Bifunctional compounds containing pyrimidine derivatives for degrading cyclin-dependent kinase 2 via ubiquitin proteasome pathway

Abstract

The present disclosure provides certain bifunctional compounds containing pyrimidine derivatives 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 / 354,233, filed on June 21, 2022, which is incorporated herein in its entirety for all purposes. Technical Field

[0003] The present disclosure provides certain bifunctional compounds containing pyrimidine derivatives that cause degradation of cyclin-dependent kinase 2 (CDK2) via the ubiquitin-proteasome pathway and are therefore useful in 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 crucial for orchestrating 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 the cell cycle process; 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 underway 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, the 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 the high expression of cyclin E leads to over-activated CDK2 / cyclin E complexes, so that the demand for CDK4 / 6 to re-enter the cell cycle is bypassed (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 entry into the S phase. During the S phase, cyclin E is degraded, and CDK2 forms a complex with cyclin A to promote substrate phosphorylation, thereby allowing DNA replication and inactivation of E2F to complete the S phase (Asghar et al. Nat. Rev. Drug. Discov. [Nature Reviews: Drug Discovery] (2015) 14: 130-146). In addition to cyclin binding, CDK2 activity is also tightly regulated through 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 cell cycle protein of CDK2) is usually overexpressed in cancer, and its overexpression is associated with poor prognosis. For example, it has been shown that the amplification or overexpression of cyclin E is related to the poor outcome in breast cancer (Keyomarsi et al., NEngl J Med. [New England Journal of Medicine] (2002) 347: 1566-75). Cyclin E2 (CCNE2) overexpression is related to endocrine resistance in breast cancer cells, and it has been reported that CDK2 inhibition restores 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, gastric, endometrial, uterine, bladder, esophageal, prostate, lung, 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 Cancer Res (2013) 19:5960-71). 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) can also lead to overexpression of cyclin E and activation of CDK2. Alternatively, certain 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 CDK2, p21, and p27 are often aberrantly downregulated in cancer. It is hypothesized that the loss or reduction of these key endogenous inhibitors leads to hyperactivation and / or transient aberrant activation of CDK2, thereby promoting tumor growth.

[0013] Furthermore, CDC25A and CDC25B, protein phosphatases responsible for dephosphorylation of activated 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. Inactivation of CDK2 has been shown to be synthetically lethal to Myc-overexpressing cancer cells.

[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, a few CDK2 inhibitors are in early clinical trials. For example, demasirib (MK-7965), which inhibits CDK1, CDK2, CDK5, and CDK9, is in clinical development in combination with other agents for solid tumors and hematological cancers; CYC065, which potently inhibits CDK2, CDK3, CDK4, CDK9, and modestly inhibits CDK1, CDK5, and CDK7, is currently being studied for the treatment of refractory CLL and other cancers; and PF-06873600, 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 would eliminate CDK2 activity and 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 addresses this 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 formula (i);

[0022]

[0023] (b) a group having formula (ii);

[0024]

[0025] (c) a group having the formula (iii):

[0026]

[0027] (d) a group having the formula (iv):

[0028]

[0029] (e) a group having the formula (v):

[0030]

[0031] as well as

[0032] (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 having formula (i) is a ring having 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 an alkyl group;

[0044] Ring B of the E3 ligase ligand having formula (ii) is phenylene, cycloamino, 5-membered or 6-membered monocyclic heteroarylene, or 9-membered or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three nitrogen ring atoms and further wherein R is independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, and cyano. 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 fluorine groups;

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

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

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

[0049] R w is hydrogen, deuterium, alkyl, haloalkyl, cycloalkyl, halogen, alkoxy, haloalkoxy, or cyano;

[0050] Q is a ring having formula (a1), (b1) or (c1):

[0051]

[0052] in:

[0053] R 1 、R 1a and R 1b are independently hydrogen, deuterium, alkyl, haloalkyl, cycloalkyl, halogen, haloalkoxy, or cyano;

[0054] R 2 、R 2a and R 2b is hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, halogen, haloalkyl, cyano, aralkyl, heteroaralkyl, heterocyclyl, fused heterocyclyl, or heterocyclylalkyl, wherein the ring portions of the alkyl, haloalkyl, cycloalkyl, and heterocyclyl groups, and the ring portions of the cycloalkylalkyl, aralkyl, heteroaralkyl, and heterocyclylalkyl groups are independently selected from the following R e 、R f and R g Substituted: hydrogen, deuterium, alkyl, halogen, haloalkyl, cycloalkyl, cyano, hydroxy, alkoxy, acyl, aminocarbonyl, aminosulfonyl, carboxyl, amino, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; and

[0055] R 3 、R3a and R 3b is alkyl, haloalkyl, deuterated haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aminocarbonylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl, wherein the ring portions of the cycloalkyl, aryl, heteroaryl and heterocyclyl groups, and the ring portions of the cycloalkylalkyl, aralkyl, heteroaralkyl and heterocyclylalkyl groups are independently selected from the following R e1 、R f1 and R g1 Substituted: hydrogen, deuterium, alkyl, halogen, haloalkyl, cycloalkyl, cycloalkylalkyl, aminoalkyl, (amino)deuterated alkyl, cyano, hydroxy, alkoxy, acyl, aminocarbonyl, aminosulfonyl, carboxyl, amino, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; and

[0056] L is -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -,in:

[0057] 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;

[0058] 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;

[0059] 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, spiroheterocyclylene or 11- to 13-membered spiroheterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. m and R n replace;

[0060] 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, hydroxy, amino, alkylamino and dialkylamino R o and R p replace;

[0061] Z 5 is a bond, -alkylene, -NR"-, -O-, -C(O)-, -S(O)2-, -NR'(CO)-, -C(O)NR-, phenylene, a monocyclic heteroarylene, or a heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, and haloalkoxy. q and R r replace; and

[0062] Z 6 is a bond, alkylene, -NR"-, -O-, -(alkylene-O)-, -C(O)-, -S(O)2-, -NR'(CO)-, or -C(O)NR-;

[0063] 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 Substituted, where R s is hydrogen or deuterium and R tis hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl or monocyclic heteroaryl, wherein the 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.

[0064] 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, 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 subembodiment 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, bronchogenic carcinoma, bronchial adenoma and / or pleuropulmonary blastoma), skin cancer (e.g., melanoma, squamous cell carcinoma, Kaposi's sarcoma and / or Merkel cell skin cancer), bladder cancer, breast cancer, cervical cancer, colorectal cancer, small 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 cholangiocellular carcinoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), gastric cancer, thyroid cancer and / or parathyroid cancer. In a third embodiment of the second aspect, the cancer is resistant to CDK4 / 6 inhibitors through a CDK2-mediated mechanism. In a fourth embodiment of the second aspect, the therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition.

[0065] In a third aspect, a method of treating noise-, cisplatin-, antibiotic-induced, or age-related hearing loss is provided, comprising administering to a patient (preferably, a patient in need of such treatment) a therapeutically effective amount of a compound of formula (I) (or any embodiment thereof as 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, the hearing loss is prevented when compared to an age-matched control.

[0066] 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.

[0067] 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 medicament. 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 second aspect above.

[0068] In a sixth aspect, provided is the 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.

[0069] In a seventh aspect, a method for degrading CDK2 via the 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 cells in vitro or in a patient.

[0070] In the above aspects relating to the treatment of cancer, further embodiments are provided comprising 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 combination therapy is used, these agents may be administered simultaneously or sequentially. DETAILED DESCRIPTION

[0071] definition:

[0072] 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:

[0073] "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.

[0074] 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.

[0075] "Alkenyl" means a straight-chain unsaturated monovalent hydrocarbon group having two to six carbon atoms or a branched-chain saturated monovalent hydrocarbon group having three to six carbon atoms containing a double bond, for example, ethenyl, propenyl, 2-propenyl, butenyl, pentenyl, etc.

[0076] The "alkynyl group" means a straight-chain unsaturated monovalent hydrocarbon group having two to six carbon atoms or a branched-chain unsaturated monovalent hydrocarbon group having three to six carbon atoms containing a triple bond, for example, ethynyl, propynyl and the like.

[0077] "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.

[0078] "Alkylsulfonyl" means -SO2R z Group (where R z is alkyl as defined above), for example, methylsulfonyl, ethylsulfonyl, etc.

[0079] "Alkylthio" means -SR z Group (where R z is alkyl as defined above), for example, methylthio, ethylthio, etc.

[0080] "Alkylcarbonyloxy" refers to -OC(O)R z Group (where R z is alkyl as defined herein).

[0081] "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.

[0082] "Alkoxyalkyl" means a straight-chain monovalent hydrocarbon radical having one to six carbon atoms or a branched-chain 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.

[0083] "Alkylcarbonyl" means -C(O)OR z Group (where R zis alkyl as defined above), for example, methoxycarbonyl, ethoxycarbonyl, and the like.

[0084] "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.

[0085] "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.

[0086] "Amino" means -NH2.

[0087] "Alkylamino" means -NHR z Group (where R z is alkyl as defined above), for example, methylamino, ethylamino, propylamino, and the like.

[0088] "Aminocarbonyl" means -CONR z 'R z " group, wherein R z ' and R z " is independently hydrogen, alkyl, cycloalkyl optionally substituted with one, two or three substituents independently selected from alkyl, halo, hydroxyalkyl, alkoxyalkyl and alkylcarbonyl, each as defined herein, e.g., aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, and the like.

[0089] "Aminocarbonylalkyl" refers to -(alkylene)-CONR z 'R z " group, wherein R z ' and R z " is independently hydrogen, alkyl, cycloalkyl optionally substituted with one, two or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, cyano, haloalkyl, hydroxyalkyl, alkoxyalkyl and alkylcarbonyl, each as defined herein.

[0090] "Aminosulfonyl" means -SO2NR z 'R z" group, wherein Rz' and Rz" are independently hydrogen, alkyl, cycloalkyl optionally substituted with one, two or three substituents independently selected from alkyl, halogen, hydroxy, alkoxy, cyano, haloalkyl, hydroxyalkyl, alkoxyalkyl and alkylcarbonyl, each as defined herein, for example, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, etc.

[0091] "Aminoalkyl" refers to a group consisting of -NR 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 the cycloalkyl and cycloalkyl ring in the 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, optionally substituted heterocyclyl, each as defined herein, for example, aminomethyl, aminoethyl, methylaminomethyl, etc.

[0092] "(Amino)deuterated alkyl" means a group replaced by one or two deuterium and -NR 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, haloalkyl, hydroxyalkyl, alkoxyalkyl or alkylcarbonyl, each as defined herein, for example, aminomethyl (wherein one or two hydrogens in the "methyl" are replaced by one or two deuteriums, respectively), aminoethyl (wherein one or two hydrogens in the "ethyl" are replaced by one or two deuteriums, respectively), methylamino-C(H)(D)-, methylamino-CD2-, and the like.

[0093] "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 ring atoms, for example, phenyl or naphthyl.

[0094] "Arylene" means a divalent aromatic radical (as defined above), for example, phenylene or naphthylene.

[0095] "Aralkyl" refers to -(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.

[0096] 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 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, the remaining annular atoms are carbon. In addition, one or two annular carbon atoms of the bicyclic heterocyclylene ring can optionally be 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 annular double bonds, provided that the ring is not aromatic.

[0097] "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 (inclusive) 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 (where n is an integer selected from 0 to 2 (inclusive)) is substituted with a heteroatom. Unless otherwise indicated, the bridged heterocyclylene group is optionally substituted with 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.

[0098] "Cycloalkyl" means a monocyclic saturated monovalent hydrocarbon radical having three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0099] "Cycloalkylalkyl" refers to 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.

[0100] The "cycloalkylene group" means a divalent saturated hydrocarbon group having three to six carbon atoms, and examples thereof include 1,1-cyclopropylene, 1,1-cyclobutylene, and 1,4-cyclohexylene.

[0101] "Cyanoalkyl" means a linear 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.

[0102] "Carboxyl" means -COOH.

[0103] "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 C. More specifically, the term cycloamino includes, but is not limited to, pyrrolidinylene, piperidinylene, homopiperidinylene, and the like.

[0104] Deuterium means 2 H or D.

[0105] "Deuterated alkyl" means an alkyl group as defined above that is substituted with one, two, or three deuterium groups.

[0106] "Deuterated haloalkyl" means a haloalkyl group, as defined herein, substituted with one, two, or three deuterium groups.

[0107] "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, etc.

[0108] As used herein, "fused heterocyclic radical" means a saturated monovalent monocyclic ring having 4 to 7 ring atoms, the saturated monovalent monocyclic ring having one to three heteroatoms independently selected from N, O and S, and the remaining ring atoms being carbon, and further wherein two adjacent ring atoms of the monocyclic ring are fused to two adjacent ring members of a phenyl or a five-membered or six-membered heteroaryl, each as defined herein, unless otherwise stated. Nitrogen and sulfur atoms are optionally oxidized, and one or more nitrogen atoms are optionally quaternized, and one or two carbon atoms of the fused ring atoms in the saturated monocyclic ring include two common ring vertices shared with the fused phenyl or five-membered or six-membered heteroaryl. The fused heterocyclic radical may be attached to any atom of the ring. Non-limiting examples of fused heterocycloalkyls include 2,3-dihydrobenzo[b][1,4]-dioxinyl, 2-oxabicyclo[3.1.0]hexane, indolin-2-one-1-yl, dihydroindole, etc.

[0109] As used herein, "fused heterocyclylene" refers to a bivalent 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 being carbon are fused to two adjacent ring members of a phenyl or five-membered or six-membered heteroaryl group (each as defined herein), unless otherwise indicated. The nitrogen atom is optionally oxidized or quaternized. The fused heterocyclylene group 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, and the like.

[0110] "Halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0111] "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 one or more fluorine atoms, it may be referred to herein as a fluoroalkyl group.

[0112] "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 one or more fluorine atoms), it is referred to herein as a fluoroalkoxy group.

[0113] "Haloalkoxyalkyl" means -(alkylene)OR z Group (where R z is a haloalkyl group as defined above), for example, trifluoromethoxyalkyl and the like.

[0114] "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 hydroxy groups, provided that if two hydroxy 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.

[0115] 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, furyl, 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 monocycle, 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.

[0116] "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, and the like. 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.

[0117] "Heteroaralkyl" refers to an -(alkylene)-R z Group (where R z is a heteroaryl group as defined above), for example, pyridylmethyl, etc. When the heteroaryl ring in the heteroarylalkyl group contains 5 or 6 ring atoms, it is also referred to herein as a 5-membered or 6-membered heteroarylalkyl group or a monocyclic heteroarylalkyl group.

[0118] 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, remaining annular atoms is C. In addition, one or two ring carbon atoms in the heterocyclic ring can optionally be replaced by-CO-group. More particularly, 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 the subset of heterocyclic group.

[0119] "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.

[0120] Unless otherwise specified, "heterocyclylene" means a saturated bivalent monocyclic radical having 4 to 6 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 (inclusive)) heteroatom, 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.

[0121] "Phenylene" refers to a divalent phenyl group.

[0122] The term "oxo," as used herein, alone or in combination, refers to =(O).

[0123] "Optionally substituted aryl" means an aryl as defined above that is optionally substituted by one, two, or three substituents independently selected from alkyl, hydroxy, cycloalkyl, carboxyl, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfonyl, amino, alkylamino, dialkylamino, halogen, haloalkyl, haloalkoxy, and cyano. In some embodiments, the optionally substituted aryl is an optionally substituted phenyl.

[0124] "Optionally substituted aralkyl" refers to -(alkylene)-R z , where R z is optionally substituted aryl as defined above.

[0125] "Optionally substituted heteroaryl" means a heteroaryl group as defined above optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alkylthio, alkylsulfonyl, hydroxy, cycloalkyl, carboxyl, alkoxycarbonyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino and cyano.

[0126] "Optionally substituted heteroaralkyl" refers to an -(alkylene)-R z , where R z is an optionally substituted heteroaryl group as defined above.

[0127] 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, carboxyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, cyanoalkyl, halo, haloalkyl, haloalkoxy and cyano.

[0128] "Optionally substituted heterocyclylalkyl" refers to an -(alkylene)-R z , where R z is an optionally substituted heterocyclyl as defined above.

[0129] As used herein, the phrase "optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, the phrase "heteroaryl optionally substituted with alkyl" is intended to encompass heteroaryl groups that are not substituted with alkyl and heteroaryl groups that are substituted with alkyl.

[0130] "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.

[0131] "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 (inclusive)) heteroatoms, 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.

[0132] "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 only by one atom, and the connecting atom is also referred to as a spiral atom, most commonly a quaternary carbon ("spiro carbon"). Unless otherwise indicated, 11 to 13 yuan of spiral heterocyclyls 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.

[0133] The present 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 can be protected by suitable blocking groups. A complete list of suitable blocking 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.

[0134] The present disclosure also encompasses polymorphic and deuterated forms of the compounds of Formula (I) or pharmaceutically acceptable salts thereof.

[0135] 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: Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because, in some cases, they are easier to administer than the compound or parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug is not. Various prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound that is administered as an ester ("prodrug") but then metabolically hydrolyzes to the carboxylic acid (the active entity). Additional examples include peptidyl derivatives of the compounds.

[0136] 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:

[0137] 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

[0138] 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 coordinated with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.) to form a salt. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pennsylvania, 1985, which is incorporated herein by reference in its entirety.

[0139] Compounds with formula (I) can have asymmetric centers. Compounds with formula (I) containing asymmetrically substituted atoms can be separated in optically active form or racemic form. The independent stereoisomer of a compound can be prepared by synthesizing from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products and then separating (such as 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 specifically indicated to have a specific stereochemical form or isomeric form, all chiral forms, diastereomeric forms, all mixtures of chiral or diastereomeric forms, and racemic form are within the scope of the present disclosure. It will also be understood by those skilled in the art that when a compound is represented as a (R) stereoisomer, it can contain corresponding (S) stereoisomers as impurities, and vice versa.

[0140] 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 have been 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 have been listed, it includes all positional isomers. In addition, all hydrates of compounds with formula (I) are within the scope of this disclosure.

[0141] Compounds of formula (I) may also contain unnatural amounts of isotopes at one or more atoms that make up such compounds. An unnatural amount of an isotope can 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 the 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. 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) substitutions 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 (IA'), (IA) or (I) (including those listed in Table 1 below), one or more hydrogen atoms are replaced by 2 H or 3 H is replaced, or one or more carbon atoms are replaced 13 C- or14 C-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.

[0142] "Pharmaceutically acceptable carrier or excipient" means a carrier or excipient useful in preparing pharmaceutical compositions 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.

[0143] As used in the specification and claims, "pharmaceutically acceptable carrier / excipient" includes both one and more than one such excipient.

[0144] As used herein, the term "about" is intended to qualify the numerical value it modifies, indicating that the value is a variable within the margin of error. When no specific error range is listed (e.g., the standard deviation of the mean value given in a data graph or table), the term "about" should be understood to mean a range covering ±10%, preferably ±5%, including the listed values ​​and ranges.

[0145] 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.

[0146] 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 1Similarly, R aa and X 1 and R aa and X bb The substituents substituted a portion of the benzo portion of the bicyclic ring.

[0147] Furthermore, as used throughout this application, including in the Examples, when a group is introduced as divalent, the left bond of the divalent group is attached to the group to its left in the remainder of the molecule, and the right bond of the divalent group is attached to the group to its right in the remainder of the molecule.

[0148] For example, in the following divalent group

[0149]

[0150] (a), (b) and (c) on the left The key is attached to the following rings:

[0151]

[0152] 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 :

[0153]

[0154] Similarly, for L, that is, -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:

[0155] 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 (ie -SO2-) is attached to Hy of atoms, as indicated below.

[0156] As used herein, the term "disease" 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 of the body that impairs its normal function, typically manifests itself by distinctive signs and symptoms, and causes the human or animal to have a reduced life span or quality of life.

[0157] The term "combination therapy" means the administration of two or more therapeutic agents to treat the diseases or disorders described in this disclosure. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as administration in a single capsule having 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.

[0158] 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.

[0159] "Treating" or "treatment" diseases include:

[0160] (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;

[0161] (2) inhibit the disease, i.e., delay, arrest (i.e., stabilize), or reduce the development or severity of the disease or its clinical symptoms; or

[0162] (3) Alleviate the disease, that is, cause the disease or its clinical symptoms to subside.

[0163] In one embodiment, treating or treating a disease includes inhibiting the disease, ie, delaying, arresting, or reducing the development or severity of the disease or its clinical symptoms; or alleviating the disease, ie, causing regression of the disease or its clinical symptoms.

[0164] "Therapeutically effective amount" means the amount of a compound of the present disclosure and / or a pharmaceutically acceptable salt thereof, when administered to a patient for treating a disease, 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.

[0165] The terms "inhibit" and "reduce" or any variations of these terms with respect to CDK2 and / or CDK1 include any measurable reduction or complete inhibition to achieve the desired result. For example, a reduction can be a decrease in CDK2 and / or CDK1 activity by about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, respectively, compared to normal activity, or any range derivable therein.

[0166] Representative compounds prepared according to the present disclosure are disclosed in the following Compound Table 1:

[0167] Compound Table I

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188] Example:

[0189] In Embodiments A1 to 175, the disclosure includes:

[0190] 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.

[0191] A2. In embodiment A2, the compound of embodiment A1 or a pharmaceutically acceptable salt thereof is wherein Q is a ring having the formula:

[0192] A3. In embodiment A3, the compound of embodiment A1 or a pharmaceutically acceptable salt thereof is wherein Q is a ring having the formula:

[0193] A4. In embodiment A4, the compound of embodiment A1 or a pharmaceutically acceptable salt thereof, wherein Q is a ring having the formula:

[0194] A5. In embodiment A5, the compound of any one of embodiments A1 to A4, or a pharmaceutically acceptable salt thereof, is wherein R 3 、R 3a and R 3b is an alkyl, halogenated alkyl, deuterated alkyl, hydroxyalkyl, phenyl or heterocyclic group, wherein the phenyl and heterocyclic groups are replaced by R e1 、R f1 and R g1 replace.

[0195] A6. In embodiment A6, the compound of any one of embodiments A1 to A5, or a pharmaceutically acceptable salt thereof, is wherein R 3 、R 3a and R 3b is an alkyl group or a halogenated alkyl group.

[0196] A7. In embodiment A7, the compound of any one of embodiments A1 to A6, or a pharmaceutically acceptable salt thereof, is wherein R 3 、R 3a and R 3b It is a halogenated alkyl group.

[0197] A8. In embodiment A8, the compound of any one of embodiments A1 to A5, or a pharmaceutically acceptable salt thereof, is wherein R 3 、R 3aand R 3b It is a hydroxyalkyl group.

[0198] A9. In embodiment A9, the compound of any one of embodiments A1 to A5, or a pharmaceutically acceptable salt thereof, wherein R 3 、R 3a and R 3b To be R e1 、R f1 and R g1 Substituted phenyl.

[0199] A10. In embodiment A10, the compound of any one of embodiments A1 to A5, or a pharmaceutically acceptable salt thereof, is wherein R 3 、R 3a and R 3b To be R e1 、R f1 and R g1 substituted heterocyclic group.

[0200] A11. In embodiment A11, the compound of any one of embodiments A1 to A10, or a pharmaceutically acceptable salt thereof, is wherein R 3 、R 3a and R 3b is methyl, ethyl, propyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl, wherein phenyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl is replaced by R e1 、R f1 and R g1 replace.

[0201] A12. In embodiment A12, the compound of any one of embodiments A1 to A11, or a pharmaceutically acceptable salt thereof, is wherein R 3 、R 3a and R 3b is methyl, ethyl, propyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl, wherein phenyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl is independently selected from hydrogen, halogen, haloalkyl, alkoxy and cyano. e1 、R f1 and R g1 replace.

[0202] A13. In embodiment A13, the compound of any one of embodiments A1 to A7, A11 and A12, or a pharmaceutically acceptable salt thereof, is wherein R 3 、R3a and R 3b It is 2,2,2-trifluoroethyl.

[0203] A14. In embodiment A14, the compound of any one of embodiments A1 to A5, A8, A11 and A12, or a pharmaceutically acceptable salt thereof, is wherein R 3 、R 3a and R 3b It is 2-hydroxy-2-methylpropyl.

[0204] A15. In embodiment A15, the compound of any one of embodiments A1 to A5 and A9 to A12, or a pharmaceutically acceptable salt thereof, is wherein R 3 、R 3a and R 3b is phenyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl, wherein phenyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl is independently selected from hydrogen, fluorine, methoxy, trifluoromethyl and cyano. e1 、R f1 and R g1 replace.

[0205] A16. In embodiment A16, the compound of any one of embodiments A1 to A15, or a pharmaceutically acceptable salt thereof, is wherein R 1 、R 1a and R 1b Each is hydrogen and R w Not hydrogen.

[0206] A17. In embodiment A17, the compound of any one of embodiments A1 to A15, or a pharmaceutically acceptable salt thereof, is wherein R w is hydrogen and R 1 、R 1a and R 1b Not hydrogen.

[0207] A18. In embodiment A18, the compound of any one of embodiments A1 to A16, or a pharmaceutically acceptable salt thereof, is wherein R w It is a halogenated alkyl group.

[0208] A19. In embodiment A19, the compound of any one of embodiments A1 to A16 and A18, or a pharmaceutically acceptable salt thereof, is wherein R w is a haloalkyl group, a halogen group or a cyano group.

[0209] A20. In embodiment A20, the compound of any one of embodiments A1 to A16, A18 and A19, or a pharmaceutically acceptable salt thereof, is wherein R wis difluoromethyl, trifluoromethyl, chlorine, fluorine or cyano.

[0210] A21. In embodiment A21, the compound of embodiment A17 or a pharmaceutically acceptable salt thereof is wherein R 1 、R 1a and R 1b is a haloalkyl group, a halogen group or a cyano group.

[0211] A22. In embodiment A22, the compound of any one of embodiments A1 to A15, A17 and A21, or a pharmaceutically acceptable salt thereof, is wherein R 1 、R 1a and R 1b is difluoromethyl, trifluoromethyl, chloro or cyano.

[0212] A23. In embodiment A23, the compound of any one of embodiments A1 to A16, A18 and A20, or a pharmaceutically acceptable salt thereof, is wherein R w It is trifluoromethyl.

[0213] A24. In embodiment A24, the compound of any one of embodiments A1 to A16 and A20, or a pharmaceutically acceptable salt thereof, is wherein R w It is a cyano group.

[0214] A25. In embodiment A25, the compound of any one of embodiments A1 to A16 and A20, or a pharmaceutically acceptable salt thereof, is wherein R w For chlorine.

[0215] A26. In embodiment A26, the compound of any one of embodiments A1 to A25, or a pharmaceutically acceptable salt thereof, 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 Substituted, where R b and R c are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy and hydroxy, and R d For hydrogen.

[0216] A27. In embodiment A27, the compound of any one of embodiments A1 to A26, or a pharmaceutically acceptable salt thereof, is wherein Hy is replaced by R b 、R c and R d Substituted heterocyclylene, wherein R b and R care independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy and hydroxy, and R d For hydrogen.

[0217] A28. In embodiment A28, the compound of any one of embodiments A1 to A27, or a pharmaceutically acceptable salt thereof, is wherein Hy is or is replaced by 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 d is hydrogen, and L is attached to the nitrogen atom of the piperidine-1,4-diyl or pyrrolidine-1,3-diyl ring of Hy.

[0218] A29. In embodiment A29, the compound of any one of embodiments A1 to A28, or a pharmaceutically acceptable salt thereof, is wherein Hy is:

[0219]

[0220] wherein the N atom of the pyrrolidine-1,3-diyl or piperidine-1,4-diyl ring is attached to L.

[0221] A30a. In embodiment A30a, the compound of any one of embodiments A1 to A29, or a pharmaceutically acceptable salt thereof, is wherein Hy is:

[0222]

[0223] wherein the N atom of the pyrrolidine-1,3-diyl or piperidine-1,4-diyl ring is attached to L.

[0224] A30. In embodiment A30, the compound of any one of embodiments A1 to A30a, or a pharmaceutically acceptable salt thereof, is wherein Hy is:

[0225]

[0226] wherein the N atom of the piperidine-1,4-diyl ring is attached to L.

[0227] A31. In embodiment A31, the compound of any one of embodiments A1 to A25, or a pharmaceutically acceptable salt thereof, is wherein Hy is a ring having the formula:

[0228]

[0229] wherein X is CH or N and forms a bond to L; Y is CH, CMe or N; with the proviso that at least one of X and Y is N; z is 0, 1 or 2; z' is 0 or 1; with the proviso that at least one of z' and z is 1; and Hy is optionally substituted with one, two or three substituents independently selected from alkyl, halogen, haloalkyl, alkoxy and hydroxy.

[0230] A32. In embodiment A32, the compound of embodiment A31, or a pharmaceutically acceptable salt thereof, is wherein X is N and Y is CH.

[0231] A33. In embodiment A33, the compound of embodiment A31, or a pharmaceutically acceptable salt thereof, is wherein Y is N and X is CH.

[0232] A34. In embodiment A34, the compound of any one of embodiments A1 to A26, or a pharmaceutically acceptable salt thereof, is wherein Hy is replaced by R b 、R c and R d Substituted cycloalkylene, wherein R b is deuterium, methyl, fluorine, methoxy or hydroxy, and R c and R d For hydrogen.

[0233] A35. In embodiment A35, the compound of embodiment A34, or a pharmaceutically acceptable salt thereof, is wherein Hy is cyclohexylene.

[0234] A36. In embodiment A36, the compound of any one of embodiments A1 to A26, A34 and A35, or a pharmaceutically acceptable salt thereof, is wherein Hy is in represents a bond to NH and Indicates the bond of L.

[0235] A37. In embodiment A37, the compound of any one of embodiments A1 to A26, or a pharmaceutically acceptable salt thereof, is wherein Hy is replaced by 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.

[0236] A38. In embodiment A38, the compound of any one of embodiments A1 to A26, or a pharmaceutically acceptable salt thereof, is wherein Hy is replaced by R b 、R c and R dSubstituted spiroheterocyclylene, wherein R b and R c are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy and hydroxy, and R d For hydrogen.

[0237] A39. In embodiment A39, the compound of any one of embodiments A1 to A25, or a pharmaceutically acceptable salt thereof, is wherein Hy is replaced by 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.

[0238] A40. In embodiment A40, the compound of any one of embodiments A1 to A39, or a pharmaceutically acceptable salt thereof, wherein the degron is an E3 ligase ligand having formula (i):

[0239]

[0240] A41. In embodiment A41, 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 (a):

[0241]

[0242] A42. In embodiment A42, the compound of any one of embodiments A1 to A41, or a pharmaceutically acceptable salt thereof, is wherein R 4 and R 5 are independently hydrogen or alkyl.

[0243] A43. In embodiment A43, the compound of any one of embodiments A1 to A42, or a pharmaceutically acceptable salt thereof, is wherein R 4 and R 5 All are hydrogen.

[0244] A44. In embodiment A44, the compound of any one of embodiments A1 to A42, or a pharmaceutically acceptable salt thereof, is wherein R 4 is hydrogen and R 5 It is a methyl group.

[0245] A45. In embodiment A45, the compound of any one of embodiments A1 to A41, or a pharmaceutically acceptable salt thereof, is wherein R 4 and R 5Together with the carbon to which they are attached they form >C=O.

[0246] 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):

[0247]

[0248] A47. In embodiment A47, the compound of any one of embodiments A1 to A40 and A46, or a pharmaceutically acceptable salt thereof, is wherein R 6 For hydrogen.

[0249] A48. In embodiment A48, the compound of any one of embodiments A1 to A40 and A46, or a pharmaceutically acceptable salt thereof, wherein R 6 It is an alkyl group.

[0250] A48a. In embodiment A48a, the compound of any one of embodiments A1 to A40, A46 and A48, or a pharmaceutically acceptable salt thereof, wherein R 6 It is a methyl group.

[0251] 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):

[0252]

[0253] 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:

[0254]

[0255] 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:

[0256]

[0257] 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:

[0258]

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

[0260] A52a. In embodiment A52a, the compound of 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 of formula (i) is:

[0261]

[0262] That is, where R bb For hydrogen.

[0263] A53. In embodiment A53, the compound of any one of embodiments A1 to A41, A45 and A50 to A52, or a pharmaceutically acceptable salt thereof, is wherein Ring A of the E3 ligase ligand of formula (i) is:

[0264]

[0265] That is, where R bb For hydrogen.

[0266] 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:

[0267]

[0268] That is, where R bb For hydrogen.

[0269] 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:

[0270]

[0271] That is, where R aa and R bb For hydrogen.

[0272] A56. In embodiment A56, 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:

[0273]

[0274] A57. In embodiment A57, the compound of any one of embodiments A1 to A40, A46, A48a, A50 to A52, or a pharmaceutically acceptable salt thereof, is wherein Ring A of the E3 ligase ligand of formula (i) is:

[0275]

[0276] That is, where R cc and R dd For hydrogen.

[0277] A58. In embodiment A58, the compound of 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 haloalkoxy.

[0278] A59. In embodiment A59, the compound of 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.

[0279] A60. In embodiment A60, the compound of 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.

[0280] A61. In embodiment A61, the compound of 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) independently selected from hydrogen and methyl.

[0281] A62. In embodiment A62, the compound of 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) independently selected from hydrogen and methoxy.

[0282] A63. In embodiment A63, the compound of 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) independently selected from hydrogen and fluorine.

[0283] A64. In embodiment A64, the compound of 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) independently selected from hydrogen, trifluoromethyl and difluoromethyl.

[0284] A65. In embodiment A65, the compound of 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) independently selected from hydrogen and trifluoromethoxy.

[0285] A66. In embodiment A66, the compound of 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) independently selected from hydrogen, fluoro and trifluoromethyl.

[0286] A67. In embodiment A67, the compound of any one of embodiments A1 to A39, or a pharmaceutically acceptable salt thereof, is wherein the degron is an E3 ligase ligand having formula (ii):

[0287]

[0288] A68. In embodiment A68, the compound of any one of embodiments A1 to A39 and A67, or a pharmaceutically acceptable salt thereof, is wherein Y a For CH.

[0289] A69. In embodiment A69, the compound of any one of embodiments A1 to A39 and A67, or a pharmaceutically acceptable salt thereof, is wherein Y a is N.

[0290] A70. In embodiment A70, the compound of any one of embodiments A1 to A39 and A67-A69, or a pharmaceutically acceptable salt thereof, is wherein Za is a bond, -NH-, O or -NHC(O)-.

[0291] A71. In embodiment A71, the compound of any one of embodiments A1 to A39 and A67-A70, or a pharmaceutically acceptable salt thereof, is wherein Z a is a bond, -NH- or -NHC(O)-.

[0292] A72. In embodiment A72, the compound of any one of embodiments A1 to A39 and A67-A71, or a pharmaceutically acceptable salt thereof, is wherein Z a is the key.

[0293] A73. In embodiment A73, the compound of any one of embodiments A1 to A39 and A67-A71, or a pharmaceutically acceptable salt thereof, is wherein Z a It is -NH- or -NHC(O)-.

[0294] A74. In embodiment A74, the compound of any one of embodiments A1 to A39 and A67-A71 and A73, or a pharmaceutically acceptable salt thereof, is wherein Z a It is -NH-.

[0295] A74a. In embodiment A74a, the compound of any one of embodiments A1 to A39 and A67-A71 and A73, or a pharmaceutically acceptable salt thereof, is wherein Z a It is -NHC(O)-.

[0296] A75. In embodiment A75, the compound of any one of embodiments A1 to A39 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.

[0297] A76. In embodiment A76, the compound of any one of embodiments A1 to A39 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 cycloamino groups.

[0298] A77. In embodiment A77, the compound of any one of embodiments A1 to A39 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.

[0299] A78. In embodiment A78, the compound of any one of embodiments A1 to A39 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.

[0300] A79. In embodiment A79, the compound of any one of embodiments A1 to A39 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-membered or 10-membered fused bicyclic heteroarylene.

[0301] A80. In embodiment A80, the compound of any one of embodiments A1 to A39 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-membered or 10-membered fused bicyclic heteroarylene.

[0302] A81. In embodiment A81, the compound of any one of embodiments A1 to A39, A67 to A80, or a pharmaceutically acceptable salt thereof, wherein the E3 ligase ligand of formula (ii) is:

[0303]

[0304] A82. In embodiment A82, the compound of any one of embodiments A1 to A39 and A67 to A81, or a pharmaceutically acceptable salt thereof, is wherein the E3 ligase ligand of formula (ii) is:

[0305]

[0306] Wherein ring B is a cycloamine group.

[0307] A83. In embodiment A83, the compound of any one of embodiments A1 to A39 and A67 to A81, or a pharmaceutically acceptable salt thereof, is wherein the E3 ligase ligand of formula (ii) is:

[0308]

[0309] A84. In embodiment A84, the compound of any one of embodiments A1 to A39, A67 to A83, 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 haloalkoxy.

[0310] A85. In embodiment A85, the compound of any one of embodiments A1 to A39 and A67 to A83, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, and cyano.

[0311] A86. In embodiment A86, the compound of any one of embodiments A1 to A39 and A67 to A83, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, or cyano.

[0312] A87. In embodiment A87, the compound of any one of embodiments A1 to A39 and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff are independently selected from hydrogen and methyl, ethyl or isopropyl.

[0313] A88. In embodiment A88, the compound of any one of embodiments A1 to A39 and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff are independently selected from hydrogen and methoxy.

[0314] A89. In embodiment A89, the compound of any one of embodiments A1 to A39 and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ffare independently selected from hydrogen, methyl, ethyl, isopropyl, chlorine and fluorine.

[0315] A90 In embodiment A90, the compound of any one of embodiments A1 to A39 and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff One of is hydrogen or fluorine, and R ee and R ff The other of the groups is selected from the group consisting of hydrogen, trifluoromethyl, 2,2,2-trifluoroethyl and difluoromethyl.

[0316] A91. In embodiment A91, the compound of any one of embodiments A1 to A39 and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff are independently selected from hydrogen, difluoromethoxy and trifluoromethoxy.

[0317] A92. In embodiment A92, the compound of any one of embodiments A1 to A39 and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff Independently selected from hydrogen, chlorine, fluorine and trifluoromethyl.

[0318] A93. In embodiment A93, the compound of any one of embodiments A1 to A39 and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff are independently hydrogen.

[0319] A94. In embodiment A94, the compound of any one of embodiments A1 to A39 and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff are independently chlorine.

[0320] A95. In embodiment A95, the compound of any one of embodiments A1 to A39 and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff are independently fluorine.

[0321] A96. In embodiment A96, the compound of any one of embodiments A1 to A39 and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff are independently trifluoromethyl or 2,2,2-trifluoroethyl.

[0322] A96a. In embodiment A96a, the compound of any one of embodiments A1 to A39, or a pharmaceutically acceptable salt thereof, is wherein the degron is an E3 ligase ligand of formula (iii), (iv), (v) or (vi).

[0323] A96b. In embodiment A96b, the compound of any one of embodiments A1 to A39, or a pharmaceutically acceptable salt thereof, is wherein the degron is an E3 ligase ligand of formula (iii), (iv), (v) or (vi), wherein R y is 1-fluorocyclopropane-1-yl and W a is a bond, S or methylene.

[0324] A97. In embodiment A97, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X 1 、X 2 、X 3 and X 4 Independently a key.

[0325] A98. In embodiment A98, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X 1 、X 2 、X 3 and X 4 are independently -alkylene-.

[0326] A98a. In embodiment A98a, the compound of 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 are independently methylene.

[0327] A99. In embodiment A99, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X 1 、X 2 、X 3 and X 4 is independently -O-.

[0328] A100a. In embodiment A100a, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X 1 、X 2 、X 3 and X 4 is independently -(O-alkylene)-.

[0329] A100. In embodiment A100, the compound of any one of embodiments A1 to A96 and A100a, or a pharmaceutically acceptable salt thereof, is wherein X 1 、X 2 、X 3 and X 4 are independently -(O-CH2)-, -O-(CH2)2- or -O-(CH2)3-.

[0330] A101a. In embodiment A101a, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X 1 、X 2 、X 3 and X 4 is independently -(alkylene-O)-.

[0331] A101. In embodiment A101, the compound of 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-.

[0332] A102. In embodiment A102, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X 1 、X 2 、X 3 and X 4 are independently -(NR gg -alkylene)-.

[0333] A103. In embodiment A103, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X 1 、X 2 、X 3 and X 4 are independently -(alkylene-NR hh )-.

[0334] A104. In embodiment A104, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X 1 、X 2 、X 3 and X 4 for

[0335] A105. In embodiment A105, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X 1 、X 2 、X 3 and X 4 It is -NH-.

[0336] A106. In embodiment A106, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X 1 、X 2 、X 3 and X 4 is independently -N(alkyl)-.

[0337] A107. In embodiment A107, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X 1 、X 2 、X 3 and X 4 It is –C(=O)-.

[0338] A108. In embodiment A108, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X 1 、X 2 、X 3 and X 4 Independently –NR jj C(=O)-.

[0339] A109. In embodiment A109, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X 1 、X 2 、X 3 and X 4 are independently -C(=O)NR kk -.

[0340] A110. In embodiment A110, the compound of 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.

[0341] A111. In embodiment A111, the compound of any one of embodiments A1 to A110, or a pharmaceutically acceptable salt thereof, is wherein Z 6 It is -S(O)2-.

[0342] A112. In embodiment A112, the compound of any one of embodiments A1 to A96b, 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:

[0343]

[0344] A113. In embodiment A113, the compound of any one of embodiments A1 to A111, or a pharmaceutically acceptable salt thereof, is wherein Z 5 is the key.

[0345] A114. In embodiment A114, the compound of any one of embodiments A1 to A96, A111 and A113, or a pharmaceutically acceptable salt thereof, 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.

[0346] A115. In embodiment A115, the compound of any one of embodiments A1 to A96b, or a pharmaceutically acceptable salt thereof, is wherein:

[0347] 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;

[0348] 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;

[0349] Z 2 is a bond, an alkylene group, or -(O-alkylene) 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;

[0350] Z 3 R 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. m and R n replace;

[0351] 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;

[0352] Z 5 is a key; and

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

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

[0355] A116. In embodiment A116, the compound of any one of embodiments A1 to A96b, or a pharmaceutically acceptable salt thereof, is wherein:

[0356] X 1 、X 2 、X 3 and X 4 and Z 1 Each is a key;

[0357] 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;

[0358] Z 3 is a bond, an alkylene, -C(O)NR-, -NR'(CO)-, -O-, -NR"-, a cycloalkylene, a phenylene, a monocyclic heteroarylene, a heterocyclylene, a bicyclic heterocyclylene, a bridged heterocyclylene, a fused heterocyclylene, or a spiroheterocyclylene, 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 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;

[0360] Z 5 R 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 each alkylene group is R s and R t replace.

[0363] A117. In embodiment A117, the compound of any one of embodiments A1 to A96b and A116, or a pharmaceutically acceptable salt thereof, is wherein:

[0364] X 1 、X 2 、X 3 and X 4 , Z 1 and Z 2 Each is a key;

[0365] Z 3 R is a 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;

[0366] Z 4R 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, hydroxy, amino, alkylamino, and dialkylamino. o and R p replace;

[0367] Z 5 R 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

[0368] Z 6 is -S(O)2-; and

[0369] Wherein the alkylene group is R s and R t replace.

[0370] A117a. In embodiment A117a, the compound of any one of embodiments A1 to A96b and A116 to A117, or a pharmaceutically acceptable salt thereof, is wherein:

[0371] X 1 、X 2 、X 3 and X 4 , Z 1 and Z 2 Each is a key;

[0372] Z 3 R is a 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;

[0373] 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, and haloalkoxy. o and R p replace;

[0374] Z 5 R is phenylene, monocyclic heteroarylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy qand R r replace; and

[0375] Z 6 is -S(O)2-; and

[0376] Wherein the alkylene group is R s and R t replace.

[0377] A118. In embodiment A118, the compound of any one of embodiments A1 to A96b, A116 and A117a, or a pharmaceutically acceptable salt thereof, is wherein:

[0378] X 1 、X 2 、X 3 and X 4 , Z 1 and Z 2 Each is a key;

[0379] Z 3 R is a heterocyclylene, a bicyclic heterocyclylene, a bridged heterocyclylene, a fused heterocyclylene, or a spiroheterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, and haloalkoxy. m and R n replace;

[0380] 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, hydroxy, amino, alkylamino, and dialkylamino. o and R p replace;

[0381] Z 5 R 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

[0382] Z 6 is -S(O)2-; and

[0383] Wherein the alkylene group is R s and R t replace.

[0384] A118a. In embodiment A118a, the compound of any one of embodiments A1 to A96b, A116 to A118, or a pharmaceutically acceptable salt thereof, wherein:

[0385] X 1 、X 2 、X 3 and X 4 , Z 1 and Z 2 Each is a key;

[0386] Z 3 R is a heterocyclylene, a bicyclic heterocyclylene, a bridged heterocyclylene, a fused heterocyclylene, or a spiroheterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, and haloalkoxy. m and R n replace;

[0387] 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 and haloalkoxy o and R p replace;

[0388] Z 5 R 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

[0389] Z 6 is -S(O)2-; and

[0390] Wherein the alkylene group is R s and R t replace.

[0391] A119. In embodiment A119, the compound of any one of embodiments A1 to A96b and A116 to A118a, or a pharmaceutically acceptable salt thereof, is wherein:

[0392] X 1 、X 2 、X 3 and X 4 , Z 1 and Z 2 Each is a key;

[0393] Z 3 R is a heterocyclylene, a bridged heterocyclylene, or a spiroheterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, and haloalkoxy. m and R n replace;

[0394] Z4 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, preferably hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy o and R p replace;

[0395] Z 5 R 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

[0396] Z 6 is -S(O)2-; and

[0397] Wherein the alkylene group is R s and R t replace.

[0398] A119a. In embodiment A119a, the compound of any one of embodiments A1 to A96b and A116 to A118a, or a pharmaceutically acceptable salt thereof, is wherein:

[0399] X 1 、X 2 、X 3 and X 4 , Z 1 and Z 2 Each is a key;

[0400] Z 3 R is a heterocyclylene, a bridged heterocyclylene, or a spiroheterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, and haloalkoxy. m and R n replace;

[0401] Z 4 R is alkylene, -O-, cycloalkylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy o and R p replace;

[0402] Z 5 R 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

[0403] Z 6 is -S(O)2-; and

[0404] Wherein the alkylene group is R s and R t replace.

[0405] A120. In embodiment A120, the compound of any one of embodiments A1 to A96b and A116 to A119a, or a pharmaceutically acceptable salt thereof, is wherein:

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

[0407] Z 3 R is a heterocyclylene, a bridged heterocyclylene, or a spiroheterocyclylene, 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 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;

[0409] Z 5 R is phenylene or 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 is -S(O)2-; and

[0411] Wherein the alkylene group is R s and R t replace.

[0412] A120a. In embodiment A120a, the compound of any one of embodiments A1 to A96b and A116 to A120, or a pharmaceutically acceptable salt thereof, wherein:

[0413] X 1 、X 2 、X 3 and X 4 , Z1 and Z 2 Each is a key;

[0414] Z 3 R is a heterocyclylene, a bridged heterocyclylene, or a spiroheterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, and haloalkoxy. m and R n replace;

[0415] Z 4 is alkylene or -O-;

[0416] Z 5 R is phenylene or monocyclic heteroarylene, each ring being independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy q and R r replace; and

[0417] Z 6 is -S(O)2-; and

[0418] Wherein the alkylene group is R s and R t replace.

[0419] A120b. In embodiment A120b, the compound of any one of embodiments A1 to A96b and A116 to A120, or a pharmaceutically acceptable salt thereof, is wherein:

[0420] X 1 、X 2 、X 3 and X 4 , Z 1 and Z 2 Each is a key;

[0421] Z 3 R is a heterocyclylene, a bridged heterocyclylene, or a spiroheterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, and haloalkoxy. m and R n replace;

[0422] Z 4 R is alkylene or -O-, cycloalkylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy o and R p replace;

[0423] Z 5 R is phenylene or monocyclic heteroarylene, each ring being independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxyq and R r replace; and

[0424] Z 6 is -S(O)2-; and

[0425] Wherein the alkylene group is R s and R t replace.

[0426] A121. In embodiment A121, the compound of any one of embodiments A1 to A96b and A116, or a pharmaceutically acceptable salt thereof, wherein:

[0427] X 1 、X 2 、X 3 、X 4 and Z 1 Each is a key;

[0428] Z 2 is 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;

[0429] Z 3 R is a 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;

[0430] Z 4 is a bond, an alkylene group or -O-;

[0431] 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

[0432] Z 6 is -S(O)2-; and

[0433] Wherein the alkylene group is R s and R t replace.

[0434] A122. In embodiment A122, the compound of any one of embodiments A1 to A96b, A116 and A121, or a pharmaceutically acceptable salt thereof, wherein:

[0435] X 1 、X 2 、X 3 and X 4 and Z 1 Each is a key;

[0436] Z 2 R is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy j and R k substituted heterocyclylene;

[0437] Z 3 R is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy m and R n substituted heterocyclylene;

[0438] Z 4 is a bond, an alkylene group or -O-;

[0439] Z 5 is phenylene or monocyclic heteroarylene, each ring being independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. q and R r replace; and

[0440] Z 6 is -S(O)2-; and

[0441] Wherein the alkylene group is R s and R t replace.

[0442] A123. In embodiment A123, the compound of any one of embodiments A1 to A96b and A116, or a pharmaceutically acceptable salt thereof, is wherein:

[0443] X 1 、X 2 、X 3 、X 4 and Z 1 Each is a key;

[0444] Z 2 R is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy j and R k substituted heterocyclylene;

[0445] Z 3 is a bond, an alkylene group or -O-;

[0446] Z 4R is a heterocyclylene, a bridged heterocyclylene, or a spiroheterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, and haloalkoxy. o and R p replace;

[0447] Z 5 R is phenylene or monocyclic heteroarylene, each ring being independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy q and R r replace; and

[0448] Z 6 It is -S(O)2-.

[0449] A123a. In embodiment A123a, the compound of any one of embodiments A1 to A96b, or a pharmaceutically acceptable salt thereof, is wherein Z 4 is a heterocyclylene or spiroheterocyclylene, wherein each ring is independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. o and R p replace.

[0450] A123b. In embodiment A123b, the compound of any one of embodiments A1 to A96b, A116 to A120 and A120b, or a pharmaceutically acceptable salt thereof, wherein:

[0451] X 1 、X 2 、X 3 、X 4 , Z 1 and Z 2 Each is a key;

[0452] Z 3 is a heterocyclylene group, wherein each ring is independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. m and R n replace;

[0453] Z 4 R is independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy o and R p substituted cycloalkylene;

[0454] Z 5 is phenylene or monocyclic heteroarylene, each ring being independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. q and R r replace; and

[0455] Z 6 It is -S(O)2-.

[0456] A124. In embodiment A124, the compound of any one of embodiments A1 to A111 and A116 to A123b, or a pharmaceutically acceptable salt thereof, 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).

[0457] A125. In embodiment A125, the compound of any one of embodiments A1 to A111 and A116 to A123b, or a pharmaceutically acceptable salt thereof, 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

[0458] A126. In embodiment A126, the compound of any one of embodiments A1 to A111 and A116 to A125, or a pharmaceutically acceptable salt thereof, is wherein -Z 5 - is R independently selected from hydrogen, deuterium, methyl, fluorine, trifluoromethyl and trifluoromethoxy q and R r Replaced

[0459] A127. In embodiment A127, the compound of 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.

[0460] A128. In embodiment A128, the compound of any one of embodiments A1 to A111, A116 to A123b and A127, or a pharmaceutically acceptable salt thereof, is wherein -Z 5- is imidazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl or pyridine-3,5-diyl, each ring of which is independently selected from hydrogen, methyl, methoxy, fluorine, chlorine, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy and trifluoromethoxy q and R r replace.

[0461] A129. In embodiment A129, the compound of any one of embodiments A1 to A128, or a pharmaceutically acceptable salt thereof, is wherein -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 Each alkylene group in - is itself and, when present, is each R s and R t substituted methylene, ethylene or propylene.

[0462] A130. In embodiment A130, the compound of any one of embodiments A1 to A128, or a pharmaceutically acceptable salt thereof, 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.

[0463] A131 In embodiment A131, the compound of any one of embodiments A1 to A130, or a pharmaceutically acceptable salt thereof, is wherein -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 Each alkylene group in - acts as another group (e.g., -(O-alkylene) a 、-(alkylene-O) a -, -(alkylene-NR")-) and when present is ethylene or propylene.

[0464] A132. In embodiment A132, the compound of any one of embodiments A1 to A131, or a pharmaceutically acceptable salt thereof, is wherein -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z6 Each alkylene group in - acts as another group (e.g., -(O-alkylene) a 、-(alkylene-O) a -, -(alkylene-NR")-) and when present is ethylene.

[0465] A133. In embodiment A133, the compound of any one of embodiments A1 to A132, or a pharmaceutically acceptable salt thereof, 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.

[0466] A134. In embodiment A134, the compound of any one of embodiments A1 to A133, or a pharmaceutically acceptable salt thereof, is wherein -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 Each R, R' and R" in -, when present, is hydrogen.

[0467] A135. In embodiment A135, the compound of any one of embodiments A1 to A133, or a pharmaceutically acceptable salt thereof, is wherein -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 Each of R, R' and R" in -, when present, is methyl.

[0468] A136. In embodiment A136, the compound of any one of embodiments A1 to A135, or a pharmaceutically acceptable salt thereof, is wherein -Z 2 -Z 3 -Z 4 -Z 5 Each cycloalkylene in -, when present, is independently selected from cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene.

[0469] A137. In embodiment A137, the compound of any one of embodiments A1 to A136, or a pharmaceutically acceptable salt thereof, is wherein -Z 2 -Z 3 -Z 4 -Z 5Each cycloalkylene in -, when present, is independently selected from 1,3-cyclopentylene, 1,3-cyclohexylene, and 1,4-cyclohexylene.

[0470] A138. In embodiment A138, the compound of any one of embodiments A1 to A137, or a pharmaceutically acceptable salt thereof, is wherein 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.

[0471] A139. In embodiment A139, the compound of any one of embodiments A1 to A138, or a pharmaceutically acceptable salt thereof, is wherein heteroarylene is a monocyclic heteroarylene, and -Z 1 -Z 3 -Z 4 -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.

[0472] A140. In embodiment A140, the compound of any one of embodiments A1 to A139, or a pharmaceutically acceptable salt thereof, is wherein -Z 1 -Z 3 -Z 4 -Z 5 The phenylene groups in -, when present, are independently selected from 1,3-phenylene and 1,4-phenylene, unless otherwise stated in any of the above Examples.

[0473] A141. In embodiment A141, the compound of any one of embodiments A1 to A140, or a pharmaceutically acceptable salt thereof, is wherein -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 The heterocyclylene, bridged heterocyclylene and spiroheterocyclylene in -, when present, are independently selected from:

[0474]

[0475] A142. In embodiment A142, the compound of any one of embodiments A1 to A96b, or a pharmaceutically acceptable salt thereof, is wherein L (when the degron is a group having formula (iii) to (vi)), -X 1 -L-, -X2 -L-, -X 3 -L- and -X 4 -L- is independently selected from:

[0476]

[0477]

[0478] A143. In embodiment A143, the compound of 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 formula (iii) to (vi)), -X 1 -L-, -X 2 -L-, -X 3 -L- and -X 4 -L- is independently selected from:

[0479]

[0480] A144. In embodiment A144, the compound of any one of embodiments A1 to A96b, A120b and A136 to A141, or a pharmaceutically acceptable salt thereof, is wherein -Z 3 -Z 4 -Z 5 -Z 6 -for:

[0481]

[0482]

[0483] where R q 、R m and R n Each of is independently selected from hydrogen, alkyl, halogen, cyano, alkoxy, haloalkyl, haloalkoxy, and cycloalkyl.

[0484] A144a. In embodiment A144a, the compound of any one of embodiments A1 to A96b, A120b, A136 to A141 and A144, or a pharmaceutically acceptable salt thereof, is wherein -Z 3 -Z 4 -Z 5 -Z 6 -for:

[0485]

[0486] where R q 、R m and R nEach of is independently selected from hydrogen, methyl, fluorine, chlorine, cyano, methoxy, difluoromethoxy, cyclopropyl, difluoromethyl and trifluoromethyl.

[0487] A145. In embodiment A145, the compound of any one of embodiments A1 to A96b, A120b and A144a, or a pharmaceutically acceptable salt thereof, is -Z 3 -Z 4 -Z 5 -Z 6 -for:

[0488]

[0489] A146. In embodiment A146, the compound of 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:

[0490]

[0491] where R j 、R k 、R q 、R m and R n Each of is independently selected from hydrogen, alkyl, halogen, cyano, alkoxy, haloalkyl, haloalkoxy, and cycloalkyl.

[0492] A146a. In embodiment A146a, the compound of 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:

[0493]

[0494] where R j 、R k 、R q 、R m and R n Each of is independently selected from hydrogen, methyl, fluorine, chlorine, cyano, methoxy, difluoromethoxy, cyclopropyl, difluoromethyl and trifluoromethyl.

[0495] A147. In embodiment A147, the compound of any one of embodiments A1 to A122, A124 to A128, A133, A144a and A145, or a pharmaceutically acceptable salt thereof, is wherein Z 4 To be R s and R t Substituted alkylene, wherein R s and R t For hydrogen.

[0496] A148. In embodiment A148, the compound of any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A135, A144 to A145 and A147, or a pharmaceutically acceptable salt thereof, is wherein Z 4 The alkylene group is -CH2-, -(CH2)2-, -CH(CH3)-, -CH2CH(CH3)CH2- or -C(CH3)2-. In a sub-embodiment, Z 4 It is -CH2-, -(CH2)2-, -CH(CH3)- or -C(CH3)2-.

[0497] A149. In embodiment A149, the compound of any one of embodiments A1 to A111, A113-A122, A124 to A128, A133-A135, A144 to A145, or a pharmaceutically acceptable salt thereof, is wherein Z 4 It is -O-.

[0498] A150. In embodiment A150, the compound of any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A135, A144 to A145, or a pharmaceutically acceptable salt thereof, is wherein Z 4 To be R s and R t Substituted alkylene, wherein R s is hydrogen and deuterium and R t is hydrogen, deuterium, a haloalkyl group, a hydroxyl group, an alkoxy group or a cyano group.

[0499] A151. In embodiment A151, the compound of any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A135, A144 to A145, A147 and A150, or a pharmaceutically acceptable salt thereof, is wherein Z 4 -CR s R t -, where R s is hydrogen and deuterium and Rt For hydrogen and deuterium.

[0500] A152. In embodiment A152, the compound of any one of embodiments A1 to A111, A113, A114, A116-A122, A124-A128, A133-A135, A144-A145, A147 and A150, or a pharmaceutically acceptable salt thereof, is wherein Z 4 To be R s and R t Substituted alkylene, wherein R s is hydrogen and R t It is a halogenated alkyl group.

[0501] A153. In embodiment A153, the compound of any one of embodiments A1 to A111, A113, A114, A116-A122, A124-A128, A133-A135, A144-A145, A147 and A150, or a pharmaceutically acceptable salt thereof, is wherein Z 4 To be R s and R t Substituted alkylene, wherein R s is hydrogen and R t It is a hydroxyl group.

[0502] A154. In embodiment A154, the compound of any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A135, A144 to A145, A147 and A150, or a pharmaceutically acceptable salt thereof, is wherein Z 4 To be R s and R t Substituted alkylene, wherein R s is hydrogen and R t It is an alkoxy group.

[0503] A155. In embodiment A155, the compound of any one of embodiments A1 to A111, A113, A114, A116-A122, A124-A128, A133-A135, A144-A145, A147, A150, and A152-A154, or a pharmaceutically acceptable salt thereof, is wherein Z 4 is -CH(CHF2)-, -CH(CF3)-, -C(CH3)(CF3)-, -CH(CH2CF3)-, -CH(CH2CH2CF3)-, -CH(CH(CF3)2)-, -CH(CH2OH)-,

[0504] -CH(CH2OCH3)-, -CH(CH2O-ethyl)-, or -CH(CH2CN)-.

[0505] A156. In embodiment A156, the compound of any one of embodiments A1 to A111, A113, A114, A116-A122, A124 to A128, A133-A135, A144 to A145, or a pharmaceutically acceptable salt thereof, is wherein Z 4 To be 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.

[0506] A157. In embodiment A157, the compound of any one of embodiments A1 to A111, A113, A114, A116-A122, A124-A128, A133-A135, A144-A145 and A156, or a pharmaceutically acceptable salt thereof, is wherein Z 4 To be 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.

[0507] A158. In embodiment A158, the compound of any one of embodiments A1 to A111, A113, A114, A116-A122, A124-A128, A133-A136, A144-A145 and A156, or a pharmaceutically acceptable salt thereof, is wherein Z 4 To be 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.

[0508] A159. In embodiment A159, the compound of any one of embodiments A1 to A111, A113, A114, A116-A122, A124-A128, A133-A135, A144-A145 and A156, or a pharmaceutically acceptable salt thereof, is wherein Z4 To be R s and R t Substituted alkylene, wherein R s is hydrogen and R t is aryl substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy or cyano.

[0509] A160. In embodiment A160, the compound of any one of embodiments A1 to A111, A113, A114, A116-A122, A124-A128, A133-A135, A144-A145 and A156, or a pharmaceutically acceptable salt thereof, is wherein Z 4 To be 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.

[0510] A161. In embodiment A161, the compound of any one of embodiments A1 to A111, A113, A114, A116-A122, A124-A128, A133-A135, A144-145, and A156-160, or a pharmaceutically acceptable salt thereof, 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, by 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.

[0511] A162. In embodiment A162, the compound of any one of embodiments A1 to A111, A113, A114, A116-A122, A124-A128, A133-A135, A144-A145, and A156-A160, or a pharmaceutically acceptable salt thereof, is wherein Z 4is -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, by 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, fluoro, chloro, methyl, methoxy, difluoromethoxy, trifluoromethoxy, or cyano.

[0512] A163. In embodiment A163, the compound of any one of embodiments A1 to A111, A113-A120, A120b, A123b, A124 to A128, A133-A135, A144 to A145, or a pharmaceutically acceptable salt thereof, is wherein Z 4 To be R o and R p Substituted 1,1-cycloalkylene.

[0513] A164. In embodiment A164, the compound of any one of embodiments A1 to A111, A113-A120, A120b, A123b, A124 to A128, A133-A135, A144 to A145, or a pharmaceutically acceptable salt thereof, is wherein Z 4 To be R o and R p Substituted heterocyclylene.

[0514] A165. In embodiment A165, the compound of any one of embodiments A1 to A120, A120b, A123b, A124 to A128, A133, A144 to A145, and A163-A164, or a pharmaceutically acceptable salt thereof, is wherein Z 4 for:

[0515]

[0516] 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:

[0517]

[0518] A166a. In embodiment A166a, the compound of any one of embodiments A1 to A166, or a pharmaceutically acceptable salt thereof, is wherein the degron is an E3 ligase ligand selected from:

[0519]

[0520] A167. In embodiment A167, the compound of any one of embodiments A1 to A165, or a pharmaceutically acceptable salt thereof, wherein the E3 ligase ligand is:

[0521]

[0522]

[0523] Each R ee is hydrogen, methyl, ethyl, cyclopropyl or 2,2,2-trifluoroethyl, and each R ff is hydrogen, methyl, cyclopropyl, fluorine, cyano, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.

[0524] A168. In embodiment A168, the compound of any one of embodiments A1 to A165, or a pharmaceutically acceptable salt thereof, wherein the E3 ligase ligand is:

[0525]

[0526]

[0527] Each R ee is hydrogen, methyl, cyclopropyl or 2,2,2-trifluoroethyl and each R ff is hydrogen, methyl, fluorine or trifluoromethyl.

[0528] A169. In embodiment A169, the compound of any one of embodiments A1 to A165, or a pharmaceutically acceptable salt thereof, is wherein R x For hydrogen.

[0529] A170. In embodiment A170, a pharmaceutical composition is provided, comprising a compound as described in any one of embodiments A1 to A169 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0530] A171. In embodiment A171, a method of degrading CDK2 in a cell is provided, the method comprising contacting the cell with a compound as described in any one of embodiments 1A to A169 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in embodiment A170.

[0531] 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.

[0532] A173. In embodiment A173, a method of treating cancer in a patient is provided, 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.

[0533] A174. In embodiment A174, the method of embodiment A149 is wherein the compound of any one of embodiments A1 to A169 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of embodiment A170 is administered in combination with at least one other anticancer agent.

[0534] 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.

[0535] It should be understood that the embodiments and sub-embodiments described above include all combinations of the embodiments and sub-embodiments listed therein.

[0536] General synthetic scheme

[0537] Compounds having formula (I) can be prepared by the methods depicted in the reaction schemes shown below.

[0538] Starting materials and reagents used to prepare these compounds are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrance, California), or Sigma (St. Louis, Missouri), or are prepared by methods known to those skilled in the art according to the procedures described in, for example, 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); and Sons (John Wiley and Sons, 1991); March's Advanced Organic Chemistry (John Wiley and Sons, 4th ed.); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some of the methods by which compounds of formula (I) may be synthesized, and various modifications may be made to these schemes and will be appreciated by those of ordinary skill in the art upon reading this disclosure. If desired, the starting materials and intermediates, as well as the final products of the reactions, may be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0539] 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), e.g., about 20°C.

[0540] 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.

[0541] Compounds of formula (I) wherein the solution modifier is an E3 ligase ligand of formula (i)-(vi) wherein the ring Hy, R w , L and Ring Q are as defined in the Summary of the Invention) can be prepared as described in Scheme 1 below.

[0542] Solution 1

[0543]

[0544] Under conditions well known in the art (such as in the presence of TEA, ZnCl2 in tert-butyl alcohol), an amine having formula 1-2 (wherein Hy is as defined in the Summary of the Invention and FG 1 is a suitable functional group, such as an acid, an amine) to treat a pyrimidine having formula 1-1 (wherein X a and X b is a halogen, such as chlorine or bromine and R w As defined in the Summary of the Invention) to obtain a compound of formula 1-3. A cross-coupling reaction between aryl halide 1-3 and metallated ring Q of formula 1-4 (wherein M is a metal, such as a borate, trialkyltin, or zinc) provides a compound of formula 1-5. The coupling reaction is typically carried out in the presence of a palladium catalyst, for example, when M is a borate, the reaction is carried out in the presence of Pd(dppf)Cl2, Na2CO3.

[0545] Compounds of Formula 1-5 and compounds of Formula 1-6 (wherein L a is L or a precursor group of L as defined in the Summary of the Invention, and FG 2 It can be used with 1-5 FG 1 For example, when the amide bond is part of L as defined in the Summary of the Invention, FG 1 and FG 2 One is a carboxylic acid and the other is an amine, and coupling of the two groups can be performed under a peptide coupling reaction.

[0546] Alternatively, compounds of formula (I) (e.g., wherein Hy is 1,4-piperidinyl, the degron is a group of formula (ii), and L is attached to the degron (ii) via a heterocyclylene group containing one or two nitrogen atoms and to Hy via -SO2-) can be synthesized as shown and described in Scheme 2.

[0547] Option 2

[0548]

[0549] A pyrimidine of formula 1-1 (wherein X a and X b Is halogen such as chlorine or bromine), provides an aryl halide compound with formula 2-3. The reaction is carried out under conditions well known in the art, such as in the presence of TEA, ZnCl2 in an alcohol such as tert-butyl alcohol. The cross-coupling reaction between 2-3 and the metallated ring Q of formula 1-4 (wherein M is a metal as described in Scheme 1 above) provides an amine compound with formula 2-4. The Boc protecting group of 2-4 is removed in the presence of an acid such as TFA to provide an amine compound with formula 2-5, which is then reacted with a sulfonyl halide with formula 2-6 (wherein LG is a suitable leaving group, such as halogen or -SO2Me, L' is a precursor group of L in the compound with formula (I) as defined in the Summary of the Invention, and X c is a halogen, such as chlorine under alkaline reaction conditions) to convert it into a sulfonamide compound having formula 2-7.

[0550] Under basic conditions (such as in the presence of DIPEA), an amine compound having formula 2-8 (wherein ring A is as defined in the Summary of the Invention and is a heterocyclyl) provides a compound of formula (I).

[0551] Compounds of formula 1-1, 1-4, 2-6, and 2-8 are commercially available, or they can be prepared by methods known in the art and / or the methods in the following synthetic examples.

[0552] Alternatively, compounds of formula (I) (e.g., wherein Hy is 1,4-piperidinyl, the degron is a group of formula (ii), and L is attached to the degron (ii) via a heterocyclylene group (e.g., 4-piperidin-1-yl) and to Hy via -SO2-) can be synthesized as shown and described in Scheme 3.

[0553] Option 3

[0554]

[0555] The compound of formula 3-1 (wherein X d Cross-coupling of a tetrahydropiperidinyl radical of formula 3-2 (wherein M is a metal as described above in Scheme 1) provides a compound of formula 3-3. Reduction of the double bond in compound 3-3 under hydrogenation conditions provides a compound of formula 3-4, and removal of the Boc protecting group of 3-4 under acidic conditions provides an amine compound of formula 3-5.

[0556] 3-5 is reacted with a compound of formula 3-6 (wherein LG 1 Is a leaving group (such as halogen or -SO2Me), Hy is as defined in the Summary of the Invention and L' is a precursor group of L as defined in the Summary of the Invention) to provide a compound of formula 3-7. The Boc protecting group in compound 3-7 is removed using an acid (such as TFA) to provide an amine compound of formula 3-8. Under suitable conditions (such as acidic, basic or transition metal catalyzed reaction conditions well known in the art), a compound of formula 3-9 (wherein LG 2 Treatment of compound 3-8 with a suitable leaving group such as Cl or SO2Me provides compounds of formula (I).

[0557] Compounds of formula 3-1, 3-2, 3-6, and 3-9 are commercially available, or they can be prepared by methods known in the art and / or the methods described in the following synthetic examples.

[0558] utility

[0559] Compounds of formula (I) can cause degradation of CDK2 protein via the ubiquitin proteasome pathway and are therefore useful in treating diseases mediated by CDK2. Increasing evidence indicates 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 involved in the degradation of cyclin A. Fbw7Loss-of-function mutations in cyclin E (a component of the 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 of endogenous CDK2 inhibitors p27 or p21 is lost or the position is altered. In addition, CDC25A and CDC25B (protein phosphatases responsible for the dephosphorylation of CDK2 that activates CDK2) are overexpressed in various tumors. These different mechanisms of CDK2 activation have been validated 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 that overexpress 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.

[0560] 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.

[0561] 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, bronchogenic 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, the 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, the ovarian cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0562] 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.

[0563] In other embodiments, compounds of formula (I) may 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.

[0564] test

[0565] 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.

[0566] Pharmaceutical composition

[0567] Typically, a compound of formula (I) (unless otherwise indicated, reference to a compound herein / a compound of formula (I) 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 a medicament for similar efficacy. The therapeutically effective amount of a compound of formula (I) can range from about 0.01 to about 500 mg / kg patient weight / day, which can be administered in a single dose or multiple doses. Suitable dosage levels can be from about 0.1 to about 250 mg / kg / day, about 0.5 to about 100 mg / kg / day. Suitable dosage levels can be about 0.01 to about 250 mg / kg / day, about 0.05 to about 100 mg / kg / day, or about 0.1 to about 50 mg / kg / day. Within this range, dosage can be about 0.05 to about 0.5, about 0.5 to about 5, or about 5 to about 50 mg / kg / day. For oral administration, the compositions can be provided in the form of tablets 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 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 used, the route and form of administration, and other factors.

[0568] 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) administration. A preferred mode of administration is oral administration using a convenient daily dosage regimen that can be adjusted based on the severity of the disease. The composition can be in the form of a tablet, pill, capsule, semisolid, powder, sustained-release formulation, solution, suspension, elixir, aerosol, or any other suitable composition.

[0569] 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.

[0570] These compositions are usually made up of a combination of a compound of formula (I) and at least one pharmaceutically acceptable excipient. Acceptable excipients are usually nontoxic, contribute to administration, and do not adversely affect the therapeutic benefit of the compound of formula (I). Such excipients can be any solid, liquid, semisolid commonly available to those of ordinary skill in the art, or in the case of aerosol compositions, are gaseous excipients.

[0571] 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.

[0572] The compound with formula (I) can be formulated for parenteral administration by injection (for example, by bolus injection or continuous infusion). Injection preparations can be provided in unit dosage form, for example, in an ampoule added with a preservative or in a multidose container. Compositions can take the form of a suspension, solution or emulsion, for example, in an oily or aqueous vehicle, and can contain a preparaton (such as a suspending agent, a stabilizer and / or a dispersant). Preparations can be present in unit dose or multidose containers (for example, sealed ampoule and vial), and can be stored in powder form or stored under freeze drying (lyophilization) conditions, only requiring immediate addition of a sterile liquid carrier (for example, 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.

[0573] 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 suitable stabilizers or agents that increase the solubility of the compound to allow the preparation of highly concentrated solutions.

[0574] 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 together with suitable polymers or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or be formulated into slightly soluble derivatives, for example, be formulated into slightly soluble salts.

[0575] For buccal or sublingual administration, these compositions may take the form of tablets, lozenges, pastilles or gels in conventional manner.Such compositions may contain the active ingredient in a flavored base such as sucrose and acacia or tragacanth.

[0576] 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.

[0577] Certain compounds of formula (I) can be administered topically, i.e., by non-systemic administration. This includes applying compounds of formula (I) topically to the epidermis or oral cavity, as well as instilling 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.

[0578] 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 eyes, ears or noses. The active ingredient of 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.

[0579] For administration by inhalation, compounds of formula (I) can be conveniently delivered from an insufflator, nebulizer pressurized packs, or other convenient methods of delivering an aerosol spray. The 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 base (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 (Mack Publishing Company, 20th edition, 2000), edited by E.W. Martin.

[0580] 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 (on a weight percentage (wt.%) basis) 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.%.

[0581] Combination and combination therapies

[0582] The compound with formula (I) can be used for treating disease or illness in combination with one or more other drugs, and for these diseases or illnesses, the compound with formula (I) or other drugs can have effectiveness.Such one or more other drugs can be used simultaneously or sequentially with the compound with formula (I) by a kind of approach and its usual amount.When the compound with formula (I) is used simultaneously with one or more other drugs, the pharmaceutical composition of the unit dosage form containing such other drugs and the compound with formula (I) is preferred.However, combination therapy can also include the therapy that wherein there is the compound with formula (I) and one or more other drugs are used with different overlapping schedules.It is also expected that, when used in combination with one or more other active ingredients, there is the compound with formula (I) and other active ingredients can be used with a lower dosage than when each is used alone.

[0583] Thus, the pharmaceutical compositions of the present disclosure also include those containing one or more additional drugs in addition to the compound of formula (I).

[0584] The above combination not only includes the combination of the compound with formula (I) and a kind of other drugs, but also includes the 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 disease or illness (for which, the compound with formula (I) is useful) or reducing its risk. Such other drugs can be used simultaneously or sequentially with the compound with formula (I) by a kind of approach and its usual amount. When the compound with formula (I) is used simultaneously with one or more other drugs, the 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 composition. Usually, respective effective doses will be used.

[0585] Where a subject in need thereof has cancer or is at risk of developing cancer, the subject may be treated with any combination of a compound of formula (I) 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, pimetinib, bimetinib, rameltinib, cometinib (GDC-0973), AZD8330, BVD-523, LTT462, neratinib, AMG510 (sotolacirib), ARS853, adagracirib, opronolacirib, 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]benzazepamocyclooctin-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-fluoronaphthalen-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;

[0586] CSF1R inhibitors (PLX3397, LY3022855, etc.) and CSF1R antibodies (IMC-054, RG7155) TGFβ receptor kinase inhibitors such as LY2157299;

[0587] 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-imin-9-yl]-2-oxoethyl]-acetamide (PF-03814735, CAS 942487-16-3);

[0588] 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);

[0589] Vascular endothelial growth factor (VEGF) receptor inhibitors: Bevacizumab (marketed by Genentech / Roche under the trademark and commercially available), axitinib (N-methyl-2-[[3-[(E)-2-pyridin-2-ylvinyl]-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[2,1f][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-pyridylmethyl)amino]-3-pyridinecarboxamide, and described in PCT Publication No. WO 02 / 066470), pasireotide (also known as SOM230 and described in PCT Publication No. WO 02 / 010192), sorafenib (trademarked under the trademark (sold); AL-2846 MET inhibitors, such as foretinib, cabozantinib, or crizotinib;

[0590] FLT3 inhibitor - sunitinib malate (trademarked by Pfizer (sold); PKC412 (midostaurin); tanutinib, sorafenib, lestaurinib, KW-2449, quizartinib (AC220), and crelanib;

[0591] Epidermal growth factor receptor (EGFR) inhibitors: Gefitinib (trade name: N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3"S")-tetrahydro-3-furyl]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);

[0592] HER2 receptor inhibitors: Trastuzumab (manufactured by Genentech / Roche under the trademark

[0014] 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 (available from GlaxoSmithKline under the trademark Trastuzumab emtansine (marketed in the United States as Ado-Trastuzumab emtansine, brand name Kadcyla) - an antibody-drug conjugate consisting of the monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent mertansine (DM1);

[0593] HER dimerization inhibitor: Pertuzumab (developed by Genentech under the trademark Sale);

[0594] 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);

[0595] 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. Patent No. 6,780,996), dasatinib (Bristol-Myers Squibb Company, sold under the trademark ), Armala (also known as Pazopanib, sold by GlaxoSmithKline under the trademark ), imatinib, and imatinib mesylate (sold by Novartis under the trademark and Sale);

[0596] DNA synthesis inhibitors: Capecitabine (manufactured by 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) is sold by GlaxoSmithKline under the trademark and Sale);

[0597] Antineoplastic agent: Oxaliplatin (manufactured by Sanofi-Aventis under the trademark sold and described in U.S. Patent No. 4,169,846);

[0598] Human granulocyte colony-stimulating factor (G-CSF) regulator: Filgrastim (available from Amgen under the trademark Sale);

[0599] Immunomodulator: Afutuzumab (available from Pegfilgrastim (available from Amgen under the trademark Sold under the trademark Sold under the trademark Sale);

[0600] 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);

[0601] 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);

[0602] Phospholipase A2 inhibitors: anagrelide (known under the trademark Sale);

[0603] 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);

[0604] MCl-1 inhibitors: MIK665, S64315, AMG 397, and AZD5991;

[0605] Aromatase inhibitors: Exemestane (brand name of Letrozole (sold by Novartis under the trademark Anastrozole (sold under the trademark Sale);

[0606] Topoisomerase I inhibitors: irinotecan (marketed by Pfizer under the trademark Topotecan hydrochloride (sold by GlaxoSmithKline under the trademark Sale);

[0607] Topoisomerase II inhibitors: Etoposide (also known as VP-16 and etoposide phosphate, sold under the trademark and Teniposide (also known as VM-26, sold under the trademark Sale);

[0608] mTOR inhibitors: Temsirolimus (trademarked by Pfizer (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]hexatricarborate-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyldimethylphosphinate, also known as AP23573 and MK8669 and described in PCT Publication No. WO 03 / 064383), irolimus (available from Novartis under the trademark Sale);

[0609] Proteasome inhibitors, such as carfilzomib, MLN9708, dextromethorphan, or bortezomib;

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

[0611] LSD1 inhibitors, such as GSK2979552 and INCB059872;

[0612] HIF-2α inhibitors, such as PT2977 and PT2385;

[0613] Osteoclast bone resorption inhibitor: l-Hydroxy-2-imidazol-l-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);

[0614] CD22 antibody-drug conjugate: inotuzumab (also known as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.);

[0615] CD20 antibody drug conjugate: Ibritumomab (trademark Sale);

[0616] Somatostatin analogs: Octreotide (also known as octreotide acetate, under the trademark and Sandostatin down sales);

[0617] Synthetic interleukin-11 (IL-11): oprelvekin (developed by Pfizer / Wyeth under the trademark Sale);

[0618] Synthetic erythropoietin: Darbepoetin alfa (produced by Amgen under the trademark Sale);

[0619] Receptor activator of nuclear factor kappa B (RANK) inhibitor: Denosumab (marketed by Amgen under the trademark Sale);

[0620] Thrombopoietin mimetic peptide: Romiplostim (trademarked by Amgen Sale);

[0621] Cell growth stimulator: Parifelmin (produced by Amgen under the trademark Sale);

[0622] 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);

[0623] Anti-CS1 antibody: Elotuzumab (HuLuc63, CAS No. 915296-00-3);

[0624] CD52 antibody: Alemtuzumab (trade name Sale);

[0625] Histone deacetylase inhibitors (HDIs): Voninostat (marketed by Merck under the trademark Sale);

[0626] 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-sarcolysin, and phenylalanine mustard, sold under the trademark Hexamethylmelamine (also known as hexamethylmelamine (HMM), sold under the trademark Carmustine (sold under the trademark Bendamustine (sold under the trademark Sales), Busulfan (trademark and Carboplatin (sold under the trademark Sold), Lomustine (also known as CCNU, sold under the trademark Cisplatin (also known as CDDP, sold under the trademark and 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 Sold under the trademarks), dichloromethyldiethylamine (also known as nitrogen mustard, mustine, and mechloroethamine hydrochloride), Sold), Streptozotocin (trademark Thiotepa (also known as phosphorothioate amide, TESPA, and TSPA, sold under the trademark Sales; Biological response modifier: BCG (trademark and BCG), denileukin (sold under the trademark Sale);

[0627] Antitumor antibiotics: Adriamycin (trademark 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), Epirubicin (sold under the trademark Ellence TM Sales), Idabixin (trademark Idamycin Mitomycin C (sold under the trademark Sale);

[0628] Antimicrotubule agents: Estramustine (trade name Sale);

[0629] 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);

[0630] 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

[0631] TpoR agonist: Eltrombopag (manufactured by GlaxoSmithKline under the trademark and Sale);

[0632] Antimitotic agents: Docetaxel (available from Sanofi under the trademark Adrenal steroid inhibitors: aminoglutethimide (marketed under the trademark Sale);

[0633] Antiandrogen: Nilutamide (trade name and Bicalutamide (sold under the trademark Flutamide (sold under the trademark Fulexin TM Sale);

[0634] Androgens: Fluoxymesterone (trade name Sale);

[0635] 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);

[0636] CDK4 / 6 inhibitors such as palbociclib, ribociclib, abemaciclib, and tricaxil; CDK9 inhibitors such as AZD 4573, P276-00, AT7519M, and TP-1287; and CDK2 / 4 / 6 inhibitors such as PF-06873600.

[0637] SHP-2 inhibitors, such as TNO155;

[0638] MDM2 / MDMX, MDM2 / p53, and / or MDMX / p53 modulators;

[0639] Gonadotropin-releasing hormone (GnRH) receptor agonists: leuprolide or leuprolide acetate (marketed by Bayer AG under the trademark Sanofi-Aventis and by Abbott Lab Sale);

[0640] Taxane antitumor agents: Cabazitaxel (l-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-ll-ene-2a,4,13a-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{[(tert-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-ll-en-2-yl benzoate);

[0641] 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);

[0642] Antimetabolite: Cladribine (2-chlorodeoxyadenosine, sold under the trademark Sold under the trademark Sold under the trademark Pemetrexed (sold under the trademark Cytosine arabinoside (also known as cytosine arabinoside (Ara-C) and marketed under the trademark Cytosar- cytarabine liposomes (also known as liposome Ara-C, sold under the trademark DepoCyt TM Sold under the trademark Sold under the trademark Droxia TM and Mylocel TMSold under the trademark Sold under the trademark Cladribine (also known as 2-chlorodeoxyadenosine (2-CdA), sold under the trademark Leustatin TM Sold under the trademarks and Trexall TM Sold under the trademark Sale);

[0643] Bisphosphonates: Pamidronate (known under the trademark Zoledronic acid (sold under the trademark demethylating agent: 5-azacitidine (sold under the trademark Sold under the trademark Sale);

[0644] Plant alkaloids: Taxol protein-bound (trademark ), vinblastine (also known as vinblastine sulfate, vinblastine, and VLB, sold under the trademark Alkaban- and Sold under the trademarks), vincristine (also known as vincristine sulfate, LCR, and VCR and Sales), Changchunorelbine (trademark Taxol and Onxal TM Sale);

[0645] Retinoids: alitretinoin (known under the trademark 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);

[0646] Glucocorticoids: Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the trademark Hydrocortisone phosphate, Solu- Hydrocort and (sold under the trademark Delta-D-Phenanthrene), 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-D-Phenanthrene), and 1,17-dihydroxy-1,17-dihydroxy-1,17-dihydroxy-1,17-dihydroxy-1,17-dihydroxy-1,17-dihydroxy-1,17-dihydroxy-1,17-dihydroxy-1 and Sold under the trademark Liquid and Sold), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, and under the trademark and Sale);

[0647] Cytokines: Interleukin-2 (also known as aldesleukin and IL-2, tradenames Interleukin-11 (also known as Oprelukin, marketed under the trademark Interferon alpha (also known as IFN-α, marketed under the trademark and

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

[0648] Antiestrogens: Tamoxifen (known under the brand name Toremifene (sold under the trademark Sale);

[0649] Selective estrogen receptor modulators (SERMs): raloxifene (trade name Sale);

[0650] Leukocyte stimulating hormone-releasing hormone (LHRH) agonists: Goserelin (trade name Progesterone: megestrol acetate (also known as megestrol acetate, sold under the trademark Sale);

[0651] Miscellaneous cytotoxic agents: Arsenic trioxide (trademark Asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the trademark and Sale);

[0652] 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.

[0653] 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, pembrolizumab, or PDR001. In some embodiments, the anti-PD1 antibody is pembrolizumab.

[0654] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, for example, an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A (atelizumab) or MEDI4736 (durvalumab).

[0655] In some embodiments, the inhibitor of an 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 an 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 an 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 an 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.

[0656] 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 present 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 (Granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccines). Anticancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses. Other immunomodulators include those that block immune cell migration, such as chemokine receptor antagonists (including CCR2 and CCR4); Sting agonists; and Toll receptor agonists.

[0657] Other anticancer agents also include those that enhance the immune system, such as adjuvants or adoptive T cell transfer. The compounds of the present application can be effective in combination with CAR (chimeric antigen receptor) T cell therapy as a booster for T cell activation.

[0658] 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

[0659] Cytoprotective agent: Amifostine (trademark (sold), leucovorin (also known as calcium folinate, leucovorin factor, and folinic acid).

[0660] Examples

[0661] The following preparations of intermediates (references) and compounds of formula (I) (examples) are given to enable those skilled in the art to more clearly understand and practice the present disclosure. They should not be considered to limit the scope of the present disclosure, but merely as its illustration and representation.

[0662] Synthesis Example

[0663] Reference 1

[0664] Synthesis of 4-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, 2,2,2-trifluoroacetate

[0665]

[0666] Step 1: tert-Butyl (14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate

[0667]

[0668] 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) and 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.

[0669] 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

[0670]

[0671] 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) was added TFA (0.3 mL, 3.92 mmol, 46.67 equiv) at 0° C. under a nitrogen atmosphere. The mixture was stirred for 2 h and then concentrated to give the crude title compound as a light yellow oil.

[0672] Reference 2

[0673] Synthesis of 2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-acetamido)ethoxy)ethoxy)ethyl methanesulfonate

[0674]

[0675] Step 1: tert-Butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetate

[0676]

[0677] 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.

[0678] Step 2: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid

[0679]

[0680] 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.

[0681] Step 3: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)acetamide

[0682]

[0683] HATU (513 mg, 1.35 mmol, 1.50 equiv) 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 equiv), 2-(2-(2-aminoethoxy)ethoxy)ethanol (201 mg, 1.35 mmol, 1.50 equiv) and DIPEA (348 mg, 2.69 mmol, 2.99 equiv) 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.

[0684] Step 4: 2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy)ethoxy)ethyl methanesulfonate

[0685]

[0686] 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.

[0687] Reference 3

[0688] Synthesis of 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy)-ethyl methanesulfonate

[0689]

[0690] Step 1: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(2-(2-hydroxyethoxy)-ethyl)acetamide

[0691]

[0692] 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 H O and extracted with DCM. The combined organic phases were washed with brine, dried over Na SO and concentrated to give the crude title compound as a yellow oil, which was used in the next step without further purification.

[0693] Step 2: 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy)-ethyl methanesulfonate

[0694]

[0695] 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.

[0696] Reference 4

[0697] 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

[0698]

[0699] Step 1: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)acetamide

[0700]

[0701] 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-aminoethoxy)ethoxy)ethoxy)ethan-1-ol (259 mg, 1.34 mmol, 1.49 equiv) in DMF (5.0 mL) was added HATU (513 mg, 1.35 mmol, 1.50 equiv) and DIPEA (348 mg, 2.69 mmol, 3.00 equiv) 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.

[0702] 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

[0703]

[0704] MsCl (271 mg, 2.37 mmol, 1.50 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-(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.

[0705] Reference 5

[0706] Synthesis of 2-(2-(2-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-acetamido)ethoxy)ethyl methanesulfonate

[0707]

[0708] Step 1: tert-Butyl 2-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetate

[0709]

[0710] 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 PPh (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.

[0711] Step 2: 2-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid

[0712]

[0713] 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.

[0714] Step 3: N-(2-(2-hydroxyethoxy)ethyl)-2-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide

[0715]

[0716] 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, which was used in the next step without further purification. Step 4: 2-(2-(2-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy)ethyl methanesulfonate

[0717]

[0718] 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.

[0719] Reference 6

[0720] 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

[0721]

[0722] Step 1: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(14-hydroxy-3,6,9,12-tetraoxatetradecyl)acetamide

[0723]

[0724] 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 H O and extracted with DCM. The combined organic phases were washed with brine, dried over Na SO and concentrated to give the crude title compound as a yellow oil, which was used in the next step without further purification. 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

[0725]

[0726] 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, 3.26 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.

[0727] Reference 7

[0728] Synthesis of 5-(3-(4-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0729]

[0730] Step 1: tert-Butyl (1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)carbamate

[0731]

[0732] At 0 DEG C, a solution of 4-fluorobenzenesulfonyl chloride (2.6 g, 13.36 mmol, 1.07 equivalents) 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 equivalents) in DCM (10.0 mL) and TEA (5.2 mL). 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.

[0733] Step 2: tert-Butyl (1-((4-((1-benzhydrylazetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)-carbamate

[0734]

[0735] To a stirred solution of 1-dibenzylazetidine-3-ol (1.0 g, 4.18 mmol, 1.00 equivalent) in THF (5.0 mL) was added NaH (60%, 251 mg, 6.28 mmol, 1.50 equivalent) at 0 ° C under N2. The resulting mixture was stirred at room temperature for 15 min, and then a solution of tert-butyl (1- ((4- fluorophenyl) sulfonyl) piperidin-4-yl) carbamate (1.65 g, 4.60 mmol, 1.10 equivalent) 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 layer was washed with a 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.

[0736] Step 3: tert-Butyl (1-((4-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0737]

[0738] 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) (300 mg, 20% on carbon) in THF (20.0 mL) was stirred at 50° C. under H (50 psi) overnight. The mixture was cooled, filtered, and then concentrated. The residue was purified by silica gel flash column (DCM:MeOH=10:1) to give the title compound as a white solid.

[0739] 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

[0740]

[0741] A mixture of tert-butyl (1-((4-(-105 azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (100 mg, 0.24 mmol, 1.00 equiv), 2-(2,6-dioxopiperidine-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.

[0742] Step 5: 5-(3-(4-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0743]

[0744] A mixture of tert-butyl (1-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-isoindolin-5-yl)-105-azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (144 mg, 0.21 mmol, 1.00 equiv) and TFA (1.0 mL) in DCM (4.0 mL) was stirred at room temperature 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.

[0745] Reference 8

[0746] 5-((3-(4-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)methyl)-2-

[0747] Synthesis of (2,6-dioxo-piperidin-3-yl)isoindoline-1,3-dione

[0748]

[0749] Step 1: 5-(Bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0750]

[0751] 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 N 2 overnight. The mixture was cooled, concentrated, and the residue was purified by flash column chromatography (EA:PE=0-100%) to give the title compound as a white solid.

[0752] 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

[0753]

[0754] 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 Reference 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 at 80° C. overnight. 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.

[0755] 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

[0756]

[0757] 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 which was used in the next step without further purification.

[0758] Reference 9

[0759] 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

[0760]

[0761] Step 1: tert-Butyl (2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)-ethoxy)ethyl)carbamate

[0762]

[0763] 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) and 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.

[0764] Step 2: 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0765]

[0766] 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) and TFA (0.5 mL) in DCM (2.0 mL) was stirred at room temperature 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.

[0767] Step 3: tert-Butyl (1-(chlorosulfonyl)piperidin-4-yl)carbamate

[0768]

[0769] Thionyl chloride (81 mg, 0.60 mmol, 1.20 equivalents) was added to a stirred solution of tert-butyl piperidin-4-ylcarbamate (100 mg, 0.50 mmol, 1.00 equivalents) and TEA (76 mg, 0.75 mmol, 1.50 equivalents) 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.

[0770] 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

[0771]

[0772] 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.

[0773] 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

[0774]

[0775] A mixture of 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 (60 mg, 0.090 mmol, 1.00 equiv) in DCM (2.0 mL) and TFA (0.5 mL) was stirred at room temperature 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.

[0776] Reference 10

[0777] Synthesis of 4-amino-N-(3-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)-propyl)-N-methylpiperidine-1-sulfonamide

[0778]

[0779] Step 1: 4-Bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0780]

[0781] A mixture of 4-bromoisobenzofuran-1,3-dione (22.8 g, 100.44 mmol, 1.00 equiv), 3-aminopiperidine-2,6-dione HCl salt (18.0 g, 109.36 mmol, 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 under vacuum to give the title compound as a gray solid.

[0782] Step 2: tert-Butyl methyl(3-(prop-2-yn-1-yloxy)propyl)carbamate

[0783]

[0784] 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% NaOH aqueous solution (30.0 mL) and tetrabutylammonium hydrogen sulfate (270 mg, 0.80 mmol, 0.050 equiv) in DCM (50.0 mL) was stirred at room temperature under N2 overnight. 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.

[0785] 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

[0786]

[0787] 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(PPh 3 ) 2 Cl 2 (288 mg, 0.41 mmol, 0.10 equiv) in DMF (15.0 mL) was stirred at 80° C. under N 2 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 Na 2 SO 4, and concentrated. The residue was purified by flash column chromatography (EA:PE = 0 to 100%) to give the title compound as a yellow oil.

[0788] Step 4: tert-Butyl (3-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)propyl)-(methyl)carbamate

[0789]

[0790] 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) / C (0.93 g, 50% w / w) in THF (50.0 mL) was stirred at room temperature under an atmosphere of H 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.

[0791] Step 5: 2-(2,6-dioxopiperidin-3-yl)-4-(3-(3-(methylamino)propoxy)propyl)isoindoline-1,3-dione

[0792]

[0793] 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) and 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 the mixture was then 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, which was used in the next step without further purification.

[0794] 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

[0795]

[0796] 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, which was used in the next step without further purification.

[0797] Step 7: 4-amino-N-(3-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)propyl)-N-methylpiperidine-1-sulfonamide

[0798]

[0799] 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 NaCO solution, and then extracted with DCM. The organic layer was washed with water, brine, dried over NaSO, and concentrated to give the title compound as a yellow oil which was used in the next step without further purification.

[0800] Reference 11

[0801] Synthesis of 4-(3-(2-(2-aminoethoxy)ethoxy)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0802]

[0803] Step 1: tert-Butyl (2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate

[0804]

[0805] NaH (1.2 g, 60%, 30.00 mmol, 1.50 equiv) was added portionwise 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.

[0806] 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

[0807]

[0808] 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.

[0809] Reference 12

[0810] Synthesis of 5-(3-(3-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0811]

[0812] Step 1: Benzyl (1-((3-methoxyphenyl)sulfonyl)piperidin-4-yl)carbamate

[0813]

[0814] 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 benzyl piperidin-4-ylcarbamate (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 Na SO , and concentrated. The residue was purified by silica gel chromatography (EA:PE=1:3) to give the title compound as a white solid.

[0815] Step 2: 3-((4-aminopiperidin-1-yl)sulfonyl)phenol

[0816]

[0817] 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.

[0818] Step 3: tert-Butyl (1-((3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamate

[0819]

[0820] 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) and TEA (1.18 g, 11.73 mmol, 3.00 equiv) in DCM (20.0 mL) 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.

[0821] Step 4: 1-Benzhydrylazetidin-3-yl methanesulfonate

[0822]

[0823] To a stirred solution of 1-dibenzylazetidine-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.

[0824] Step 5: (1-((3-((1-Benzhydrylazetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)-carbamic acid tert-butyl ester

[0825]

[0826] A mixture of tert-butyl (1-((3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamate (533 mg, 1.49 mmol, 1.00 equiv), 1-diphenylmethylazetidin-3-yl methanesulfonate (570 mg, 1.79 mmol, 1.20 equiv) and 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.

[0827] Step 6: tert-Butyl (1-((3-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0828]

[0829] 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) / C (20 wt.%, 250 mg) and AcOH (0.5 mL) at room temperature. The resulting mixture was stirred at 50 ° C under H (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. 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

[0830]

[0831] Proceeding similarly as described above in step 4 of reference 7, 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.

[0832] Step 8: 5-(3-(3-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0833]

[0834] Proceeding similarly as described above in step 5 of reference 7, 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.

[0835] Reference 13

[0836] 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

[0837] Synthesis of -2,6-diketone

[0838]

[0839] 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

[0840]

[0841] 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) and 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.

[0842] 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

[0843]

[0844] 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.

[0845] 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

[0846]

[0847] 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.

[0848] 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

[0849]

[0850] 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 provided the title compound.

[0851] Reference 14

[0852] 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

[0853]

[0854] Step 1: 3-Hydroxy-1-(4-methoxybenzyl)piperidine-2,6-dione

[0855]

[0856] T-BuOK (2.3 g, 20.50 mmol, 1.02 equiv) was added to a stirred mixture of N-(4-methoxybenzyl)-5-oxotetrahydrofuran-2-carboxamide (5.0 g, 20.06 mmol, 1.00 equiv) in THF (50.0 mL) at -78 ° C. After stirring for 1 h at -78 ° C, the mixture was quenched with saturated aqueous NH4Cl 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.

[0857] Step 2: 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate

[0858]

[0859] 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.

[0860] 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

[0861]

[0862] 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.

[0863] Step 4: 3-(4-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0864]

[0865] 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 solid filter cake was dried to give the title compound as a white solid.

[0866] Step 5: tert-Butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate

[0867]

[0868] NaH (60%, 240 mg, 6.00 mmol, 1.21 equiv) was added to a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1.0 g, 4.97 mmol, 1.00 equiv) in THF (20.0 mL) at 0 ° C., followed by 3-bromoprop-1-yne (704 mg, 5.92 mmol, 1.19 equiv). 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.

[0869] 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

[0870]

[0871] 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.

[0872] 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

[0873]

[0874] 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.

[0875] 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

[0876]

[0877] 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.

[0878] 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

[0879]

[0880] 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.

[0881] Reference 15

[0882] 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

[0883]

[0884] Step 1: 4-Aminocyclohexanone hydrochloride

[0885]

[0886] A mixture of tert-butyl (4-oxocyclohexyl)carbamate (500 mg, 2.34 mmol, 1.00 equiv) in 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.

[0887] Step 2: 2-(2,6-dioxopiperidin-3-yl)-4-((4-oxocyclohexyl)amino)isoindoline-1,3-dione

[0888]

[0889] 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.

[0890] Step 3: 2-(2,6-dioxopiperidin-3-yl)-4-((4-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione

[0891]

[0892] 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 one drop of AcOH. The resulting mixture was stirred at room temperature for 1 h, and then NaBH(OAc) (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 NaHCO aqueous solution, and then washed with brine. The organic layer was dried over NaSO and then concentrated to give the title compound as a yellow solid, which was used in the next step without further purification. 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

[0893]

[0894] 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.

[0895] 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

[0896]

[0897] 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.

[0898] Reference 16

[0899] 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

[0900]

[0901] 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

[0902]

[0903] 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.

[0904] Reference 17

[0905] Synthesis of 5-((3-(3-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0906]

[0907] 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

[0908]

[0909] 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.

[0910] 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

[0911]

[0912] 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.

[0913] Reference 18

[0914] 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

[0915]

[0916] Step 1: tert-Butyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate

[0917]

[0918] Proceeding similarly as described above in step 2 of reference 10, but using tert-butyl (2-hydroxyethyl)carbamate and 3-bromoprop-1-yne, provided the title compound.

[0919] 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

[0920]

[0921] 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.

[0922] Reference 19

[0923] 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

[0924]

[0925] Step 1: 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carbaldehyde

[0926]

[0927] 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) and 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.

[0928] 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

[0929]

[0930] A mixture of 1- (2,6- dioxopiperidin-3-yl) -3- methyl -2- oxo -2,3- dihydro -1H- benzo [d] -imidazole -4- carbaldehyde (360 mg, 1.25 mmol, 1.00 equivalent) and tert-butyl N- methyl (piperidin-4-yl) carbamate (403 mg, 1.88 mmol, 1.50 equivalent) in THF / DMF = 2 / 1 (5 mL) was stirred at room temperature for 2 h. NaBH (OAc) (413 mg, 1.95 mmol, 1.60 equivalents) was then 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.

[0931] Reference 20

[0932] 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

[0933]

[0934] Step 1: Dimethyl 3-iodophthalate

[0935]

[0936] To a stirred mixture of 3-iodophthalic acid (5.00 g, 17.12 mmol, 1.00 equiv) and 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.

[0937] Step 2: 4-(((tert-Butyldimethylsilyl)oxy)methyl)aniline

[0938]

[0939] 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.

[0940] Step 3: Dimethyl 3-((4-(((tert-Butyldimethylsilyl)oxy)methyl)phenyl)amino)phthalate

[0941]

[0942] 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) and 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.

[0943] Step 4: Dimethyl 3-((4-(((tert-Butyldimethylsilyl)oxy)methyl)phenyl)(methyl)amino)phthalate

[0944]

[0945] A mixture of dimethyl 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino)-phthalate (1.50 g, 3.49 mmol, 1.00 equiv), iodomethane (991 mg, 6.98 mmol, 2.00 equiv) and 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.

[0946] Step 5: 3-[(4-Hydroxymethyl-phenyl)-methyl-amino]-phthalic acid dimethyl ester

[0947]

[0948] 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 of reaction, 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.

[0949] Step 6: Dimethyl 3-((4-formylphenyl)(methyl)amino)phthalate

[0950]

[0951] A mixture of dimethyl 3-[(4-hydroxymethyl-phenyl)methylamino]phthalate (300 mg, 0.91 mmol, 1.00 equiv) and MnO (800 mg, 9.20 mmol, 10.11 equiv) in DCM (10.0 mL) was stirred at room temperature overnight. 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.

[0952] Step 7: Dimethyl 3-((4-(((2-((tert-Butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl)phenyl)(methyl)amino)phthalate

[0953]

[0954] A mixture of dimethyl 3-((4-formylphenyl)(methyl)amino)phthalate (300 mg, 0.92 mmol, 1.00 equivalent), methyl-(2-methylamino-ethyl)-carbamic acid tert-butyl ester (205 mg, 1.09 mmol, 1.18 equivalent) 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 equivalent) 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.

[0955] Step 8: 3-((4-(((2-((tert-Butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl)phenyl)(methyl)amino)phthalic acid

[0956]

[0957] 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 / HO=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.

[0958] 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

[0959]

[0960] 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.

[0961] Reference 21

[0962] 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

[0963]

[0964] 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

[0965]

[0966] 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 / HO=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.

[0967] 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

[0968]

[0969] 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) (30 mg) in THF (10 mL) was stirred at 50° C. under 50 psi H pressure. The reaction mixture was filtered and then concentrated to give the title compound as a white solid.

[0970] 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

[0971]

[0972] 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.

[0973] 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

[0974]

[0975] 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, tert-butyl methyl(3-oxopropyl)carbamate (63.6 mg, 0.34 mmol, 2.62 equiv) was added at room temperature. The mixture was stirred at 20 ° C for 2 h, followed by the addition of NaBH(OAc) (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 Na SO, 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.

[0976] Reference 22

[0977] 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

[0978]

[0979] Step 1: 2,2-Dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-oic acid

[0980]

[0981] 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 for 1 h at 0 ° C, 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 H o at 0 ° C, the pH was then adjusted to 2-3 with 1N HCl aqueous solution, and then extracted with EtOAc. The organic layer was washed with brine, dried over Na sO , filtered, and then concentrated to give the title compound as a yellow oil.

[0982] 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

[0983]

[0984] 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 NaHCO , and extracted with EtOAc. The organic layer was washed with brine, dried over Na SO , 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.

[0985] Reference 23

[0986] 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

[0987]

[0988] Step 1: Benzyl 4-(3-(3-((4-((tert-Butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenoxy)-azetidin-1-yl)piperidine-1-carboxylate

[0989]

[0990] By tert-butyl (1- ((3- (azetidin-3-yloxy) phenyl) sulfonyl) piperidin-4-yl) carbamate (100mg, 0.24mmol, 1.00 equivalent), benzyl 4-oxopiperidine-1-carboxylate (113mg, 0.48mmol, 2.00 equivalent) and 1 drop of AcOH in THF (3.0mL) solution is stirred at room temperature for 1h, then NaBH (OAc) is added (102mg, 0.48mmol, 2.00 equivalent). The reaction mixture is stirred at room temperature overnight, diluted with water, and then extracted with DCM. The organic layer is concentrated and then purified by silica gel flash column (DCM / MeOH=20 / 1) to give the title compound as a white solid.

[0991] Step 2: (1-((3-((1-(Piperidin-4-yl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)-carbamic acid tert-butyl ester

[0992]

[0993] 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 an atmosphere of H2 overnight. The reaction mixture was filtered and concentrated to give the title compound as a white solid.

[0994] 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

[0995]

[0996] 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 an 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.

[0997] Reference 24

[0998] (1-((3-((1-(azetidin-3-yl)piperidin-4-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)-

[0999]

[1000] Step 1: tert-Butyl (1-((3-(piperidin-4-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1001]

[1002] The title compound was prepared by proceeding as described in steps 1 to 6 of reference 12 using 1-diphenylmethylpiperidin-4-yl methanesulfonate.

[1003] Step 2: (1-((3-((1-(azetidin-3-yl)piperidin-4-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)-carbamic acid tert-butyl ester

[1004]

[1005] tert-Butyl (1-((3-(piperidin-4-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate was converted to the title compound by proceeding analogously to that described in steps 1 and 2 of reference 23 above using benzyl 3-oxoazetidine-1-carboxylate.

[1006] Reference 25

[1007] 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

[1008]

[1009] Step 1: Methyl 3-(2-hydroxyethoxy)-2-methylbenzoate

[1010]

[1011] A mixture of methyl 3-hydroxy-2-methylbenzoate (2.50 g, 15.04 mmol, 1.00 equivalent) and 1,3-dioxolane-2-one (1.98 g, 22.48 mmol, 1.50 equivalent), KCO (2.07 g, 14.98 mmol, 1.00 equivalent) in DMF (30.0 mL) was stirred at 120 ° C under N2 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 Na2SO4, 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.

[1012] Step 2: Methyl 2-(bromomethyl)-3-(2-hydroxyethoxy)benzoate

[1013]

[1014] 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 CCl (45.0 mL) was stirred at 75 ° C for 3 h under N. 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.

[1015] Step 3: 3-(4-(2-hydroxyethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[1016]

[1017] 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) was added 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). The resulting mixture was stirred at 80 ° C. under N2 overnight, 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.

[1018] Step 4: 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethyl 4-methylbenzenesulfonate

[1019]

[1020] 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.

[1021] Step 5: Benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate

[1022]

[1023] To a stirred solution of benzyl 4-hydroxypiperidine-1-carboxylate (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 at room temperature overnight, 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.

[1024] Step 6: tert-Butyl (1-((3-(piperidin-4-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1025]

[1026] Benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate was converted to the title compound by proceeding similarly to that described in steps 5-6 of reference 12 above.

[1027] 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

[1028]

[1029] A mixture of 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethyl 4-methylbenzenesulfonate (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.

[1030] Reference 26

[1031] 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

[1032]

[1033] 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): 444.48;

[1034] Reference 27

[1035] 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

[1036]

[1037] 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.

[1038] Reference 28

[1039] 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

[1040]

[1041] Step 1: Benzyl 4-(3-((4-((tert-Butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

[1042]

[1043] 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.

[1044] Step 2: tert-Butyl (1-((3-(piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1045]

[1046]

[0147] 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 10% Pd / C (800 mg) in MeOH (40.0 mL) was stirred at 50 °C under H2 (50 psi) for 16 h. The mixture was filtered and concentrated to give the title compound as a white solid. Step 3: Benzyl 4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-1-yl)methyl)piperidine-1-carboxylate

[1047]

[1048] To a stirred 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 resulting 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.

[1049] Step 4: tert-Butyl (1-((3-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)-carbamate

[1050]

[1051]

[0149] 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 10% 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. 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

[1052]

[1053] 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 DIPEA (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.

[1054] 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

[1055]

[1056] 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), NaHPO.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 a nitrogen atmosphere for 16 h. The resulting mixture was filtered, diluted with EtOAc, and then washed with water, brine, dried over anhydrous NaSO 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.

[1057] 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

[1058]

[1059] A mixture of 3-aminopiperidine-2,6-dione hydrochloride (126 mg, 0.77 mmol, 1.30 equiv) and DIPEA (184 mg, 1.43 mmol, 2.40 equiv) in anhydrous DCM (5.0 mL) was stirred at room temperature for 10 min before the addition of 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). The mixture was stirred at 45 ° C under N 2 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 N 2 for 16 h. The mixture was cooled, diluted with water, and then extracted with DCM. The combined organic layer was washed with water, dried over anhydrous Na 2 SO 4, 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.

[1060] Reference 29

[1061] 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

[1062]

[1063] Step 1: 3-5-Bromo-1-oxoisoindolin-2-ylpiperidine-2,6-dione

[1064]

[1065] 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) and KCO (26.87 g, 194.71 mmol, 3.00 equiv) in DMF was stirred at 70 ° C under N2 atmosphere overnight. The mixture was poured into water and extracted with DCM. The combined organic layer was washed with water, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column (PE: EA = 2: 1) to give the title compound as a white solid.

[1066] Step 2: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate

[1067]

[1068] 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), K 3 PO 4 (800 mg, 3.73 mmol, 1.20 equiv) and Pd(dppf)Cl 2 (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.

[1069] Step 3: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate

[1070]

[1071] 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 an atmosphere of H 2 for 12 h, filtered and concentrated to give the title compound as a white solid.

[1072] Step 4: 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[1073]

[1074] DCM / TFA=4:1 (2.5 mL) was added to 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 resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated to give the title compound as a brown solid.

[1075] 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

[1076]

[1077] 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. NaBHCN (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, 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.

[1078] Reference 30

[1079] 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

[1080]

[1081] Step 1: Benzyl 4-(dimethoxymethyl)piperidine-1-carboxylate

[1082]

[1083] To a mixture of benzyl 4-formylpiperidine-1-carboxylate (1.00 g, 4.04 mmol, 1.00 equiv) in MeOH (9.0 mL) was added p-TsOH (38 mg, 0.22 mmol, 0.054 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. Step 2: 4-(dimethoxymethyl)piperidine

[1084]

[1085] To a stirred mixture of benzyl 4-(dimethoxymethyl)piperidine-1-carboxylate (948 mg, 3.23 mmol, 1.00 equiv) in MeOH (10.0 mL) was added 10% Pd / C (400 mg), and the reaction mixture was stirred at room temperature under an H2 atmosphere overnight. The resulting mixture was filtered through celite, and the filtrate was concentrated to give the title compound as a colorless oil. Step 3: tert-butyl (1-((3-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)-carbamate

[1086]

[1087] A mixture of 4-(dimethoxymethyl)piperidine (100 mg, 0.63 mmol, 1.20 equiv), KCO (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, 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.

[1088] Step 4: tert-Butyl (1-((3-(4-formylpiperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1089]

[1090] To a stirred 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 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, 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.

[1091] 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

[1092]

[1093] This compound was prepared analogously to that described in step 5 of reference 29.

[1094] Reference 31

[1095] Synthesis of 3-(5-(azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[1096]

[1097] Step 1: (1-(tert-Butoxycarbonyl)azetidin-3-yl)zinc(II) iodide

[1098]

[1099] To a mixture of Zn powder (300 mg, 4.59 mmol, 1.30 equivalents) in DMA (3.0 mL) was added 1,2-dibromoethylene (66 mg, 0.35 mmol, 0.10 equivalents) 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.

[1100] Step 2: tert-Butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidine-1-carboxylate

[1101]

[1102] 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.

[1103] Step 3: 3-(5-(azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[1104]

[1105] To a stirred 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 resulting solution was stirred at room temperature for 3 h. The resulting mixture was concentrated to give the crude product as a brown oil.

[1106] Reference 32

[1107] (1-((3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)

[1108] Synthesis of tert-butyl (4-(2-(2-methyl)piperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1109]

[1110] Step 1: Benzyl 4-(3-((4-((tert-Butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazine-1-carboxylate

[1111]

[1112] 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 (25.0 mL) was stirred at 100 ° C for 12 h. The mixture was quenched with H O 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. Step 2: tert-Butyl (1-((3-(piperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1113]

[1114] The title compound was prepared analogously to that described in step 2 of reference 30.

[1115] Step 3: Benzyl 4-((4-(3-((4-(tert-Butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate

[1116]

[1117] 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.

[1118] 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

[1119]

[1120] 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.

[1121] Reference 33

[1122] Synthesis of 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

[1123]

[1124] Step 1: (1-((3-(1,4-Dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)sulfonyl)piperidin-4-yl)-carbamic acid tert-butyl ester

[1125]

[1126] 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.

[1127] Step 2: tert-Butyl (1-((3-(4-oxopiperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1128]

[1129] A mixture of tert-butyl (1-((3-(1,4-dioxa-8-azaspiro[4.5]decan-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 Na SO 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. 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

[1130]

[1131] To a mixture of tert-butyl (1-((3-(4-oxopiperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (44 mg, 1.02 mmol, 1.00 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, 1.11 equiv) in THF (5.0 mL). The mixture was stirred at 40 °C for 0.5 h. NaBHCN (142 mg, 2.60 mmol, 2.55 equiv) was added at room temperature, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched 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 DCM / MeOH (10:1) to give the title compound as a yellow solid.

[1132] Reference 34

[1133] Synthesis of 3-(4-(azetidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[1134]

[1135] 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

[1136]

[1137] 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 stirred 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.

[1138] Step 2: 3-(4-(azetidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[1139]

[1140] To a stirred 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.

[1141] Reference 35

[1142] 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

[1143]

[1144] Step 1: tert-Butyl 4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[1145]

[1146] 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) and KCO (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 EtOAc. The combined organic layers were washed with brine, dried over NaSO and concentrated. The residue was purified by flash chromatography (PE: EA = 3: 1) to give the title compound as a colorless oil.

[1147] Step 2: tert-Butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[1148]

[1149] 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 cooled, quenched with aqueous ammonia and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, concentrated, and the residue was purified by flash chromatography (PE:EA=3:1) to give the title compound as a white solid.

[1150] Step 3: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate

[1151]

[1152] By proceeding analogously to that described in Reference 28, Steps 6-7, tert-butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate was converted to the title compound.

[1153] Step 4: 3-(6-Fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[1154]

[1155] 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 room temperature for 2 h. The reaction mixture was concentrated to give the title compound as a yellow oil.

[1156] 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

[1157]

[1158] A mixture of 3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (74 mg, 0.21 mmol, 1.00 equiv), tert-butyl (1-((3-(bromomethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (138 mg, 0.32 mmol, 1.50 equiv) and 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.

[1159] Reference 36

[1160] 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

[1161]

[1162] Step 1: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate

[1163]

[1164] 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) and DIPEA (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 EtOAc. 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.

[1165] Step 2: 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione

[1166]

[1167] 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 room temperature for 2 h. The reaction mixture was concentrated to give the title compound as a yellow oil.

[1168] Step 3: 3-(Bromomethyl)benzenesulfonyl chloride

[1169]

[1170] A mixture of 3-methylbenzenesulfonyl chloride (8.00 g, 41.96 mol, 1.00 equiv), NBS (8.22 g, 46.16 mol, 1.10 equiv) and benzoyl peroxide (1.46 g, 4.20 mol, 0.10 equiv) in CCl4 (80.0 mL) was stirred at 80° C. for 12 h. The reaction mixture was cooled, filtered, and the filtrate was concentrated to give the crude product as a colorless oil.

[1171] Step 4: tert-Butyl (1-((3-(bromomethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1172]

[1173] At 0 DEG C, a solution of tert-butyl piperidin-4-ylcarbamate (5.64g, 21.05mol, 1.11 equivalents) in THF (20.00mL) was added to a stirred solution of 3-(bromomethyl)benzenesulfonyl chloride (3.79g, 18.95mol, 1.00 equivalents) and TEA (4.25g, 42.10mmol, 2.22 equivalents) in THF (40.0mL). The resulting mixture was stirred at room temperature for 12h, quenched with H o, and then extracted with DCM. The combined organic layer was washed with water, dried over anhydrous Na sO , filtered and concentrated. The residue was purified by silica gel column chromatography using PE / EA (3: 1) elution to obtain the title compound as a white solid.

[1174] 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

[1175]

[1176] 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) and TEA (854 mg, 8.46 mmol, 6.00 equiv) in THF (10.0 mL) was stirred at 55 ° C overnight. The mixture was cooled, quenched with water, and extracted with DCM. 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.

[1177] Reference 37

[1178] Synthesis of 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

[1179]

[1180] Step 1: tert-Butyl 8-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3,8-di-azabicyclo[3.2.1]octane-3-carboxylate

[1181]

[1182] A mixture of 2- (2,6-dioxopiperidin-3-yl) -5,6-difluoroisoindoline -1,3- dione (200 mg, 0.68 mmol, 1.00 equiv), 3,8-diazabicyclo [3.2.1] octane -3- carboxylic acid tert-butyl ester (144 mg, 0.68 mmol, 1.00 equiv) and DIPEA (263 mg, 2.04 mmol, 3.00 equiv) in NMP (3.0 mL) was stirred at 110 ° C overnight. The reaction mixture was cooled, quenched with H o, and then extracted with DCM. The combined organic layer was washed with water, dried over anhydrous Na sO , 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.

[1183] 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

[1184]

[1185] 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 by proceeding similarly to that described in steps 2-5 of reference 36.

[1186] Reference 38

[1187] 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

[1188]

[1189] Step 1: tert-Butyl 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[1190]

[1191] To a stirred solution of methyl 2-cyano-4-fluorobenzoate (10.00 g, 55.80 mmol, 1.00 equivalent) in DMSO (150.0 mL) is added tert-butyl piperazine-1-carboxylate (11.40 g, 61.38 mmol, 1.10 equivalents) and DIPEA (34.70 g, 268.96 mmol, 4.80 equivalents). The resulting mixture is stirred at 110 ° C for 12 h. The mixture is cooled, quenched with water, and extracted with EtOAc. The combined organic layer is washed with brine and concentrated. The residue is purified by silica gel column chromatography with PE / EtOAc (3: 1) elution to give the title compound as a yellow solid.

[1192] Step 2: tert-Butyl 4-(3-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[1193]

[1194] 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 cooled, adjusted to pH=7-8 with aqueous NaHCO3 solution, 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.

[1195] Step 3: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate

[1196]

[1197] A mixture of 3-aminopiperidine-2,6-dione hydrochloride (2.60 g, 15.50 mmol, 1.20 equiv), DIPEA (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 reaction mixture was stirred at 40 ° C. for 12 h, 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.

[1198] Step 4: 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[1199]

[1200] 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.

[1201] 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

[1202]

[1203] 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 the residue was purified by silica gel column chromatography eluting with DCM / MeOH (20:1) to give the title compound as a yellow solid.

[1204] Reference 39

[1205] Compound 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

[1206]

[1207] Step 1: tert-Butyl 7-(3-cyano-4-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[1208]

[1209] 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) and DIPEA (719 mg, 16.74 mmol, 3.00 equiv) in DMSO (10.0 mL) was stirred at 110 ° C overnight. The mixture was cooled, diluted with water and extracted with EtOAc. 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. Step 2: tert-butyl 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[1210]

[1211] 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 to that described in steps 6-7 of reference 28.

[1212] Step 3: 3-(1-oxo-5-(2,7-diazaspiro[3.5]nonan-7-yl)isoindolin-2-yl)piperidine-2,6-dione

[1213]

[1214] 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 room temperature for 2 h. The reaction mixture was concentrated to give the title compound as a yellow oil.

[1215] 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

[1216]

[1217] 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) and 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.

[1218] Reference 40

[1219] 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

[1220]

[1221] Step 1: rac-tert-butyl ((3R,4S)-1-((3-(bromomethyl)phenyl)sulfonyl)-3-fluoropiperidin-4-yl)carbamate

[1222]

[1223] 3-(Bromomethyl)-benzene-1-sulfonyl chloride (122 mg, 0.46 mmol, 1.00 equiv) in THF (1.0 mL) was slowly added to a stirred solution of tert-butyl racemate (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 reaction mixture was diluted with water and extracted with EtOAc. 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.

[1224] 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

[1225]

[1226] To a stirred 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 rac-tert-butyl((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.

[1227] Reference 41

[1228] 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

[1229]

[1230] Step 1: 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile

[1231]

[1232] A mixture of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (2.00 g, 6.21 mmol, 1.66 equiv), Zn(CN) (438 mg, 3.73 mmol, 1.00 equiv) and Pd(PPh) (714 mg, 0.62 mmol, 0.10 equiv) in DMF (30.0 mL) was stirred at 100 ° C overnight. The reaction mixture was cooled, diluted with water and extracted with DCM. 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.

[1233] Step 2: 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbaldehyde

[1234]

[1235] A mixture of 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile (1.20 g, 4.46 mmol, 1.00 equiv), NaH2PO2 HO (993 mg, 9.37 mmol, 2.10 equiv) and Raney nickel (500 mg) in pyridine: HO: AcOH (40.0 mL, 2:2:1) was stirred at 70 ° C overnight. The reaction mixture was filtered and the solid filter cake was 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.

[1236] Step 3: Benzyl 4-(3-((4-((tert-Butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenoxy)piperidine-1-carboxylate

[1237]

[1238] 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, 24.0 mmol, 1.50 equiv) and CsCO (10.4 g, 32.0 mmol, 2.00 equiv) in DMSO (70.0 mL) was stirred at 90 ° C for 4 h. The reaction mixture was cooled, diluted with water, 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.

[1239] Step 4: tert-Butyl (1-((3-(piperidin-4-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1240]

[1241] 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), HCOONH (3.3 g, 52.35 mmol, 5.00 equiv) and Pd(OH) (1.2 g) in EtOH (60.0 mL) was stirred at 70° C. for 4 h. The reaction mixture was cooled, filtered and concentrated to give the title compound as a white solid.

[1242] 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

[1243]

[1244] To a stirred 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 resulting mixture was stirred at 40 ° C for 0.5 h. NaBH3CN (47 mg, 0.74 mmol, 2.00 equiv) was added, and the mixture was 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.

[1245] Reference 42

[1246] 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

[1247]

[1248] Step 1: Benzyl 3-(4-(3-((4-(tert-Butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazin-1-yl)azetidine-1-carboxylate

[1249]

[1250] To a stirred mixture of tert-butyl (1-((3-(piperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (740 mg, 1.75 mmol, 1.00 equiv) in THF (10.0 mL) was added AcOH (3 drops) and benzyl 3-oxoazetidine-1-carboxylate (718 mg, 3.50 mmol, 2.00 equiv). 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 resulting mixture was stirred at room temperature overnight. 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.

[1251] 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

[1252]

[1253] Using similar 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.

[1254] Reference 43

[1255] 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

[1256]

[1257] Step 1: tert-Butyl (1-((3-(3-hydroxyazetidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1258]

[1259] 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 H O 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.

[1260] Step 2: tert-Butyl (1-((3-(3-oxoazetidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[1261]

[1262] To a stirred solution of tert-butyl (1-((3-(3-hydroxyazetidin-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.

[1263] 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

[1264]

[1265] 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 preparative TLC eluting with DCM / MeOH (20:1) to give the title compound as a white solid.

[1266] Reference 44

[1267] 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

[1268]

[1269] To a stirred 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 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, 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.

[1270] Reference 45

[1271] Synthesis of 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione 2,2,2-trifluoroacetate

[1272]

[1273] Step 1: 2,6-Bis(benzyloxy)pyridine

[1274]

[1275] 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) followed by 2,6-dichloropyridine (10.00 g, 67.57 mmol, 1.00 equiv). The mixture was stirred at 75 ° C under N 2 for 20 h. The mixture was diluted with water and extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated to give the crude title compound as a light yellow solid.

[1276] Step 2: 2,6-Bis(benzyloxy)-3-bromopyridine

[1277]

[1278] 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 N for 4 h. The mixture was diluted with water and extracted with EtOAc, and the combined organic layers were washed with brine, dried over NaSO, and concentrated to give the crude title compound as a yellow solid.

[1279] Step 3: 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[1280]

[1281] 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, 1.60 equiv), KOAc (10.00 g, 0.10 mol, 2.00 equiv) and Pd(dppf)Cl (3.7 g, 5.00 mmol, 0.10 equiv) in 1,4-dioxane (200.0 mL) was stirred at 100° C. under N for 25 h. The mixture was diluted with water and extracted with EtOAc, and the combined organic layers were washed with brine, dried over NaSO, filtered 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.

[1282] Step 4: 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine

[1283]

[1284] 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), K 3 PO 4 (5.63 g, 26.50 mmol, 3.00 equiv) and Pd(PPh 3 ) 4 (510 mg, 0.44 mmol, 0.05 equiv) in 1,4-dioxane / H 2 O=10:1 (40.0 mL) was stirred at 100° C. under N 2 for 16 h. The mixture was cooled, diluted with water and extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na 2 SO 4, filtered 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.

[1285] Step 5: tert-Butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carboxylate

[1286]

[1287] 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), CsCO (730 mg, 2.24 mmol, 2.00 equiv), Pd(dba) (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 N for 20 h. The mixture was diluted with water and extracted with EtOAc, and the combined organic layers were washed with brine, dried over NaSO, filtered 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.

[1288] Step 6: tert-Butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate

[1289]

[1290] 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 EtOAc (5.0 mL) and 1,4-dioxane (5.0 mL) was stirred at room temperature under H for 20 h. The mixture was filtered and the filtrate was concentrated to give the crude title compound as a yellow oil.

[1291] Step 7: 3-(4-(Piperazin-1-yl)phenyl)piperidine-2,6-dione 2,2,2-trifluoroacetate

[1292]

[1293] 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 N for 2 h. The mixture was concentrated to give the title compound as a yellow oil.

[1294] Reference 46

[1295] Synthesis of 3-(3-fluoro-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione

[1296]

[1297] The title compound was prepared by proceeding analogously to Reference 45, substituting 1-bromo-2-fluoro-4-iodobenzene for 1-bromo-4-iodobenzene in Step 4. MS (ESI): 444.1;

[1298] Reference 47

[1299] Synthesis of 1-(3-fluoro-4-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1300]

[1301] Step 1: tert-Butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate

[1302]

[1303] A mixture of 1,2-difluoro-4-nitrobenzene (5.00 g, 31.43 mmol, 1.00 equiv), DIPEA (12.16 g, 94.29 mmol, 3.00 equiv) and tert-butyl piperazine-1-carboxylate (6.15 g, 33.00 mmol, 1.05 equiv) in MeCN (30.0 mL) was stirred overnight at 70° C. The solution was concentrated, filtered, and the solid filter cake was washed with EA / PE (1 / 10) to give the title compound as a yellow solid.

[1304] Step 2: tert-Butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate

[1305]

[1306] A mixture of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (10.00 g, 30.8 mmol, 1.00 equiv) and 10% Pd / C (1.0 g) in MeOH (100.0 mL) was stirred at room temperature under an atmosphere of H overnight. The mixture was filtered and concentrated to give the crude title compound as a pink solid.

[1307] Step 3: tert-Butyl 4-(2-fluoro-4-((3-methoxy-3-oxopropyl)amino)phenyl)piperazine-1-carboxylate

[1308]

[1309] A mixture of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (4.00 g, 13.56 mmol, 1.00 equiv) and methyl acrylate (1.75 g, 20.34 mmol, 1.50 equiv) in DBU (1.65 g, 10.85 mmol, 0.80 equiv) and lactic acid (977 mg, 10.85 mmol, 0.80 equiv) was stirred at 90 ° C for 3 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and then concentrated. The residue was purified by silica flash column (PE / EA=3 / 1) to obtain the title compound as a yellow solid.

[1310] Step 4: tert-Butyl 4-(2-fluoro-4-(N-(3-methoxy-3-oxopropyl)cyanamido)phenyl)piperazine-1-carboxylate

[1311]

[1312] BrCN (70 mg, 0.66 mmol, 1.00 equiv) was added to a stirred mixture of tert-butyl 4-(2-fluoro-4-((3-methoxy-3-oxopropyl)amino)phenyl)piperazine-1-carboxylate (500 mg, 1.32 mmol, 2.00 equiv) and NaOAc (164 mg, 2.00 mmol, 3.03 equiv) in EtOH (8.0 mL) and the mixture was stirred at room temperature for 16 h. The mixture was quenched with H2O and then extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and then concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give the title compound as a yellow oil.

[1313] Step 5: tert-Butyl 4-(2-fluoro-4-(1-(3-methoxy-3-oxopropyl)ureido)phenyl)piperazine-1-carboxylate

[1314]

[1315] InCl3 (55.3 mg, 0.25 mmol, 0.34 equiv) was added to a stirred solution of tert-butyl 4-(2-fluoro-4-(N-(3-methoxy-3-oxopropyl)cyanamido)phenyl)piperazine-1-carboxylate (300 mg, 0.74 mmol, 1.00 equiv) and (E)-acetaldehyde oxime (132 mg, 2.22 mmol, 3.00 equiv) in toluene (2.0 mL). The resulting mixture was stirred at 110 °C for 1 h, cooled, quenched with H2O and then extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and then concentrated to give the title compound as a yellow solid. Step 6: tert-Butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluorophenyl)piperazine-1-carboxylate

[1316]

[1317] N, N-dimethyl-1-benzylamine (178 mg, 1.07 mmol, 1.50 equiv) was added to a stirred solution of tert-butyl 4-(3-fluoro-4-(1-(3-methoxy-3-oxopropyl)ureido)phenyl)piperazine-1-carboxylate (300 mg, 0.71 mmol, 1.00 equiv) in MeCN (10.0 mL), and the mixture was stirred at 60 ° C for 1 h. The mixture was quenched with H2O and then extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and then 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.

[1318] Step 7: 1-(3-Fluoro-4-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1319]

[1320] To a stirred solution of tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluorophenyl)piperazine-1-carboxylate (100 mg, 0.26 mmol, 1.00 equiv) in DCM (2.0 mL) was added TFA (0.5 mL). The resulting mixture was stirred at room temperature for 2 h and then concentrated to give the title compound as a white solid.

[1321] Reference 48

[1322] Synthesis of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[1323]

[1324] Step 1: 6-Bromo-1-methyl-1H-indazol-3-amine

[1325]

[1326] NaH (2.10 g, 60%, 52.50 mmol, 2.00 equivalents) was added to a stirred solution of 6-bromo-1H-indazole-3-amine (5.60 g, 26.42 mmol, 1.00 equivalents) in DMF (20.0 mL) at 0 ° C and the mixture was stirred for 1 h at 0 ° C. CH 1 (4.10 g, 29.06 mmol, 1.10 equivalents) was added and the mixture was stirred for 3 h at room temperature under N . The mixture was poured into cold water and filtered. The solid filter cake was washed with water and dried to give the title compound as a yellow solid.

[1327] Step 2: 3-((6-Bromo-1-methyl-1H-indazol-3-yl)amino)propanoic acid

[1328]

[1329] Acrylic acid (1.60 g, 22.12 mmol, 1.00 equiv) was added to a stirred solution of 6-bromo-1-methyl-1H-indazol-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 resulting mixture was stirred at 105 ° C. under N 2 for 20 h. The mixture was poured into cold water and the pH was adjusted to 6-7 by adding 6N HCl (aq). The mixture was filtered, and the solid filter cake was washed with water and dried to give the title compound as a yellow solid.

[1330] Step 3: 1-(6-Bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[1331]

[1332] A mixture of 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propanoic acid (3.11 g, 10.43 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. 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 EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (EA:PE=0 to 100%) to give the title compound as a yellow solid.

[1333] Step 4: tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate

[1334]

[1335] 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, brine, dried over Na 2 SO 4 , filtered, concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to give the title compound as a yellow solid.

[1336] Step 5: tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate

[1337]

[1338] 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)2 / C (150 mg, 50% wt) in THF (20 mL) was stirred at 50 psi H2 at 50 °C overnight. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:1) to give the title compound as a yellow solid.

[1339] Step 6: 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[1340]

[1341] TFA (0.5 mL) was added to a stirred solution of tert-butyl 4-(3-(2,4-dioxotetrahydro-pyrimidin-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.

[1342] Reference 49

[1343] Synthesis of 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione

[1344]

[1345] Step 1: tert-Butyl 4-(4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate

[1346]

[1347] 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 cooled, filtered, diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and then concentrated. The residue was purified by silica flash column using PE / EtOAc (10:1) to give the title compound as a yellow solid.

[1348] Step 2: tert-Butyl 4-(4-aminophenyl)piperidine-1-carboxylate

[1349]

[1350] A mixture of tert-butyl 4-(4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (1.20 g, 3.95 mmol, 1.00 equiv), 10% Pd / C (360 mg) in MeOH / THF (30 mL, 1:1) was stirred at 45° C. under an atmosphere of H 2 overnight. The mixture was filtered and concentrated, and the residue was purified by silica flash column using PE / EtOAc (3:1) to give the title compound as a yellow solid.

[1351] Step 3: tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate

[1352]

[1353] 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 cooled, diluted with water, and extracted with EtOAc. The combined organic layers were dried over anhydrous Na SO, filtered, and then concentrated. The residue was purified by silica flash column using PE / EtOAc (1: 1) to give the title compound as a yellow solid.

[1354] Step 4: 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione

[1355]

[1356] 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) was added TFA (0.5 mL) and the mixture was stirred at room temperature for 2 h. The solution was concentrated to give the title compound as a yellow solid.

[1357] Reference 50

[1358] Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione

[1359]

[1360] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione

[1361]

[1362] A mixture of 5,6-difluoroisobenzofuran-1,3-dione (5.00 g, 27.16 mmol, 1.00 equiv), KOAc (3.00 g, 30.15 mmol, 1.11 equiv) and 3-aminopiperidine-2,6-dione (4.70 g, 28.52 mmol, 1.05 equiv) in CHCOOH (100.0 mL) was stirred at 90 ° C for 16 h. The mixture was quenched with H O and then extracted with DCM. The combined organic layers were dried over anhydrous Na SO , filtered, and then concentrated to give the crude title compound as a purple solid.

[1363] Step 2: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate

[1364]

[1365] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (2.00 g, 6.81 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (1.27 g, 6.81 mmol, 1.00 equiv) and DIPEA (2.64 g, 20.41 mmol, 3.00 equiv) in NMP (20.0 mL) was stirred at 110 ° C for 16 h. The mixture was cooled, quenched with H2O, and then extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and then concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (3: 1) to obtain the title compound as a yellow solid.

[1366] Step 3: 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione

[1367]

[1368] TFA (0.5 mL) was added to a stirred solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate (20 mg, 0.05 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 title product as a yellow oil, which was used in the next step without further purification.

[1369] Reference 51

[1370] Synthesis of 5-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[1371]

[1372] The title compound was prepared by proceeding analogously to Reference 50, substituting tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate for tert-butyl piperazine-1-carboxylate in Step 2. MS (ESI): 444.184 (E) 444.7 ...F) 444.7 (E) 44

[1373] Reference 52

[1374] Synthesis of 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[1375]

[1376] Step 1: tert-Butyl 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[1377]

[1378] 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 DIPEA (34.70 g, 268.96 mmol, 4.80 equiv). The resulting mixture was stirred at 110 ° C for 12 h. The mixture was cooled, diluted with water, and extracted with EtOAc. The organic layer was 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. Step 2: tert-butyl 4- (3-formyl-4- (methoxycarbonyl) phenyl) piperazine-1-carboxylate

[1379]

[1380] To a stirred solution of tert-butyl 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (8.00 g, 23.20 mmol, 1.00 equiv) in pyridine:HO:AcOH=2:1:1 (80.0 mL) was added NaHPOHO (5.20 g, 48.70 mmol, 2.10 equiv) and Raney nickel (5.10 g). The resulting mixture was stirred at 70 ° C for 12 h. The mixture was adjusted to pH = 7-8 with aqueous NaHCO, 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.

[1381] Step 3: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate

[1382]

[1383] To a stirred solution of 3-aminopiperidine-2,6-dione hydrochloride (2.60 g, 15.50 mmol, 1.20 equiv) in DCM (50.0 mL) was added DIPEA (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) at room temperature. The reaction mixture 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 reaction mixture was stirred at 40 ° C for 12 h, quenched 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.

[1384] Step 4: 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[1385]

[1386] To a stirred 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.

[1387] Reference 53

[1388] Synthesis ...

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); (b) a group having formula (ii); and 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 (i) is a ring 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 w is hydrogen, deuterium, alkyl, haloalkyl, cycloalkyl, halogen, alkoxy, haloalkoxy or cyano; Q is a ring having formula (a1), (b1) or (c1); in: R 1 , R 1a and R 1b are independently hydrogen, deuterium, alkyl, haloalkyl, cycloalkyl, halogen, haloalkoxy or cyano; R 2 , R 2a and R 2b is hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, halogen, haloalkyl, cyano, aralkyl, heteroaralkyl, heterocyclyl, fused heterocyclyl or heterocyclylalkyl, wherein the ring portions of alkyl, haloalkyl, cycloalkyl and heterocyclyl, and cycloalkylalkyl, aralkyl, heteroaralkyl and heterocyclylalkyl are independently selected from the following R e , R f and R g Substituted: hydrogen, deuterium, alkyl, halogen, haloalkyl, cycloalkyl, cyano, hydroxy, alkoxy, acyl, aminocarbonyl, aminosulfonyl, carboxyl, amino, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; and R 3 , R 3a and R 3b is alkyl, haloalkyl, deuterated haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aminocarbonylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl, wherein the ring portions of the cycloalkyl, aryl, heteroaryl and heterocyclyl, and the cycloalkylalkyl, aralkyl, heteroaralkyl and heterocyclylalkyl groups are independently selected from the following R e1 , R f1 and R g1 Substituted: hydrogen, deuterium, alkyl, halogen, haloalkyl, cycloalkyl, cycloalkylalkyl, aminoalkyl, (amino)deuteratedalkyl, cyano, hydroxy, alkoxy, acyl, aminocarbonyl, aminosulfonyl, carboxyl, amino, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; 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: X 1 , X 2 , X 3 and X 4 and Z 1 Each is a key; Z 2 is a bond, an alkylene group, a cycloalkylene group or a heterocyclylene group, wherein each ring is R j and R k replace; 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 spiro heterocyclylene group, wherein each ring is surrounded by R m and R n replace; 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; Z 5 is phenylene, monocyclic heteroarylene or heterocyclylene, wherein each ring is R q and R r replace; and Z 6 is -S(O)2-; and Each alkylene group is R s and R t replace.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: X 1 , X 2 , X 3 and 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 R m and R n replace; Z 4 is alkylene, -O-, cycloalkylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. o and R p replace; Z 5 R 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 Z 6 is -S(O)2-; and Where the alkylene group is R s and R t replace.

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, 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 R m and R n replace; Z 4 is alkylene, -O-, cycloalkylene or heterocyclylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy. o and R p replace; Z 5 is a phenylene group or a monocyclic heteroarylene group, each ring being R q and R r replace; and Z 6 is -S(O)2-; and Where the alkylene group is R s and R t replace.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein Z 5 Is R q and R r replace and Z 6 It is -S(O)2-.

6. The compound according to claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein: -Z 3 -Z 4 -Z 5 -Z 6 - is: Each R q , R m and R n are independently selected from hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, haloalkoxy, alkoxy and cyano.

7. The compound or pharmaceutically acceptable salt thereof according to claim 1 to 4 or 6, wherein -Z 3 -Z 4 -Z 5 -Z 6 -yes: Where R q , R m and R n Each of is independently selected from hydrogen, methyl, fluorine, chlorine, methoxy, difluoromethoxy, difluoromethyl and trifluoromethyl.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein: Q is a ring having the formula:

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein: R 3 is an alkyl group or a halogenated alkyl group.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 3 It is a haloalkyl group.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein: R 1 and R 2 is hydrogen and R w Not hydrogen.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein: R 1 and R 2 is hydrogen and R w It is a haloalkyl group.

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, 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.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein: Hy is wherein the N atom of the piperidine-1,4-diyl ring is attached to L.

15. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein: The degron is an E3 ligase ligand having formula (i), wherein loop A:

16. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein: The degron is an E3 ligase ligand selected from the group consisting of: Each R ee is hydrogen, methyl, ethyl, cyclopropyl or 2,2,2-trifluoroethyl, and each R ff is hydrogen, methyl, cyclopropyl, fluorine, cyano, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

18. 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 16 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 17.

19. The method of claim 18, 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.

20. The method of claim 18 or 19, 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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