but using tert-butyl 4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate provided the title compound.

[0809] Step 3: tert-butyl (1-((4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate

[0810]

[0811] Proceeding similarly as described in step 6 of reference 10 above, but using 3-(3-methyl-2-oxo-4-(3-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione and tert-butyl (1-(chlorosulfonyl)piperidin-4-yl)carbamate provided the title compound.

[0812] Step 4: 3-(4-(3-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)piperidin-4-yl)-oxy)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0813]

[0814] Proceeding similarly as described in step 7 of reference 10 above, but using tert-butyl (1-((4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate to provide the title compound.

[0815] Reference 14

[0816] Synthesis of 3-(4-(3-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0817]

[0818] Step 1: 3-Hydroxy-1-(4-methoxybenzyl)piperidine-2,6-dione

[0819]

[0820] t-BuOK (2.3 g, 20.50 mmol, 1.02 eq) was added to a stirred mixture of N-(4-methoxybenzyl)-5-oxotetrahydrofuran-2-carboxamide (5.0 g, 20.06 mmol, 1.00 eq) in THF (50.0 mL) at -78 °C. After stirring for 1 h at -78 °C, the mixture was quenched with saturated NH4Cl aqueous solution and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated, and then purified by silica gel chromatography (PE / EA=3 / 1) to give the title compound as a white solid.

[0821] Step 2: 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate

[0822]

[0823] Trifluoromethanesulfonic anhydride (3.2 g, 11.34 mmol, 1.49 equiv) was slowly added to a stirred solution of 3-hydroxy-1-(4-methoxybenzyl)piperidine-2,6-dione (1.9 g, 7.62 mmol, 1.00 equiv) and pyridine (1.2 g, 15.17 mmol, 1.99 equiv) in DCM (40.0 mL) at 0 °C. After stirring for 2 h at 0 °C, the reaction mixture was quenched with water and then extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, concentrated, and then purified by silica gel chromatography (PE / EA=5 / 1) to give the title compound as a yellow oil.

[0824] Step 3: 3-(4-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxy-benzyl)piperidine-2,6-dione

[0825]

[0826] To a stirred solution of 7-bromo-1-methyl-1H-benzo[d]imidazol-2(3H)-one (1.1 g, 4.84 mmol, 1.23 equiv) in THF (30.0 mL) was added t-BuOK (632 mg, 5.63 mmol, 1.43 equiv) at 0°C. After stirring at 0°C for 0.5 h, a solution of 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (1.5 g, 3.93 mmol, 1.00 equiv) in THF (10.0 mL) was added at 0°C. The reaction mixture was stirred at 0°C for 1 h, diluted with water, and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated, and the residue was purified by silica gel chromatography (PE / EA=2 / 1) to give the title compound as a white solid.

[0827] Step 4: 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0828]

[0829] A mixture of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (900 mg, 1.96 mmol, 1.00 equiv) in toluene / methanesulfonic acid=2 / 1 (3.0 mL) was stirred at 120° C. for 3 h. The reaction mixture was cooled, concentrated and poured into ice water. The resulting mixture was filtered and the filter cake was dried to give the title compound as a white solid.

[0830] Step 5: tert-Butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate

[0831]

[0832] NaH (60%, 240 mg, 6.00 mmol, 1.21 eq) was added to a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1.0 g, 4.97 mmol, 1.00 eq) in THF (20.0 mL) at 0 ° C, followed by 3-bromoprop-1-yne (704 mg, 5.92 mmol, 1.19 eq). The resulting mixture was stirred at room temperature for 2 h, quenched with water, and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated, and then purified by silica gel chromatography (PE / EA=10 / 1) to give the title compound as a white solid.

[0833] Step 6: tert-Butyl 4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate

[0834]

[0835] Proceeding similarly as described in step 3 of reference 10 above, but using 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione and tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate in DMF provided the title compound.

[0836] Step 7: 3-(3-methyl-2-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0837]

[0838] Proceeding similarly as described in step 5 of reference 10 above, but using tert-butyl 4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate provided the title compound.

[0839] Step 8: tert-Butyl (1-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate

[0840]

[0841] Proceeding similarly as described in step 6 of reference 10 above, but using 3-(3-methyl-2-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione and tert-butyl (1-(chlorosulfonyl)piperidin-4-yl)carbamate in DMF provided the title compound.

[0842] Step 9: 3-(4-(3-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0843]

[0844] Proceeding similarly as described in step 7 of reference 10 above, but using tert-butyl (1-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate provided the title compound.

[0845] Reference 15

[0846] Synthesis of 4-amino-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-cyclohexyl)-N-methylpiperidine-1-sulfonamide 2,2,2-trifluoroacetate

[0847]

[0848] Step 1: 4-Aminocyclohexanone hydrochloride

[0849]

[0850] A mixture of tert-butyl (4-oxocyclohexyl)carbamate (500 mg, 2.34 mmol, 1.00 equiv) in a solution of HCl in ethyl acetate (1.0 M, 10.0 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated to give the title compound, which was used in the next step without further purification.

[0851] Step 2: 2-(2,6-dioxopiperidin-3-yl)-4-((4-oxocyclohexyl)amino)isoindoline-1,3-dione

[0852]

[0853] A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (276 mg, 1.00 mmol, 1.00 equiv) and 4-aminocyclohexanone hydrochloride (300 mg, 2.00 mmol, 2.00 equiv) in NMP (2.5 mL) was stirred at 140 ° C under microwave for 3 h. The reaction mixture was cooled, diluted with DCM, and then washed with brine. The organic layer was concentrated, and the residue was then triturated with DCM and filtered to give the title compound as a yellow solid.

[0854] Step 3: 2-(2,6-dioxopiperidin-3-yl)-4-((4-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione

[0855]

[0856] To a stirred mixture of 2-(2,6-dioxopiperidin-3-yl)-4-((4-oxocyclohexyl)amino)-isoindoline-1,3-dione (200 mg, 0.54 mmol, 1.00 equiv) and methylamine (40% in MeOH, 210 mg, 2.71 mmol, 5.02 equiv) in MeOH / DCE (2.0 mL / 2.0 mL) was added a drop of AcOH. The resulting mixture was stirred at room temperature for 1 h, and then NaBH(OAc)3 (345 mg, 1.63 mmol, 3.02 equiv) was added. The reaction mixture was stirred at room temperature overnight, diluted with DCM, washed with saturated aqueous NaHCO3 solution, and then washed with brine. The organic layer was dried over Na2SO4 and then concentrated to give the title compound as a yellow solid.

[0857] Step 4: tert-butyl (1-(N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-cyclohexyl)-N-methylsulfamoyl)piperidin-4-yl)carbamate

[0858]

[0859] Proceeding similarly as described in step 6 of reference 10 above, but using 2-(2,6-dioxopiperidin-3-yl)-4-((4-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione and tert-butyl (1-(chlorosulfonyl)piperidin-4-yl)carbamate provided the title compound.

[0860] Step 5: 4-amino-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexyl)-N-methylpiperidine-1-sulfonamide 2,2,2-trifluoroacetate

[0861]

[0862] Proceeding similarly as described in step 7 of reference 10 above, but using tert-butyl (1-(N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexyl)-N-methylsulfamoyl)piperidin-4-yl)carbamate provided the title compound.

[0863] Reference 16

[0864] Synthesis of tert-butyl 4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]-imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate

[0865]

[0866] Step 1: tert-Butyl 4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]-imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate

[0867]

[0868] Proceeding similarly as described in step 3 of reference 10 above, but using 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione and tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate provided the title compound.

[0869] Reference 17

[0870] 5-((3-(3-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)methyl)-2-

[0871] Synthesis of (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0872]

[0873] Step 1: tert-Butyl (1-((3-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)-azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0874]

[0875] Proceeding similarly as described in step 5 of reference 8 above, but using tert-butyl (1-((3-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate and 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione provided the title compound.

[0876] Step 2: 5-((3-(3-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0877]

[0878] Proceeding similarly as described in step 6 of reference 8 above, but using (1-((3-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)azetidin-3-yl)oxy)phenyl)-sulfonyl)piperidin-4-yl)carbamate and TFA provided the title compound.

[0879] Reference 18

[0880] Synthesis of 4-amino-N-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propoxy)ethyl)piperidine-1-sulfonamide

[0881]

[0882] Step 1: tert-Butyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate

[0883]

[0884] Proceeding similarly as described in step 2 of reference 10 above, but using tert-butyl (2-hydroxyethyl)carbamate and 3-bromoprop-1-yne provided the title compound.

[0885] Step 2: 4-amino-N-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propoxy)ethyl)piperidine-1-sulfonamide

[0886]

[0887] Proceeding similarly as described above in steps 3-7 of reference 10, but using tert-butyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate provided the title compound.

[0888] Reference 19

[0889] Synthesis of tert-butyl (1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)piperidin-4-yl)(methyl)carbamate

[0890]

[0891] Step 1: 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carbaldehyde

[0892]

[0893] A mixture of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-piperidine-2,6-dione (700 mg, 2.07 mmol, 1.00 equiv), TEA (630 mg, 6.23 mmol, 3.01 equiv), Pd(dppf)Cl2 (230.6 mg, 0.32 mmol, 0.15 equiv), Et3SiH (733 mg, 6.30 mmol, 3.04 equiv) in DMF (10 mL) was stirred overnight at 80 °C under a 15 psi carbon monoxide atmosphere. The reaction mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and then concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give the title compound as a yellow oil.

[0894] Step 2: tert-Butyl (1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)piperidin-4-yl)(methyl)carbamate

[0895]

[0896] A mixture of 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]-imidazole-4-carboxaldehyde (360 mg, 1.25 mmol, 1.00 equiv), tert-butyl N-methyl(piperidin-4-yl)carbamate (403 mg, 1.88 mmol, 1.50 equiv) in THF / DMF=2 / 1 (5 mL) was stirred at room temperature for 2 h. NaBH(OAC)3 (413 mg, 1.95 mmol, 1.60 equiv) was added at room temperature. After the reaction was complete, the mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. The residue was purified by preparative HPLC to give the title compound as a yellow solid.

[0897] Reference 20

[0898] Synthesis of tert-butyl (2-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)(methyl)amino)benzyl)(methyl)amino)ethyl)(methyl)carbamate

[0899]

[0900] Step 1: Dimethyl 3-iodophthalate

[0901]

[0902] To a stirred mixture of 3-iodophthalic acid (5.00 g, 17.12 mmol, 1.00 equiv), Na2CO3 (5.40 g, 50.95 mmol, 2.98 equiv) in DMF (30 mL) was added iodomethane (7.30 g, 51.43 mmol, 3.00 equiv) at room temperature. The reaction mixture was stirred at 70 ° C overnight, cooled, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (PE / EA=10 / 1) to give the title compound as a white solid.

[0903] Step 2: 4-(((tert-Butyldimethylsilyl)oxy)methyl)aniline

[0904]

[0905] A mixture of (4-aminophenyl)methanol (2.00 g, 16.24 mmol, 1.00 equiv), DMAP (595 mg, 4.87 mmol, 0.30 equiv), TEA (2.00 g, 19.76 mmol, 1.22 equiv) and TBSCl (2.70 g, 17.91 mmol, 1.10 equiv) in DMF (40 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and then concentrated. The residue was purified by silica gel chromatography (PE / EA=10 / 1) to give the title compound as a colorless oil.

[0906] Step 3: Dimethyl 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino)phthalate

[0907]

[0908] A mixture of dimethyl 3-iodophthalate (3.00 g, 9.37 mmol, 1.00 equiv), 4-(tert-butyldimethylsilyloxymethyl)-aniline (2.67 g, 11.25 mmol, 1.20 equiv), Pd2(dba)3 (436 mg, 0.48 mmol, 0.051 equiv), Cs2CO3 (6.11 g, 18.75 mmol, 2.00 equiv), BINAP (143 mg, 0.23 mmol, 0.025 equiv) in toluene (30.0 mL) was stirred at 120° C. under a nitrogen atmosphere overnight. The reaction mixture was cooled, concentrated and the residue was purified by silica gel chromatography (PE / EA=10 / 1) to give the title compound as a yellow oil.

[0909] Step 4: Dimethyl 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)(methyl)amino)phthalate

[0910]

[0911] A mixture of 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino)-phthalic acid dimethyl ester (1.50 g, 3.49 mmol, 1.00 equiv), iodomethane (991 mg, 6.98 mmol, 2.00 equiv), CsCO (3.41 g, 10.47 mmol, 3.00 equiv) in DMF (30.0 mL) was stirred at 20 ° C under a nitrogen atmosphere for 8 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered, and then concentrated. The residue was purified by silica gel chromatography (PE / EA=5 / 1) to give the title compound as a yellow oil.

[0912] Step 5: 3-[(4-Hydroxymethyl-phenyl)-methyl-amino]-phthalic acid dimethyl ester

[0913]

[0914] A solution of TBAF in THF (3.0 M, 2.0 mL) was added to a stirred solution of dimethyl 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-(methyl)amino)phthalate (500 mg, 1.13 mmol, 1.00 equiv) in THF (5.0 mL) at room temperature. After 2 h, the mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and then concentrated. The residue was purified by silica gel chromatography (PE / EA=2 / 1) to give the title compound as a yellow oil.

[0915] Step 6: Dimethyl 3-((4-formylphenyl)(methyl)amino)phthalate

[0916]

[0917] A mixture of dimethyl 3-[(4-hydroxymethyl-phenyl)methylamino]phthalate (300 mg, 0.91 mmol, 1.00 equiv) and MnO2 (800 mg, 9.20 mmol, 10.11 equiv) in DCM (10.0 mL) was stirred overnight at room temperature. The reaction mixture was filtered and concentrated to give the title compound as a yellow oil which was used in the next step without further purification.

[0918] Step 7: Dimethyl 3-((4-(((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl)phenyl)(methyl)amino)phthalate

[0919]

[0920] A mixture of dimethyl 3-((4-formylphenyl)(methyl)amino)phthalate (300 mg, 0.92 mmol, 1.00 equiv), methyl-(2-methylamino-ethyl)-carbamic acid tert-butyl ester (205 mg, 1.09 mmol, 1.18 equiv) and a drop of AcOH in DCE (5.0 mL) was stirred at room temperature for 2 h. NaBH(OAc) (290 mg, 1.37 mmol, 1.49 equiv) was then added and stirred for 4 h. The reaction mixture was concentrated and purified by preparative HPLC to give the title compound as a white solid.

[0921] Step 8: 3-((4-(((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl)phenyl)(methyl)amino)phthalic acid

[0922]

[0923] A mixture of dimethyl 3-((4-(((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl)phenyl)(methyl)amino)phthalate (250 mg, 0.50 mmol, 1.00 equiv) and NaOH (40 mg, 1.00 mmol, 2.00 equiv) in EtOH / H2O=2 / 1 (5.0 mL) was stirred at 80°C for 5 h. The reaction mixture was concentrated and purified by preparative HPLC to give the title compound as a white solid.

[0924] Step 9: tert-Butyl (2-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)(methyl)amino)benzyl)(methyl)amino)ethyl)(methyl)carbamate

[0925]

[0926] A mixture of 3-((4-(((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl)phenyl)(methyl)amino)phthalic acid (120 mg, 0.25 mmol, 1.00 equiv) and 3-aminopiperidine-2,6-dione hydrochloride (41 mg, 0.25 mmol, 1.00 equiv) in pyridine (3.0 mL) was stirred at 100 °C overnight. The reaction mixture was cooled and concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the title compound as a yellow solid.

[0927] Reference 21

[0928] Synthesis of tert-butyl (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)carbamate

[0929]

[0930] Step 1: tert-Butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]-imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0931]

[0932] A mixture of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-piperidine-2,6-dione (100 mg, 0.30 mmol, 1.00 equiv), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (119 mg, 0.38 mmol, 1.27 equiv), X-Phos-Pd-G3 (38 mg, 0.045 mmol, 0.15 equiv) and K3PO4 (191 mg, 0.90 mmol, 3.0 equiv) in 1,4-dioxane / H2O=10 / 1 (2.2 mL) was stirred at 60° C. for 3 h. The reaction mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and then concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give the title compound as a brown solid.

[0933] Step 2: tert-Butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-1-carboxylate

[0934]

[0935] A mixture of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (70 mg, 0.16 mmol, 1.00 equiv), 10% Pd / C (30 mg) and Pd(OH)2 (30 mg) in THF (10 mL) was stirred at 50° C. under 50 psi H2 pressure. The reaction mixture was filtered and then concentrated to give the title compound as a white solid.

[0936] Step 3: 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione TFA salt

[0937]

[0938] A mixture of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-1-carboxylate (60 mg, 0.14 mmol, 1.00 equiv) and TFA (0.5 mL) in DCM (2 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated to give the title compound as a yellow oil.

[0939] Step 4: tert-Butyl (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)carbamate

[0940]

[0941] To a stirred mixture of 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione TFA salt (60 mg, 0.13 mmol, 1.00 equiv) in THF (5.0 mL) and DMF (1.0 mL) was added a drop of AcOH. After stirring at room temperature for 0.5 h, methyl(3-oxopropyl)carbamic acid tert-butyl ester (63.6 mg, 0.34 mmol, 2.0 equiv) was added at room temperature. The mixture was stirred at 20 ° C for 2 h, followed by the addition of NaBH(OAC) 3 (72 mg, 0.34 mmol, 2.62 equiv). After stirring at room temperature overnight, the mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and then concentrated. The residue was purified by silica gel chromatography (DCM / MeOH = 50 / 1) to give the title compound as a yellow solid.

[0942] Reference 22

[0943] Synthesis of tert-butyl (14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-14-oxo-3,6,9,12-tetraoxatetradecyl)carbamate

[0944]

[0945] Step 1: 2,2-Dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-oic acid

[0946]

[0947] NaH (60% in mineral oil, 204 mg, 5.10 mmol, 3.00 equiv) was added to a stirred solution of tert-butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate (500 mg, 1.70 mmol, 1.00 equiv) in DMF (2 mL) at 0 °C under nitrogen. After stirring at 0 °C for 1 h, 2-iodoacetic acid (793 mg, 4.26 mmol, 2.51 equiv) was added at 0 °C. The resulting mixture was slowly warmed to room temperature and then stirred overnight. The reaction mixture was quenched with H2O at 0 °C, the pH was adjusted to 2-3 with 1N HCl aqueous solution, and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and then concentrated to give the title compound as a yellow oil.

[0948] Step 2: tert-Butyl (14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-14-oxo-3,6,9,12-tetraoxatetradecyl)carbamate

[0949]

[0950] To a stirred solution of 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-oic acid (372 mg, 1.06 mmol, 2.00 equiv) in THF (6 mL) was added isobutyl chloroformate (109 mg, 0.80 mmol, 1.51 equiv) and N-methylmorpholine (161 mg, 1.59 mmol, 3.00 equiv) at 0°C, followed by dropwise addition of a solution of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (145 mg, 0.53 mmol, 1.00 equiv) in DMF (2 mL). The resulting mixture was stirred at 30°C overnight, quenched with saturated NaHCO3, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and then concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:1) to give the title compound as a yellow solid.

[0951] Reference 23

[0952] Synthesis of tert-butyl (1-((3-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0953]

[0954] Step 1: Benzyl 4-(3-(3-((4-((tert-Butyloxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenoxy)-azetidin-1-yl)piperidine-1-carboxylate

[0955]

[0956] A solution of tert-butyl (1-((3-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (100 mg, 0.24 mmol, 1.00 equiv), benzyl 4-oxopiperidine-1-carboxylate (113 mg, 0.48 mmol, 2.00 equiv) and 1 drop of AcOH in THF (3.0 mL) was stirred at room temperature for 1 h, followed by the addition of NaBH(OAc)3 (102 mg, 0.48 mmol, 2.00 equiv). The reaction mixture was stirred at room temperature overnight, diluted with water, and then extracted with DCM. The organic layer was concentrated and then purified by silica gel flash column (DCM / MeOH=20 / 1) to give the title compound as a white solid.

[0957] Step 2: (1-((3-((1-(piperidin-4-yl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)-carbamic acid tert-butyl ester

[0958]

[0959] To a stirred solution of benzyl 4-(3-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)piperidine-1-carboxylate (60 mg, 0.095 mmol, 1.00 equiv) in MeOH (10.0 mL) was added 10% Pd / C (20 mg). The resulting mixture was stirred at 45 °C under H2 atmosphere overnight. The reaction mixture was filtered and concentrated to give the title compound as a white solid.

[0960] Step 3: tert-Butyl (1-((3-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0961]

[0962] A mixture of tert-butyl (1-((3-((1-(piperidin-4-yl)azetidin-3-yl)oxy)phenyl)-sulfonyl)piperidin-4-yl)carbamate (39.6 mg, 0.080 mmol, 1.00 equiv), 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (38 mg, 0.12 mmol, 1.50 equiv), CsCO (78 mg, 0.24 mmol, 3.00 equiv), Xantphos (15 mg, 0.027 mmol, 0.34 equiv) and Pd(OAc) (15 mg, 0.067 mmol, 0.84 equiv) in 1,4-dioxane (2.0 mL) was stirred at 100° C. under N atmosphere overnight. The mixture was cooled and then filtered. The filtrate was diluted with water and then extracted with DCM. The organic layer was concentrated and then purified by preparative TLC (DCM / MeOH=10 / 1) to give the title compound as a yellow solid.

[0963] Reference 24

[0964] (1-((3-((1-(azetidin-3-yl)piperidin-4-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)-

[0965] Synthesis of tert-butyl carbamate

[0966]

[0967] Step 1: tert-Butyl (1-((3-(piperidin-4-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0968]

[0969] The title compound was prepared by proceeding as described in steps 1 to 6 of reference 12 using 1-benzhydrylpiperidin-4-yl methanesulfonate.

[0970] Step 2: (1-((3-((1-(azetidin-3-yl)piperidin-4-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)-carbamic acid tert-butyl ester

[0971]

[0972] Tert-butyl (1-((3-(piperidin-4-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate was converted to the title compound by proceeding analogously as described in steps 1 and 2 of reference 23 above using benzyl 3-oxoazetidine-1-carboxylate.

[0973] Reference 25

[0974] Synthesis of tert-butyl (1-((3-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-oxy)ethyl)piperidin-4-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0975]

[0976] Step 1: Methyl 3-(2-hydroxyethoxy)-2-methylbenzoate

[0977]

[0978] A mixture of methyl 3-hydroxy-2-methylbenzoate (2.50 g, 15.04 mmol, 1.00 equiv) and 1,3-dioxolane-2-one (1.98 g, 22.48 mmol, 1.50 equiv), KCO (2.07 g, 14.98 mmol, 1.00 equiv) in DMF (30.0 mL) was stirred at 120 ° C under N for 2 h. The reaction mixture was cooled, diluted with water, and then extracted with EtOAc. The organic layer was washed with water, brine, dried over NaSO, filtered, and then concentrated. The residue was purified by silica gel chromatography (EA: PE = 1: 4) to give the title compound as a white solid.

[0979] Step 2: Methyl 2-(bromomethyl)-3-(2-hydroxyethoxy)benzoate

[0980]

[0981] A mixture of methyl 3-(2-hydroxyethoxy)-2-methylbenzoate (1.50 g, 7.14 mmol, 1.00 equiv.), NBS (1.46 g, 8.20 mmol, 1.15 equiv.) and AIBN (117 mg, 0.71 mmol, 0.10 equiv.) in CCl4 (45.0 mL) was stirred for 3 h at 75 ° C in N2. The mixture was cooled and then concentrated. The residue was purified by silica gel chromatography (EA: PE = 1: 3) to give the title compound as a white solid.

[0982] Step 3: 3-(4-(2-Hydroxyethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0983]

[0984] 3-aminopiperidine-2,6-dione hydrochloride (1.48 g, 8.99 mmol, 1.30 equiv) and TEA (1.04 g, 10.28 mmol, 1.49 equiv) were added to a stirred solution of methyl 2-(bromomethyl)-3-(2-hydroxyethoxy)benzoate (2.00 g, 6.92 mmol, 1.00 equiv) in ACN (70.0 mL). The resulting mixture was stirred at 80 ° C. overnight under N2, cooled and then concentrated. The residue was purified by silica gel chromatography (DCM: MeOH = 20: 1) to give the title compound as a blue solid.

[0985] Step 4: 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethyl 4-methylbenzenesulfonate

[0986]

[0987] To a stirred solution of 3-(4-(2-hydroxyethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (500 mg, 1.64 mmol, 1.00 equiv) in DCM (10.0 mL) was added TEA (333 mg, 3.29 mmol, 2.00 equiv), TsCl (377 mg, 1.98 mmol, 1.21 equiv) and DMAP (20 mg, 0.16 mmol, 0.10 equiv) at 0°C. The resulting mixture was stirred at room temperature overnight, diluted with DCM, washed with water, brine, dried over Na2SO4, filtered, and then concentrated. The residue was purified by silica gel chromatography (DCM:MeOH=30:1) to give the title compound as a green solid.

[0988] Step 5: Benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate

[0989]

[0990] To a stirred solution of 4-hydroxypiperidine-1-carboxylic acid benzyl ester (2.00 g, 8.50 mmol, 1.00 equiv) in DCM (20.0 mL) was added TEA (2.57 g, 25.40 mmol, 3.00 equiv) and MsCl (1.16 g, 10.13 mmol, 1.20 equiv) at 0 ° C. The resulting mixture was stirred overnight at room temperature, diluted with water, and then extracted with DCM. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated to give the crude title compound as a yellow oil, which was used in the next step without further purification.

[0991] Step 6: tert-Butyl (1-((3-(piperidin-4-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0992]

[0993] Benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate was converted to the title compound by proceeding similarly as described in steps 5-6 of reference 12 above.

[0994] Step 7: tert-Butyl (1-((3-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethyl)piperidin-4-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0995]

[0996] A mixture of 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethyl 4-methyl-benzenesulfonate (50 mg, 0.11 mmol, 1.10 equiv), tert-butyl (1-((3-(piperidin-4-yloxy)phenyl)-sulfonyl)piperidin-4-yl)carbamate (44 mg, 0.10 mmol, 1.00 equiv), KI (15 mg, 0.090 mmol, 0.90 equiv) and DIPEA (35 mg, 0.27 mmol, 2.70 equiv) in ACN (2.0 mL) was stirred at 100 °C under microwave for 3 h. The reaction mixture was cooled and concentrated, and the residue was purified by silica gel chromatography (DCM:MeOH=20:1) to give the title compound as a yellow oil.

[0997] Reference 26

[0998] Synthesis of tert-butyl (1-((3-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)-ethyl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0999]

[1000] Tert-butyl (1-((3-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate was converted to the title compound by proceeding analogously to that described in step 7 of reference 25. MS (ESI): 444.1;

[1001] Reference 27

[1002] Synthesis of tert-butyl (1-((3-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1003]

[1004] A mixture of tert-butyl (1-((3-(piperidin-4-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (300 mg, 0.93 mmol, 1.00 equiv), 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (448 mg, 1.02 mmol, 1.10 equiv), CsCO (603 mg, 1.86 mmol, 2.00 equiv), Pd(OAc) (41 mg, 0.19 mmol, 0.20 equiv) and X-Phos (176 mg, 0.37 mmol, 0.40 equiv) in 1,4-dioxane (10.0 mL) was stirred at 105 °C under N for 2 days. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over NaSO and concentrated. The residue was purified by flash chromatography to give the title compound as a yellow solid.

[1005] Reference 28

[1006] Synthesis of tert-butyl (1-((3-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1007]

[1008] Step 1: Benzyl 4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

[1009]

[1010] A mixture of tert-butyl (1-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (3.00 g, 7.18 mmol, 1.00 equiv), benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (3.20 g, 9.33 mmol, 1.30 equiv), X-Phos-Pd-G3 (608.0 mg, 0.72 mmol, 0.10 equiv) and K3PO4 (4.57 g, 21.54 mmol, 3.00 equiv) in 1,4-dioxane (70.0 mL) and H2O (7.0 mL) was stirred at 60°C under N2 for 6 h. The resulting mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (4:1) to give the title compound as a yellow solid.

[1011] Step 2: tert-Butyl (1-((3-(piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1012]

[1013] A mixture of benzyl 4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (4.00 g, 7.20 mmol, 1.00 equiv) and Pd / C (800 mg) in MeOH (40.0 mL) was stirred at 50° C. under H (50 psi) for 16 h. The mixture was filtered and concentrated to give the title compound as a white solid.

[1014] Step 3: Benzyl 4-((4-(3-((4-(tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-1-yl)methyl)piperidine-1-carboxylate

[1015]

[1016] To a solution of tert-butyl (1-((3-(piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (3.00 g, 7.10 mmol, 1.00 equiv) in DCE (20.0 mL) and MeOH (20.0 mL) was added benzyl 4-formylpiperidine-1-carboxylate (2.63 g, 10.65 mmol, 1.50 equiv) and AcOH (426.0 mg, 7.10 mmol, 1.00 equiv), and the solution was stirred at room temperature for 1 h. NaBHCN (1.34 g, 21.30 mmol, 3.00 equiv) was added and the mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (60: 1) to give the title compound as a white solid.

[1017] Step 4: (1-((3-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)-carbamic acid tert-butyl ester

[1018]

[1019] A mixture of benzyl 4-((4-(3-((4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-sulfonyl)phenyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (3.80 g, 5.81 mmol, 1.00 equiv) and Pd / C (800 mg) in MeOH (40.0 mL) was stirred at 50° C. under H (50 psi) for 16 h. The mixture was filtered and concentrated to give the title compound as a white solid.

[1020] Step 5: Methyl 4-(4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)-phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-cyanobenzoate

[1021]

[1022] A solution of tert-butyl (1-((3-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)-sulfonyl)piperidin-4-yl)carbamate (2.80 g, 5.40 mmol, 1.00 equiv), methyl 2-cyano-4-fluorobenzoate (1.06 g, 5.94 mmol, 1.10 equiv) and DIEA (2.09 g, 16.20 mmol, 3.00 equiv) in DMSO (30.0 mL) was stirred at 120 °C under N for 16 h. The mixture was cooled to room temperature, diluted with water, and then extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and then concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (100: 1) to give the title compound as a brown solid.

[1023] Step 6: Methyl 4-(4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)-phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-formylbenzoate

[1024]

[1025] A mixture of methyl 4-(4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-sulfonyl)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-cyanobenzoate (1.01 g, 1.50 mmol, 1.00 equiv), NaH2PO2.HO (1.59 g, 15.00 mmol, 10.00 equiv) and Raney nickel (1.60 g) in pyridine (10.0 mL), HO (5.0 mL) and AcOH (5.0 mL) was stirred at 70 °C under nitrogen atmosphere for 16 h. The resulting mixture was diluted with EtOAc and washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (80: 1) to give the title compound as a light yellow solid.

[1026] Step 7: tert-Butyl (1-((3-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1027]

[1028] A mixture of 3-aminopiperidine-2,6-dione hydrochloride (126 mg, 0.77 mmol, 1.30 equiv) and DIEA (184 mg, 1.43 mmol, 2.40 equiv) in anhydrous DCM (5.0 mL) was stirred at room temperature for 10 min, then a solution of methyl 4-(4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-formylbenzoate (400 mg, 0.59 mmol, 1.00 equiv) in anhydrous DCM (5.0 mL) and AcOH (134 mg, 2.23 mmol, 3.80 equiv) was added. The mixture was stirred at 45 °C under N2 for 3 h. The mixture was cooled to 0 °C and NaBH(OAc)3 (375 mg, 1.77 mmol, 3.00 equiv) was added. The mixture was stirred at room temperature for 1 h, and then at 45 °C under N2 for 16 h. The mixture was cooled, diluted with water, and then extracted with DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (40:1) to give the title compound as a yellow solid.

[1029] Reference 29

[1030] Synthesis of tert-butyl (1-((3-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1031]

[1032] Step 1: 3-5-Bromo-1-oxoisoindolin-2-ylpiperidine-2,6-dione

[1033]

[1034] A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (20.00 g, 64.91 mmol, 1.00 equiv) and 3-aminopiperidine-2,6-dione (11.71 g, 71.41 mmol, 1.10 equiv), KCO (26.87 g, 194.71 mmol, 3.00 equiv) in DMF was stirred overnight at 70 ° C under N atmosphere. After the reaction was complete, the mixture was poured into water and extracted with DCM. The combined organic layers were washed with water, dried over anhydrous NaSO, filtered and concentrated. The residue was purified by flash column (PE: EA = 2: 1) to give the title compound as a white solid.

[1035] Step 2: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate

[1036]

[1037] A mixture of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.00 g, 3.11 mmol, 1.00 equiv), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.25 g, 4.04 mmol, 1.30 equiv), K3PO4 (800 mg, 3.73 mmol, 1.20 equiv) and Pd(dppf)Cl2 (114 mg, 0.16 mmol, 0.05 equiv) in DMF (10.0 mL) was stirred at 90° C. for 12 h. The mixture was concentrated and purified by silica gel column chromatography eluting with PE / EA (1:2) to give the title compound as a yellow solid.

[1038] Step 3: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate

[1039]

[1040] To a stirred solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.47 mmol, 1.00 equiv) in THF (2.0 mL) was added Pd / C (40 mg, 20% w / w). The resulting mixture was stirred at 40 °C under H2 for 12 h, filtered and concentrated to give the title compound as a white solid.

[1041] Step 4: 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[1042]

[1043] DCM / TFA=4:1 (2.5 mL) was added to a stirred solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate (100 mg, 0.234 mmol, 1.00 equiv), and the mixture was stirred at room temperature for 2 h. The mixture was concentrated to give the title compound as a brown solid.

[1044] Step 5: tert-butyl (1-((3-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1045]

[1046] To a stirred solution of 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (76.60 mg, 0.23 mmol, 1.00 equiv) in THF (1.0 mL) was added DMF (1.0 mL), HCOOH (1 drop) and tert-butyl (1-((3-(4-formylpiperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (105.60 mg, 0.23 mmol, 1.00 equiv). The resulting mixture was stirred at 45 °C for 0.5 h. NaBH3CN (29.40 mg, 0.47 mmol, 2.00 equiv) was added at room temperature, and the reaction 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 water and brine, and concentrated. The residue was purified by silica gel column chromatography eluting with DCM:MeOH (0-100%) to give the title compound as a white solid.

[1047] Reference 30

[1048] Synthesis of tert-butyl (1-((3-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)-methyl)piperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1049]

[1050] Step 1: Benzyl 4-(dimethoxymethyl)piperidine-1-carboxylate

[1051]

[1052] To a mixture of benzyl 4-formylpiperidine-1-formate (1.00 g, 2.40 mmol, 1.00 equiv) in MeOH (9.0 mL) was added p-TsOH (38 mg, 0.20 mmol, 0.05 equiv) and trimethoxymethane (2.14 g, 20.22 mmol, 5.00 equiv). The mixture was stirred at room temperature for 12 h and then extracted with EtOAc. The crude product was purified by silica gel column chromatography eluting with PE / EtOAc (10: 1) to give the title compound as a colorless oil.

[1053] Step 2: 4-(Dimethoxymethyl)piperidine

[1054]

[1055] To a mixture of benzyl 4-(dimethoxymethyl)piperidine-1-carboxylate (948 mg, 3.23 mmol, 1.00 equiv) in MeOH (10.0 mL) was added Pd / C (400 mg), and the reaction mixture was stirred at room temperature under H overnight. The resulting mixture was filtered through celite, and the filtrate was concentrated to give the title compound as a colorless oil.

[1056] Step 3: (1-((3-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)-carbamic acid tert-butyl ester

[1057]

[1058] A mixture of 4-(dimethoxymethyl)piperidine (100 mg, 0.63 mmol, 1.20 equiv), K2CO3 (215 mg, 1.56 mmol, 3.00 equiv), CuI (20 mg, 0.104 mmol, 0.20 equiv), L-proline (18 mg, 0.16 mmol, 0.30 equiv) and tert-butyl (1-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (219 mg, 0.52 mmol, 1.00 equiv) in DMSO (4.0 mL) was stirred at 90 °C overnight. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give the title compound as a white solid.

[1059] Step 4: tert-Butyl (1-((3-(4-formylpiperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1060]

[1061] To a mixture of tert-butyl (1-((3-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (640 mg, 1.29 mmol, 1.00 equiv) in DCM (4.0 mL) was added TFA (4.0 mL), and the mixture was stirred at 45 ° C overnight. The reaction mixture was concentrated and dissolved in DCM (5.0 mL), followed by the addition of TEA (261 mg, 2.58 mmol, 2.00 equiv) and (Boc) O (562 mg, 2.58 mmol, 2.00 equiv). The solution was stirred at room temperature for 4 h and concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3: 1) to give the title compound as a yellow solid.

[1062] Step 5: tert-butyl (1-((3-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)-methyl)piperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1063]

[1064] This compound was prepared analogously to that described in reference 29, step 5.

[1065] Reference 31

[1066] Synthesis of 3-(5-(azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[1067]

[1068] Step 1: (1-(tert-Butyloxycarbonyl)azetidin-3-yl)zinc(II) iodide

[1069]

[1070] To a mixture of Zn powder (300 mg, 4.59 mmol, 1.30 equivalents) in DMA (3.0 mL), 1,2-dibromoethylene (66 mg, 0.35 mmol, 0.10 equivalents) was added 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 equivalents) was added. After stirring the mixture for 30 min, a solution of tert-butyl 3-iodine azetidine-1-formate (1.00 g, 3.53 mmol, 1.00 equivalents) in DMA (1.0 mL) was added dropwise. The mixture was stirred at 65 ° C under N2 for 2 h, cooled to room temperature and used in the next step without further purification.

[1071] Step 2: tert-Butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidine-1-carboxylate

[1072]

[1073] A solution of (1-(tert-butoxycarbonyl)azetidin-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), 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 (EA) to give the title compound as a brown solid.

[1074] Step 3: 3-(5-(azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[1075]

[1076] To a solution of tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidine-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 at rt for 3 h. The resulting mixture was concentrated to give the crude product as a brown oil.

[1077] Reference 32

[1078] Synthesis of tert-butyl (1-((3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1079]

[1080] Step 1: Benzyl 4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazine-1-carboxylate

[1081]

[1082] A mixture of tert-butyl (1-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (5.00 g, 11.96 mmol, 1.00 equiv), KCO (5.78 g, 41.86 mmol, 3.50 equiv), CuI (0.45 g, 2.39 mmol, 0.20 equiv), L-proline (0.41 g, 3.59 mmol, 0.30 equiv) and benzyl piperazine-1-carboxylate (3.43 g, 15.55 mmol, 1.30 equiv) in DMSO (25.00 mL) was stirred at 100 °C for 12 h. The mixture was quenched with H0 and extracted with EtOAc. The organic layer was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to give the title compound as a white solid.

[1083] Step 2: tert-Butyl (1-((3-(piperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1084]

[1085] The title compound was prepared analogously to that described in step 2 of reference 30.

[1086] Step 3: Benzyl 4-((4-(3-((4-(tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate

[1087]

[1088] A mixture of tert-butyl (1-((3-(piperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (1.07 g, 2.52 mmol, 1.00 equiv), AcOH (3 drops) and benzyl 4-formylpiperidine-1-carboxylate (933 mg, 3.78 mmol, 1.50 equiv) in MeOH (10.0 mL) was stirred at 45 °C for 1 h. The solution was cooled to room temperature and NaBHCN (475 mg, 7.56 mmol, 3.00 equiv) was added. The mixture was stirred at room temperature for 12 h, and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO and concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (60: 1) to give the title compound as a white solid.

[1089] Step 4: tert-butyl (1-((3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1090]

[1091] Using analogous procedures as described in steps 4-7 of reference 28, benzyl 4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate was converted to the title compound.

[1092] Reference 33

[1093] tert-Butyl (1-((3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1094]

[1095] Step 1: (1-((3-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)sulfonyl)piperidin-4-yl)-carbamic acid tert-butyl ester

[1096]

[1097] A mixture of tert-butyl (1-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (1.00 g, 2.40 mmol, 1.00 equiv), KCO (1.16 g, 8.40 mmol, 3.50 equiv), CuI (91 mg, 0.480 mmol, 0.20 equiv), L-proline (83 mg, 0.72 mmol, 0.30 equiv) and 1,4-dioxa-8-azaspiro[4.5]decane (412 mg, 2.88 mmol, 1.20 equiv) in DMSO (10.0 mL) was stirred at 90 °C overnight. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give the title compound as a yellow solid.

[1098] Step 2: tert-Butyl (1-((3-(4-oxopiperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1099]

[1100] A mixture of tert-butyl (1-((3-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)-sulfonyl)piperidin-4-yl)carbamate (624 mg, 1.30 mmol, 1.00 equiv), TsOH.HO (49 mg, 0.26 mmol, 0.20 equiv) in acetone (6.0 mL) and HO (12.0 mL) was stirred at 60 °C overnight. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give the title compound as a yellow solid.

[1101] Step 3: tert-Butyl (1-((3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1102]

[1103] To a mixture of tert-butyl (1-((3-(4-oxopiperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (44 mg, 1.02 mmol, 0.90 equiv) and 1 drop of AcOH was added 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (387 mg, 1.13 mmol, 1.00 equiv) in THF (5.0 mL). The reaction mixture was stirred at 40 °C for 0.5 h. NaBHCN (142 mg, 2.60 mmol, 2.00 equiv) was added at room temperature and stirred at room temperature overnight. The reaction mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO and concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to give the title compound as a yellow solid.

[1104] Reference 34

[1105] Synthesis of 3-(4-(azetidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[1106]

[1107] Step 1: tert-Butyl 3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]-imidazol-4-yl)azetidine-1-carboxylate

[1108]

[1109] A solution of (1-(tert-butoxycarbonyl)azetidin-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 (EA) to give the title compound as a yellow solid.

[1110] Step 2: 3-(4-(azetidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[1111]

[1112] To a solution of tert-butyl 3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)azetidine-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 crude product as a brown oil which was used in the next step without further purification.

[1113] Reference 35

[1114] Synthesis of tert-butyl (1-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1115]

[1116] Step 1: tert-Butyl 4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[1117]

[1118] A mixture of methyl 2-bromo-4,5-difluorobenzoate (2.00 g, 8.00 mmol, 1.00 equiv) and tert-butyl piperazine-1-carboxylate (2.23 g, 12.00 mmol, 1.50 equiv), K2CO3 (1.65 g, 12.00 mmol, 1.50 equiv) in DMA (6.0 mL) was stirred at 80 ° C overnight. The mixture was diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (PE:EA=3:1) to give the title compound as a colorless oil.

[1119] Step 2: tert-Butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[1120]

[1121] A mixture of tert-butyl 4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)-piperazine-1-carboxylate (1.50 g, 3.60 mmol, 1.00 equiv) and CuCN (484 mg, 5.40 mmol, 1.50 equiv) in DMF (6.0 mL) was stirred at 100 ° C overnight. The mixture was extracted with EA and washed with NH 3 .H 2 O. The organic layer was washed with water and brine, dried over Na 2 SO 4, concentrated and purified by flash chromatography (PE: EA = 3: 1) to give the title compound as a white solid.

[1122] Step 3: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate

[1123]

[1124] Tert-butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate was converted to the title compound by proceeding similarly as described in Reference 28, Steps 6-7.

[1125] Step 4: 3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[1126]

[1127] To a stirred solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (95 mg, 0.21 mmol, 1.00 equiv) in DCM (2.0 mL) was added TFA (0.5 mL) and the mixture was stirred at rt for 2 h. The reaction mixture was concentrated to give the title compound as a yellow oil.

[1128] Step 5: tert-Butyl (1-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1129]

[1130] A mixture of 3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (74 mg, 0.33 mmol, 1.00 equiv), tert-butyl (1-((3-(bromomethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (138 mg, 0.32 mmol, 1.50 equiv), TEA (127 mg, 1.26 mmol, 6.00 equiv) in THF (5.0 mL) was stirred at 55 °C overnight. The mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, concentrated, and the residue was purified by flash chromatography (DCM:MeOH=20:1) to give the title compound as a yellow solid.

[1131] Reference 36

[1132] Synthesis of tert-butyl (1-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1133]

[1134] Step 1: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate

[1135]

[1136] A mixture of tert-butyl piperazine-1-carboxylate (950 mg, 5.10 mmol, 1.00 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (1.50 g, 5.10 mmol, 1.00 equiv), DIEA (1.97 g, 15.30 mmol, 3.00 equiv) in NMP (15.0 mL) was stirred at 110 ° C overnight. The mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, concentrated, and the residue was purified by flash chromatography (PE:EA=1:2) to give the title compound as a yellow solid.

[1137] Step 2: 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione

[1138]

[1139] To a stirred solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate (800 mg, 1.74 mmol, 1.00 equiv) in DCM (4.0 mL) was added TFA (1.0 mL) and the mixture was stirred at rt for 2 h. The reaction mixture was concentrated to give the title compound as a yellow oil.

[1140] Step 3: 3-(Bromomethyl)benzenesulfonyl chloride

[1141]

[1142] A mixture of 3-methylbenzenesulfonyl chloride (8.00 g, 41.96 mol, 1.00 eq), NBS (8.22 g, 46.16 mol, 1.10 eq) and benzoyl peroxide (1.46 g, 4.20 mol, 0.01 eq) in CCl4 (80.00 mL) was stirred at 80° C. for 12 h. The solution was filtered, and the filtrate was concentrated to give the crude product as a white oil.

[1143] Step 4: tert-Butyl (1-((3-(bromomethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1144]

[1145] At 0 ° C, tert-butyl piperidin-4-ylcarbamate (5.64g, 21.05mol, 1.00 equivalent) in THF (20.00mL) was added to a stirred solution of 3-(bromomethyl)benzenesulfonyl chloride (3.79g, 18.95mol, 0.90 equivalent) in THF (40.00mL) and TEA (4.25g, 42.10mmol, 2.00 equivalent). The resulting mixture was stirred at room temperature for 12h, quenched with H2O, and then extracted with DCM. The combined organic layer was washed with water, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography with PE / EA (3:1) elution to obtain the title compound as a white solid.

[1146] Step 5: tert-Butyl (1-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1147]

[1148] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione (509 mg, 1.41 mmol, 1.00 equiv), tert-butyl (1-((3-(bromomethyl)phenyl)sulfonyl)-piperidin-4-yl)carbamate (916 mg, 2.12 mmol, 1.50 equiv), TEA (854 mg, 8.46 mmol, 6.00 equiv) in THF (10.0 mL) was stirred at 55 °C overnight. The mixture was extracted with DCM and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (DCM:MeOH=20:1) to give the title compound as a yellow solid.

[1149] Reference 37

[1150] (1-((3-((8-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)aminomethyl

[1151]

[1152] Step 1: 8-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3,8-di-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester

[1153]

[1154] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (200 mg, 0.68 mmol, 1.00 equiv), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (144 mg, 0.68 mmol, 1.00 equiv) and DIEA (263 mg, 2.04 mmol, 3.00 equiv) in NMP (3.0 mL) was stirred overnight at 110 ° C. The reaction mixture was quenched with H2O and then extracted with DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1: 1) to give the title compound as a yellow solid.

[1155] Step 2: tert-Butyl (1-((3-((8-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1156]

[1157] By proceeding similarly to that described in steps 2-5 of reference 36, tert-butyl 8-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate was converted to the title compound.

[1158] Reference 38

[1159] Synthesis of tert-butyl (1-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)-methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1160]

[1161] Step 1: tert-Butyl 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[1162]

[1163] 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 tert-butyl piperazine-1-carboxylate (11.40 g, 61.38 mmol, 1.10 equiv) and DIEA (34.70 g, 268.96 mmol, 4.80 equiv). The resulting mixture was stirred at 110 ° C for 12 h. The mixture was extracted with EtOAc, washed with brine, concentrated, and purified by silica gel column chromatography eluting with PE / EtOAc (3: 1) to give the title compound as a yellow solid.

[1164] Step 2: tert-Butyl 4-(3-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[1165]

[1166] A mixture of tert-butyl 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (8.00 g, 23.20 mmol, 1.00 equiv), NaH2PO2 · H2O (5.20 g, 48.70 mmol, 2.10 equiv) and Raney 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 aqueous NaHCO3, filtered, and extracted with EtOAc. The organic layer was washed with brine, concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3: 1) to give the title compound as a yellow solid.

[1167] Step 3: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate

[1168]

[1169] 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)piperazine-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 at room temperature. The mixture was stirred at 40 °C for 12 h, and diluted with water and extracted with EtOAc. The organic layer was washed with brine, concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:2) to give the title compound as a white solid.

[1170] Step 4: 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[1171]

[1172] To a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-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 give the title compound as a yellow oil.

[1173] Step 5: tert-Butyl (1-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)-methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1174]

[1175] To a stirred solution of 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (55 mg, 0.17 mmol, 1.00 equiv) in THF (2.0 mL) was added TEA (52 mg, 0.51 mmol, 3.00 equiv) and tert-butyl (1-((3-(bromomethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (95 mg, 0.22 mmol, 1.30 equiv). The reaction mixture was stirred at 55 °C overnight. The reaction mixture was concentrated and purified by silica gel column chromatography eluting with DCM / MeOH (20: 1) to give the title compound as a yellow solid.

[1176] Reference 39

[1177] Synthesis of tert-butyl (1-((3-((7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,7-diazaspiro-[3.5]nonan-2-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1178]

[1179] Step 1: tert-Butyl 7-(3-cyano-4-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[1180]

[1181] A mixture of methyl 2-cyano-4-fluorobenzoate (1.00 g, 5.58 mmol, 1.00 equiv) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (1.39 g, 6.14 mmol, 1.10 equiv), DIEA (719 mg, 16.74 mmol, 3.00 equiv) in DMSO (10.0 mL) was stirred overnight at 110 ° C. The mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (PE:EA=3:1) to give the title compound as a white solid.

[1182] Step 2: tert-Butyl 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[1183]

[1184] Tert-butyl 7-(3-cyano-4-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate was converted to the title compound by proceeding similarly as described in Reference 28, Steps 6-7.

[1185] Step 3: 3-(1-oxo-5-(2,7-diazaspiro[3.5]nonan-7-yl)isoindolin-2-yl)piperidine-2,6-dione

[1186]

[1187] To a stirred solution of tert-butyl 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (220 mg, 0.32 mmol, 1.00 equiv) in DCM (2.0 mL) was added TFA (0.5 mL) and the mixture was stirred at rt for 2 h. The reaction mixture was concentrated to give the title compound as a yellow oil.

[1188] Step 4: tert-Butyl (1-((3-((7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,7-diazaspiro-[3.5]nonan-2-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1189]

[1190] A mixture of 3-(1-oxo-5-(2,7-diazaspiro[3.5]nonan-7-yl)isoindolin-2-yl)piperidine-2,6-dione (173 mg, 0.47 mmol, 1.00 equiv) and tert-butyl (1-((3-(bromomethyl)phenyl)sulfonyl)-piperidin-4-yl)carbamate (264 mg, 0.61 mmol, 1.30 equiv), TEA (285 mg, 2.82 mmol, 6.00 equiv) in THF (5.0 mL) was stirred at 55 °C overnight. The mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (DCM:MeOH=20:1) to give the title compound as a yellow solid.

[1191] Reference 40

[1192] Synthesis of tert-butyl ((3R,4S)-1-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)phenyl)sulfonyl)-3-fluoropiperidin-4-yl)carbamate

[1193]

[1194] Step 1: tert-butyl ((3R,4S)-1-((3-(bromomethyl)phenyl)sulfonyl)-3-fluoropiperidin-4-yl)carbamate

[1195]

[1196] 3-(Bromomethyl)-benzene-1-sulfonyl chloride (122 mg, 0.46 mmol, 1.00 equiv) in THF (1.0 mL) was slowly added to a solution of tert-butyl racemate ((3R, 4S)-3-fluoropiperidin-4-yl)carbamate (100 mg, 0.46 mmol, 1.00 equiv) and TEA (93 mg, 0.92 mmol, 2.00 equiv) in THF (2.0 mL) at -10 °C for 3 h. The mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (PE:EA=4:1) to give the title compound as a white solid.

[1197] Step 2: tert-butyl ((3R,4S)-1-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)phenyl)sulfonyl)-3-fluoropiperidin-4-yl)carbamate

[1198]

[1199] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione (94 mg, 0.26 mmol, 1.00 equiv) and tert-butyl rac-((3R,4S)-1-((3-(bromomethyl)phenyl)-sulfonyl)-3-fluoropiperidin-4-yl)carbamate (141 mg, 0.31 mmol, 1.20 equiv) in THF (4.0 mL) was added TEA (131 mg, 1.30 mmol, 5.00 equiv), and the mixture was stirred at 55 °C overnight. The mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (DCM:MeOH=20:1) to give the title compound as a yellow solid.

[1200] Reference 41

[1201] Synthesis of tert-butyl (1-((3-((1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-methyl)piperidin-4-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1202]

[1203] Step 1: 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile

[1204]

[1205] A mixture of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (2.00 g, 6.21 mmol, 1.00 equiv) and Zn(CN)2 (438 mg, 3.73 mmol, 0.60 equiv), Pd(pph3)4 (714 mg) in DMF (30.0 mL) was stirred overnight at 100° C. The mixture was extracted with DCM and purified by silica gel column chromatography eluting with PE / EtOAc (1:2) to give the title compound as a yellow solid.

[1206] Step 2: 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbaldehyde

[1207]

[1208] A mixture of 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile (1.20 g, 4.46 mmol, 1.00 equiv), NaH2PO2·H2O (993 mg, 9.37 mmol, 2.10 equiv) and Raney nickel (500 mg) in pyridine:H2O:AcOH (40.0 mL, 2:2:1) was stirred at 70 °C overnight. The reaction mixture was filtered and washed with NaHCO3 aqueous solution. The organic layer was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:2) to give the title compound as a yellow solid.

[1209] Step 3: Benzyl 4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenoxy)piperidine-1-carboxylate

[1210]

[1211] A mixture of tert-butyl (1-((3-((tert-butoxycarbonyl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (7.30 g, 16.0 mmol, 1.00 equiv), benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (7.52 g, 24 mmol, 1.50 equiv) and CsCO (10.4 g, 32 mmol, 2.00 equiv) in DMSO (70.0 mL) was stirred at 90 °C for 4 h and then extracted with EtOAc. The organic layer was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to give the title compound as a yellow solid.

[1212] Step 4: tert-Butyl (1-((3-(piperidin-4-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1213]

[1214] A mixture of benzyl 4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)-phenoxy)piperidine-1-carboxylate (6.0 g, 10.47 mmol, 1.00 equiv), HCOONH4 (3.3 g, 52.35 mmol, 5.00 equiv) and Pd(OH)2 (1.2 g) in EtOH (60.0 mL) was stirred at 70° C. for 4 h. The mixture was filtered and concentrated to give the title compound as a white solid.

[1215] Step 5: tert-Butyl (1-((3-((1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperidin-4-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1216]

[1217] To a mixture of 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbaldehyde (100 mg, 0.37 mmol, 1.00 equiv) in THF (3.0 mL) was added tert-butyl (1-((3-(piperidin-4-yloxy)phenyl)-sulfonyl)piperidin-4-yl)carbamate (169 mg, 0.39 mmol, 1.05 equiv) and 1 drop of AcOH. The mixture was stirred at 40 °C for 0.5 h. NaBH3CN (47 mg, 0.74 mmol, 2.00 equiv) was added and stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (20:1) to give the title compound as a yellow solid.

[1218] Reference 42

[1219] Synthesis of tert-butyl (1-((3-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1220]

[1221] Step 1: 3-(4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazine

[1222] -1-yl)benzyl azetidine-1-carboxylate

[1223]

[1224] To a mixture of tert-butyl (1-((3-(piperazine-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (740 mg, 1.75 mmol, 1.00 equiv) in THF (10.0 mL), AcOH (3 drops) and benzyl 3-oxoazetidine-1-carboxylate (718 mg, 3.50 mmol, 2.00 equiv) were added. The solution was stirred at 45 °C for 0.5 h. The solution was cooled to room temperature and NaBHCN (220 mg, 3.50 mmol, 2.00 equiv) was added. The solution was stirred at room temperature overnight and then extracted with EtOAc. The mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (20: 1) to give the title compound as a white oil.

[1225] Step 2: tert-Butyl (1-((3-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1226]

[1227] Using analogous procedures as described in steps 4-7 of reference 28, benzyl 3-(4-(3-((4-(tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperazin-1-yl)azetidine-1-carboxylate was converted to the title compound.

[1228] Reference 43

[1229] Synthesis of tert-butyl (1-((3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)-azetidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1230]

[1231] Step 1: tert-Butyl (1-((3-(3-hydroxyazetidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1232]

[1233] A mixture of tert-butyl (1-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (5.83 g, 13.95 mmol, 1.00 equiv), KCO (6.74 g, 48.83 mmol, 3.50 equiv), CuI (0.53 g, 2.79 mmol, 0.20 equiv), L-proline (481 mg, 4.19 mmol, 0.30 equiv) and 3-hydroxyazetidine (2.28 g, 20.92 mmol, 1.50 equiv) in DMSO (50.00 mL) was stirred at 90 °C for 12 h. The mixture was quenched with H0 and extracted with EtOAc. The organic layer was concentrated and purified by silica gel column chromatography eluting with PE / EtOAc (2: 1) to give the title compound as a white solid.

[1234] Step 2: tert-Butyl (1-((3-(3-oxoazetidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1235]

[1236] To a stirred solution of tert-butyl (1-((3-(3-hydroxyazetidine-1-yl)phenyl)sulfonyl)-piperidin-4-yl)carbamate (0.50 g, 1.22 mmol, 1.00 equiv) in DCM (5.00 mL) was added Dess-Martin (1.03 g, 2.44 mmol, 2.00 equiv) and the mixture was stirred at 0 °C for 3 h. The mixture was diluted with sodium thiosulfate (aq.) and extracted with DCM. The organic layer was concentrated and the residue was purified by silica gel column chromatography eluting with EtOAc / PE (3: 1) to give the title compound as a white solid.

[1237] Step 3: tert-Butyl (1-((3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)-azetidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1238]

[1239] To a solution of tert-butyl (1-((3-(3-oxoazetidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (40.00 mg, 0.10 mmol, 1.00 equiv) in THF (1.00 mL) and DMF (0.50 mL) was added AcOH (3 drops) and 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (39.00 mg, 0.12 mmol, 1.20 equiv). The solution was stirred at 45 °C for 45 min. The solution was cooled to room temperature and NaBHCN (13.00 mg, 0.20 mmol, 2.00 equiv) was added. The mixture was stirred at room temperature for 12 h, and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO and concentrated. The residue was purified by TLC eluting with DCM / MeOH (20:1) to give the title compound as a white solid.

[1240] Reference 44

[1241] Synthesis of tert-butyl (1-((3-(3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)azetidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1242]

[1243] To a solution of 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (41.00 mg, 0.12 mmol, 1.00 equiv) in THF (2.00 mL) and DMF (0.50 mL) was added AcOH (3 drops) and tert-butyl (1-((3-(3-oxoazetidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (98.00 mg, 0.24 mmol, 2.00 equiv). The solution was stirred at 45 °C for 0.5 h. The solution was then cooled to room temperature and NaBHCN (15.08 mg, 0.24 mmol, 2.00 equiv) was added. The mixture was stirred at room temperature for 12 h, and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by TLC eluting with DCM / MeOH (20:1) to give the title compound as a white solid.

[1244] Reference 45

[1245] Synthesis of rac-1-(6-(1-(3-(((3R,4S)-4-amino-3-fluoropiperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[1246]

[1247] Step 1: 6-Bromo-1-methyl-1H-indazol-3-amine

[1248]

[1249] NaH (2.10 g, 52.83 mmol, 2.00 equiv) was added to a stirred solution of 6-bromo-1H-indazole-3-amine (5.60 g, 26.42 mmol, 1.00 equiv) in DMF (20.0 mL) at 0 ° C, and the mixture was stirred for 1 h at 0 ° C. CH3I (4.10 g, 29.06 mmol, 1.10 equiv) was added, and the mixture was stirred for 3 h at room temperature under N2. 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.

[1250] Step 2: 3-((6-Bromo-1-methyl-1H-indazol-3-yl)amino)propanoic acid

[1251]

[1252] Acrylic acid (1.60 g, 22.12 mmol, 1.00 equiv) was added to a stirred solution of 6-bromo-1-methyl-1H-indazole-3-amine (5.00 g, 22.12 mmol, 1.00 equiv) in AcOH (3.17 g, 52.43 mmol, 2.37 equiv) and water (5.0 mL), and the mixture was stirred at 105 ° C. under N2 for 20 h. The mixture was poured into cold water and the mixture was adjusted to pH 6-7 by adding 6N HCl aqueous solution. The mixture was filtered and the solid was washed with water and dried to give the title compound as a yellow solid.

[1253] Step 3: 1-(6-Bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[1254]

[1255] A mixture of 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propanoic acid (3.11 g, 1.90 mmol, 1.00 equiv) and urea (3.02 g, 50.31 mmol, 5.00 equiv) in AcOH (30.0 mL) was stirred at 120 ° C under N2 for 20 h. After the mixture was cooled to room temperature, concentrated HCl (6.0 mL) was added, and the mixture was then heated again for 30 min. The crude mixture was diluted with water and extracted with EA, and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography (EA:PE=0 to 100%) to give the title compound as a yellow solid.

[1256] Step 4: tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate

[1257]

[1258] 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), tert-butyl 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), K3PO4 (2.20 g, 10.22 mmol, 3.00 equiv) and X-Phos-G3 (289 mg, 0.34 mmol, 0.10 equiv) in 1,4-dioxane / H2O (10 mL / 1 mL) was stirred at 60°C under N2 for 3 h. The mixture was diluted with DCM, and the organic layer was washed with water and brine, dried over Na 2 SO 4 , concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to give the title compound as a yellow solid.

[1259] Step 5: tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate

[1260]

[1261] A mixture of tert-butyl 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) / C (150 mg, 50% wt) in THF (20 mL) was stirred under 50 psi H at 50° C. overnight. The mixture was filtered, the filtrate was concentrated and the residue was purified by silica gel column chromatography (PE:EA=1:1) to give the title compound as a yellow solid.

[1262] Step 6: 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[1263]

[1264] TFA (0.5 mL) was added to a solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate (35.0 mg, 0.08 mmol, 1.00 equiv) in DCM (2.5 mL), and the mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated to give the crude product as a white oil, which was used in the next step without further purification.

[1265] Step 7: tert-butyl ((3R,4S)-1-((3-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)phenyl)sulfonyl)-3-fluoropiperidin-4-yl)carbamate

[1266]

[1267] A mixture of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (82 mg, 0.25 mmol, 1.00 equiv), rac-tert-butyl((3R,4S)-1-((3-(bromomethyl)-phenyl)sulfonyl)-3-fluoropiperidin-4-yl)carbamate (115 mg, 0.25 mmol, 1.00 equiv) in DCM (4.0 mL) and TEA (76 mg, 0.75 mmol, 3.00 equiv) was stirred at 50 °C for 16 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH=15:1) to give the title compound as a white solid.

[1268] Step 8: rac-1-(6-(1-(3-(((3R,4S)-4-amino-3-fluoropiperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[1269]

[1270] A mixture of tert-butyl ((3R,4S)-1-((3-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)phenyl)sulfonyl)-3-fluoropiperidin-4-yl)carbamate (45 mg, 0.07 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 its TFA salt as a brown oil.

[1271] Reference 46

[1272] Synthesis of 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione

[1273]

[1274] Step 1: tert-Butyl 4-(4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate

[1275]

[1276] A mixture of 1-bromo-4-nitrobenzene (1.0 g, 4.95 mmol, 1.00 equiv), tert-butyl 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), KCO (1.37 g, 9.90 mmol, 2.00 equiv) and Pd(dppf)Cl (724 mg, 0.99 mmol, 0.20 equiv) in dioxane / HO (15 mL, 5 / 1) was stirred at 100 °C for 4 h. The mixture was filtered and extracted with EA. The combined organic layers were dried over anhydrous NaSO, filtered and concentrated. The residue was purified by silica flash column PE / EtOAc (10:1) to give the product as a yellow solid.

[1277] Step 2: tert-Butyl 4-(4-aminophenyl)piperidine-1-carboxylate

[1278]

[1279] A mixture of tert-butyl 4-(4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (1.20 g, 3.95 mmol, 1.00 equiv), Pd / C (360 mg) in MeOH / THF (30 mL, 1:1) was stirred at 45° C. under H2 overnight. The mixture was filtered and concentrated, and the residue was purified by silica flash column PE / EtOAc (3:1) to give the product as a yellow solid.

[1280] Step 3: tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate

[1281]

[1282] A mixture of tert-butyl 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 NaHCO (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 EA. The combined organic layers were dried over anhydrous Na SO, filtered, and then concentrated. The residue was purified by silica flash column PE / EtOAc (1: 1) to give the title compound as a yellow solid.

[1283] Step 4: 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione

[1284]

[1285] TFA (0.5 mL) was added to a mixture of tert-butyl 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 rt for 2 h. The solution was concentrated to give the title compound as a yellow solid.

[1286] Reference 47

[1287] Synthesis of 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione

[1288]

[1289] Step 1: 2,6-Bis(benzyloxy)pyridine

[1290]

[1291] To a stirred solution of benzyl alcohol (14.60 g, 135.14 mmol, 2.00 equiv) in THF (250.0 mL) was added t-BuOK (38.00 g, 337.84 mmol, 5.00 equiv) and 2,6-dichloropyridine (10.00 g, 67.57 mmol, 1.00 equiv). The mixture was stirred at 75 °C under N2 for 20 h. The mixture was diluted with water and extracted with EA, and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the title compound as a light yellow solid.

[1292] Step 2: 2,6-Bis(benzyloxy)-3-bromopyridine

[1293]

[1294] NBS (8.70 g, 0.05 mol, 0.95 eq) was added to a stirred solution of 2,6-bis(benzyloxy)-pyridine (15.00 g, 0.05 mol, 1.00 eq) in MeCN (100.0 mL), and the mixture was stirred at 80 °C under N2 for 4 h. The mixture was diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the title compound as a yellow solid.

[1295] Step 3: 2,6-Bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[1296]

[1297] 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-dioxane (200.0 mL) was stirred at 100 °C under N2 for 25 h. The mixture was diluted with water and extracted with EA, and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with EA:PE=0 to 100% to give the title compound as a yellow solid.

[1298] Step 4: 2,6-Bis(benzyloxy)-3-(4-bromophenyl)pyridine

[1299]

[1300] 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), K3PO4 (5.63 g, 26.50 mmol, 3.00 equiv) and Pd(PPh3)4 (510 mg, 0.44 mmol, 0.05 equiv) in 1,4-dioxane / H2O=10:1 (40.0 mL) was stirred at 100° C. under N2 for 16 h. The mixture was diluted with water and extracted with EA, and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with EA:PE = 0 to 100% to give the title compound as a yellow solid.

[1301] Step 5: tert-Butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carboxylate

[1302]

[1303] A mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (500 mg, 1.12 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (417 mg, 2.24 mmol, 2.00 equiv), Cs2CO3 (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 EA, and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with EA:PE=0 to 100% to give the title compound as a yellow solid.

[1304] Step 6: tert-Butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate

[1305]

[1306] A mixture of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carboxylate (260 mg, 0.47 mmol, 1.00 equiv), 10% Pd / C (260 mg) in EA (5.0 mL) and 1,4-dioxane (5.0 mL) was stirred at rt under H2 for 20 h. The mixture was filtered and the filtrate was concentrated to give the title compound as a yellow oil.

[1307] Step 7: 3-(4-(Piperazin-1-yl)phenyl)piperidine-2,6-dione

[1308]

[1309] TFA (0.5 mL) was added to a stirred solution of tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-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 its TFA salt as a yellow oil.

[1310] Reference 48

[1311] Synthesis of 8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[1312]

[1313] Step 1: Ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate

[1314]

[1315] A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.00 g, 21.55 mmol, 1.00 equiv), methylamine (8.75 mL) in DCM (120.0 mL) was stirred at 0 °C for 12 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10: 1) to give the title compound as a white solid.

[1316] Step 2: (4-(Methylamino)-2-(methylthio)pyrimidin-5-yl)methanol

[1317]

[1318] A mixture of ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate (2.90 g, 12.78 mmol, 1.00 equiv) and LiAlH4 (971 mg, 25.55 mmol, 2.00 equiv) in THF (45 mL) was stirred at room temperature for 4 h before Na2SO4·10H2O was added. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to give the title compound as a white solid.

[1319] Step 3: 4-(Methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde

[1320]

[1321] To a stirred solution of (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (500 mg, 2.70 mmol, 1.00 equiv) in DCM (2.0 mL) was added MnO (2.20 g, 27.00 mmol, 10.00 equiv) at -30°C and the mixture was stirred for 16 h. The mixture was filtered and concentrated to give the crude title compound as a white solid.

[1322] Step 4: 8-Methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[1323]

[1324] Ethyl acetate (529 mg, 6.00 mmol, 2.20 equiv) was added to a stirred solution of LiHMDS (8.2 mL, 8.20 mmol, 3.00 equiv) in THF (8.0 mL) at -70 ° C under a nitrogen atmosphere. The mixture was stirred at -70 ° C for 0.25 h, 4- (methylamino) -2- (methylthio) pyrimidine -5- carbaldehyde (500 mg, 2.73 mmol, 1.00 equiv) was added, and the mixture was slowly warmed to room temperature. After 2 h, the mixture was diluted with NH4Cl aqueous solution and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1: 1) to obtain the title compound as a white solid.

[1325] Step 5: 8-Methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[1326]

[1327] Potassium monopersulfate (1.60 g, 2.60 mmol, 2.00 equiv) was added to a mixture of 8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (270 mg, 1.30 mmol, 1.00 equiv) in THF:MeOH:H2O=2:2:1 (15.0 mL). The mixture was stirred at 30°C under a nitrogen atmosphere for 2 h, then the mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated to give the title compound as a yellow solid.

[1328] Reference 49

[1329] Synthesis of 2-(Methylsulfonyl)-8-(2,2,2-trifluoroethyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[1330]

[1331] Step 1: Ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate

[1332]

[1333] NH3.HO (162 mg, 1.61 mmol, 1.51 equiv) and TEA (3.88 mg, 3.88 mmol, 3.00 equiv) were added to a stirred solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (300 mg, 1.24 mmol, 1.00 equiv) in THF (5.0 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 dried over Na2SO4 and concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give the title compound as a yellow solid.

[1334] Step 2: (4-amino-2-(methylthio)pyrimidin-5-yl)methanol

[1335]

[1336] 4-amino-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (300 mg, 1.41 mmol, 1.00 equiv) in THF (3.0 mL) was slowly added to a stirred mixture of LiAlH (65 mg, 2.12 mmol, 1.50 equiv) in THF (5.0 mL) at 0 ° C under N2. The mixture was stirred at room temperature for 4 h, and the mixture was quenched with Na2SO4·10H2O, and then filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1: 1) to give the title compound as a white solid.

[1337] Step 3: 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde

[1338]

[1339] MnO2 (1759 mg, 20.63 mmol, 8.00 equiv) was added to a stirred solution of (4-amino-2-(methylthio)pyrimidin-5-yl)methanol (442 mg, 2.58 mmol, 1.00 equiv) in DCM, and the mixture was stirred at room temperature under N2 for 16 h. The mixture was filtered and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to give the title compound as a yellow solid.

[1340] Step 4: (E)-ethyl 3-(4-amino-2-(methylthio)pyrimidin-5-yl)acrylate

[1341]

[1342] 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde (1.50 g, 8.88 mmol, 1.00 equiv) and 2-(triphenyl-λ 5 A mixture of ethyl acetate (4.63 g, 13.3 mmol, 1.50 equiv) in THF (40 mL) was refluxed at 75 ° C. under N2 for 3 h, and then at room temperature for 16 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give the title compound as a white solid.

[1343] Step 5: 2-(Methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[1344]

[1345] A mixture of (E)-ethyl 3-(4-amino-2-(methylthio)pyrimidin-5-yl)acrylate (2.78 g, 11.63 mmol, 1.00 equiv) and NaSCH (1.63 g, 23.26 mmol, 2.00 equiv) in EtOH was stirred at 80 °C under N for 2 h. The mixture was concentrated and then diluted with water. 1 M aqueous HCl was added to the mixture until pH = 5. The resulting white precipitate was filtered and washed with water and EA to give the title compound as a white solid.

[1346] Step 6: 2-(Methylthio)-8-(2,2,2-trifluoroethyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[1347]

[1348] NaH (94 mg, 2.33 mmol, 1.50 equiv) was added to a solution of 2-(methylthio)pyrido[2,3-d]-pyrimidin-7(8H)-one (300 mg, 1.55 mmol, 1.00 equiv) in DMF at 0°C, and the mixture was stirred for 15 min. 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.19 g, 5.13 mmol, 3.30 equiv) in DMF was added to the mixture at 0°C, and the mixture was warmed to room temperature and stirred for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with PE:EtOAc (3:1) to give the title compound as a white solid.

[1349] Step 7: 2-(Methylsulfonyl)-8-(2,2,2-trifluoroethyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[1350]

[1351] Potassium monopersulfate (447 mg, 0.73 mmol, 2.00 equiv) was added to a solution of 2-(methylthio)-8-(2,2,2-trifluoroethyl)pyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.36 mmol, 1.00 equiv) in THF / HO 3:1 (3 ml / 1 ml), and the mixture was stirred at room temperature under N for 12 h. The mixture was diluted with HO and extracted with DCM. The organic layer was washed with brine and dried over NaSO and concentrated. The residue was purified by silica gel column chromatography eluting with PE:EtOAc (1:1) to give the title compound as a white solid.

[1352] Example 1

[1353] Synthesis of rac-1-(6-(1-(3-(((3R,4S)-3-fluoro-4-((8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)-dihydropyrimidine-2,4(1H,3H)-dione

[1354]

[1355] A mixture of rac-1-(6-(1-(3-(((3R,4S)-4-amino-3-fluoropiperidin-1-yl)sulfonyl)benzyl)-piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (38.5 mg, 0.07 mmol, 1.00 equiv), DIEA (26 mg, 0.20 mmol, 3.00 equiv) and 8-methyl-2-(methylsulfonyl)pyrido-[2,3-d]pyrimidin-7(8H)-one (21 mg, 0.09 mmol, 1.30 equiv) in DMSO (3.0 mL) was stirred at 65 °C for 16 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, brine and dried over Na2SO4. The organic layer was concentrated and purified by preparative TLC (DCM:MeOH=20:1) to give the title compound as a white solid.

[1356] Example 2

[1357] Synthesis of rac-1-(6-(1-(3-(((3R,4S)-3-fluoro-4-((7-oxo-8-(2,2,2-trifluoroethyl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[1358]

[1359] A mixture of rac-1-(6-(1-(3-(((3R,4S)-4-amino-3-fluoropiperidin-1-yl)sulfonyl)benzyl)-piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (49 mg, 0.083 mmol, 1.00 equiv), DIPEA (33 mg, 0.25 mmol, 3.00 equiv) and 2-(methylsulfonyl)-8-(2,2,2-trifluoroethyl)pyrido[2,3-d]pyrimidin-7(8H)-one (28 mg, 0.0915 mmol, 1.10 equiv) in DMSO (2.0 mL) was stirred at 65° C. under nitrogen atmosphere overnight. The resulting mixture was diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (20:1) to give the title compound as a white solid. MS (ES, m / z): [M+1] + =825.0

[1360] Biological Examples

[1361] Example 1

[1362] Inhibition of CDK2: Phospho-Rb Measurement in Cells

[1363] RB protein phosphorylation at S807 / 811 was measured using the HTRF Phosphorylation RB Cell Kit from Cisbio (Cat. No. 64RBS807PEG).

[1364] On day 1, OVCAR3 (CDK2-dependent cell line) cells were seeded into 96-well tissue culture treated plates at 200 μL at 20,000 cells / well 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 10,000 nM using an HP D300 digital dispenser. Twenty-four hours after compound treatment, cell culture medium was removed by flicking the plate and tapping the plate with a clean paper towel. 30 μL of 1X lysis buffer was immediately supplemented from the kit and the plate was incubated on a shaker at room temperature for 30 min. After homogenization by pipetting up and down, 8 μL of cell lysate was transferred from the 96-well cell culture plate to a 384-well small-volume white detection plate. 2 μL of premixed detection solution was added and the plate was covered with a blocking agent. To prepare the detection solution, d2-conjugated phosphorylated RB antibody and Eu-cryptand-conjugated phosphorylated RB antibody were diluted into detection buffer according to the manufacturer's instructions. The assay plates were incubated at room temperature for 4 h and read on a ClarioStar (BMG Labtech) 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. Half maximal inhibitory concentration (IC 50 ) values ​​were calculated using GraphPad Prism (version 8; La Jolla, CA) with a four-parameter logistic fit.

[1365] Table 1 below reports the CDK2 IC of PROTAC Compound 1 and Compound 2 in the pRB (S807 / 811) assay. 50 In the following table, A represents an IC greater than or equal to 0.1 μM but less than 1.0 μM 50 ; and B represents an IC greater than or equal to 1.0 μM but less than or equal to 10 μM 50 .

[1366] Table 1

[1367]

[1368] Example 2

[1369] High-throughput measurement of endogenous CDK2 in cells

[1370] The effects of compounds on cellular CDK2 levels can be monitored using a high-throughput HTRF assay.

[1371] In order to determine the half-maximal degradation concentration (DC 50 ) values, cellular CDK2 levels were measured in a 96-well format using the HTRF Total CDK2 Cell Kit from Cystech (Cat. No. 64CDK2TPEG).

[1372] On day 1, OVCAR3 cells were seeded at 20,000 cells / well in 96-well tissue culture treated plates in 200 μL and incubated overnight at 37°C in a CO2 atmosphere. On day 2, cells were treated with compounds ranging from 0.3 to 10,000 nM using an HP D300 digital dispenser. 24 hours after compound treatment, cell culture medium was removed by flicking the plate and tapping the plate with a clean paper towel. 30 μL of 1X lysis buffer was immediately supplemented from the kit and the plate was incubated on a shaker at room temperature for 30 min. After homogenization by pipetting up and down, 8 μL of cell lysate was transferred from the 96-well cell culture plate to a 384-well small-volume white detection plate. 2 μL of premixed detection solution was added and the plate was covered with a blocking agent. To prepare the detection solution, d2-conjugated CDK2 antibody and Eu-cryptand-conjugated CDK2 antibody were diluted into detection buffer according to the manufacturer's instructions. The assay plates were incubated overnight at room temperature and read on a ClarioStar (BMG Labtech) in TR-FRET mode (665 nM and 620 nM). TR-FRET ratios (665 nM / 620 nM) were plotted against compound concentration and norma...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: The degron is an E3 ligase ligand selected from the group consisting of: (a) a group having the formula (i): as well as (b) a group having the formula (ii): in: R x It is hydrogen; Y a is CH or N; Z a is a bond, -CH2-, -NH-, -O- or -NHC(O)-, wherein the NH of -NHC(O)- is attached to Y a ; Ring A of the E3 ligase ligand of formula (ii) is a group of formula (a), (b) or (c): in: R aa , R bb , R cc and R dd independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano; R 4 and R 5 are independently hydrogen or alkyl; or R 4 and R 5 Together with the carbon to which they are attached, form >C=O; and R 6 is hydrogen or alkyl; The ring B of the E3 ligase ligand of formula (ii) is a phenylene, a cycloamine, a 5-membered or 6-membered monocyclic heteroarylene or a 9-membered or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three nitrogen ring atoms and further wherein the phenylene, cycloamine and each heteroarylene are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano R ee and R ff replace; and X 1 , X 2 , X 3 and X 4 are independently a bond, alkylene, -O-, -(O-alkylene)-, -(alkylene-O)-, -(NR gg -alkylene)-, -(alkylene-NR hh )-、 -NH-, -N(alkyl)-, -C(=O)-, -NR jj C(=O)- or -C(=O)NR kk -, where R gg , R hh , R jj and R kk are independently hydrogen, alkyl or cycloalkyl, and each alkylene group is optionally substituted with one or two fluorines; Hy is a cycloalkylene, arylene, heterocyclylene, bicyclic heterocyclylene, spiro heterocyclylene, bridged heterocyclylene or fused heterocyclylene, wherein each of the above rings is independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxyl and cyano. b , R c and R d replace; R 1 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkylalkyl or heterocyclylalkyl, wherein aryl, by itself or as part of aralkyl, heteroaryl, by itself or as part of heteroaralkyl, cycloalkyl of cycloalkylalkyl and heterocyclyl of heterocyclylalkyl are independently selected from hydrogen, deuterium, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, halogen and hydroxyl. e , R f and R g replace; R 2 is hydrogen, alkyl or haloalkyl; R 3 is hydrogen, cyano, halogen, NH2, alkyl or haloalkyl, wherein alkyl and haloalkyl are optionally substituted with hydroxy, cyano, alkoxy, haloalkoxy, C(O)NH2 and -C(O)OH; and L is -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -, where: Z 1 is a bond, alkylene, -C(O)NR-, -NR'(CO)-, -S(O)2NR-, -NR'S(O)2-, -(O-alkylene) a -, -(alkylene-O) a -, phenylene, monocyclic heteroarylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy R h and R i replace; Z 2 is a bond, alkylene, alkynylene, -C(O)-, -C(O)N(R)-, -NR'(CO)-, -(O-alkylene) b -, -(alkylene-O) b -, -O(CH2)7-, -O(CH2)8-, cycloalkylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. j and R k replace; Z 3 is a bond, alkylene, alkynylene, -C(O)NR-, -NR'(CO)-, -O-, -NR"-, -(O-alkylene) c -, -(alkylene-O) c -, cycloalkylene, spirocycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, spiro heterocyclylene, or 11- to 13-membered spiro heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, and haloalkoxy R m and R n replace; Z 4 is a bond, alkylene, alkynylene, -(alkylene-NR")-, -O-, -C(O)-, -NR"-, -(O-alkylene) d -, -(alkylene-O) d -, cycloalkylene, spirocycloalkylene, phenylene, heteroarylene, heterocyclylene, fused heterocyclylene, bridged heterocyclylene or spiro heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxyl, amino, alkylamino and dialkylamino R o and R p replace; Z 5 is a bond, -alkylene, -NR"-, -O-, -C(O)-, -S(O)2-, -NR'(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. q and R r Replace, and Z 6 is a bond, alkylene, -NR"-, -O-, -(alkylene-O)-, -C(O)-, -S(O)2-, -NR'(CO)-, or -C(O)NR-; wherein each R, R' and R" is independently hydrogen or alkyl, each a, b, c and d is independently an integer selected from 1 to 6, and -Z 1 -、-Z 2 -、-Z 3 -、-Z 4 -、-Z 5 -and-Z 6 - Each alkylene group in R s and R t Substitution, where R s is hydrogen or deuterium and R t is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl or monocyclic heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano; provided that -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -At least one of them is not a key.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein -Z 5 -quilt R q and R r replace; and Z 6 It is -S(O)2-.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: X 1 , X 2 , X 3 , X 4 , Z 1 and Z 2 Each is a key; Z 3 is a heterocyclylene, a bridged heterocyclylene or a spiro heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. m and R n replace; Z 4 R is alkylene, -O-, cycloalkylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino and dialkylamino o and R p replace; Z 5 is phenylene or a monocyclic heteroarylene, each ring being independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. q and R r replace; and Z 6 is -S(O)2-; and Where the alkylene group is R s and R t replace.

4. The compound according to claim 1, 2 or 3 or a pharmaceutically acceptable salt thereof, wherein: -Z 3 -Z 4 -Z 5 -Z 6 - is: Where R q , R m and R n are independently selected from hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, haloalkoxy, alkoxy and cyano.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein -Z 3 -Z 4 -Z 5 -Z 6 - is: Where R q and R m Each of is independently selected from hydrogen, methyl, fluorine, chlorine, cyano, methoxy, difluoromethoxy, cyclopropyl, difluoromethyl and trifluoromethyl.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein: R 1 It is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein: R 1 It is an alkyl group.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 3 is hydrogen, cyano, halogen, haloalkyl or alkyl optionally substituted by hydroxy.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein: R 2 It's hydrogen.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein Hy is heterocyclylene, phenylene, spiroheterocyclylene or cycloalkylene, wherein each of the above rings is replaced by R b , R c and R d Substitution, where R b and R c are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy and hydroxy, and R d It's hydrogen.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein: Hy is wherein the N atom of the piperidine-1,4-diyl ring is attached to L.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein: The degron is an E3 ligase ligand having formula (i), wherein loop A:

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein: The degron is an E3 ligase ligand selected from the group consisting of: Where R ee is hydrogen, methyl, ethyl, cyclopropyl or 2,2,2-trifluoroethyl, and R ff is hydrogen, methyl, cyclopropyl, fluorine, cyano, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

15. A method of treating cancer in a patient, the method comprising administering to a patient in recognized need thereof a therapeutically effective amount of a compound as claimed in any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 14.

16. The method of claim 15, wherein: a) the compound or a pharmaceutically acceptable salt thereof, or b) the pharmaceutical composition is administered in combination with at least one other anticancer agent.

17. The method according to claim 15 or 16, wherein: The cancer is lung cancer, skin cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, stomach cancer, head and neck cancer, liver cancer, ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, stomach cancer, thyroid cancer or parathyroid cancer.

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