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WO2025235298A1 - Composés bifonctionnels contenant des dérivés thiazolyle pour dégrader une certaine kinase dépendante de la cycline par l'intermédiaire d'une voie ubiquitine-protéasome - Google Patents

Composés bifonctionnels contenant des dérivés thiazolyle pour dégrader une certaine kinase dépendante de la cycline par l'intermédiaire d'une voie ubiquitine-protéasome

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Publication number
WO2025235298A1
WO2025235298A1 PCT/US2025/027391 US2025027391W WO2025235298A1 WO 2025235298 A1 WO2025235298 A1 WO 2025235298A1 US 2025027391 W US2025027391 W US 2025027391W WO 2025235298 A1 WO2025235298 A1 WO 2025235298A1
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WIPO (PCT)
Prior art keywords
heterocyclylene
alkylene
compound
substituted
acceptable salt
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PCT/US2025/027391
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English (en)
Inventor
Zhiyong Yu
Yan Lou
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Nikang Therapeutics Inc
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Nikang Therapeutics Inc
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Publication of WO2025235298A1 publication Critical patent/WO2025235298A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present disclosure provides certain bifunctional compounds containing thiazolyl derivatives that cause degradation of Cyclin-dependent kinase 2 (CDK2) and/or Cyclin-dependent kinase 4 (CDK4) via ubiquitin proteasome pathway and are therefore useful for the treatment of 15 diseases mediated by CDK2 and/or CDK4.
  • pharmaceutical compositions containing such compounds and processes for preparing such compounds are also provided.
  • Background Cyclin-dependent kinases (CDKs) are essential cellular serine/threonine kinases that play 20 an important role in orchestrating signaling events, such as DNA replication and protein synthesis, to ensure faithful eukaryotic cell division and proliferation.
  • CDK activity is tightly controlled by the fluctuating levels of various cyclins, which form heterodimeric complexes with CDKs to activate them.
  • CDK1/Cyclin B, CDK2/Cyclin E, CDK2/Cyclin A, CDK4/Cyclin D, CDK6/Cyclin D complexes are well known to 25 be vital regulators of cell cycle progression.
  • Other CDKs are involved in regulating gene transcription, DNA repair, differentiation, and apoptosis (see Morgan, D. O. Annu. Rev. Cell. Dev. Biol. (1997) 13: 261-291).
  • mitogenic signaling upregulates D-type cyclins, which directly bind and activate CDK4/6.
  • Active CDK4/6-cyclin D complexes partially phosphorylate Rb, disrupting the Rb/E2F interaction and de-repressing E2F activity,30 leading to upregulation of cyclin E, a CDK2 activator.
  • Cdk2-cyclin E further hyper- phosphorylates Rb, releasing E2F to transcribe genes required for S-phase entry.
  • CDK1-Cyclin A and CDK1-Cyclin B complexes - 1 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT are activated in late S and G2 phases to drive the transition into and completion of mitosis, respectively (Katsuno et al., 2009; Lindqvist et al., 2009; Lohka et al., 1988). Due to their crucial roles in regulating cell cycle and other essential cellular processes, increased activity or temporally abnormal activation of CDKs has been shown to promote 5 tumorigenesis and disease progression (Cordon-Cardo C. Am. J. Pathol. (1995) 147:545-560; Karp JE, Broder S. Nat. Med. (1995) 1:309-320; Hall M, Peters G. Adv. Cancer Res. (1996) 68:67-108).
  • CDK-cyclin complexes and the proteins that regulate them are widespread in various cancers and are often associated with poor clinical outcomes. Common alterations include amplifications/overexpression of cyclin D, cyclin E, CDK4 and CDK6; loss of 10 Rb; deficiency in CDK inhibitory regulators such as p16, p21, p27, and loss ⁇ of ⁇ function mutations in FBXW7, a component of SCF Fbw7 ubiquitin E3 ligase responsible for cyclin E degradation. (Smalley et al. Cancer Res. (2008) 68: 5743-52). Over the last two decades, there has been significant interest in developing CDK inhibitors for therapeutic purposes.
  • CDK4 and CDK6 have revolutionized the therapeutic management for hormone receptor-positive (HR+) metastatic breast cancer (MBC).
  • HR+ hormone receptor-positive metastatic breast cancer
  • CDK4/6 inhibitors have some limitations.
  • One major drawback is the development of primary or acquired resistance over time. An important mechanism of resistance involves the abnormal activation of CDK2.
  • CDK2/Cyclin E complex caused by elevated Cyclin E expression (Asghar, U. et al. Clin. Cancer Res. (2017) 23:5561) or formation of the 25 noncanonical CDK2/cyclin D1 complex in response to CDK4/6 inhibition (Herrera-Abreu MT et al, Cancer Res. (2006) 15: 2301), which bypasses the need for CDK4/6 for cell cycle reentry.
  • CDK4/6 inhibitors palbociclib and ribociclib exhibit relatively high hematological toxicity, primarily neutropenia.
  • CDK6 is highly expressed in the blood system and plays a role in regulating the growth of hematopoietic cells.
  • CDK6 the inhibition 30 of CDK6 leads to neutropenia, while breast cancer cells mainly depend on CDK4 for proliferation.
  • Abemaciclib exhibits weaker inhibition of CDK6 than CDK4, resulting in lower hematological toxicity.
  • CDK2 inhibitors are under clinical development in solid tumors including PF-07104091 (NCT04553133), BLU-222 (NCT05252416), INCB123667 - 2 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT NKT-24-003PCT (NCT05238922), INX-315 (NCT05735080), ARTS-021 (NCT05867251), AZD8421 (NCT06188520) and BG-68501 (NCT06257264).
  • PF-07104091 and BLU-222 have demonstrated single agent activities in CDK4/6 inhibitor refractory breast cancer patients
  • PF-07220060 (NCT04557449)
  • NCT04557449 in combination with endocrine 5 therapy, has demonstrated clinical responses and lower neutropenia adverse events in CDK4/6 inhibitor refractory breast cancer patients.
  • a molecule blocking both CDK2 and CDK4 as single agent or in combination with endocrine therapy may address the primary and acquired resistance to CDK4/6 inhibitors, leading to enhanced antitumor activities and reduced adverse effects to achieve greater therapeutic efficacy in HR+ HER2- breast cancer.
  • a small molecule inhibitor or a proteolysis-targeting chimeric molecule that specifically targets CDK4 and/or CDK2 could represent a therapeutic opportunity with reduced toxicity and improved overall therapeutic efficacy.
  • PROTACs are bifunctional molecules comprised of target protein-recruitment moiety and a ligand for E3 ligase, connected by a biocompatible linker.
  • PROTACs bring the protein of 15 interest and the E3 ligase into close proximity and induce ubiquitination and subsequent degradation of the target protein by proteasome.
  • PROTACs display several unique and attractive features that make them desirable drug candidates. For example, PROTACs have been shown to be more selective than their 20 inhibitor counterparts, potentially reducing off-target toxicity.
  • PROTACs can perform multiple rounds of target ubiquitination and degradation. Due to this catalytic mode of action, PROTACs can function at sub-stoichiometric receptor occupancies.
  • the E3 ligases used in PROTACs mainly include cereblon (CRBN), Von Hippel–Lindau-containing complex (VHL), inhibitor of apoptosis protein (IAP), and mouse double minute 2 (MDM2). 25 Therefore, PROTACs that could recruit CDK2 and/or CDK4 to a ubiquitin ligase, and thereby causing ubiquitylation and proteasomal degradation of CDK2 and/or CDK4 are desirable.
  • the present disclosure fulfills this and related needs. Summary 30 In a first aspect, provided is a compound of Formula (I): 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT (I) wherein R 1 is alkyl, cycloalkyl, cycloalkylalkyl, bridged cycloalkyl, cycloalkoxy, heterocyclyl, alkoxy, aryl, arylalkyl, arylalkoxy, heteroaryl, halo, cyano, haloalkyl, haloalkoxy, hydroxy, 5 hydroxyalkyl, alkoxyalkyl, amino, alkylamino, or dialkylamino, where each of the aforementioned rings, by itself or as part of another group, is substituted with one or two substitutions independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano; R 2 is hydrogen or deuterium; and 10 Hy is cycloalkylene, arylene, heteroarylene, heterocyclylene, bicyclic heterocyclylene, spiro heterocyclylene, bridged heterocycl
  • NKT-24-003PCT (d) a group of formula (iv): ( 5 ( 10 w Y a is CH or N; Z a is a bond, -CH 2 -, -NH-, -O-, or -NHC(O)- where NH of -NHC(O)- is attached to Y a ; - 5 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • Z 2 is a bond, alkylene, alkynylene, -C(O)-, -C(O)N(R)-, -NR’(CO)-, -(O-alkylene)b-, -(alkylene-O) b -, -O(CH 2 ) 7 -, -O(CH 2 ) 8 -, cycloalkylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R j and R k independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, 5 haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;
  • Z 3 is a bond, alkylene, alkenylene, alkynylene, heteroalkylene, -C(O)NR-, -NR’
  • a method of treating a disease mediated by CDK2 and/or CDK4 in a patient in one embodiment the patient is in need of such treatment, which method comprises administering to the patient, in one embodiment a patient in need of such treatment, a 5 therapeutically effective amount of a compound of Formula (I) or (IB) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof.
  • the disease is cancer.
  • the cancers are those that are resistant to CDK4/6 20 inhibitors through CDK2-mediated mechanisms e.g., breast cancer.
  • the disease is an autoimmune disease, or a condition associated with an autoimmune disease, which method comprises administering to the patient, in one embodiment a patient in need of such treatment, a therapeutically effective amount of a compound of any one of first and second aspects (or any of the embodiments thereof described herein), or a pharmaceutically 25 acceptable salt thereof.
  • the autoimmune disease or condition associated with an autoimmune disease is selected from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (pSS), multiple sclerosis (MS), Crohn’s disease (CD), uveitis, pemphigus vulgaris, and sepsis.
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • pSS primary Sjogren’s syndrome
  • MS multiple sclerosis
  • Crohn’s disease CD
  • uveitis pemphigus vulgaris
  • sepsis sepsis
  • the disease is gout.
  • the therapeutically effective amount 30 of a compound of Formulas (I) and (IB) (or any embodiment thereof disclosed herein including specific compounds), or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition.
  • a method of treating noise-induced, chemotherapy-induced (cisplatin-induced), antibiotic-induced, or age-related hearing loss comprises - 9 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT administering to a patient, in one embodiment a patient in need of such treatment, a therapeutically effective amount of a compound of any one of first and second aspects, (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof.
  • the amount of hearing loss is reduced when compared to an 5 age-matched control.
  • the hearing loss is prevented when compared to an age-matched control.
  • a pharmaceutical composition comprising a compound of Formula (I) or (IB) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.
  • a compound of (I) or (IB) or any of the embodiments thereof described herein, or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the compound of Formula (I) or (IB) (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof is useful for the treatment of one or more diseases disclosed in the third and fourth aspects above.
  • a compound of Formula (I) or (IB) or any of the embodiments thereof described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease in a patient in which the activity of CDK2 and/or CDK4 contributes to the pathology and/or symptoms of the disease.
  • the disease is one or more diseases disclosed in the third or fourth aspect 20 above.
  • a method of degrading CDK2 and/or CDK4 in a cell via ubiquitin proteasome pathway which method comprises contacting the cell with a compound of Formula (I) or (IB) (or embodiments thereof as disclosed herein, including specific compounds).
  • CDK2 and/or CDK4 are degraded in vitro. In another 25 embodiment of the eighth aspect, CDK2 and/or CDK4 are degraded in vivo. In another embodiment of the eighth aspect, CDK2 and/or CDK4 are degraded in a cell in a patient. In an embodiment of any one of the above aspects, CDK2 is selectively degraded over CDK1 by a compound of Formula (I) or (IB). In another embodiment of any one of above aspects, CDK2 is selectively degraded over CDK1 and CDK4; or CDK4 is selectively degraded over 30 CDK1 and CDK2 by a compound of Formula (I) or (IB).
  • both CDK2 and CDK4 are degraded by a compound of Formula (I) or (IB), including CDK2 and CDK4 are selectively degraded over CDK1.
  • the ability of compounds of Formula (I) and (IB) to degrade CDK2 and CDK4 selectively over CDK1 was measured by determining potency of the compounds in inhibiting retinoblastoma - 10 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • the compounds of Formula (I) and (IB) degrade 5 both CDK2 and CDK4, they can, however, cause degradation of CDK2 to a greater extent than CDK4 or visa-versa.
  • the degree of degradation of CDK2 and CDK4 can be determined by determining the ratio of Rb IC50 from OVCAR3 and T47D.
  • selectively degrade as used herein means the compound disclosed herein may cause degradation of one protein to a greater extent than the other.
  • further embodiments are provided comprising administering the compound of any one of first aspect, second aspect, third aspect, and Formula (IB), or a pharmaceutically acceptable salt thereof (or any embodiments thereof disclosed herein) or the pharmaceutical composition of the seventh aspect, in combination with at least one additional anticancer agent.
  • the agents can be 15 administered simultaneously or sequentially.
  • Alkyl means a linear or branched saturated monovalent hydrocarbon radical of one to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like.
  • Alkylene means a linear or branched saturated divalent hydrocarbon radical of one to six carbon atoms unless otherwise stated.
  • alkylene When alkylene contains three to six carbon atoms it is also 25 referred to herein as C3 to C6 alkylene, Examples include, but are not limited to, methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
  • Alkenylene means a linear or branched unsaturated divalent hydrocarbon radical of two to six carbon atoms containing a double bond, e.g., ethen-diyl, propen-diyl, 2-propen-diyl, buten- diyl, penten-diyl, and the like.
  • Alkynylene means a linear or branched unsaturated divalent hydrocarbon radical of two t o eight carbon atoms containing a triple bond, e.g., , , and the like.
  • Alkoxy means a -OR z radical where R z is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.
  • - 11 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • Alkoxyalkyl means alkyl as defined above that is substituted with alkoxy as defined above e.g., methoxymethyl, methoxyethyl, ethoxyethyl, and the like.
  • Alkoxycarbonyl and alkyloxycarbonyl mean a –C(O)OR z radical where R z is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.
  • Alkylcarbonylamino means a –NR z ’C(O)R z radical where R z is alkyl and R z ’ is H or alkyl, as defined above, e.g., methylcarbonylamino, ethylcarbonylamino, and the like.
  • “Acyl” means a –C(O)R z radical where R z is alkyl, haloalkyl, cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, as defined herein, e.g., methylcarbonyl, ethylcarbonyl, benzoyl, trifluoromethylcarbonyl, 10 cyclopropylcarbonyl, and the like.
  • Alkylaminocarbonyl means -C(O)NHR z radical where R z is alkyl as defined above e.g., methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and the like.
  • Dialkylaminocarbonyl means -C(O)NR z1 R z radical where R z and R z1 are independently alkyl as defined above e.g., dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, and the like.
  • Alkylamino means -NHR z radical where R z is alkyl as defined above e.g., methylamino, ethylamino, propylamino, and the like.
  • R z is alkyl as defined above e.g., methylamino, ethylamino, propylamino, and the like.
  • Alkylsulfonyl means -S(O)2R z where R z is alkyl as defined above e.g., methylsulfonyl, ethylsulfonyl, and the like.
  • Alkylamino means -NHR z radical where R z is alkyl as defined above e.g., methylamino, ethylamino, propylamino, and the like.
  • Aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 30 10 ring atoms e.g., phenyl or naphthyl.
  • Arylene means a divalent aryl (as defined above) radical e.g., phenylene or naphthylene.
  • Aralkyl means an –(alkylene)-R z radical where R z is aryl as defined above e.g. benzyl.
  • Arylalkoxy means an -OR z radical where R z is arylalkyl as defined above. - 12 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • Bicyclic heterocyclylene means a saturated or unsaturated, divalent fused bicyclic group of 8 to 12 ring atoms in which one, two, or three ring atoms are heteroatoms independently selected from N, O, and S(O)n, where n is an integer selected from 0 to 2, the remaining ring atoms being carbon, unless stated otherwise. Additionally, one or two ring 5 carbon atoms of the bicyclic heterocyclylene ring can optionally be replaced by a –CO- group.
  • bicyclic heterocyclylene includes, but is not limited to, isoindolin- diyl, decahydro-2,6-naphthyridin-diyl, octahydrocyclopenta[c]pyrrol-diyl, octahydro-1H- pyrrolo[3,4-c]pyridin-diyl, hexahydrofuro[3,2-b]furan-3,6-diyl, and the like.
  • the heterocyclylene ring is unsaturated it can contain one or two ring double bonds provided that the 10 ring is not aromatic.
  • “Bridged cycloalkyl” means a saturated monovalent bicyclic ring having 5 to 8 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CR z R z ’) n group where n is an integer selected from 1 to 3 and R z and R z ’ are independently H or methyl (also may be referred to herein as “bridging” group). Examples include, but are not limited to, bicyclo[1.1.1]pent-1-yl, 15 bicyclo[2.2.1]heptyl, (in one embodiment bicyclo[2.2.1]hept-2-yl), and the like.
  • Bridged cycloalkylene means a saturated divalent bicyclic ring having 5 to 8 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CR z R z ’)n group where n is an integer selected from 1 to 3 and R z and R z ’ are independently H or methyl (also may be referred to herein as “bridging” group).
  • Bridged cycloalkyl is optionally substituted with one or two 20 substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano unless stated otherwise.
  • Examples include, but are not limited to, bicyclo[2.2.1]heptylene (in one embodiment bicyclo[2.2.1]hept-2,5-ylene).
  • “Bridged heterocyclyl” means a saturated monovalent bicyclic ring having 5 to 9 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CR p R p ’) n group where n 25 is an integer selected from 1 to 3 and R p and R p ’ are independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring carbon atoms, including an atom in the bridging group, is replaced by a heteroatom selected from N, NH, O, and S(O) n , where n is an integer selected from 0 to 2.
  • Bridged heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano 30 unless stated otherwise.
  • Examples include, but are not limited to, 3,8-diazabicyclo[3.2.1]octanyl, 7-oxabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo-[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 6-azabicyclo[3.1.1]heptanyl, 8-azabicyclo[3.2.1]octanyl, and the like.
  • “Bridged heterocyclylene” means a saturated divalent bicyclic ring having 5 to 9 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CR z R z ’) n group where n is an integer selected from 1 to 3 and R z and R z ’ are independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring carbon atoms, 5 including an atom in the bridging group, is replaced by a heteroatom selected from N, O, and S(O) n , where n is an integer selected from 0 to 2.
  • Bridged heterocyclylene is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano unless stated otherwise.
  • Examples include, but are not limited to, 3,8-diazabicyclo[3.2.1]octa-3,8- diyl, 7-oxabicyclo[2.2.1]heptan-diyl, 2,5-diazabicyclo[2.2.1]heptan-diyl, 3,6-diazabicyclo- 10 [3.1.1]heptan-diyl, 2,5-diazabicyclo[2.2.2]octan-diyl, 3,8-diazabicyclo[3.2.1]octan-diyl, 6-azabicyclo[3.1.1]heptan-diyl, 8-azabicyclo[3.2.1]octan-diyl, and the like.
  • Cycloalkyl means a monocyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. 15 “Cycloalkylalkyl” means an -(alkylene)-R z radical where R z is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
  • Cycloalkyloxy and “cycloalkoxy” mean a -OR z radical where R z is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, 20 cyclohexyloxy, and the like.
  • Cycloalkylene means a divalent saturated cyclic hydrocarbon radical of three to six carbon atoms, unless stated otherwise e.g., 1,1-cyclopropylene, 1,1-cyclobutylene, 1,4- cyclohexylene, and the like.
  • Carbonyl means -C(O)-. 25
  • Carboxy means –COOH.
  • Cyclylaminylene means a saturated divalent monocyclic ring of 4 to 8 ring atoms in which one or two ring atoms are nitrogen, the remaining ring atoms being carbon. More specifically, the term cyclylaminyl includes, but is not limited to, pyrrolidinylene, piperidinylene, homopiperidinylene, piperazinylene, and the like. 30 “Cyanoalkyl” means alkyl as defined above that is substituted with a cyano e.g., cyanomethyl, cyanoethyl, and the like.
  • Cyanoalkoxy and “cyanoalkyloxy” mean an -OR z radical where R z is cyanoalkyl as defined above. Examples include, but are not limited to, cyanomethoxy, cyanoethoxy, and the like. - 14 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT “Deuterium” means refers to 2 H or D.
  • Dialkylamino means a -NR z R z radical where each R z is independently alkyl as defined above, e.g., dimethylamino, methylethylamino, n-propylmethylamino, 2-propylmethylamino, n-, iso-, or tert-butylmethylamino, and the like.
  • R z is independently alkyl as defined above, e.g., dimethylamino, methylethylamino, n-propylmethylamino, 2-propylmethylamino, n-, iso-, or tert-butylmethylamino, and the like.
  • 5 “Ether” means an -O- group.
  • “Fused heterocyclylene” means a divalent bicyclic ring in which two adjacent ring atoms of a saturated or partially unsaturated (but not aromatic) monocyclic ring of 4 to 7 ring atoms having one or two heteroatoms independently selected from N, O, and S(O)n (where n is 0, 1, or 2) and the remaining ring atoms being carbon, are fused to two adjacent ring members of a phenyl, 10 or a five or six membered heteroaryl, each as defined herein, unless stated otherwise.
  • the nitrogen atom is optionally oxidized or quaternized.
  • the fused heterocyclylene can be attached at any two atoms of the ring.
  • Representative examples include, but are not limited to, 1,2,3,4- tetrahydroquinolin-1,4-diyl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-5,8-diyl, 3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-diyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-diyl, and the like.
  • “Halo” means fluoro, chloro, bromo, or iodo, in one embodiment fluoro or chloro.
  • Haloalkyl means alkyl radical as defined above, which is 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, e.g., -CH 2 Cl, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -CF(CH3)2, and the like.
  • halogen atoms e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH 2 Cl, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -CF(CH3)2, and the like.
  • fluoroalkyl When the alkyl is substituted with only fluoro, it can be referred to in this 20 Application as fluoroalkyl
  • Haloalkoxy means a –OR z radical where R z is haloalkyl as defined above e.g., -OCF3, -OCHF 2 , and the like. When R z is haloalkyl where the alkyl is substituted with only fluoro (in some examples, one or more fluoro), it is referred to in this Application as fluoroalkoxy.
  • “Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon 25 atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present, they are not both present on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2- 30 hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl (in one embodiment 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2- hydroxyethyl).
  • Heteroalkylene means is a linear or branched saturated divalent hydrocarbon radical of (a) two to six carbon atoms where one carbon atom of the linear portion of the divalent - 15 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT hydrocarbon radical is replaced by X a where X a is -O-, -S-, -SO-, -SO2-, -CO-, or -NR q1 - or (b) three to six carbon atoms where two adjacent carbon atoms of the linear portion of the divalent hydrocarbon radical are replaced by X a1 where X a1 is -NR q1 CO-, -CONR q1 -, -NR q1 SO-, -SONR q1 -, -NR q1 SO 2 -, or -SO 2 NR q1 - (where each R q1 is hydrogen, alkyl, alkylcarbonyl, or alkylsulfonyl) and 5 furthermore wherein, when the linear portion of the hydrocarbon radical of (a) has 3 to 6 carbon atoms and the hydrocarbon radical of (b) has 4 to 6 carbon atoms, then an additional carbon atom in the linear portion of the hydrocarbon
  • the linear portion of 10 the heteroalkylene means the consecutive atoms of the heteroalkylene connecting Z 2 and Z 4 when Z 3 is heteroalkylene and Z 3 and Z 5 when Z 4 is heteroalkylene; e.g., in the structure , the atoms with * form the linear portion of C5 heteroalkylene.
  • heteroalkylene When the h ins only one or two -O-, it can be referred to herein as “oxoalkylene.” When the heteroalkylene contains only one or two -NR q – and/or -NR q1 -, it can be referred to herein as 15 “aminylalkylene.” When the heteroalkylene contains only -S-, it can be referred to herein as “sulfanylalkylene.” When the heteroalkylene contains only -SO-, it can be referred to herein as “sulfinylalkylene.” When the heteroalkylene contains only -SO 2 -, it can be referred to herein as “sulfonylalkylene.” Representative examples, of heteroalkylene include, e.g., 20 a “Heteroaryl” means a monovalent monocyclic or fused bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one embodiment, one,
  • NKT-24-003PCT carbon Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, indazolyl, imidazo[1,2-a]pyridinyl, imidazo[1,2- a]pyrazinyl, oxazolyl, isoxazolyl, oxadiazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.
  • heteroaryl and “aryl” are mutually exclusive.
  • the heteroaryl ring contains 5- or 6 ring atoms and is a monocyclic ring, it is also referred to herein as 5-or 6-membered monocyclic heteroaryl or monocyclic heteroarylene.
  • the heteroaryl ring contains 9- or 10 ring atoms and is a fused bicyclic ring, it is also referred to herein as 9-or 10-membered fused bicyclic heteroaryl.
  • 10 “Heteroarylene” means a divalent heteroaryl radical as defined above, unless stated otherwise.
  • heteroarylene ring contains 5- or 6 ring atoms and is a monocyclic ring, it is also referred to herein as monocyclic heteroarylene or as 5- or 6-membered monocyclic heteroarylene e.g., pyrazolyl-1.4-diyl.
  • heteroarylene ring 15 contains 9- or 10 ring atoms and is a fused bicyclic ring, it is also referred to herein as 9-or 10-membered fused bicyclic heteroarylene.
  • Heteroarylalkyl and “heteroaralkyl” mean an –(alkylene)-R z radical where R z is heteroaryl as defined above.
  • Heterocyclyl means a saturated, monovalent, monocyclic group of 4 to 8 ring atoms in 20 which one or two ring atoms are heteroatom independently selected from N, O, and S(O) n , where n is an integer selected from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a –CO- group.
  • heterocyclyl includes, but is not limited to, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, 25 morpholinyl, piperazinyl, tetrahydro-furanyl, tetrahydro-pyranyl, thiomorpholinyl, and the like.
  • the heterocyclyl ring is unsaturated, it can contain one or two ring double bonds provided that the ring is not aromatic.
  • the heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocycloamino and is a subset of the heterocyclyl group.
  • Heterocyclylcarbonyl means a -C(O)R radical where R is heterocyclyl as defined herein. 30 More specifically, the term heterocyclyl includes, but is not limited to, piperidinylcarbonyl, piperazinylcarbonyl, pyrrolidinylcarbonyl, azetidinylcarbonyl, and the like. “Heterocyclyloxy” means an –OR z radical where R z is heterocyclyl as defined above e.g. 1-methylpyrrolidin-3-oxy, 1-methylpyrrolidin-2-oxy, piperidin-3-oxy, piperidin-4-oxy and the like.
  • Heterocyclylene means a saturated or unsaturated, divalent, monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S(O)n, where n is an integer selected from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclylene ring can optionally 5 be replaced by a –CO- group.
  • heterocyclylene includes, but is not limited to, , piperidin-1,4-diyl, azetidin-1,3-diyl, and the like.
  • the Linker ‘L’ ” is a connector with a linear non-hydrogen atom number in the range of 1 to 20 (preferably, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; more preferably, 8 to 16, 9 to 14, 9 to 13, 9 to 12; more preferably 8, 9, 10, 11, 12, or 13; most 10 preferably, 12 or 13).
  • Linker “L” can contain one or more (preferably 2, 3, 4, 5, 6, 7, or 8; more preferably, 3 to 6 or 3, 4, 5, or 6; most preferably, 4 or 5), groups which are independently selected, such as, but not limited to, ether, polyether, thioether, -NH-, -N(alkyl)-, amido, sulfonamido, alkylene, alkenylene, alkynylene, carbonyl, -C(O)O-, -OC(O)-, sulfinyl, sulfonyl, ureido, thioureido, cycloalkylene, bridged cycloalkylene, spiro cycloalkylene, arylene, 15 heteroarylene, heterocyclylene, bridged heterocycylene, spiro heterocyclylene, bicyclic heterocyclylene, or fused heterocyclylene, and wherein cycloalkylene, bridged cycloalkylene
  • Linker L contains 3 to 5 groups independently selected from -O-, -NH-, -N(CH3)-, sulfonyl, phenylene, alkylene (in one embodiment -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH2CH(CH3)CH2-, -CH(CH3)CH2-, -CH(CH3)-, -CH2C(CH3)2CH2-, heterocyclylene (in one 25 embodiment azetidin-diyl, piperidin-diyl, or piperazin-diyl), spiro heterocyclylene (in one embodiment 2,6-diazaspiro[3.3]heptan-diyl), and monocyclic heteroarylene (in one embodiment imidazolyl or pyridinyl; in another embodiment imidazolyl), wherein heterocyclylene, spiro heterocyclylene, and monocyclic heteroarylene are optionally
  • Phenylene means divalent phenyl. - 18 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT
  • Polyether means a group where d is an integer selected from 2 to 5 and R z is C2-6alkylene.
  • the phrase “optionally” or “optional” as used herein means that the subsequently 5 described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • alkylene optionally substituted with halo is intended to cover alkylene that is unsubstituted and alkyene that is substituted with halo.
  • “Spiro cycloalkylene” means a saturated bicyclic divalent hydrocarbon ring having 6 to 12 10 ring atoms wherein the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon (“spiro carbon”). Spiro cycloalkylene is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano, unless stated otherwise.
  • “Spiro heterocyclylene” means a saturated bicyclic divalent ring having 6 to 10 ring atoms in which one, two, or three ring atoms are heteroatom selected from N, O, and S(O) n , where n is an integer selected from 0 to 2, the remaining ring atoms being C and the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon (“spiro carbon”).
  • Spiro heterocyclylene is optionally substituted with one or two 20 substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano, unless stated otherwise.
  • Representative examples include, but are not limited to, 2-azaspiro[3.3]heptan-diyl, 2,6-diazaspiro[3.3]heptan-diyl, 1,7-diazaspiro[3.5]nonan-diyl, 2,7-diazaspiro[3.5]nonan-diyl, 3,9-diazaspiro[5.5]undecan-diyl, and the like.
  • Representative examples include, but are not limited to, diazaspiro[5.5]undecan-diyl, 1-oxa-diazaspiro[5.5]undecan-diyl, and the like.
  • “Sulfinyl” means an -S(O)- group.
  • “Sulfonyl” means an -S(O)2- group. - 19 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT
  • “Substituted sulfonyl” means an -S(O)2R z where R z is alkyl as defined above e.g., methyl or ethylsulfonyl.
  • Substituted sulfonyl is also referred to herein as alkylsulfonyl.
  • Thioether means an -S- group.
  • Thioureido means an -NHC(S)NH- group.
  • 5 “Ureido” means an -NHC(O)NH- group.
  • Unsaturated heterocyclylene means divalent, monocyclic nonaromatic group of 5 to 8 ring atoms having one, two, or three double bonds and in which one or two ring atoms are heteroatom(s) independently selected from N, O, and S(O) n , where n is an integer selected from 0 to 2, the remaining ring atoms being C, unless stated otherwise.
  • the present disclosure also includes protected derivatives of compounds of first aspect, second aspect, or Formula (IB) (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof.
  • compounds of Formula (I) or (IB) contain groups such as hydroxy, carboxy, or any group containing a nitrogen atom(s)
  • these 15 groups can be protected with suitable protecting groups.
  • suitable protecting groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, 5 th Ed., John Wiley & Sons, Inc. (2014), the disclosure of which is incorporated herein by reference in its entirety.
  • the protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art. 20
  • the present disclosure also includes polymorphic forms and deuterated forms of the compound of first aspect, second aspect, or Formula (IB) (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof.
  • prodrug refers to a compound that is made more active in vivo. Certain compounds Formula (I) or (IB) (and any embodiment thereof disclosed herein including specific 25 compounds) may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003).
  • Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because, in 30 some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • a wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug”), but then is metabolically hydrolyzed - 20 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • Such 5 salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or 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 10 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-toluenesulf
  • the 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, PA, 1985, which is incorporated herein by reference in its entirety.
  • the compounds of Formula (I) (and any embodiment thereof disclosed herein including 25 specific compounds) may have asymmetric centers.
  • Compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) containing an asymmetrically substituted atom may be isolated in optically active or racemic forms.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products 30 followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. All chiral, diastereomeric, all mixtures of chiral or diastereomeric forms, and racemic forms are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically - 21 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT indicated.
  • cyclic groups such as aryl
  • it includes all the positional isomers albeit only a 10 few examples are set forth.
  • all hydrates of a compound of Formula (I) are within the scope of this disclosure.
  • the compounds of Formula (I) may also contain unnatural amounts of isotopes at one or more of the 15 atoms that constitute such compounds. Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100% of the atom in question. that differ only in the presence of one or more isotopically enriched atoms.
  • Exemplary isotopes that can be incorporated into compounds of the present disclosure include isotopes of 20 hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, 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, respectively.
  • Isotopically labeled compounds e.g., those labeled with 3 H and 14 C
  • Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with (or 25 isotopically enriched for) heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).
  • one or more hydrogen atoms are replaced by 2 H or 3 H, or one or more carbon atoms are replaced 30 by 13 C- or 14 C-enriched carbon.
  • Positron emitting isotopes such as 15 O, 13 N, 11 C, and 15 F are useful for 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 in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. - 22 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • the left bond of the divalent group is attached to the group which is to its left in the remainder of the molecule
  • the right bond of the divalent group is attached to the group which is to its right in the remainder of the molecule.
  • divalent groups 25 the bond on the l , g: - 23 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT an on the right side of (a), (b), and (c) (i.e., X 1 , X 2 , and X 3 ) is attached to Z 1 of L of the following structure: . 5 L i.e, -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -, the left side in L (i.e., Z 1 ) is attached to X 1 , X 2 , X 3 , or X 4 or point of attachment delineated in Degrons of formula (c), (d), (e), or (f) and Z 6 is attached to an atom of Hy.
  • a nd Degron is a group of formula (a), i.e., , the left bond in L (i.e., the -NH- 10 group) is attached to X 1 and the right han -SO2-) is attached to an atom of the Hy .
  • ease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its 15 parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • combination therapy means the administration of two or more therapeutic agents to treat a disease or disorder described in the present disclosure.
  • Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous 20 manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, - 24 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT separate capsules for each active ingredient.
  • administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein. 5
  • patient is generally synonymous with the term “subject” and includes all mammals including humans.
  • Treating” or “treatment” of a disease includes: 10 (1) preventing the disease, i.e., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., delaying, arresting, or reducing the development or severity of the disease or its clinical symptoms; or 15 (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • treating or treatment of a disease includes inhibiting the disease, i.e., delaying, arresting or reducing the development or severity of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • a “therapeutically effective amount” means the amount of a compound of the present 20 disclosure and/or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease, is sufficient to affect such treatment for 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.
  • a “condition associated with an autoimmune disease” means a condition that a patient 25 with an autoimmune disease is susceptible to, e.g., sepsis, or a condition that is caused by the autoimmune disease, e.g., uveitis.
  • the compounds of Formula (I) or (IB) can also inhibit CDK2 and/or CDK4.
  • a compound of Formula (I) or (IB) may independently decrease about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, of CDK2 and/or CDK4 activity, compared to their/its normal activity.
  • the CDK2 and/or CDK4 activity is reduced by at least 40% in the presence - 25 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • the inhibitory activity of a compound of Formula (I) or (IB) can be measure using Biological Example 1, by converting a compound of Formula ( (I) or (IB) to a 5 corresponding compound of Formula (I) or (IB) that cannot be degraded by the ubiquitin proteosome pathway e.g., by methylating the nitrogen atom group of ligase ligand (i) or (ii) present in the compound of Formula (I) or (IB).
  • degradation and “degrade,” or any variation of these terms in relation to CDK2, CDK4, and CDK1, means any measurable decrease in the concentration of CDK2, CDK4, and 10 CDK1, respectively, over time in a sample containing of Formula (I) or (IB).
  • CDK2 and CDK4 concentration there may be a decrease of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, in CDK2 and CDK4 concentration in a sample containing CDK2 or CDK4, respectively and a compound disclosed herein in the Summary, Embodiments, and Compound Table 1 disclosed herein as 15 compared to an equivalent sample comprising CDK2 or CDK4, in the absence of said compound.
  • the % degradation can be determined as described in Biological Example 2 below.
  • the decrease in the concentration of CDK2 is ⁇ 20%.
  • the decrease in the concentration of CDK2 is ⁇ 40%. In another embodiment, the decrease in the concentration of CDK2 is ⁇ 50%. In another embodiment, the decrease in the concentration of 20 CDK2 is ⁇ 60%. In another embodiment, the decrease in the concentration of CDK2 ⁇ 70%. In another embodiment, the decrease in the concentration of CDK2 is ⁇ 80%. In one embodiment, the decrease in the concentration of CDK4 is ⁇ 20%. In another embodiment, the decrease in the concentration of CDK4 is ⁇ 40%. In another embodiment, the decrease in the concentration of CDK4 is ⁇ 50%. In another embodiment, the decrease in the 25 concentration of CDK4 is ⁇ 60%. In another embodiment, the decrease in the concentration of CDK4 ⁇ 70%.
  • the decrease in the concentration of CDK4 is ⁇ 80%.
  • E3 ubiquitin ligase refers to a family of proteins that operate in conjunction with E1 ubiquitin-activating enzyme and E2 ubiquitin-conjugating enzyme, assist or directly catalyze the covalent ligation of ubiquitin to a lysine residue of a substrate protein.
  • E3 ubiquitin ligases 30 directly bind to substrate proteins and thus confer substrate specificity for the ubiquitination process.
  • Ubiquitination can serve as a versatile signal mark for substrate proteins, which are targeted to degradation by proteasome or other regulations ranging from translocation to - 26 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT transcription.
  • the cereblon (CRBN) and von Hippel-Lindau (VHL) proteins are substrate recognition subunits of two ubiquitously expressed and biologically important Cullin RING E3 ubiquitin ligase complexes. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1).
  • DDB1 DNA binding protein 1
  • CUL4A Cullin-4A
  • ROC1 regulator of cullins 1
  • VHL is part of 5 the E3 ligase complex VCB, which also consists of elongins B and C, Cul2 and Rbx1.
  • E3 ubiquitin ligase ligand means a small molecule ligand (i.e., having a molecular weight of below 2,000, 1,000, 500, or 200 Daltons), which is capable of binding to an E3 ubiquitin ligase or a subunit of E3 ligase, such as Cereblon, VHL, IAP, or MDM2.
  • A1 provided is a compound of Formula (I) or a pharmaceutically acceptable salt as described in the first aspect of the Summary.
  • R 1 is alkyl, cycloalkyl, cycloalkoxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, 15 hydroxyalkyl, alkoxyalkyl, amino, alkylamino, or dialkylamino.
  • the compound of embodiment A1, or a pharmaceutically acceptable salt thereof is wherein R 1 is alkyl or cycloalkyl.
  • the compound of embodiment A1 or A2, or a pharmaceutically acceptable salt thereof is wherein R 1 is alkyl. 20 A4.
  • the compound of embodiment A1 or A2, or a pharmaceutically acceptable salt thereof is wherein R 1 is cycloalkyl.
  • the compound of any one of embodiments A1, or a pharmaceutically acceptable salt thereof is wherein R 1 is halo, haloalkyl, or haloalkoxy.
  • A6 the compound of any one of embodiments A1 or A5, or a 25 pharmaceutically acceptable salt thereof, is wherein R 1 is haloalkyl.
  • A7 the compound of any one of embodiments A1 or A5, or a pharmaceutically acceptable salt thereof, is wherein R 1 is haloalkoxy.
  • the compound of any one of embodiments A1 or A5, or a pharmaceutically acceptable salt thereof is wherein R 1 is halo. 30 A9.
  • the compound of any one of embodiments A1, or a pharmaceutically acceptable salt thereof is wherein R 1 alkoxy.
  • the compound of any one of embodiments A1, or a pharmaceutically acceptable salt thereof is wherein R 1 is hydroxyalkyl. - 27 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A11.
  • the compound of any one of embodiments A1, or a pharmaceutically acceptable salt thereof is wherein R 1 is alkoxyalkyl. A12.
  • the compound of any one of embodiments A1, or a pharmaceutically acceptable salt thereof is wherein R 1 is amino, alkylamino, or dialkylamino 5 A13.
  • the compound of embodiment A1 or A12, or a pharmaceutically acceptable salt thereof is wherein R 1 is amino.
  • A14 the compound of embodiment A1 or A12, or a pharmaceutically acceptable salt thereof, is wherein R 1 is alkylamino.
  • A15 the compound of embodiment A1 or A12, or a 10 pharmaceutically acceptable salt thereof, is wherein R 1 is dialkylamino.
  • A16 the compound of any one of embodiments A1, or a pharmaceutically acceptable salt thereof
  • the compound of embodiment A1, or a pharmaceutically acceptable salt thereof is wherein R 1 is cycloalkoxy.
  • A17 the compound of any one of embodiments A1 to A16, or a pharmaceutically acceptable salt thereof, is wherein R 1 is methyl, ethyl, isopropyl, methoxy, 15 ethoxy, propoxy, cyclopropyl, cyclopentyl, cyclopropoxy, cyclopentyloxy, chloro, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, methyloxymethyl, methoxyethyl, methoxypropyl, amino, methylamino, ethylamino, or propylamino.
  • A18 the compound of any one of embodiments A1, A2, A4 to A8, 20 and A17, or a pharmaceutically acceptable salt thereof, is wherein R 1 is cyclopropyl, chloro, trifluoromethyl, or trifluoromethoxy.
  • A19 the compound of any one of embodiments A1, A5, A6, A17, and A18, or a pharmaceutically acceptable salt thereof, is wherein R 1 is trifluoromethyl.
  • the compound of any one of embodiments A1, A5, A7, A17, 25 and A18, or a pharmaceutically acceptable salt thereof, is wherein R 1 is trifluoromethoxy.
  • A21 the compound of any one of embodiments A1, A5, A7, A17, 25 and A18, or a pharmaceutically acceptable salt thereof, is wherein R 1 is trifluoromethoxy.
  • the compound of any one of embodiments A1, A5, A8, A17, and A18, or a pharmaceutically acceptable salt thereof is wherein R 1 is chloro.
  • the compound of any one of embodiments A1, A10, A11, and A17, or a pharmaceutically acceptable salt thereof is wherein R 1 is hydroxymethyl, 30 methyloxymethyl, methoxyethyl, or methoxypropyl.
  • R 2 is hydrogen.
  • the compound of any one of embodiments A1 to A22, or a pharmaceutically acceptable salt thereof is wherein one of R 2 is deuterium.
  • - 28 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A25.
  • the compound of any one of embodiments A1 to A24, or a pharmaceutically acceptable salt thereof is wherein Hy is heterocyclylene, arylene, spiro heterocyclylene, bridged heterocyclylene, or cycloalkylene, wherein each of the aforementioned rings is substituted with R a , R b , and R c where R a and R b are independently selected from 5 hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen.
  • Hy is heterocyclylene, arylene, spiro heterocyclylene, bridged heterocyclylene, or cycloalkylene, wherein each of the aforementioned rings is substituted with R a , R b , and R c where R a and R b are independently selected from 5 hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c
  • the compound of any one of embodiments A1 to A25, or a pharmaceutically acceptable salt thereof is wherein Hy is heterocyclylene substituted with R a , R b , and R c where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen. 10 A27.
  • the compound of any one of embodiments A1 to A26, or a pharmaceutically acceptable salt thereof is wherein the heterocyclylene of Hy is pyrrolidin-1,3- diyl or piperidin-1,4-diyl, where Hy is substituted with R a , R b , and R c where R a and R b are independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxy, R c is hydrogen, and L is attached to the nitrogen atom of the piperidin-1,4-diyl or pyrrolidin-1,3-diyl ring of Hy. 15 A28.
  • the compound of any one of embodiments A1 to A27, or a pharmaceutically acceptable salt thereof is wherein the heterocyclylene of Hy is: where the N atom of -diyl rings is attached to L.
  • the compound of any one of embodiments A1 to A28, or a 20 pharmaceutically acceptable salt thereof is wherein the heterocyclylene of Hy is: where the N atom of t ,4-diyl rings is attached to L.
  • A29a the compound of any one of embodiments A1 to A29, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylene of Hy is: 25 where the N atom of the piperidin-1, yl ring is attached to L.
  • the compound of any one of embodiments A1 to A25, or a pharmaceutically acceptable salt thereof, is wherein Hy is bridged heterocyclylene substituted with R a , R b , and R c independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano. 5 A31.
  • the compound of any one of embodiments A1 to A25, and A30, or a pharmaceutically acceptable salt thereof is wherein the bridged heterocyclylene of Hy is a ring of formula: and each ri , and L is attached to 10 the nitrogen atom of each ring.
  • the compound of embodiment A30 or A31, or a pharmaceutically acceptable salt thereof is wherein R a and R b are independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxy.
  • the compound of embodiment A30, A31, or A32, or a 15 pharmaceutically acceptable salt thereof is wherein R b is hydrogen.
  • the compound of any one of embodiments A1 to A25, or a pharmaceutically acceptable salt thereof is wherein Hy is cycloalkylene substituted with R a , R b , and R c where R a is deuterium, methyl, fluoro, methoxy, or hydroxy and R b and R c are hydrogen.
  • R a is deuterium, methyl, fluoro, methoxy, or hydroxy and R b and R c are hydrogen.
  • the compound of any one of embodiments A1 to A25, and 20 A34, or a pharmaceutically acceptable salt thereof is wherein the cycloalkylene of Hy is cyclohexylene.
  • A36 is
  • the compound of any one of embodiments A1 to A25, A34, and A35, or a pharmaceutically acceptable salt thereof is wherein the cycloalkylene of Hy is where denotes bond to NH and denotes bond of L. 25 A37.
  • the co und of any one of embodiments A1 to A25, or a pharmaceutically acceptable salt thereof is wherein Hy is arylene wherein the arylene is phenylene substituted with R a , R b , and R c where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen.
  • the compound of any one of embodiments A1 to A25, or a pharmaceutically acceptable salt thereof is wherein Hy is spiro heterocyclylene substituted (such as 2-azaspiro[3.3]heptan-2-yl) with R a , R b , and R c where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen. 5 A39.
  • the compound of any one of embodiments A1 to A25, and A37, or a pharmaceutically acceptable salt thereof is wherein the phenylene of Hy is 1,4- phenylene according to structure denotes bond to NH and denotes bond of L and where R b is hydrogen (i a R is methoxy).
  • the phenylene of Hy is 1,4- phenylene according to structure denotes bond to NH and denotes bond of L and where R b is hydrogen (i a R is methoxy).
  • the compound of any one of embodiments A1 to A24, or a 10 pharmaceutically acceptable salt thereof is wherein Hy is fused heterocyclylene substituted with R a , R b , and R c where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen.
  • R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen.
  • the compound of any one of embodiments A1 to A24, or a pharmaceutically acceptable salt thereof is wherein Hy is bicyclic heterocyclylene substituted 15 with R a , R b , and R c where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen.
  • R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen.
  • the compound of any one of embodiments A1 to A39b, or a pharmaceutically acceptable salt thereof is wherein the Degron is an E3 ubiquitin ligase ligand of formula (i) or (ii). 20 A40.
  • the compound of any one of embodiments A1 to A40A, or a pharmaceutically acceptable salt thereof is wherein the Degron is an E3 ubiquitin ligase ligand of formula (i): . 25 A41.
  • the compound of any one of embodiments A1 to A40, or a pharmaceutically acceptable salt thereof is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (a): - 31 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT . A42.
  • the ny one of embodiments A1 to A41, or a pharmaceutically acceptable salt thereof is wherein R 4 and R 5 are independently hydrogen or alkyl. 5 A43.
  • the compound of any one of embodiments A1 to A42, or a pharmaceutically acceptable salt thereof is wherein R 4 and R 5 are hydrogen.
  • 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 is methyl.
  • the compound of any one of embodiments A1 to A40, or a pharmaceutically acceptable salt thereof is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (b): 15 where M is -NR 6 -.
  • A47 the compound of any one of embodiments A1 to A40, and A46, or a pharmaceutically acceptable salt thereof, is wherein R 6 is hydrogen.
  • A48 the compound of any one of embodiments A1 to A40, and 20 A46, or a pharmaceutically acceptable salt thereof, wherein R 6 is alkyl. In one embodiment, R 6 is methyl.
  • the compound of any one of embodiments A1 to A48, or a pharmaceutically acceptable salt thereof is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is: - 32 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT .
  • ts A1 to and A49, or a pharmaceutically acceptable salt thereof is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is: 5 . A51.
  • ring A of the E3 ubiquitin ligase ligand of formula (i) is: - 33 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT .
  • the compound of any one of embodiments A1 to A51, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of 5 formula (i) is: i,e, R aa is hydrogen dd , and R are H. A52a.
  • the compound of any one of embodiments A1 to A41, A45, and A47 to A52, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 10 ubiquitin ligase ligand of formula (i) is: . A53.
  • the ny one of embodiments A1 to A41, A45, and A47 to A52, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: - 34 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT . A54.
  • th y one of embodiments A1 to A43 and A47 to A52, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: 5 .
  • th y one of embodiments A1 to A43 and A47 to A52, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: . 10 A56.
  • any one of embodiments A1 to A40, A42 to A46, and A48 to A52, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: .
  • the ny one of embodiments A1 to A40, A42 to 15 A46, and A48 to A52, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: . A58.
  • th ny one of embodiments A1 to A54, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently 20 selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy.
  • R aa , R bb , R cc , and/or R dd are hydrogen when they are not specifically drawn out in structures of formula (i) and (ii), respectively.
  • 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 are independently 5 selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and cyano. A60.
  • the compound of any one of embodiments A1 to A54, A58, and A59, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen, methyl, methoxy, ethoxy, fluoro, trifluoromethyl, difluoromethyl, and trifluoromethoxy. 10 A61.
  • the compound of any one of embodiments A1 to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen and methyl.
  • the compound of any one of embodiments A1 to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are 15 independently selected from hydrogen and methoxy.
  • R aa , R bb , R cc , and R dd are independently selected from hydrogen and fluoro.
  • the compound of any one of embodiments A1 to A54, and 20 A58 to A60, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen, trifluoromethyl, and difluoromethyl.
  • R aa , R bb , R cc , and R dd are independently selected from hydrogen and trifluoromethoxy.
  • the compound of any one of embodiments A1 to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen, fluoro, and trifluoromethyl.
  • R aa , R bb , R cc , and R dd are independently selected from hydrogen, fluoro, and trifluoromethyl.
  • the compound of any one of embodiments A1 to A40A, or a pharmaceutically acceptable salt thereof is wherein the Degron is an E3 ubiquitin ligase ligand of 30 formula (ii): - 36 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A68.
  • the compound of any one of embodiments A1 to A40A and A67, or a pharmaceutically acceptable salt thereof is wherein Y a is CH. A69.
  • the compound of any one of embodiments A1 to A40A, and A67, or a pharmaceutically acceptable salt thereof is wherein Y a is N. 5 A70.
  • the compound of any one of embodiments A1 to A40A, and A67 to A69, or a pharmaceutically acceptable salt thereof is wherein Z a is a bond, -NH-, -O-, or -NHC(O)-. A71.
  • the compound of any one of embodiments A1 to A40A, and A67 to A70, or a pharmaceutically acceptable salt thereof is wherein Z a is a bond, -NH-, 10 or -NHC(O)-.
  • A72 the compound of any one of embodiments A1 to A40A, and A67 to A71, or a pharmaceutically acceptable salt thereof, is wherein Z a is a bond.
  • A73 the compound of any one of embodiments A1 to A40A, and A67 to A71, or a pharmaceutically acceptable salt thereof, is wherein Z a is -NH-, or -NHC(O)-. 15 A74.
  • the compound of any one of embodiments A1 to A40A, and A67 to A74a, or a pharmaceutically acceptable salt thereof is wherein ring B is cyclylaminylene substituted with R ee and R ff . 25 A77.
  • the compound of any one of embodiments A1 to A40A, and A67 to A74a, or a pharmaceutically acceptable salt thereof is wherein ring B is 5- or 6-membered monocyclic heteroarylene or a 9- or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three nitrogen ring atoms and each ring is substituted with R ee and R ff . 30 A78.
  • the compound of any one of embodiments A1 to A40A, A67 to A74a, and A77, or a pharmaceutically acceptable salt thereof is wherein ring B is 5- or 6- membered monocyclic heteroarylene containing one or two nitrogen ring atoms substituted with R ee and R ff . - 37 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A79.
  • the compound of any one of embodiments A1 to A40A, A67 to A74a, and A77, or a pharmaceutically acceptable salt thereof is wherein ring B is a 9- or 10-membered fused bicyclic heteroarylene containing one to three nitrogen ring atoms (and not containing any additional heteroatoms) and substituted with R ee and R ff . 5 A80.
  • embo diments A1 to A40A, and 15 A67 to A81, or a pharmaceutically acceptable salt thereof is wherein the E3 ubiquitin ligase ligand of formula (ii) is: , , , - 38 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT w is cyclylaminylene.
  • R ee and R ff are hydrogen if they are not s out in the above structures of embodiment A82-1. 5 A82.
  • the compound of any one of embodiments A1 to A40A, and A67 to A82-1, or a pharmaceutically acceptable salt thereof is wherein the E3 ubiquitin ligase ligand of formula (ii) is: , , 10 , or w is cyclylaminylene and R ff is hydrogen when not drawn out in the above st - 39 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A82A.
  • the compound of any one of embodiments A1 to A40A, A67, A68, A70 to A72, A77, and A79 to A82, or a pharmaceutically acceptable salt thereof is wherein the E3 ubiquitin ligase ligand of formul .
  • the compou ents A1 to A40A, and 5 A67 to A82, or a pharmaceutically acceptable salt thereof is wherein the E3 ubiquitin ligase ligand of formula (ii) is: , 10 A83A.
  • the compound of any one of embodiments A1 to A40A, and A67, A69 to A72, A77, A79 to A82, and A83, or a pharmaceutically acceptable salt thereof is wherein the E3 ubiquitin ligase ligand of formul . 15 A84.
  • the compou iments A1 to A40A, and A67 to A83A, or a pharmaceutically acceptable salt thereof is wherein each R ee and R ff are independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, and haloalkoxy.
  • the compound of any one of embodiments A1 to A40A, and A67 to A83A, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and cyano.
  • R ee and R ff are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and cyano.
  • the compound of any one of embodiments A1 to A40A, and 5 A67 to A85, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, and cyano.
  • R ee and R ff are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, and cyano.
  • the compound of any one of embodiments A1 to A40A, and 10 A67 to A86, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently selected from hydrogen, methyl, ethyl, and isopropyl.
  • R ee and R ff are independently selected from hydrogen, methoxy. 15 A89.
  • the compound of any one of embodiments A1 to A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently selected from hydrogen, methyl, ethyl, isopropyl, chloro, and fluoro.
  • R ee and R ff are independently selected from hydrogen, methyl, ethyl, isopropyl, chloro, and fluoro.
  • the compound of any one of embodiments A1 to A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof is wherein one of R ee and R ff is 20 hydrogen or fluoro and the other of R ee and R ff is selected from hydrogen, trifluoromethyl, 2,2,2-trifluoroethyl, and difluoromethyl.
  • the compound of any one of embodiments A1 to A40A, 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. 25 A92.
  • the compound of any one of embodiments A1 to A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently selected from hydrogen, chloro, fluoro, and trifluoromethyl.
  • the compound of any one of embodiments A1 to A40A, and A67 to A92, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are hydrogen.
  • the compound of any one of embodiments A1 to A40A, A67 to A86, A89, and A92, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are chloro. - 41 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A95.
  • the compound of any one of embodiments A1 to A40A, A67 to A86, A89, and A92, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are fluoro.
  • the compound of any one of embodiments A1 to A40A, A67 5 to A86, and A90, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently trifluoromethyl or 2,2,2-trifluoroethyl.
  • the compound of any one of embodiments A1 to A39b, or a pharmaceutically acceptable salt thereof is wherein the Degron is an E3 ubiquitin ligase ligand of formula (iii), (iv), (v), or (vi). 10 A96b.
  • the compound of any one of embodiments A1 to A39b, and A96a, or a pharmaceutically acceptable salt thereof is wherein the Degron is an E3 ubiquitin ligase ligand of formula (iv) or (v).
  • A96c the compound of any one of embodiments A1 to A39b, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of formula (iv) or (v).
  • the compound of any one of embodiments A1 to A39b, A96a, and A96b, or a pharmaceutically acceptable salt thereof is wherein R y , R y1 , and R y2 are 15 1-fluorocycloprop-1-yl and W a is bond, S, or methylene.
  • the compound of any one of embodiments A1 to A39b and A96a to A96c, or a pharmaceutically acceptable salt thereof is wherein W a is S. 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 are each a bond. 20 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 each independently selected from alkylene. In a subembodiment of embodiment A98, X 1 , X 2 , X 3 , and X 4 are each methylene. A99.
  • the compound of any one of embodiments A1 to A96, or a 25 pharmaceutically acceptable salt thereof is wherein X 1 , X 2 , X 3 , and X 4 are each -O-.
  • 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 each independently selected from -(O-alkylene)-.
  • A101 is
  • the compound of any one of embodiments A1 to A96, or a 30 pharmaceutically acceptable salt thereof is wherein X 1 , X 2 , X 3 , and X 4 are each independently selected from -(alkylene-O)-.
  • 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 each independently selected from -(NR gg -alkylene)-. - 42 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT 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 each independently selected from -(alkylene-NR hh )-.
  • A104 the compound of any one of embodiments A1 to A96, or a 5 pharmaceutically acceptable salt thereof, is wherein X 1 , X 2 , X 3 , and X 4 are each .
  • the compound of any one of embodim A96, or a pharmaceutically acceptable salt thereof is wherein X 1 , X 2 , X 3 , and X 4 are each -NH-.
  • A106 is
  • 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 each independently hydrogen or alkyl.
  • R gg , R hh , R jj , and R kk are each independently hydrogen or alkyl.
  • the compound of any one of embodiments A1 to A110 is wherein at least two of -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 - are not a bond.
  • the 25 compound is wherein at least three of -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 - are not a bond.
  • the compound is wherein at least four of -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 - are not a bond.
  • the compound of any one of embodiments A1 to A110a, or a pharmaceutically acceptable salt thereof, is wherein Z 6 is -S(O)2-.
  • the compound of any one of embodiments A1 to A111, or a 30 pharmaceutically acceptable salt thereof is wherein Z 5 is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with R q and R r .
  • the compound of any one of embodiments A1 to A112, or a pharmaceutically acceptable salt thereof is wherein Z 5 is phenylene, monocyclic heteroarylene, or - 43 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT heterocycylene where each ring is substituted with R q and R r and one and only one of Z 1 and X 1 is a bond, one and only one of Z 1 and X 2 is a bond, one and only one of Z 1 and X 3 , and one and only one of Z 1 and X 4 is a bond (for sake of clarity, when X 1 , X 2 , X 3 , and X 4 are not a bond, then X 1 , X 2 , X 3 , and X 4 are as described in any one of embodiments A1 and A98 to A110). 5 A114.
  • the compound for use of any one of embodiments A1 to A96d and A111, or a pharmaceutically acceptable salt thereof is wherein: 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 is independe onally substituted with one or two fluoro (or X 1 , X 2 , X 3 , and X 4 are absent in ligands (iii) to (vi)); 10 Z 1 is a bond, alkylene, -(CO)NR-, -(O-alkylene)a-, -(alkylene-O)a-, phenylene, or heterocyclylene, where each ring is substituted with R h and R i ; Z 2 is a bond, alkylene, -(
  • the compound of any one of embodiments A1 to A96d, A97, and A111, or a pharmaceutically acceptable salt thereof is wherein: X 1 , X 2 , X 3 , X 4 , and Z 1 are each a bond; - 44 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT Z 2 is a bond, alkylene, cycloalkylene, or heterocyclylene, where each ring is substituted with R j and R k ;
  • Z 3 is a bond, alkylene, -C(O)NR-, -NR’(CO)-, -O-, -NR”-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, 5 fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R m and R n ;
  • Z 4 is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R o and R p ;
  • Z 5 is phenylene, monocyclic hetero
  • the compound of any one of embodiments A1 to A96d, A97, A111, and A115, or a pharmaceutically acceptable salt thereof is wherein: 15 X 1 , X 2 , X 3 , X 4 , Z 1 , and Z 2 are each a bond; Z 3 is cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R m and R n ; Z 4 is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, 20 heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R o and R p independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, hal
  • the compound of any one of embodiments A1 to A96d, A97, A111, A115, and A116, or a pharmaceutically acceptable salt thereof is wherein: X 1 , X 2 , X 3 , X 4 , Z 1 , and Z 2 are each a bond; 30 Z 3 is heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R m and R n independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; - 45 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref.
  • No. NKT-24-003PCT Z 4 is alkylene, -O-, cycloalkylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R o and R p independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; 5 Z 5 is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with R q and R r independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and Z 6 is -S(O) 2 -; and wherein alkylene in Z 4 is substituted with substituted with R s , R t , and R u .
  • the compound of any one of embodiments A1 to A96d, A97, A111, and A115 to A117, or a pharmaceutically acceptable salt thereof is wherein: X 1 , X 2 , X 3 , and X 4 , Z 1 , and Z 2 are each a bond; Z 3 is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R m and R n independently selected from hydrogen, deuterium, alkyl, alkoxy, 15 hydroxy, cyano, halo, haloalkyl, and haloalkoxy; Z 4 is alkylene, -O-, cycloalkylene, or heterocyclylene, where each ring is substituted with R o and R p independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, and hydroxy; Z 5 is
  • the compound of any one of embodiments A1 to A96d, A97, 25 A111, and A115 to A118, or a pharmaceutically acceptable salt thereof is wherein: X 1 , X 2 , X 3 , X 4 , Z 1 , and Z 2 are each a bond; Z 3 is heterocyclylene, bridged heterocyclylene or spiro heterocyclylene, where each ring is substituted with R m and R n independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; 30 Z 4 is alkylene, -O-, cycloalkylene, or heterocyclylene, where each ring is substituted with R o and R p independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, and hydroxy, (in one embodiment R
  • NKT-24-003PCT Z 5 is phenylene or monocyclic heteroarylene, each ring substituted with R q and R r independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and Z 6 is -S(O) 2 -; and 5 wherein alkylene in Z 4 is substituted with R s , R t , and R u . A120.
  • the compound of any one of embodiments A1 to A96d, A97, A111, and A115, or a pharmaceutically acceptable salt thereof is wherein: X 1 , X 2 , X 3 , X 4 , and Z 1 are each a bond; Z 2 is cycloalkylene or heterocyclylene, where each ring is substituted with R j and R k 10 independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; Z 3 is cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R m and R n independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy
  • the compound of any one of embodiments A1 to A96d, A97, A111, A115, and A120, or a pharmaceutically acceptable salt thereof is wherein: X 1 , X 2 , X 3 , X 4 , and Z 1 are each a bond; Z 2 is heterocyclylene substituted with R j and R k independently selected from hydrogen, 25 deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; Z 3 is heterocyclylene substituted with R m and R n independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; Z 4 is a bond, alkylene, or -O-; Z 5 is phenylene or monocyclic heteroarylene, each ring substituted with R q and R r 30 independently selected from hydrogen, deuterium, alkyl, alkoxy,
  • the compound of any one of embodiments A1 to A96d, A97, A111, and A112, or a pharmaceutically acceptable salt thereof is wherein: X 1 , X 2 , X 3 , X 4 , and Z 1 are each a bond; Z 2 is heterocyclylene substituted with R j and R k (in one embodiment R j and R k are 5 independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy); Z 3 is a bond, alkylene, or -O-; Z 4 is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R o and R p ( in one embodiment R o and R p are independently selected from hydrogen, de
  • the compound of any one of embodiments A1 to A117 and A122, or a pharmaceutically acceptable salt thereof is wherein Z 4 is heterocyclylene or spiro heterocyclylene, where each ring is substituted with R o and R p (in one embodiment R o and R p are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy).
  • R o and R p are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy.
  • the compound of any one of embodiments A1 to A96d, or a pharmaceutically acceptable salt thereof is wherein one and only one of X 1 and Z 1 , or one and only one of X 2 and Z 1 , or one and only one of X 3 and Z 1 , or one and only one of X 4 and Z 1 is a bond.
  • the compound of any one of embodiments A1 to A96d, or a 25 pharmaceutically acceptable salt thereof is wherein X 1 , X 2 , X 3 , X 4 , and Z 1 are each a bond.
  • the compound of any one of embodiments A1 to A96d, A124, and A125, or a pharmaceutically acceptable salt thereof is wherein Z 2 is heterocyclylene or bridged heterocyclylene, each ring substituted with R j and R k .
  • Z 2 is heterocyclylene or bridged heterocyclylene, each ring substituted with R j and R k .
  • the compound of any one of embodiments A1 to A96d, and A124 to A127, or a pharmaceutically acceptable salt thereof is wherein: Z 3 is alkylene, cycloalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene- - 48 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT (alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bicyclic heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, fused heterocyclylene, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene-, or -spiro heterocyclylene-(alkylene), where each ring, by itself or as part of 5 another group, is substituted with R m and R n ;
  • Z 4 is alkylene, -(alkylene-NR”)-, -(NR”-alkylene)-, -O-, -NR”-, -(O-alkylene) d -, -(alkylene-O)d-, cycloalkylene, -(
  • the compound of any one of embodiments A1 to A97, A111, 20 A112, A125, A127, and A128, or a pharmaceutically acceptable salt thereof is wherein: X 1 , X 2 , X 3 , X 4 , Z 1 , and Z 2 are each a bond; Z 3 is -heterocyclylene-(alkylene)-, where heterocyclylene is substituted with R m and R n and alkylene is substituted with R s , R t , and R u ; Z 4 is phenylene or monocyclic heteroarylene, where each ring is substituted with R o and 25 R p ; Z 5 is phenylene substituted with R q and R r ; and Z 6 is -S(O)2-.
  • the compound of any one of embodiments A1 to A112 and A124 to A128, or a pharmaceutically acceptable salt thereof is wherein: 30 Z 3 is alkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiro - 49 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref.
  • Z 4 is alkylene, -(alkylene-NR”)-, -(NR”-alkylene)-, -O-, -NR”-, -(O-alkylene)d-, -(alkylene-O) d -, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spiro 5 cyclolalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(al
  • the compound of any one of embodiments A1 to A111, A124 to A128, and A130, or a pharmaceutically acceptable salt thereof is wherein: Z 3 is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R m and R n ; Z 4 is alkylene, -O-, heterocyclylene, -(alkylene)-heterocyclylene-, -(alkylene)-bridged 20 heterocyclylene-, where each ring, by itself or as part of another group, is substituted with R o and R p ; Z 5 is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with R q and R r ; and Z 6 is -S(O) 2 ; and 25 and each alkylene in Z 4 , itself or as part of another group, is substituted with R s and R t .
  • the compound of any one of embodiments A1 to A96d and A111, or a pharmaceutically acceptable salt thereof is wherein: X 1 , X 2 , X 3 , X 4 , Z 1 , and Z 2 are each a bond; Z 3 is -O-, -NR ” - (where R ” is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic 30 heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R m and R n ; Z 4 is alkylene, alkenylene, alkynylene, heteroalkylene, where alkylene and heteroalkylene are substituted with R s , R t , and R u and alkenylene is substituted with R v ; - 50 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.0028
  • NKT-24-003PCT Z 5 is phenylene, monocyclic heteroarylene, heterocycylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R q and R r ; and Z 6 is -S(O)2.
  • the compound of any one of embodiments A1 to A96d, A111, and A132, or a pharmaceutically acceptable salt thereof is wherein: X 1 , X 2 , X 3 , X 4 , Z 1 , and Z 2 are each a bond; Z 3 is -O-, -NR ” - (where R ” is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro 20 heterocyclylene, where each ring is substituted with R m and R n ; Z 4 is alkynylene where alkynylene substituted with R w and R x ; Z 5 is phenylene, monocyclic heteroarylene, heterocycylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R q and R r ; and Z
  • the compound of any one of embodiments A1 to A97 and A111, or a pharmaceutically acceptable salt thereof is wherein: X 1 , X 2 , X 3 , X 4 , Z 1 , Z 2 and Z 5 are each a bond; Z 3 is -O-, -NR ” - (where R ” is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro 30 heterocyclylene, where each ring is substituted with R m and R n ; Z 4 is C3 to C6 alkylene substituted with R s , R t , and R u ; and Z 6 is -S(O) 2 .
  • the compound of any one of embodiments A1 to A113 and A115 to A134, or a pharmaceutically acceptable salt thereof is wherein -Z (i.e., Z 5 is phenylene where Z 4 and Z 6 are attached at meta position of the pheny bstituted with R q and R r independently selected from hydrogen, deuterium, alkyl, alkoxy, cyano, halo, 5 haloalkyl, and haloalkoxy.
  • -Z i.e., Z 5 is phenylene where Z 4 and Z 6 are attached at meta position of the pheny bstituted with R q and R r independently selected from hydrogen, deuterium, alkyl, alkoxy, cyano, halo, 5 haloalkyl, and haloalkoxy.
  • the compound of any one of embodiments A1 to A113, A115 to A134, and A135, or a pharmaceutically acceptable salt thereof is wherein -Z 5 - is substituted with R q and R r independently selected from hydrogen, deuterium, methyl, m no, fluoro, chloro, difluoromethyl, trifluoromethyl, difluoromethoxy, and 10 trifluoromethoxy.
  • R q and R r independently selected from hydrogen, deuterium, methyl, m no, fluoro, chloro, difluoromethyl, trifluoromethyl, difluoromethoxy, and 10 trifluoromethoxy.
  • R q and R r independently selected from hydrogen, deuterium, methyl, m no, fluoro, chloro, difluoromethyl, trifluoromethyl, difluoromethoxy, and 10 trifluoromethoxy.
  • a A113, 15 A115 to A128, and A130 to A134, or a pharmaceutically acceptable salt thereof, is wherein -Z 5 - is monocyclic heteroarylene (such as imidazol-1,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, or pyridin-3,5-diyl) substituted with R q and R r independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy.
  • R q and R r independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy.
  • the compound of any one of embodiments A1 to A113, 20 A115 to A128, A130 to A134, and A138, or a pharmaceutically acceptable salt thereof is wherein -Z 5 - is imidazol-2,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, or pyridin-3,5-diyl, each ring substituted with R q and R r independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy, and trifluoromethoxy. 25 A140.
  • the compound of any one of embodiments A1 to A113, A115 to A128, A130 to A134, A138, and A139, or a pharmaceutically acceptable salt thereof is wherein -Z 5 - is imidazol-2,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, or pyridin-3,5-diyl, each ring substituted with R q and R r independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy.
  • the compound of any one of embodiments A1 to A113, A115 to A118, A120, A123 to A128, and A130 to A134, or a pharmaceutically acceptable salt thereof is wherein -Z 5 - is heterocyclylene substituted with R q and R r independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 5 difluoromethoxy, and trifluoromethoxy.
  • R q and R r independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 5 difluoromethoxy, and trifluoromethoxy.
  • the compound of any one of embodiments A1 to A113, A115 to A118, A120, A123 to A128, A130 to A134, and A141, or a pharmaceutically acceptable salt thereof, is wherein -Z 5 - is azetidinyl, pyrrolidinyl, piperazinyl, or piperidinyl.
  • -Z 5 - is azetidinyl, pyrrolidinyl, piperazinyl, or piperidinyl.
  • the compound of any one of embodiments A1 to A142, or a 10 pharmaceutically acceptable salt thereof is wherein each alkylene of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 , by itself and when present, is methylene, ethylene, propylene, or butylene, each substituted with R s , R t , and R u .
  • each alkylene of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 by itself and when present, is methylene, ethylene, propylene, or butylene, each substituted with R s , R t , and R u .
  • the compound of any one of embodiments A1 to A134 and A135 to A143, or a pharmaceutically acceptable salt thereof is wherein each alkylene of Z 1 , Z 2 , 15 Z 3 , Z 4 , Z 5 , and Z 6 , by itself and when present, is methylene substituted with R s , R t , and R u .
  • each alkylene of Z 1 , Z 2 , 15 Z 3 , Z 4 , Z 5 , and Z 6 by itself and when present, is methylene substituted with R s , R t , and R u .
  • the compound of any one of embodiments A1 to A134 and A135 to A142, or a pharmaceutically acceptable salt thereof is wherein each alkylene of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 , by itself or as part of –(O-alkylene) a - in Z 1 , –(alkylene-O) a - in Z 1 , -(O- alkylene)b- in Z 2 , -(alkylene-O)b- in Z 2 , -(O-alkylene)c- in Z 3 , -(alkylene-O)c- in Z 3 , -(O- 20 alkylene) d - in Z 4 , and -(alkylene-O) d - in Z 4 , and -(alkylene-O)- in Z 6 , and when present, is ethylene or propylene; as part of –(alkylene-NR”)- and
  • the compound of any one of embodiments A1 to A134, 30 A135 to A142 and A145, or a pharmaceutically acceptable salt thereof is wherein each alkylene of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 , by itself or as part of -(O-alkylene)a- in Z 1 , -(alkylene-O)a- in Z 1 , -(O- alkylene) b - in Z 2 , -(alkylene-O) b - in Z 2 , -(O-alkylene) c - in Z 3 , -(alkylene-O) c - in Z 3 , -(O- alkylene) d - in Z 4 , and -(alkylene-O) d - in Z 4 , and -(alkylene-O)- in Z 6 , and when present, is ethylene; as part of -(alkylene
  • NKT-24-003PCT as part of -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, -(alkylene)-phenylene- , -phenylene-(alkylene)-, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene- (alkylene)-, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, -(alkylene)-spiro heterocyclylene-, 5 and -spiro heterocyclylene-(alkylene)- and when present, is methylene.
  • the compound of any one of embodiments A1 to A146, or a pharmaceutically acceptable salt thereof is wherein each R, R’ and R” of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 , when present, is independently hydrogen or methyl.
  • the compound of any one of embodiments A1 to A147, or a 10 pharmaceutically acceptable salt thereof is wherein each R, R’ and R” of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 , when present, is hydrogen.
  • the compound of any one of embodiments A1 to A149, or a pharmaceutically acceptable salt thereof is wherein each cycloalkylene of Z 2 , Z 3 , and Z 4 , by itself or as part of –(alkylene)-cycloalkylene- and -cycloalkylene-(alkylene)-, and when present, is independently selected from cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene.
  • each cycloalkylene of Z 2 , Z 3 , and Z 4 by itself or as part of –(alkylene)-cycloalkylene- and -cycloalkylene-(alkylene)-, and when present, is independently selected from cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene.
  • the compound of any one of embodiments A1 to A150, or a 20 pharmaceutically acceptable salt thereof is wherein each cycloalkylene of Z 2 , Z 3 , and Z 4 , by itself or as part of –(alkylene)-cycloalkylene and -cycloalkylene-(alkylene)-, and when present, is independently selected from 1,2-cyclopropylene, 1,3-cyclopentylene, 1,3-cyclohexylene, and 1,4-cyclohexylene.
  • each cycloalkylene of Z 2 , Z 3 , and Z 4 by itself or as part of –(alkylene)-cycloalkylene and -cycloalkylene-(alkylene)-, and when present, is independently selected from 1,2-cyclopropylene, 1,3-cyclopentylene, 1,3-cyclohexylene, and 1,4-cyclohexylene.
  • the compound of any one of embodiments A1 to A134a, 25 A138, and A143 to A151, or a pharmaceutically acceptable salt thereof is wherein heteroarylene is monocyclic heteroarylene and each monocyclic heteroarylene of Z 1 , Z 3 , Z 4 , and Z 5 , by itself or as part of -(alkylene)-monocyclic heteroarylene- and -monocyclic heteroarylene-(alkylene)-, and when present, is independently selected from imidazoldiyl, pyridindiyl and pyrimidindiyl.
  • heteroarylene is monocyclic heteroarylene and each monocyclic heteroarylene of Z 1 , Z 3 , Z 4 , and Z 5 , by itself or as part of -(alkylene)-monocyclic heteroarylene- and -monocyclic heteroarylene-(alkylene)-, and when present, is independently selected from imidazoldiyl, pyridindiyl and pyrimidindi
  • the compound of any one of embodiments A1 to A134a, 30 A138, and A143 to A152, or a pharmaceutically acceptable salt thereof is wherein heteroarylene is monocyclic heteroarylene and each monocyclic heteroarylene of Z 1 , Z 3 , Z 4 , and Z 5 , by itself or as part of -(alkylene)-monocyclic heteroarylene- and -monocyclic heteroarylene-(alkylene)-, and when present, is independently selected from imidazol-2,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, and pyridin-3,5-diyl.
  • the compound of any one of embodiments A1 to A134a and A143 to A153, or a pharmaceutically acceptable salt thereof, is wherein each phenylene of Z 1 , Z 3 , and Z 4 , by itself or as part of -(alkylene)-phenylene- and -phenylene-(alkylene)-, and when present, is independently selected from 1,3-phenylene and 1,4-phenylene. 5 A155.
  • the compound of any one of embodiments A1 to A141 and A143 to A154, or a pharmaceutically acceptable salt thereof is wherein each heterocyclylene, bridged heterocyclylene, and spiro heterocyclylene of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 , by itself or as part of -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, -(alkylene)-spiro heterocyclylene- and -spiro 10 heterocyclylene-(alkylene)-, respectively, and when present, are independently selected from: re ethyl, unless stated otherwise in any of the embodiments above.
  • the compound of any one of embodiments A1 to A141 and 15 A143 to A155, or a pharmaceutically acceptable salt thereof is wherein each heterocyclylene, bridged heterocyclylene, and spiro heterocyclylene, of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 , by itself or as part of -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, -(alkylene)-spiro heterocyclylene- and -spiro heterocyclylene-(alkylene)-, respectively, and when present, are independently selected from: - 55 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref.
  • the compound of any one of embodiments A1 to A141 and 5 A143 to A156, or a pharmaceutically acceptable salt thereof is wherein heterocyclylene of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 , by itself or as part of -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)- and when present, is selected from: nts A1 to A141 and 10 A143 to A157, or a pharmaceutically acceptable salt thereof, is wherein heterocyclylene of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 , by itself or as part of -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)- and when present, is A159.
  • I t A159 the compound of any one of embodiments A1 to A112, A115 to A121, A124 to A128, and A130 to A134, or a pharmaceutically acceptable salt thereof, is 15 wherein -Z 3 -Z 4 -Z 5 -Z 6 - is: - 56 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT , , , 5 ; lo, haloalkyl, haloalkoxy, alkoxy, and cyano(i.e., R r is hydrogen).
  • each R q and R m are independently selected from hydrogen, methyl, fluoro, chloro, cyano, methoxy, 10 difluoromethoxy, difluoromethyl, and trifluoromethyl.
  • A160 the compound of any one of embodiments A1 to A112, A115 to A121, A124 to A128, A130 to A134, and A159, or a pharmaceutically acceptable salt thereof, is wherein -Z 3 -Z 4 -Z 5 -Z 6 - is: - 57 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT or wh l, halo, 5 haloalkyl, haloalkoxy, alkoxy, hydroxy and cyano (i.e., Rr is hydrogen).
  • Rr is hydrogen
  • the compound of any one of embodiments A1 to A112, A115 to A121, A124 to A128, A130 to A134, A159, and A160, or a pharmaceutically acceptable salt thereof, is wherein -Z 3 -Z 4 -Z 5 -Z 6 - is: . 10 A162.
  • one of embodiments A1 to A112, A115 to A121, A124 to A128, A130 to A134, A159, and A160, or a pharmaceutically acceptable salt thereof, is wherein -Z 3 -Z 4 -Z 5 -Z 6 - is: .
  • A164 one of embodiments A1 to A112, 15 A115 to A121, A124 to A128, A130 to A134, A159, and A160, or a pharmaceutically acceptable salt thereof, is wherein -Z 3 -Z 4 -Z 5 -Z 6 - is: . A165.
  • one of embodiments A1 to A112, A115 to A121, A124 to A128, A130 to A134, A159, and A160, or a pharmaceutically acceptable 20 salt thereof, is wherein -Z 3 -Z 4 -Z 5 -Z 6 - is: - 58 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT . A166.
  • y one of embodiments A1 to A111, A115 to A120, A124 to A128, A130 to A134, A159, and A160, or a pharmaceutically acceptable salt thereof, is wherein -Z 3 -Z 4 -Z 5 -Z 6 - is: 5 . A167.
  • one of embodiments A1 to A111, A115 to A120, A124 to A128, A130 to A134, A159, A160, or a pharmaceutically acceptable salt thereof, is wherein -Z 3 -Z 4 -Z 5 -Z 6 - is: Z 4 SO 2 N . 10 A168A.
  • one of embodiments A1 to A112, 15 A115 to A136, and A159 to 168A, or a pharmaceutically acceptable salt thereof is wherein the p A128, A130, A131, A135 to A154, and A159 to A168, or a pharmaceutically acceptable salt thereof, is 20 wherein Z 4 is –(alkylene)-heterocyclylene-, where heterocyclylene is substituted with R o and R p . - 59 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A170.
  • the compound of any one of A1 to A114, A124 to A128, A130, A131, A135 to A154, and A159 to A169 or a pharmaceutically acceptable salt thereof is wherein Z 4 is –(CH2)-heterocyclylene- where heterocyclylene is substituted with R o and R p . A171.
  • the compound of any one of A1 to A114, A124 to A128, 5 A130, A131, A135 to A154, and A159 to A170, or a pharmaceutically acceptable salt thereof is wherein Z 4 is: A A112, A124 to A128, A130, A131, A135 to A137, and A143 to A171, or a pharmaceutically acceptable salt 10 thereof, is wherein -Z 3 -Z 4 -Z 5 -Z 6 - is: - 60 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT 7 to A112, A124 to A128, A130, A131, A135 to A137, and A143 to A172, or a pharmaceutically acceptable salt thereof, is wherein -Z 3 -Z 4 -Z 5 -Z 6 - is: 5 . 2, A124 to A127, A132, A133, and A135 to A168, or a pharmaceutically acceptable salt thereof, is wherein Z 4 is C3 to C6 alkenylene substituted with R v where R v is hydrogen. A175.
  • the compound of any one of embodiments A1 to A112, 10 A124 to A127, A132, A133, and A135 to A168, or a pharmaceutically acceptable salt thereof is wherein Z 4 is C3 to C6 alkenylene substituted with R v where R v is fluoro or cyano.
  • Z 4 is C3 to C6 alkenylene substituted with R v where R v is fluoro or cyano.
  • the compound of any one of embodiments A1 to A112, A115 to A121, A124 to A128, A130 to A133, A134a, and A135 to A168 (except for Z 4 in A143 and A144), or a pharmaceutically acceptable salt thereof, is wherein Z 4 is C3 to C6 alkylene 15 substituted with R s , R t , and R u where R s , R t , and R u are hydrogen.
  • Z 4 is C3 to C6 alkylene 15 substituted with R s , R t , and R u where R s , R t , and R u are hydrogen.
  • the compound of any one of embodiments A1 to A112, A115 to A121, A124 to A128, A130 to A133, A134a, and A135 to A148 is wherein Z 4 is C 3 to C 6 alkylene substituted with R s , R t , and R u where R s , R t , and R u are hydrogen or halo, provided at least one of 20 R g , R h , and R i is halo, in one embodiment the halo is fluoro.
  • - 61 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT A178 the compound of any one of embodiments A1 to A112, A115 to A121, A124 to A128, A130 to A133, A134a, and A135 to A148 (except for Z 4 in A143 and A144), or a pharmaceutically acceptable salt thereof, is wherein Z 4 is C3 to C6 alkylene substituted with R s , R t , and R u where R t is other than hydrogen and R u is hydrogen or when R t and 5 R u are attached to the same carbon or to adjacent carbon atoms of the linear portion of the C3 to C6 alkylene, R t and R u together with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene where the cycloalkylene and heterocyclylene formed by R t and R u are substituted with R 9 and R 10 .
  • the compound of embodiment A178, or a pharmaceutically10 acceptable salt thereof is wherein Z 4 is C 3 to C 6 alkylene substituted with R s , R t , and R u where R t is other than hydrogen and R u is hydrogen.
  • the compound of any one of embodiments A174 to A179, or a pharmaceutically acceptable salt thereof is wherein the C3 to C6 alkenylene and C3 to C6 alkylene of Z 4 are linear alkenylene and alkylene, respectively, and substituted as defined therein. 15 A181.
  • the compound of any one of embodiments A178 to A181, or a pharmaceutically acceptable salt thereof is wherein the linear C3 to C6 alkylene of Z 4 is -CH 2 CH(R t )CH 2 - where R t is other than hydrogen.
  • the compound of any one of embodiments A178 to A182, or a pharmaceutically acceptable salt thereof is wherein R s of linear C 3 to C 6 alkylene of Z 4 is as 25 defined therein and R t of linear C3 to C6 alkylene of Z 4 is halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, or bridged heterocyclyl, each ring substituted as defined therein unless stated otherwise.
  • R s of linear C 3 to C 6 alkylene of Z 4 is as 25 defined therein and R t of linear C3 to C6 alkylene of Z 4 is halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, amino
  • the compound of any one of embodiments A178 to A183, or 30 a pharmaceutically acceptable salt thereof is wherein R s of linear C 3 to C 6 alkylene of Z 4 is hydrogen and R t of linear C3 to C6 alkylene of Z 4 is halo, haloalkoxy, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, heterocyclyl, or heteroaryl, each ring substituted as defined therein.
  • R s of linear C 3 to C 6 alkylene of Z 4 is hydrogen and R t of linear C3 to C6 alkylene of Z 4 is halo, haloalkoxy, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, heterocyclyl, or heteroaryl, each ring substituted as defined therein.
  • the compound of any one of embodiments A178 to A184, or a pharmaceutically acceptable salt thereof is wherein the heteroaryl, heterocyclyl, and bridged - 62 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT heterocyclyl of R t of linear C3 to C6 alkylene of Z 4 , when present, are five or six membered rings and each ring is substituted as defined therein.
  • the heteroaryl, heterocyclyl, and bridged - 62 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT heterocyclyl of R t of linear C3 to C6 alkylene of Z 4 , when present, are five or six membered rings and each ring is substituted as defined therein.
  • the compound of any one of embodiments A178 to A185, or a pharmaceutically acceptable salt thereof is wherein R s of linear C 3 to C 6 alkylene of Z 4 is as 5 defined therein and R t of linear C3 to C6 alkylene of Z 4 is fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, furanyl, thiazolyl, pyridinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, or tetrahydrofurany
  • the compound of any one of embodiments A174 to A179, or a pharmaceutically acceptable salt thereof is wherein the C 3 to C 6 alkenylene and C 3 to C 6 15 alkylene of Z 4 are branched C4 to C6 alkenylene and C4 to C6 alkylene, respectively, and each is substituted as defined therein.
  • the compound of any one of embodiments A176 to A179 and A187, or a pharmaceutically acceptable salt thereof is wherein Z 4 is branched C 4 to C 6 alkylene substituted as defined therein. 20 A189.
  • NKT-24-003PCT -CH2CH(C(R s )(R t )(R u ))CH2-, -CH2CH2CH(C(R s )(R t )(R u ))CH2-, or -CH 2 CH 2 CH 2 CH(C(R s )(R t )(R u ))- where R s , R t , and R u are as defined therein.
  • R s , R t , and R u are as defined therein.
  • the compound of any one of embodiments A176 to A179 and A187 to A190, or a pharmaceutically acceptable salt thereof is wherein the R s and R u of 5 branched C4 to C6 alkylene of Z 4 are independently hydrogen or halo (unless stated otherwise) and R t of branched C 4 to C 6 alkylene of Z 4 is hydrogen, halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl (unless stated otherwise), where each ring of R t is 10 substituted as defined therein.
  • the compound of any one of embodiments A176 to A179 and A187 to A191, or a pharmaceutically acceptable salt thereof is wherein the R s and R u of branched C4 to C6 alkylene of Z 4 are hydrogen or fluoro (unless stated otherwise) and R t of branched C 4 to C 6 alkylene of Z 4 is hydrogen, halo, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, 15 alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl (unless stated otherwise), where each ring of R t is substituted as defined therein.
  • the compound of any one of embodiments A176 to A179 and A187 to A192, or a pharmaceutically acceptable salt thereof is wherein R s and R u of branched 20 C 4 to C 6 alkylene of Z 4 are hydrogen or fluoro (unless stated otherwise) and R t of branched C 4 to C6 alkylene of Z 4 is hydrogen, halo, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, or heteroaryl substituted as defined therein.
  • R s and R u of branched 20 C 4 to C 6 alkylene of Z 4 are hydrogen or fluoro (unless stated otherwise)
  • R t of branched C 4 to C6 alkylene of Z 4 is hydrogen, halo, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, or heteroaryl substituted as defined therein.
  • the compound of embodiment A178, or a pharmaceutically acceptable salt thereof is wherein Z 4 is C 3 to C 6 alkylene substituted with R s , R t , and R u where R t 25 and R u are attached to the same carbon or to adjacent carbon atoms of the linear portion of the C3 to C 6 alkylene and R t and R u together with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene where the cycloalkylene and heterocyclylene formed by R t and R u are substituted with R 9 and R 10 .
  • Z 4 is C 3 to C 6 alkylene substituted with R s , R t , and R u where R t 25 and R u are attached to the same carbon or to adjacent carbon atoms of the linear portion of the C3 to C 6 alkylene and R t and R u together with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene where the
  • the compound of any one of embodiments A178 and A194, 30 or a pharmaceutically acceptable salt thereof is wherein Z 4 is C 3 to C 6 alkylene substituted with R s , R t , and R u where R t and R u are attached to the same carbon atom of the linear portion of C3 to C 6 alkylene and together with the carbon atom to which they are attached can form cycloalkylene substituted with R 9 and R 10.
  • - 64 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A196.
  • the compound of embodiment A178 or A194, or a pharmaceutically acceptable salt thereof is wherein Z 4 is C 3 to C 6 alkylene substituted with R s , R t , and R u where R t and R u are attached to the same carbon atom of the linear portion of the C3 to C6 alkylene and together with the carbon atom to which they are attached can form heterocyclylene 5 substituted with R 9 and R 10 .
  • Z 4 is C 3 to C 6 alkylene substituted with R s , R t , and R u where R t and R u are attached to the same carbon atom of the linear portion of the C3 to C6 alkylene and together with the carbon atom to which they are attached can form heterocyclylene 5 substituted with R 9 and R 10 .
  • the compound of embodiment A178 or A194, or a pharmaceutically acceptable salt thereof is wherein Z 4 is C3 to C6 alkylene substituted with R s , R t , and R u where R t and R u are attached to adjacent carbon atoms of the linear portion of the C 3 to C 6 alkylene and together with the carbon atoms to which they are attached can form cycloalkylene 10 substituted with R 9 and R 10 .
  • Z 4 is C3 to C6 alkylene substituted with R s , R t , and R u where R t and R u are attached to adjacent carbon atoms of the linear portion of the C 3 to C 6 alkylene and together with the carbon atoms to which they are attached can form cycloalkylene 10 substituted with R 9 and R 10 .
  • the compound of embodiment A178 or A194, or a pharmaceutically acceptable salt thereof is wherein Z 4 is C 3 to C 6 alkylene substituted with R s , R t , and R u where R t and R u are attached to adjacent same carbon atoms of the linear portion of the C3 to C 6 alkylene and together with the carbon atoms to which they are attached can form 15 heterocyclylene substituted with R 9 and R 10 .
  • Z 4 is C 3 to C 6 alkylene substituted with R s , R t , and R u where R t and R u are attached to adjacent same carbon atoms of the linear portion of the C3 to C 6 alkylene and together with the carbon atoms to which they are attached can form 15 heterocyclylene substituted with R 9 and R 10 .
  • the compound of any one of embodiments A178 and A194 to A196, or a pharmaceutically acceptable salt thereof is wherein R t and R u are attached to the same carbon atom of the linear portion C 3 to C 6 alkylene and together with the carbon atom to which they are attached can form cycloalkylene of formula: 20 o w ment, R 9 is hydrogen, halo, methyl or ethyl and R 10 is hydrogen. 25 A200.
  • the compound of any one of embodiments A178, A194, A197, and A198, or a pharmaceutically acceptable salt thereof is wherein R t and R u are attached to adjacent carbon atoms of the linear portion of the C 3 to C 6 alkylene and together with the carbon atoms to which they are attached can form cycloalkylene of formula: - 65 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT or heterocyclylene of formula: , w mbodime 9 nt R is hydrogen, halo, 5 methyl or ethyl and R 10 is hydrogen.
  • R t and R u are attached to adjacent carbon atoms of the linear portion of the C 3 to C 6 alkylene and together with the carbon atoms to which they are attached can form cycloalkylene of formula: - 65 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • the compound of any one of embodiments A1 to A112, A124 to A127, A132, A133, and A135 to A168, or a pharmaceutically acceptable salt thereof is wherein the Z 4 is C 3 to C 6 heteroalkylene substituted with R s , R t , and R u .
  • the compound of embodiment A201, or a pharmaceutically10 acceptable salt thereof is wherein the Z 4 is C 3 to C 6 heteroalkylene substituted with R s , R t , and R u where R s , R t , and R u are hydrogen.
  • A203 is
  • the compound of embodiment A201, or a pharmaceutically acceptable salt thereof is wherein the Z 4 is C3 to C6 heteroalkylene substituted with R s , R t , and R u where R s , R t , and R u are hydrogen or halo, provided at least one of R s , R t , and R u is halo. 15 A204.
  • the compound of embodiment A201, or a pharmaceutically acceptable salt thereof is wherein Z 4 is C 3 to C 6 heteroalkylene substituted with R s , R t , and R u where R t is other than hydrogen and R u is hydrogen, or when R t and R u are attached to the same carbon or to adjacent carbon atoms of the linear portion of the C 3 to C 6 heteroalkylene, R t and R u together with the carbon atom to which they are attached can form cycloalkylene or 20 heterocyclylene where the cycloalkylene and heterocyclylene are substituted with R 9 and R 10 .
  • Z 4 is C 3 to C 6 heteroalkylene substituted with R s , R t , and R u where R t is other than hydrogen and R u is hydrogen, or when R t and R u are attached to the same carbon or to adjacent carbon atoms of the linear portion of the C 3 to C 6 heteroalkylene, R t and R u together with the carbon atom to
  • the compound of embodiment A204, or a pharmaceutically acceptable salt thereof is wherein R t and R u are attached to the same carbon atom of the linear portion of the C3 to C6 heteroalkylene and together with the carbon atom to which they are attached can form cycloalkylene of formula: 25 o - 66 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT w ment, R 9 is hydrogen, halo, methyl or ethyl and R 10 is hydrogen.
  • R t and R u are attached to the same carbon atom of the linear portion of the C3 to C6 heteroalkylene and together with the carbon atom to which they are attached can form cycloalkylene of formula: 25 o - 66 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT w ment, R 9 is hydrogen, halo,
  • the compound of embodiment A204, or a pharmaceutically 5 acceptable salt thereof is wherein R t and R u are attached to adjacent carbon atoms of the linear portion of the C3 to C6 heteroalkylene and together with the carbon atoms to which they are attached can form cycloalkylene of formula: or heterocyclylene of formula: , 10 w mbodiment, R 9 is hydrogen, halo, methyl or ethyl and R 10 is hydrogen.
  • R t and R u are attached to adjacent carbon atoms of the linear portion of the C3 to C6 heteroalkylene and together with the carbon atoms to which they are attached can form cycloalkylene of formula: or heterocyclylene of formula: , 10 w mbodiment, R 9 is hydrogen, halo, methyl or ethyl and R 10 is hydrogen.
  • the compound of any one of embodiments A201 to A206, or a pharmaceutically acceptable salt thereof is wherein the C3 to C6 heteroalkylene of Z 4 is linear C3 15 to C 6 heteroalkylene substituted with R s , R t , and R u .
  • the C3 to C6 heteroalkylene of Z 4 is linear C3 15 to C 6 heteroalkylene substituted with R s , R t , and R u .
  • the compound of any one of embodiments A201 to A204, and A207, or a pharmaceutically acceptable salt thereof is wherein the linear heteroalkylene of Z 4 is -CH2CH2X a CH2-, -CH2X a CH2CH2-, -CH2CH2CH2X a -, -X a CH2CH2CH2-, - X y CH2CH2X a -, -X y CH 2 CH 2 X a CH 2 -, -CH 2 CH 2 CH 2 X a CH 2 -, -CH 2 X a CH 2 -, -X a CH 2 CH 2 -, -CH 2 CH 2 X a -, 20 -CH2CONR q1 CH2-, -CH2SO2NR q1 CH2-, -CH2NR q1 COCH2-, -CH2NR q1 SO2CH2-, -CH 2 CH 2 CH 2 NR q1 CO-, -CH 2 CH 2 NR
  • the compound of any one of embodiments A201 to A204, 25 A207, and A208, or a pharmaceutically acceptable salt thereof is wherein R q1 is hydrogen, methyl, ethyl, methylcarbonyl, or methylsulfonyl. - 67 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A210.
  • the compound of any one of embodiments A201 to A204, and A207 to 209, or a pharmaceutically acceptable salt thereof is wherein the linear C 3 to C 6 heteroalkylene of Z 4 is -CH2X a CH2-, -X a CH2CH2-, -CH2CH2X a -, -CH2CH2CH2X a -, -CH 2 CH(R t )X a -, -X a CH(R t )CH 2 -, -CH 2 CONR q1 -, -CH 2 SO 2 NR q1 -, -CH 2 NR q1 CO-, -CH 2 NR q1 SO 2 -, 5 -CONR q1 CH2-, -SO2NR q1 CH2-, -NR q1 COCH2-, or -NR q1 SO2CH2- where X a is -S-, -SO2-, -O-, or -NR q1 SO2CH2-
  • the compound of any one of embodiments A201 to A204, and A207 to 210, or a pharmaceutically acceptable salt thereof is wherein the linear C 3 to C 6 heteroalkylene of Z 4 is -CH2CH2CH2X a - or -CH2CH2X a - substituted with R s , R t , and R u as defined 10 therein.
  • the linear C 3 to C 6 heteroalkylene of Z 4 is -CH2CH2CH2X a - or -CH2CH2X a - substituted with R s , R t , and R u as defined 10 therein.
  • the compound of any one of embodiments A201 to A204, and A207 to A211, or a pharmaceutically acceptable salt thereof is wherein R s of linear C 3 to C 6 heteroalkylene of Z 4 is hydrogen or halo (unless stated otherwise therein above) and R t of linear heteroalkylene of Z 4 is (unless stated otherwise therein above) hydrogen, halo, haloalkoxy, 15 cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, or bridged heterocyclyl, each ring substituted as defined therein and R u is hydrogen.
  • the compound of any one of embodiments A201 to A204, and A207 to A212, or a pharmaceutically acceptable salt thereof is wherein R s of linear C3 to C6 20 heteroalkylene of Z 4 is hydrogen or fluoro (unless stated otherwise therein above) and R t of linear heteroalkylene of Z 4 (unless stated otherwise therein above) is hydrogen halo, haloalkoxy, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, or heteroaryl substituted as defined therein.
  • R s of linear C3 to C6 20 heteroalkylene of Z 4 is hydrogen or fluoro (unless stated otherwise therein above)
  • R t of linear heteroalkylene of Z 4 is hydrogen halo, haloalkoxy, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, or heteroaryl substituted as defined therein.
  • the compound of any one of embodiments A201 to A204, and A207 to A213, or a pharmaceutically acceptable salt thereof is wherein the heteroaryl, 25 heterocyclyl, and bridged heterocyclyl of R t of linear C3 to C6 heteroalkylene of Z 4 , when present, are five or six membered ring and each ring is substituted as defined therein.
  • the compound of any one of embodiments A201 to A204, and A207 to A214, or a pharmaceutically acceptable salt thereof is wherein R s of linear heteroalkylene of Z 4 , when present and unless stated otherwise herein above, is hydrogen, 30 deuterium, or fluoro, and R t of linear heteroalkylene of Z 4 , unless stated otherwise, is hydrogen, deuterium, fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, thiazolyl, furanyl, pyridinyl, pyrrolidinyl
  • R 7 and R 8 independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino, dimethylamino, and cyano.
  • R 7 and R 8 independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino, dimethylamino, and cyano.
  • -NR q1 - (where R q1 is hydrogen or methyl), -O-, or -S-.
  • A217 the compound of any one of embodiments A201 to A216, or a pharmaceutically acceptable salt thereof, is wherein X y is -O-.
  • A218 the compound of any one of embodiments A201 to A216, or 10 a pharmaceutically acceptable salt thereof, is wherein X y is -NH- or -NCH 3 -. A219.
  • the compound of any one of embodiments A201 to A206, or a pharmaceutically acceptable salt thereof is wherein the C 3 to C 6 heteroalkylene of Z 4 is branched C4 to C6 heteroalkylene substituted with R s , R t , and R u .
  • A220 the compound of any one of embodiments A201 to A206, or a pharmaceutically acceptable salt thereof, is wherein the C 3 to C 6 heteroalkylene of Z 4 is branched C4 to C6 heteroalkylene substituted with R s , R t , and R u .
  • the compound of any one of embodiments A201 to A204,15 and A219, or a pharmaceutically acceptable salt thereof is wherein the branched C4 to C6 heteroalkylene of Z 4 is -CH 2 X a CH(CH 3 )CH 2 -, -CH 2 X y CH 2 CH(CH 3 )X a -, -CH 2 CH 2 CH(CH 3 )X a -, -X a CH(CH3)CH2CH2-, -X y CH2CH(CH3)X a -, -X y CH(CH3)CH2X a -, -CH2CH2CH2CH(CH3)X a -, -X a CH(CH 2 R t )CH 2 -, -CH 2 CH(CH 2 R t )X a -, -X a CH(CH 2 CH 2 R t )CH 2 -, -CH 2 CH(CH 2 R t )X a -, -X
  • the compound of any one of embodiments A201 to A204, A219, and A220, or a pharmaceutically acceptable salt thereof is wherein the branched C4 to C6 heteroalkylene of Z 4 is -CH 2 C(CH 3 )(CH 3 )X a -, -CH(CH 3 )CH(CH 3 )X a -, -X a CH(CH 2 CH 2 R t )CH 2 -, 25 -CH2CH(CH2CH2R t )X a -, -X a CH(CH2R t )CH2-, or -CH2CH(CH2R t )X a -.
  • the branched C4 to C6 heteroalkylene of Z 4 is -CH 2 C(CH 3 )(CH 3 )X a -, -CH(CH 3 )CH(CH 3 )X a -, -X a CH(CH 2 CH 2 R t )CH 2 -, 25
  • the compound of any one of embodiments A201 to A204, and A219 to A221, or a pharmaceutically acceptable salt thereof is wherein the R s and R u of branched C 4 to C 6 heteroalkylene of Z 4 are hydrogen or halo (unless stated otherwise herein above) and R t of branched C4 to C6 heteroalkylene of Z 4 is hydrogen, halo, haloalkoxy, cycloalkyl, 30 cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl substituted as defined therein.
  • the compound of any one of embodiments A201 to A204, and A219 to A221, or a pharmaceutically acceptable salt thereof is wherein R s and R u are - 69 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT hydrogen and R t is hydrogen, heteroaryl, alkylaminocarbonyl, or cyano (unless stated otherwise herein above).
  • R s and R u are - 69 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT hydrogen and R t is hydrogen, heteroaryl, alkylaminocarbonyl, or cyano (unless stated otherwise herein above).
  • the compound of any one of embodiments A201 to A204, and A219 to A221, or a pharmaceutically acceptable salt thereof is wherein the heteroaryl, 5 heterocyclyl of branched C4 to C6 heteroalkylene of Z 4 , by itself or as part of heterocyclyloxy, heterocyclylcarbonyl, and bridged heterocyclyl, when present, are five or six membered ring and each ring is substituted as defined therein.
  • the heteroaryl, 5 heterocyclyl of branched C4 to C6 heteroalkylene of Z 4 by itself or as part of heterocyclyloxy, heterocyclylcarbonyl, and bridged heterocyclyl, when present, are five or six membered ring and each ring is substituted as defined therein.
  • the compound of any one of embodiments A201 to A204, and A219 to A224, or a pharmaceutically acceptable salt thereof is wherein R t of branched C4 to 10 C 6 heteroalkylene of Z 4 , when present and unless stated otherwise herein above, is hydrogen, deuterium, fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, thiazolyl, furanyl, pyrrolidinyl, pyridinyl, piperidinyl, piperazinyl, or 15 tetrahydrofuranyl,
  • the compound of any one of embodiments A201 to A204 and A219 to A225, or a pharmaceutically acceptable salt thereof, is wherein X a is -NR q1 -, -O-, -S-, 20 or -SO 2 -. In one embodiment X a is -NR q1 - or -O-. A227.
  • the compound of any one of embodiments A1 to A112, A124 to A127, A132, and A134 to A168, or a pharmaceutically acceptable salt thereof is wherein Z 4 is alkynylene substituted with R w and R x independently selected from hydrogen, halo, haloalkyl, alkoxy, hydroxy, and cyano. 25 A228.
  • the compound of any one of embodiments A227, or a pharmaceutically acceptable salt thereof is wherein Z 4 is alkynylene substituted with R w and R x independently selected from hydrogen, fluoro, difluoromethyl, trifluoromethyl, hydroxy, methoxy, and cyano. A229.
  • the compound of embodiment A227, or a pharmaceutically 30 acceptable salt thereof is wherein Z 4 is alkynylene substituted with R w and R x which are attached to the same carbon atoms of the alkynylene and are combined to form cycloalkylene or heterocyclylene wherein the cycloalkylene and heterocyclylene are substituted with R 11 and R 12 independently selected from hydrogen, alkyl, and halo.
  • Z 4 is alkynylene substituted with R w and R x which are attached to the same carbon atoms of the alkynylene and are combined to form cycloalkylene or heterocyclylene wherein the cycloalkylene and heterocyclylene are substituted with R 11 and R 12 independently selected from hydrogen, alkyl, and halo.
  • - 70 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A230.
  • the compound of any one of embodiments A227 to A229, or a pharmaceutically acceptable salt thereof is wherein alkynylene of Z 4 is: . 5
  • a embodiments A227, A228, and A230, or a pharmaceutically acceptable salt thereof, is wherein alkynylene of Z 4 is: .
  • a ound of any one of embodiments A174 to A226, or a pharmaceutically acceptable salt thereof, is wherein the alkylene, heteroalkylene, and alkenylene 10 of Z 4 are selected from: - 71 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • the compound of any one of embodiments A174 to A226, and A232, or a pharmaceutically acceptable salt thereof, is wherein the alkylene, heteroalkylene, 5 and alkenylene of Z 4 are selected from: - 73 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT re A234.
  • the compound of any one of embodiments A174 to A226, 5 A232, and A233, or a pharmaceutically acceptable salt thereof is wherein the alkylene, heteroalkylene, and alkenylene of Z 4 are selected from: - 74 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT , , O - 75 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT respe A235.
  • the compound of any one of embodiments A174, A176, 5 A178, A179 to A184, A187 to A193, A201, A202, A204, A217, A219 to A223, A225, A226, and A232 to 234, or a pharmaceutically acceptable salt thereof is wherein Z 4 is: 76, A178, A179 to A184, A187 to A193, A201, A202, A204, A217, A219 to A223, A225,A226, and 10 A232 to 235, or a pharmaceutically acceptable salt thereof, is wherein Z 4 is: - 76 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT to A194, A197, A200, to 202, A204, A207 to A213, A215 to A226, and A232 to 234, or a pharmaceutically acceptable salt thereof, is wherein Z 4 is: 5 d, or a pharmaceutically acceptable salt thereof, is wherein L (when the Degron is a group of formula (iii) to (vi)), -X 1 -L-, -X 2 -L-, -X 3 -L- and -X 4 -L- (when the Degron is a group of formula (i) or (ii)) are independently: - 77 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT 2 - 78 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT 5 - - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT A23 to A96d and A238, or a pharmaceutically acceptable salt thereof is wherein L (when the Degron is a group of formula (iii) to (vi)), -X 1 -L-, -X 2 -L-, -X 3 -L-, and -X 4 -L- (when the Degron is a group of formula 5 (i) or (ii)) are independently: - 80 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT 6d, 5 A238, and A239, or a pharmaceutically acceptable salt thereof, is wherein L (when the Degron is a group of formula (iii) to (vi)), -X 1 -L-, -X 2 -L-, -X 3 -L- and -X 4 -L- (when the Degron is a group of formula (i) or (ii)) are independently: - 81 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT 6d and 5 A238 to A240, or a pharmaceutically acceptable salt thereof is wherein L (when the Degron is a group of formula (iii) to (vi)), -X 1 -L-, -X 2 -L-, -X 3 -L- and -X 4 -L- (when the Degron is a group of formula (i) or (ii)) are independently: . - 82 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A242.
  • the compound of any one of embodiments A1 to A96d, or a pharmaceutically acceptable salt thereof is wherein L (when the Degron is a group of formula (iii) to (vi)), -X 1 -L-, -X 2 -L-, -X 3 -L- and -X 4 -L- (when the Degron is a group of formula (i) or (ii)) are independently: 5 , , , 10 ; lo, haloalkyl, haloalkoxy, alkoxy, and cyano (i.e., R r is hydrogen).
  • each R q and R m are independently selected from hydrogen, methyl, fluoro, chloro, cyano, methoxy, difluoromethoxy, difluoromethyl, and trifluoromethyl; and 15 Z 4 is alkylene, alkynylene, alkenylene, or heteroalkylene wherein alkylene and heteroalkylene are substituted with R s , R t , and R u , alkenylene is substituted with R v and alkynylene is substituted with R w and R x as defined in the first aspect of the Summary. - 83 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • the compound of any one of A1 to A96d and A242, or a pharmaceutically acceptable salt thereof is wherein L (when the Degron is a group of formula (iii) to (vi)), -X 1 -L-, -X 2 -L-, -X 3 -L- and -X 4 -L- (when the Degron is a group of formula (i) or (ii)) are independently: 5 , , or wherein ea haloalkyl, haloalkoxy, alkoxy, hydroxy and cyano (i.e., R r is hydrogen). 10 A244.
  • the compound of embodiment A242 or A243, or a pharmaceutically acceptable salt thereof is wherein: ; and 15 ynylene is as provided in embodiment 231); and alkylene, alkenylene, and heteroalkylene of Z 4 are those as provided in embodiment A233.
  • alkenylene, and heteroalkylene of Z 4 are those as provided in embodiment A234, respectively.
  • alkenylene, and heteroalkylene of Z 4 are those as provided in embodiment A235, 20 respectively.
  • alkenylene, and heteroalkylene of Z 4 are - 84 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT those as provided in embodiment A236, respectively.
  • alkenylene, and heteroalkylene of Z 4 are those as provided in embodiment A237, respectively.
  • the compound of any one of embodiments A1 to A96d and A134a, or a pharmaceutically acceptable salt thereof is wherein L (when the Degron is a group of 5 formula (iii) to (vi)); and -X 1 -L-, -X 2 -L-, -X 3 -L- and -X 4 -L- (when the Degron is a group of formula (i) or (ii)) are independently: , w , haloalkyl, 10 haloalkoxy, alkoxy, and cyano; and Z 4 is C 3 to C 6 alkylene substituted with R s , R t , and R u .
  • L when the Degron is a group of 5 formula (iii) to (vi)
  • the compound of embodiment A245, or a pharmaceutically acceptable salt thereof is wherein: e R m and R n are independently selected from hydrogen, 15 methyl, xy, difluoromethoxy, difluoromethyl, and trifluoromethyl; and Z 4 is propylene, butylene, or pentylene.
  • e R m and R n are independently selected from hydrogen, 15 methyl, xy, difluoromethoxy, difluoromethyl, and trifluoromethyl; and Z 4 is propylene, butylene, or pentylene.
  • A247 the compound of embodiment A245 or A246, or a pharmaceutically acceptable salt thereof, is wherein Z 4 is n-propylene. 20 A248.
  • the compound of any one of embodiments A1 to A46, A48 to A56, A59 to A67, A69 to A75, A77 to A82, A83 to A93, A97, and A110a to A247, or a pharmaceutically acceptable salt thereof is wherein Degron is the E3 ubiquitin ligase ligand selected from: H O N O O F , - 85 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT , 5 , , , , , hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl.
  • the compound of any one of embodiments A1 to A46, A48 to A56, A59 to A67, A69 to A75, A77 to A82, A83 to A93, A97, and A110a to A248, or a 10 pharmaceutically acceptable salt thereof is wherein Degron is the E3 ubiquitin ligase ligand selected from: H O N O O F , , - 86 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT and y g , y , y , y p py , , , y 5 hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl.
  • y g , y , y , y p py , , , y 5 hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl.
  • the compound of embodiment A249, or a pharmaceutically acceptable salt thereof is wherein Degron is the E3 ligase ligand selected from: 10 A250, or a pharmaceutically acceptable salt thereof, is wherein Degron is the E3 ubiquitin ligase ligand is s hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl and R f ethyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl. 15 A252.
  • the compound of embodiment A250, or a pharmaceutically acceptable salt thereof is wherein Degron is the E3 ubiquitin ligase ligand is . - 87 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT
  • Degron is the E3 ubiquitin ligase ligand is . - 87 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT
  • Reference to an embodiment includes combination of the embodiment and subembodiment(s) thereof.
  • reference to embodiment A includes combination of embodiment A and subembodiment(s) thereof.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, 10 Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
  • NKT-24-003PCT Scheme 1 bromine and R 1 and R 2 are as defined in the first aspect of the Summary, with an amine of formula 1-2, 5 where Hy is as defined in the Summary and FG 1 is a suitable functional group such as an acid or amine, under conditions well known in the art (such as in the presence of TEA and ZnCl2 in tert- butanol), provides a compound of formula 1-3.
  • FG 2 suitable functional group
  • the reaction 10 is a peptide coupling reaction, where the resulting amide bond is part of L as defined in the Summary, and FG 1 and FG 2 are a combination of carboxylic acid and an amine, in the presence of suitable coupling reagents, such as a combination of HATU and DIPEA in DMF.
  • suitable coupling reagents such as a combination of HATU and DIPEA in DMF.
  • a compound of Formula (I) such as where Hy is 1,4-piperidindiyl, Degron is 15 a group of formula (i) and L is attached to Degron (i) via heterocyclylene containing at least one nitrogen ring atom and to Hy via -SO2-, can be synthesized as illustrated and described in Scheme 2.
  • NKT-24-003PCT of an acid, such as TFA, is converted to a sulfonamide compound of formula 2-6 by treating it with a sulfonyl halide of formula 2-5 where L’ is a precursor group of L in the compound of Formula (I) as defined in the Summary and A 2 is halogen such as chlorine and LG is a suitable leaving group such as halo or methylsulfonyl. 5
  • a compound of formula 2-6 with an amine compound of formula 2-7, where ring A is defined as in the Summary and is heterocyclylene containing at least one nitrogen ring atom e.g. piperidin-1,4-d basic conditions such as in the presence of DIPEA, provides a compound of formula (I).
  • a compound of Formula (I) such as where R 2 is hydrogen, Degron is a group of formula (i), Z 1 is heterocyclylene such as 4-piperidin-1-yl, Z 2 and Z 3 are bond, Z 4 is but-1-ynlene, Z 5 is aryl (Ar), and Z 6 is -SO2- can be synthesized as illustrated and described in Scheme 3.
  • Scheme 3 Tr ng group such as chlorine or bromine, with an amine of formula 3-1 under basic or catalytic conditions known in the art provides an alkyne of formula 3-3.
  • cyclin D1 has been found in many cancers, including breast invasive ductal carcinoma, invasive breast 25 carcinoma, bladder urothelial carcinoma, breast invasive lobular carcinoma, and lung adenocarcinoma.
  • Translocation of cyclin D1 Amplification of CDK4 is common in liposarcoma.
  • CDK4 amplification has also been observed at lower frequency in other solid tumors and hematologic malignancies.
  • CDKN2A Loss of the CDK4 inhibitor p16 (CDKN2A) is also a common event in many cancers, including glioblastoma multiforme, head and neck squamous cell carcinoma, 30 pancreatic adenocarcinoma, esophageal adenocarcinoma, mesothelioma, lung squamous cell - 96 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT carcinoma bladder urothelial carcinoma, skin cutaneous melanoma, diffuse large B-cell lymphoma, cholangiocarcinoma, lung adenocarcinoma, and stomach adenocarcinoma.
  • Cyclin E has been found to be frequently amplified in cancers, for example, in uterine cancer, ovarian cancer, stomach cancer, and breast cancer.
  • loss-of-function 5 mutations in FBXW7 or overexpression of USP28 which control the turnover of cyclin E, leads to cyclin E overexpression and CDK2 activation.
  • certain cancer cells express a hyperactive, truncated form of cyclin E or cyclin A.
  • CDK2/cyclin E phosphorylates 15 oncogenic Myc to oppose 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 over-expressing cancer cells.
  • CDK2 inhibition resulted in anaphase catastrophe and apoptosis.
  • inhibiting CDK2 effectively induced granulocytic differentiation in AML cell lines and arrested tumor 20 growth in AML mice models.
  • CDK2 activation as a result of cyclin E amplification or overexpression has also been identified as a key primary or acquired resistance pathway to HR+ or HER2+ breast cancers treated by CDK4/6 inhibitors or trastuzumab. Accordingly, compounds of Formula (I) can be used in combination with CDK4/6 inhibitors or anti-HER2 therapies for the treatment of cancers that 25 become refractory to CDK4/6 inhibitors or anti-HER2 therapies.
  • a compound of this disclosure may be useful for treating tumors characterized by 1) overexpression of CDK2 and/or CDK4; 2) amplification /overexpression of cyclin D, cyclin E or cyclin A; 3) hyperphosphorylation of CDK2 (Thr160) or CDK4 (Thr172); 4) loss-of-function of mutation in FBXW7, depletion of AMBRA1, overexpression of USP28, or 30 amplification/overexpression of CDC25A or/and CDC25B; 5) expression of truncated cyclin E or cyclin A, 6) dysregulation of p16, p21 or p27, or overexpression of SKP2;and 7) hyperactive MYC/RAS; 8) Aneuploid cancers, and 9) CDK4 and/or CDK6 inhibitor refractory cancers.
  • the cancer is ovarian cancer (e.g. serous, clear cell, endometrioid, and mucinous ovarian carcinomas), uterine cancer (e.g. endometrial cancer and uterine sarcoma), - 97 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT stomach cancer (i.e. gastric cancer), lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, parvicellular and non-parvicellular carcinoma, bronchial carcinoma, bronchial adenoma, pleuropulmonary blastoma), renal cancer (e.g.
  • ovarian cancer e.g. serous, clear cell, endometrioid, and mucinous ovarian carcinomas
  • uterine cancer e.g. endometrial cancer and uterine sarcoma
  • brain cancer 5 including astrocytoma, meningioma and glioblastoma), neuroblastoma, paraganglioma, pheochromocytoma, pancreatic neuroendocrine tumors, somatostatinomas, hemangioblastomas, gastrointestinal stromal tumors, pituitary tumors, leiomyomas, leiomyosarcomas, polycythaemia, retinal cancers, hereditary leiomyomatosis, renal cell cancer, astrocytoma, skin cancer (e.g.
  • exocrine pancreatic carcinoma and 15 neuroendocrine pancreatic cancer thyroid cancer, and parathyroid cancer, fallopian tube cancer, peritoneal cancer, vaginal cancer, biliary tract cancer, esophageal cancer (e.g. esophageal squamous cell carcinoma and esophageal adenocarcinoma), sarcoma (e.g. liposarcoma and osteosarcoma), bone cancer, chondrosarcoma, leukemia (including acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and chronic lymphocytic leukemia), 20 lymphoma (e.g.
  • non-Hodgkin lymphoma NHL including mantel cell lymphoma, MCL and Hodgkin lymphoma
  • multiple myeloma the cancer is breast cancer, including, e.g., ER-positive/HR-positive breast cancer, HER2-negative breast cancer; ER-positive/HR-positive breast cancer, HER2- positive breast cancer; ER-negative/HR-negative, HER2-positive breast cancer, triple negative 25 breast cancer (TNBC); or inflammatory breast cancer.
  • the breast cancer is endocrine resistant breast cancer, anti-HER2 therapy (e.g. trastuzumab) resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition.
  • the breast cancer is advanced or metastatic breast cancer.
  • the breast cancer is characterized by amplification or overexpression of 30 CCNE1 and/or CCNE2.
  • compounds of Formula (I) or (IB) as described in the Summary as described in the first aspect (or any of the embodiments thereof herein above) are useful in treating autoimmune diseases autoimmune diseases e.g., rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (pSS), multiple sclerosis (MS), Crohn’s - 98 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT disease CD
  • gout NKT-24-003PCT disease
  • uveitis NKT-24-003PCT disease
  • pemphigus vulgaris NKT-24-003PCT disease
  • sepsis NKT-24-003PCT disease
  • Testing CDK2/4 potency and CDK2/4 degradation activities of the compounds of the present 5 disclosure can be tested using the in vitro assays described in Biological Examples below.
  • Pharmaceutical Compositions In general, the compounds Formula (I) (unless stated otherwise, reference to compound/compounds of Formula (I) herein includes any embodiments thereof described herein 10 or a pharmaceutically acceptable salt thereof) will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • Therapeutically effective amounts of compounds of Formula (I) may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses.
  • a suitable 15 dosage level may be from about 0.1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day.
  • compositions can be provided in the form of tablets containing about 1.0 to 20 about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient.
  • the actual amount of the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds), i.e., the active ingredient will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of 25 the compound being utilized, the route and form of administration, and other factors.
  • compositions will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • routes e.g., oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • parenteral e.g., intramuscular, intravenous or subcutaneous
  • the preferred manner of 30 administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction.
  • Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • compositions are comprised of in general, a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are generally non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds).
  • excipient may 10 be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may 15 be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
  • the compounds of Formula (I) (and any embodiment thereof disclosed herein 20 including specific compounds) may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing 25 agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame - 100 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for 5 the preparation of highly concentrated solutions.
  • the compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may also be formulated as a depot preparation. Such long -acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • suitable polymeric or hydrophobic materials for example as an emulsion in an acceptable oil
  • ion exchange resins for example, as an emulsion in an acceptable oil
  • sparingly soluble derivatives for example, as a sparingly soluble salt.
  • the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • Such compositions may comprise 15 the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • the compounds of Formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • Certain compounds of Formula (I) may be administered topically, that is by non-systemic administration. This includes the application of a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound 25 does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, 30 ear or nose.
  • the active ingredient for topical administration may comprise, for example, from 0.001% to 10% w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w/w. In other embodiments, it may comprise less than 5% w/w. In certain embodiments, the active ingredient may comprise from 2% w/w to 5% w/w.
  • compounds of Formula (I) may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, 5 trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds of Formula (I) may take the form of a dry powder composition, for example a powder mix of the compound and a 10 suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W.
  • the level of the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. % of a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) based on the total formulation, with the balance being one 20 or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1-80 wt. %.
  • the compounds of Formula (I) may be used in combination with one or more other drugs in the treatment of 25 diseases or conditions for which compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) or the other drugs may have utility.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds).
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) is preferred.
  • the combination therapy may also include therapies in which the compound of Formula (I) (or any embodiment thereof disclosed herein - 102 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT including specific compounds) and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) and the other active ingredients may be used in lower doses 5 than when each is used singly. Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other drugs, in addition to a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds).
  • the above combinations include combinations of a compound of Formula (I) (or any 10 embodiment thereof disclosed herein including specific compounds) not only with one other drug, but also with two or more other active drugs.
  • a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which a compound of Formula (I) (or any embodiment 15 thereof disclosed herein including specific compounds) is useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds).
  • compositions of the present disclosure also include those that also contain one or more other active ingredients, in addition to a compound of Formula (I) (or any embodiment thereof disclosed herein including specific 25 compounds).
  • the weight ratio of the compound of this disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • the subject in need is suffering from or at risk of suffering from cancer
  • the subject can be treated with a compound of Formula (I) (or any embodiment thereof disclosed herein 30 including specific compounds) in any combination with one or more other anti-cancer agents including but not limited to: MAP kinase pathway (RAS/RAF/MEK/ERK) inhibitors including but not limited to: Vemurafanib (PLX4032), Dabrafenib, Encorafenib (LGX818), TQ-B3233, XL- 518 (Cas No.1029872-29-4, available from ACC Corp); trametinib, selumetinib (AZD6244), TQ- B3234, PD184352, PD325901, TAK-733, pimasertinib, binimetinib, refametinib, cobimetinib - 103 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client
  • NKT-24-003PCT GDC-0973
  • AZD8330 BVD-523, LTT462, Ulixertinib, AMG510, ARS853, and any RAS inhibitors disclosed in patents WO2016049565, WO2016164675, WO2016168540, WO2017015562, WO2017058728, WO2017058768, WO2017058792, WO2017058805,WO2017058807, WO2017058902, WO2017058915, WO2017070256, 5 WO2017087528, WO2017100546, WO2017172979, WO2017201161, WO2018064510, WO2018068017, WO2018119183; CSF1R inhibitors (PLX3397, LY3022855, etc.) and CSF1R antibodies (IMC-054, RG7155) TGF beta receptor kinase inhibitor such as LY2157299; BTK inhibitor such as ibrutini
  • VEGF receptor inhibitors Bevacizumab (sold under the trademark Avastin® by Genentech/Roche), axitinib, (N-methyl-2-[[3-[(E)-2-pyridin-2- 25 ylethenyl]-lH-indazol-6-yl]sulfanyl]benzamide, also known as AG013736, and described in PCT Publication No.
  • Brivanib Alaninate ((S)-((R)-l-(4-(4-fluoro-2-methyl-lH-indol- 5-yloxy)-5-methylpyrrolo[2,l-f][l,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-lH-indol-6-yl)-2-[(4- pyridinyl- methyl)amino]-3-pyridinecarboxamide, and described in PCT Publication No.
  • WO 02/066470 30 pasireotide (also known as SOM230, and described in PCT Publication No. WO 02/010192), sorafenib (sold under the tradename Nexavar®); AL-2846 MET inhibitor such as foretinib, carbozantinib, or crizotinib; FLT3 inhibitors - sunitinib malate (sold under the tradename Sutent® by Pfizer); PKC412 (midostaurin); tanutinib, sorafenib, lestaurtinib, KW-2449, quizartinib (AC220) and crenolanib; - 104 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref.
  • NKT-24-003PCT Epidermal growth factor receptor (EGFR) inhibitors Gefitnib (sold under the tradename Iressa®), N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3"S")-tetrahydro-3-furanyl]oxy]-6- quinazolinyl]-4(dimethylamino)-2-butenamide, sold under the tradename Tovok® by Boehringer Ingelheim), cetuximab (sold under the tradename Erbitux® by Bristol-Myers Squibb), 5 panitumumab (sold under the tradename Vectibix® by Amgen); HER2 receptor inhibitors: Trastuzumab (sold under the trademark Herceptin® by Genentech/Roche), Trastuzumab deruxtecan (sold under the trademark Enhertu), neratinib (also known as HKI-272, (2E)-N-[
  • lapatinib or lapatinib ditosylate sold under the trademark Tykerb® by GlaxoSmithKline
  • Trastuzumab emtansine in the United States, ado- trastuzumab emtansine, trade name Kadcyla
  • an antibody-drug conjugate consisting of the monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent mertansine (DM1)
  • HER dimerization inhibitors Pertuzumab (sold under the trademark Omnitarg®, by 15 Genentech);
  • G-CSF modulators Filgrastim (sold under the tradename Neupogen® by Amgen); Immunomodulators: Afutuzumab (available from Roche®), pegfilgrastim (sold under the tradename Neulasta® by Amgen), lenalidomide (also known as CC-5013, sold under the 5 tradename Revlimid®), thalidomide (sold under the tradename Thalomid®); CD40 inhibitors: Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc); Pro-apoptotic receptor agonists (PARAs): Dulanermin (also known as AMG-951, available from Amgen/Genentech); Hedgehog antagonists: 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)- 10 benzamide (also known
  • Phospholipase A2 inhibitors Anagrelide (sold under the tradename Agrylin®); BCL-2 inhibitors: 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohexen-l-yl]methyl]-l- piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-l-[(phenylthio)m ethyl]propyl]amino]-3- [(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in 15 PCT Publication No.
  • MCl-1 inhibitors MIK665, S64315, AMG 397, and AZD5991
  • Aromatase inhibitors Exemestane (sold under the trademark Aromasin® by Pfizer), letrozole (sold under the tradename Femara® by Novartis), anastrozole (sold under the tradename Arimidex®);
  • Topoisomerase I inhibitors Irinotecan (sold under the trademark Camptosar® by Pfizer), topotecan hydrochloride (sold under the tradename Hycamtin® by GlaxoSmithKline);
  • Topoisomerase II inhibitors etoposide (also known as VP-16 and Etoposide phosphate, sold under the tradenames Toposar®, VePesid® and Etopophos®), teniposide (also known as VM-26, sold under the tradename Vumon®);
  • 25 mTOR inhibitors Temsirolimus (sold under the
  • WO 03/064383 everolimus (sold under the tradename Afinitor® by Novartis); Proteasome inhibitor such as carfilzomib, MLN9708, delanzomib, or bortezomib; BET inhibitors such as INCB054329, OTX015, and CPI-0610; LSD1 inhibitors such as GSK2979552, and INCB059872; - 106 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT HIF-2 ⁇ inhibitors such as PT2977 and PT2385; Osteoclastic bone resorption inhibitors: l-Hydroxy-2-imidazol-l-yl-phosphonoethyl) phosphonic acid monohydrate (sold under the tradename Zometa® by Novartis); CD33 Antibody Drug Conjugates: Gemtuzumab ozogamicin (sold under the tradename Mylotarg® by 5 Pfizer/Wyeth); CD22 Antibody Drug Conjugates: Inotuzumab ozogamicin (also referred to as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.); CD20 Antibody Drug Conjugates: Ibritumomab tiuxetan (sold under the tradename Zevalin®); 10 Somatostain analogs: octreotide (also known as octreotide acetate, sold under the tradenames
  • NKT-24-003PCT the tradenames Platinol® and Platinol®-AQ
  • chlorambucil sold under the tradename Leukeran®
  • cyclophosphamide sold under the tradenames Cytoxan® and Neosar®
  • dacarbazine also known as DTIC, DIC and imidazole carboxamide, sold under the tradename DTIC-Dome®
  • altretamine also known as hexamethylmelamine (HMM) sold under the tradename Hexalen®
  • 5 ifosfamide sold under the tradename Ifex®
  • procarbazine sold under the tradename Matulane®
  • mechlorethamine also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, sold under the tradename Mustargen®
  • streptozocin sold under the tradename Zanosar®
  • thiotepa also known as thiophosphoamide, TESPA and TSPA, sold under the
  • Epothilone B analogs Ixabepilone (sold under the tradename Lxempra® by Bristol-Myers Squibb); Heat Shock Protein (HSP) inhibitors: Tanespimycin (17-allylamino-17- demethoxy- 25 geldanamycin, also known as KOS-953 and 17-AAG, available from SIGMA, and described in US Patent No.4,261,989), NVP-HSP990, AUY922, AT13387, STA-9090, Debio 0932, KW-2478, XL888, CNF2024, TAS-116 TpoR agonists: Eltrombopag (sold under the tradenames Promacta® and Revolade® by GlaxoSmithKline); 30 Anti-mitotic agents: Docetaxel (sold under the tradename Taxotere® by Sanofi-Aventis); Adrenal steroid inhibitors: aminoglutethimide (sold under the tradename Cy
  • NKT-24-003PCT CDK (CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, CDK11/12, or CDK16) inhibitors including but not limited to Alvocidib (pan-CDK inhibitor, also known as flovopirdol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-l-methyl-4-piperidinyl]-4- chromenone, and described in US Patent No.5,621,002); 5 CDK4/6 inhibitors palbociclib, ribociclib, abemaciclib, and Trilaciclib; CDK9 inhibitors AZD 4573, P276-00, AT7519M, TP-1287; CDK2/4/6 inhibitor such as PF-06873600; SHP-2 inhibitor such as TNO155; MDM2/MDMX, MDM2/p53 and/or MDMX/p53 modulators; Gonadotropin-releasing hormone (G
  • HPC vaccines Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck; Iron 20 Chelating agents: Deferasinox (sold under the tradename Exjade® by Novartis); Anti-metabolites: Claribine (2-chlorodeoxyadenosine, sold under the tradename leustatin®), 5-fluorouracil (sold under the tradename Adrucil®), 6-thioguanine (sold under the tradename Purinethol®), pemetrexed (sold under the tradename Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the tradename Cytosar-U®), cytarabine liposomal (also 25 known as Liposomal Ara-C, sold under the tradename DepoCytTM), decitabine (sold under the tradename Dacogen®), hydroxyurea (sold under the tradenames Hydrea®,
  • NKT-24-003PCT Plant Alkaloids Paclitaxel protein-bound (sold under the tradename Abraxane®), vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, sold under the tradenames Alkaban-AQ® and Velban®), vincristine (also known as vincristine sulfate, LCR, and VCR, sold under the tradenames Oncovin® and Vincasar Pfs®), vinorelbine (sold under the 5 tradename Navelbine®), paclitaxel (sold under the tradenames Taxol and OnxalTM); Retinoids: Ali tretinoin (sold under the tradename Panretin®), tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename Vesanoid®), Isotretinoin (13-cis-retinoic acid, sold under the tradenames Accutane®, Amnesteem®, Claravi
  • NKT-24-003PCT Miscellaneous cytotoxic agents Arsenic trioxide (sold under the tradename Trisenox®), asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the tradenames Elspar® and Kidrolase®); One or more immune checkpoint inhibitors CD27, CD28, CD40, CD122, CD96, CD73, 5 CD39, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM kinase, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, HIF-2 ⁇ , B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1 and PD-L2.
  • Trisenox® Arsenic trioxide
  • the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, CD137 and STING.
  • the immune checkpoint 10 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.
  • 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 TGFR beta inhibitors.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody.
  • the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224.
  • the anti-PD-1 monoclonal antibody is nivolumab, or pembrolizumab or PDR001.
  • the anti-PD1 antibody is pembrolizumab.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody.
  • the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C.
  • the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab).
  • the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody.
  • the anti-CTLA-4 antibody is ipilimumab or tremelimumab.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody.
  • the anti- LAG3 antibody is BMS-986016 or LAG525.
  • the inhibitor of an immune 30 checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody.
  • the anti-GITR antibody is TRX518 or, MK-4166, INCAGN01876 or MK-1248.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusion protein.
  • the anti-OX40 antibody is - 111 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT MEDI0562 or, INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525.
  • the OX40L fusion protein is MEDI6383
  • Compounds of Formula (I) can also be used to increase or enhance an immune response, including 5 increasing the immune response to an antigen; to improve immunization, including increasing vaccine efficacy; and to increase inflammation.
  • the compounds of the invention can be used to enhance the immune response to vaccines including, but not limited, Listeria vaccines, oncolytic viral vaccines, and cancer vaccines such as GVAX® (granulocyte- macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine).
  • Anti-cancer 10 vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.
  • immune-modulatory agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4; Sting agonists and Toll receptor agonists.
  • Other anti-cancer agents also include those that augment the immune system such as 15 adjuvants or adoptive T cell transfer. Compounds of this application may be effective in combination with CAR (Chimeric antigen receptor) T cell treatment as a booster for T cell activation.
  • a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) can also be used in combination with the following adjunct therapies: anti- 20 nausea drugs: NK-1 receptor antagonists: Casopitant (sold under the tradenames Rezonic® and Zunrisa® by GlaxoSmithKline); and Cytoprotective agents: Amifostine (sold under the tradename Ethyol®), leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid). 25 Examples 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 to practice the present disclosure.
  • 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 -((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate 20 (50 mg, 0.084 mmol, 1.00 eq.) in DCM (1.0 mL) at 0 o C under nitrogen atmosphere.
  • Step 2 2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid
  • a solution of tert-bu xoisoindolin-4-yl)oxy)- 15 acetate (1.0 g, 2.57 mmol, 1.00 eq.) and TFA (5.0 mL) in DCM (10.0 mL) was stirred at rt for 2 h.
  • Step 3 2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(2-(2-(2-hydroxyethoxy) ethoxy)ethyl)acetamide 20 HATU (51 ((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (300 mg, 0.90 mmol, 1.00 eq.), 2-(2-(2-aminoethoxy)ethoxy)ethanol (201 mg, 1.35 mmol, 1.50 eq.) and DIPEA (348 mg, 2.69 mmol, 2.99 eq.) in DMF (6.0 mL) at 0 o C and the mixture was stirred at RT for 1 h.
  • DMF 6.0 mL
  • NKT-24-003PCT Step 4 2-(2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy) ethoxy)ethyl methanesulfonate MsCl (2 2-(2,6- 5 dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N- (2-(2-(2- hydroxyethoxy)ethoxy)ethyl)acetamide (800 mg, 1.73 mmol, 1.00 eq.) and TEA (524 mg, 5.18 mmol, 2.99 eq.) in DCM (8.0 mL) at 0 o C and the mixture was stirred at 0 o C for 1 h.
  • Step 2 2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy)- ethyl methanesulfonate - 115 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT MsCl (16 n of 2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N- (2-(2-hydroxyethoxy)ethyl) acetamide (400 mg, 0.95mmol, 1.00 eq.) and TEA (288 mg, 2.85 mmol, 3.00 eq.) in DCM (8.0 mL) at 0 o C. 5 The resulting mixture was stirred at 0 o C for 1 h, diluted with H2O and extracted with DCM.
  • Step 2 1-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12-trioxa-3- azatetradecan-14-yl methanesulfonate 25 - 116 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT MsCl (271 mg, 2.37 mmol, 1.50 eq.) was added slowly to a stirred solution of 2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N- (2-(2-(2-(2-(2-hydroxyethoxy)ethoxy)- ethoxy)ethyl)acetamide (800 mg, 1.58 mmol, 1.00 eq.) and TEA (479 mg, 4.73 mmol, 3.00 eq.) in DCM (8.0 mL) at 0 o C.
  • 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 25 Ms -((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 eq.) and TEA (479 mg, 4.73 mmol, 326 eq.) in D
  • reaction mixture was stirred at 0 o C for 1 h, diluted with H2O - 117 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT and extracted with DCM.
  • Step 2 tert-Butyl (1-((4-((1-benzhydrylazetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)- carbamate
  • THF 5.0 mL
  • Step 3 tert-Butyl (1-((4-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate 5
  • 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 A mix eridin-4-yl) carbamate (100 mg, 0.24 mmol, 1.00 eq.), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3- 15 dione (74 mg, 0.27 mmol, 1.13 eq.) and DIPEA (94 mg, 0.73 mmol, 3.04 eq.) in NMP (1.5 mL) was stirred at 140 o C 2 h under microwave irradi
  • Step 5 5-(3-(4-((4-Aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- 20 yl) isoindoline-1,3-dione
  • a mixtur ioxo-isoindolin-5- yl)- 119 -zetidine-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate 144 mg, 0.21 mmol, 1.00 eq.
  • TFA 1.0 mL
  • DCM 4.0 mL
  • 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 15 A mix -4-yl)carbamate (100 mg, 0.24 mmol, 1.00 eq., from Reference 7, Step 3), 5-(bromomethyl)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione (111 mg, 0.32 mmol, 1.33 eq.) and K 2 CO 3 (67 mg, 0.48 mmol, 2.00 eq.) in MeCN (2.0 m
  • 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 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT 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 eq.) 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.
  • Step 2 4-((2-(2-(2-Aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- 20 dione
  • a mixtu -isoindolin-4- yl)amino)ethoxy)ethoxy)ethyl)carbamate 180 mg, 0.36 mmol, 1.00 eq.
  • TFA 0.5 mL
  • DCM 2.0 mL
  • the mixture was concentrated to give title compound as a 25 yellow oil, which was used for next step without further purification.
  • Step 3 tert-Butyl (1-(chlorosulfonyl)piperidin-4-yl)carbamate Sulfuryl dichloride (81 mg, 0 as added to a stirred solution of tert- butyl piperidin-4-ylcarbamate (100 mg, 0.50 mmol, 1.00 eq.) and TEA (76 mg, 0.75 mmol, 1.50 5 eq.) in DCM (2.0 mL) at 0 o C and the mixture was stirred at 0 o C for 3 h.
  • Step 4 tert-Butyl (1-(N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)- 10 ethoxy)ethoxy)ethyl)sulfamoyl)piperidin-4-yl)carbamate
  • a sti (2,6-dioxo- piperidin-3-yl)isoindoline-1,3-dione 70 mg, 0.17 mmol, 1.00 eq.
  • tert-butyl (1-(chloro- sulfonyl)piperidin-4-yl)carbamate 51.9 mg, 0.17 mmol, 1.00 eq.
  • 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 20
  • a mixtu 3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethyl)sulfamoyl)piperidin-4-yl)carbamate 60 mg, 0.090 mmol, 1.00 eq.
  • DCM 2.0 mL
  • TFA 0.5 mL
  • Step 2 tert-Butyl methyl(3-(prop-2-yn-1-yloxy)propyl)carbamate A mixture of g, 15.85 mmol, 1.00 eq.) 15 in DCM (50.0 mL), 3-bromoprop-1-yne (3.0 g, 25.22 mmol, 1.59 eq.), 40% aqueous NaOH (30.0 mL) and tetrabutylammonium hydrogen sulfate (270 mg, 0.80 mmol, 0.050 eq.) was stirred at RT overnight under N2.
  • 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
  • 4 -dione (1.38 g, 4.09 25 mmol, 1.00 eq.)
  • tert-butyl methyl(3-(prop-2-yn-1-yloxy)-propyl)carbamate 1. g, 6.16 mmol, - 123 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • Step 4 tert-Butyl (3-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)propyl)- (methyl)carbamate
  • Pd(OH)2/C (0.93 g, 50% w/w) in THF (50.0 mL) was stirred at RT overnight under H 2 atmosphere.
  • Step 5 2-(2,6-Dioxopiperidin-3-yl)-4-(3-(3-(methylamino)propoxy)propyl)isoindoline-1,3-dione 15
  • 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 25 A mixture of poxy)- propyl)isoindoline-1,3-dione (150 mg, 0.39 mmol, 1.00 eq.), tert-butyl (1-(chlorosulfonyl)- - 124 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref.
  • Step 7 4-Amino-N-(3-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)propyl)- N-methylpiperidine-1-sulfonamide
  • TFA 0.5 mL
  • NKT-24-003PCT 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 g tert-Butyl 5 (2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate provided the title compound.
  • Step 2 3-((4-Aminopiperidin-1-yl)sulfonyl)phenol 20
  • the solution of b in-4-yl)carbamate (3.5 g, 8.66 mmol, 1.00 eq.) in CF3SO3H (20.0 mL) was stirred under N2 at 100 o C for 3 h.
  • the reaction - 126 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • Step 3 tert-Butyl (1-((3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamate 5
  • a solution of (B (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 eq.) in DCM (20.0 mL) and TEA (1.18 g, 11.73 mmol, 3.00 eq.) at 0 o C.
  • Step 4 1-Benzhydrylazetidin-3-yl methanesulfonate To a stirred solution of g, 2.09 mmol, 1.00 eq.) in DCM (10.0 mL) was added TEA (633 mg, 6.27 mmol, 3.00 eq.) and MsCl (479 mg, 4.18 mmol, 15 2.00eq.) at 0 o C.
  • Step 5 tert-Butyl (1-((3-((1-benzhydrylazetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)- carbamate 20
  • a mixture of t 4-yl)carbamate (533 mg, 1.49 mmol, 1.00 eq.), 1-benzhydrylazetidin-3-yl methanesulfonate (570 mg, 1.79 mmol, 1.20 eq.), Cs2CO3 (1.46 g, 4.49 mmol, 3.00 eq.) in DMSO (10.0 mL) was stirred at 90 o C under N2 for 3 h.
  • Step 7 tert-Butyl (1-((3-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)- 10 oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate Proceeding ana e, 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.
  • Step 8 5-(3-(3-((4-Aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione Proceeding anal ve, but using tert-butyl (1-((3-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)oxy)phenyl)- 20 sulfonyl)piperidin-4-yl)carbamate provided the title compound.
  • 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 Proceedin ut using tert-butyl 20 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.
  • 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 5 Proceedi t 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-di
  • Step 4 3-(4-(3-((1-((1-((4-Aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)piperidin-4-yl)- 10 oxy)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione Proceedi t using tert-butyl (1-((4-((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 15 provided the title compound.
  • Step 2 1-(4-Methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate 5 Trifluoromethanesu 9 eq.) was added slowly to a stirred solution of 3-hydroxy-1-(4-methoxybenzyl)piperidine-2,6-dione (1.9 g, 7.62 mmol, 1.00 eq.) and pyridine (1.2 g, 15.17 mmol, 1.99 eq.) in DCM (40.0 mL) at 0 o C. After stirring at 0 o C for 2 h, the reaction mixture was quenched with water and then extracted with DCM.
  • 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 15
  • t-BuOK 6-(trimethoxy- benzyl)
  • Step 4 3-(4-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione
  • a mixture of 3-(4- nzo[d]imidazol-1-yl)-1-(4- 25 methoxybenzyl)piperidine-2,6-dione (900 mg, 1.96 mmol, 1.00 eq.) in toluene/methanesulfonic acid 2/1 (3.0 mL) was stirred at 120 o C for 3 h.
  • the reaction mixture was cooled, concentrated - 131 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref.
  • Step 5 tert-Butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate 5 NaH (60%, 240 mg, irred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1.0 g, 4.97 mmol, 1.00 eq.) in THF (20.0 mL) at 0 o C, followed by 3-bromoprop-1-yne (704 mg, 5.92 mmol 1.19 eq.).
  • 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 Proceeding analogo 3 above, but using 3-(4-bromo- 15 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.
  • 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 20 Proceeding analogo 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.
  • 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 Proceeding a , but using 3-(3- 5 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
  • 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 10
  • 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.
  • Step 2 2-(2,6-Dioxopiperidin-3-yl)-4-((4-oxocyclohexyl)amino)isoindoline-1,3-dione 5
  • 2-( 3-dione (276 mg.1.00 mmol, 1.00 eq.) and 4-aminocyclohexanone hydrochloride (300 mg, 2.00 mmol, 2.00 eq.) in NMP (2.5 mL) was stirred at 140 o C under microwave for 3 h.
  • Step 3 2-(2,6-Dioxopiperidin-3-yl)-4-((4-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione
  • a stirred mixt clohexyl)amino)- isoindoline-1,3-dione 200 mg, 0.54 mmol, 1.00 eq.
  • methylamine 40% in MeOH, 210 mg, 2.71 mmol, 5.02 eq.
  • MeOH/DCE 2.0 mL/2.0 mL
  • Step 4 tert-Butyl (1-(N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)- 20 cyclohexyl)-N-methylsulfamoyl)piperidin-4-yl)carbamate
  • 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.
  • 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 Proc ing tert-butyl 5 (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.
  • NKT-24-003PCT 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 Proceeding anal ve, but using tert-butyl 5 (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.
  • 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 10 Proceed sing (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.
  • NKT-24-003PCT 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 Proceeding ve, but using tert-butyl 5 (2-(prop-2-yn-1-yloxy)ethyl)carbamate provided the title compound.
  • 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
  • 1-(2,6 3-dihydro-1H-benzo[d]- 25 imidazole-4-carbaldehyde 360 mg, 1.25 mmol, 1.00 eq.
  • tert-butyl N-methyl piperidin-4- - 137 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NaBH(OAC) 3 (413 mg, 1.95 mmol, 1.60 eq.) was added at RT.
  • the mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 and then concentrated. The residue was purified by Prep-HPLC to 5 give the title compound as a yellow solid.
  • Step 2 4-(((tert-Butyldimethylsilyl)oxy)methyl)aniline 20
  • DMAP 595 mg, 4.87 mmol, 0.30 eq.
  • TEA 2.00 g, 19.76 mmol, 1.22 eq.
  • TBSCl 2.70 g, 17.91 mmol, 1.10 eq.
  • NKT-24-003PCT Step 3 Dimethyl 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino)phthalate A mixture of 3-iodo-pht , 9.37 mmol, 1.00 eq.), 4-(tert- butyl-dimethyl-silanyloxymethyl)-phenylamine (2.67 g, 11.25 mmol, 1.20 eq.), Pd2(dba)3 (436 5 mg, 0.48 mmol, 0.051 eq.), Cs 2 CO 3 (6.11 g, 18.75 mmol, 2.00 eq.), BINAP (143 mg, 0.23 mmol, 0.025 eq.) in toluene (30.0 mL) was stirred at 120 o C overnight under nitrogen atmosphere.
  • Step 4 Dimethyl 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)(methyl)amino)phthalate 10
  • Step 5 3-[(4-Hydroxymethyl-phenyl)-methyl-amino]-phthalic acid dimethyl ester 20
  • a solution of TBAF in T a stirred solution of dimethyl 3- ((4-(((tert-butyl dimethylsilyl)oxy)methyl)phenyl)-(methyl)amino)phthalate (500 mg, 1.13 mmol, 1.00 eq.) in THF (5.0 mL) at rt. After 2 h, the mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and then concentrated.
  • Step 6 Dimethyl 3-((4-formylphenyl)(methyl)amino)phthalate A mixture of 3-[(4-yy hthalic acid dimethyl ester (300 mg, 0.91 mmol, 1.00 eq.) and MnO2 (800 mg, 9.20 mmol, 10.11 eq.) in DCM (10.0 mL) was 5 stirred at rt overnight.
  • Step 7 Dimethyl 3-((4-(((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl) phenyl)(methyl)amino)phthalate 10
  • a mixture of d ate (300 mg, 0.92 mmol, 1.00 eq.), methyl-(2-methylamino-ethyl)-carbamic acid tert-butyl ester (205 mg, 1.09 mmol, 1.18 eq.) and a drop of AcOH in DCE (5.0 mL) was stirred at RT for 2 h.
  • Step 8 3-((4-(((2-((tert-Butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl)phenyl) (methyl)amino)phthalic acid
  • a mixture of mino)ethyl)(methyl) amino)methyl)phenyl)(methyl)amino)phthalate 250 mg, 0.50 mmol, 1.00 eq.
  • NaOH 40 mg, 20 1.00 mmol, 2.00 eq.
  • 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 - 140 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • 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 25 - 141 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT 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 eq.), 10% Pd/C (30 mg) and Pd(OH)2 (30 mg) in THF (10 mL) was stirred at 50 o C under 50psi H2 pressure. The reaction mixture was filtered and then concentrated to give the title as a white solid.
  • 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
  • a mixture o xo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)piperidine-1-carboxylate (60 mg, 0.14 mmol, 1.00 eq.) and TFA (0.5 mL) 10 in DCM (2 mL) was stirred at RT for 2 h. The reaction mixture was concentrated to give the title compound as a yellow oil.
  • 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 15
  • m ihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione TFA salt 60 mg, 0.13 mmol, 1.00 eq.
  • 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 ecan-19-oic 20 acid (372 mg, 1.06 mmol, 2.00 eq.) in THF (6 mL) was added isobutyl chloroformate (109 mg, 0.80 mmol, 1.51 eq.) and N-methylmorpholine (161 mg, 1.59 mmol, 3.00 eq.), followed by a solution of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (145 mg, 0.53 mmol, 1.00 eq.) in DMF (2 mL) dropwise at 0 o C.
  • Step 2 tert-Butyl (1-((3-((1-(piperidin-4-yl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)- carbamate
  • a stirr o piperidin-1- yl)sulfonyl)phenoxy)azetidin-1-yl)piperidine-1-carboxylate (60 mg, 0.095 mmol, 1.00 eq.) in 20 MeOH(10.0 mL) was added 10% Pd/C (20 mg).
  • Step 2 tert-Butyl (1-((3-((1-(azetidin-3-yl)piperidin-4-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)- carbamate tert-Butyl (1-((3-(piperidin-4-yl onyl)piperidin-4-yl)carbamate was 5 converted to the title compound by proceeding analogously as described in Reference 27, Steps 1 and 2 above using benzyl 3-oxoazetidine-1-carboxylate.
  • Step 3 3-(4-(2-Hydroxyethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
  • me droxyethoxy)benzoate (2.00 g, 6.92 mmol, 1.00 eq.) in ACN (70.0 mL)
  • 3-aminopiperidine-2,6-dione hydrochloride 10 (1.48 g, 8.99 mmol, 1.30 eq.)
  • TEA 1.04 g, 10.28 mmol, 1.49 eq.
  • Step 4 2-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethyl 4-methylbenzenesulfonate 15
  • olin-2-yl)piperidine-2,6-dione 500 mg, 1.64 mmol, 1.00 eq.
  • DCM 1,0.0 mL
  • TEA 333 mg, 3.29 mmol, 2.00 eq.
  • TsCl 377 mg, 1.98 mmol, 1.21 eq.
  • DMAP 20 mg, 0.16 mmol, 0.10 eq.
  • Step 5 Benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate
  • benzyl 4-hydroxypiperidine-1-carboxylate (2.00 g, 8.50 mmol, 1.00 eq.) in DCM (20.0 mL) was added TEA (2.57 g, 25.40 mmol, 3.00 eq.) and MsCl (1.16 g, 25 10.13 mmol, 1.20 eq.) at 0 o C.
  • TEA 2.57 g, 25.40 mmol, 3.00 eq.
  • MsCl (1.16 g, 25 10.13 mmol, 1.20 eq.
  • Step 6 tert-Butyl (1-((3-(piperidin-4-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate 5 Benzyl 4-((methylsulfo e was converted to the title compound by proceeding analogously as described in Reference 12, Steps 5-6 above.
  • 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 10
  • a mixture o l)oxy)ethyl 4-methylbenzenesulfonate 50 mg, 0.11 mmol, 1.10 eq.
  • tert-butyl (1-((3-(piperidin-4- yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate 44 mg, 0.10 mmol, 1.00 eq.
  • KI 15 mg, 0.090 mmol, 0.90 eq.
  • DIPEA 35 mg, 0.27 mmol, 2.70 eq.
  • NKT-24-003PCT tert-Butyl (1-((3-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate was converted to the title compound by proceeding analogously as described in Reference 25, Step 7.
  • NKT-24-003PCT A mixture of tert-butyl (1-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (3.00 g, 7.18 mmol, 1.00 eq.), 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 eq.), X-Phos-Pd-G3 (608.0 mg, 0.72 mmol, 0.10 eq.) and K 3 PO 4 (4.57 g, 21.54 mmol, 3.00 eq.) in 1,4-dioxane (70.0 mL) and H 2 O (7.0 mL) was stirred 5 at 60 o C under N2 for 6 h.
  • Step 2 tert-Butyl (1-((3-(piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate 10
  • Step 3 Benzyl 4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin- 15 1-yl)methyl)piperidine-1-carboxylate
  • benzyl 4-formylpiperidine-1-carboxylate (2.63 g, 10.65 mmol, 1.50 eq.) and AcOH (426.0 mg, 7.10 20 mmol, 1.00 eq.) and the solution was stirred at RT for 1 h.
  • NKT-24-003PCT Step 4 tert-Butyl (1-((3-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)- carbamate A mixtur n-1-yl)- 5 sulfonyl)phenyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (3.80 g, 5.81 mmol, 1.00 eq.) and Pd/C (800 mg) in MeOH (40.0 mL) was stirred at 50 o C under H2 (50 psi) for 16 h. The mixture was filtered and concentrated to afford 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 10
  • 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 20 A mixt in-1-yl)- sulfonyl)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-cyanobenzoate (1.01g, 1.50 mmol, 1.00 eq.), NaH2PO2.H2O (1.59 g, 15.00 mmol, 10.00 eq.) and Raney Ni (1.60 g) in pyridine (10.0 mL), H 2 O (5.0 mL) and AcOH (5.0 mL) was stirred for 16 h at 70 o C under nitrogen atmosphere.
  • Step 7 tert-Butyl (1-((3-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4- 5 yl)methyl)piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate A mixt mmol, 1.30 eq.) and DIEA (184 mg, 1.43 mmol, 2.40 eq.) in dry DCM (5.0 mL) was stirred at RT for 10 min and then a solution of methyl 4-(4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1- 10 yl)sulfonyl)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-formylbenzoate (400 mg, 0.59 mmol, 1.00 eq.) in
  • the mixture was stirred at 45 o C under N2 for 3 h.
  • the mixture was cooled to 0 o C and NaBH(OAc)3 (375 mg, 1.77 mmol, 3.00 eq.) was added.
  • the mixture was stirrd at rt for 1h and then at 45 o C under N 2 for 16 h.
  • the mixture was cooled, diluted with water, and then extracted with DCM.
  • the combined 15 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, eluted with DCM/MeOH (40:1), to afford the title compound as a yellow solid.
  • NKT-24-003PCT A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (20.00 g, 64.91 mmol, 1.00 eq.) and 3-aminopiperidine-2,6-dione (11.71 g, 71.41 mmol, 1.10 eq.), K 2 CO 3 (26.87 g, 194.71 mmol, 3.00 eq.) in DMF was stirred at 70 o C overnight under N2 atmosphere. The mixture was poured into water after the reaction was complete and extracted with DCM. The combined organic layer 5 was washed with water, dried over anhydrous Na2SO4, filtered, and concentrated.
  • Step 2 tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5,6-dihydropyridine- 1(2H)-carboxylate 10 A mixtur .00 g, 3.11 mmol, 1.00 eq.), 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 eq.), K 3 PO 4 (800 mg,3.73 mmol,1.20 eq) and Pd(dppf)Cl 2 (114 mg,0.16 mmol,0.05 eq) in DMF (10.0 mL) was stirred at 90 o C for 12 h.
  • Step 3 tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate To a stir oindolin-5-yl)-5,6- dihydropyridine-1(2H)-carboxylate (200 mg, 0.47 mmol, 1.00eq.) in THF (2.0 mL) was added 20 Pd/C(40 mg, 20%w/w).
  • Step 4 3-(1-Oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione DC (2,6- 25 dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate (100 mg, 0.234 mmol, 1.00 - 153 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT eq.) and the mixture was stirred at RT for 2 h.
  • 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 5
  • a sti idine-2,6-dione 76.60 mg, 0.23 mmol, 1.00 eq
  • THF 1.0 mL
  • DMF 1.0 mL
  • HCOOH(1 drop) tert-butyl (1-((3-(4-formylpiperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (105.60 mg,0.23 mmol 1.00 eq).
  • Step 2 4-(Dimethoxymethyl)piperidine To a mixture of benzyl e-1-carboxylate (948 mg, 3.23 mmol, 1.00 eq.) in MeOH (10.0 mL) was added Pd/C (400 mg) and the reaction mixture was 5 stirred at RT under H 2 for overnight.
  • Step 3 tert-Butyl (1-((3-(4-(dimethoxymethyl) piperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)- carbamate 10
  • reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with water and brine 15 and concentrated. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to give the title compound as white solid.
  • Step 4 tert-Butyl (1-((3-(4-formylpiperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate
  • DCM 4.0 mL
  • TFA 4.0 mL
  • NKT-24-003PCT 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 The comp Step 5.
  • Step 2 tert-Butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidine-1-carboxylate
  • a solut mg, 1.72 mmol, 20 3.00 eq.) 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 eq.), CuI (12 mg, 0.06 mmol, 0.10 eq.), Pd(dppf)Cl2 (44 mg, 0.06 mmol, 0.10 eq.) in DMA (2.0 mL).
  • Step 3 3-(5-(Azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 5
  • DCM 1.0 mL
  • TFA 0.2 mL
  • Step 2 tert-Butyl (1-((3-(piperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT
  • the title compound was prepared analogously as described in Reference 30, Step 2.
  • Step 3 Benzyl 4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazin- 1-yl)methyl)piperidine-1-carboxylate 5
  • 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 15 B yl)piperazin- 1-yl)methyl)piperidine-1-carboxylate was converted to the title compound using similar procedure as described in Reference 28, Step 4-7.
  • NKT-24-003PCT Step 1 tert-Butyl (1-((3-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)sulfonyl)piperidin-4-yl)- carbamate A mixture o carbamate (1.00 g, 5 2.40 mmol, 1.00 eq.), K2CO3(1.16 g, 8.40 mmol, 3.50 eq.), CuI (91 mg, 0.480 mmol, 0.20 eq.), L-proline (83 mg, 0.72 mmol, 0.30 eq.) and 1,4-dioxa-8-azaspiro[4.5]decane (412 mg, 2.88 mmol, 1.20 eq.) in DMSO (10.0 mL) was stirred at 90 o C overnight.
  • reaction mixture was diluted with water and extracted with DCM.
  • the combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated.
  • the residue was purified by silica gel column 10 chromatography eluting with PE/EtOAc (1:1) to give the title compound as yellow solid.
  • Step 2 tert-Butyl (1-((3-(4-oxopiperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate
  • a mixture henyl)- sulfonyl)piperidin-4-yl)carbamate (624 mg, 1.30 mmol, 1.00 eq.), TsOH.H 2 O (49 mg, 0.26 mmol, 15 0.20 eq.) in acetone (6.0 mL) and H2O (12.0 mL) was stirred at 60 o C overnight.
  • the mixture was extracted with DCM.
  • the combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated.
  • Step 3 tert-Butyl (1-((3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- 20 benzo[d]imidazol-4-yl)-[1,4'-bipiperidin]-1'-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate tert-But rbamate (44 mg, 1.02 mmol, 0.90 eq.) and 1 drop of AcOH was added to a mixture of 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, 25
  • Step 2 3-(4-(Azetidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine- 20 2,6-dione O Boc O N N N NH N N
  • Step 2 tert-Butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate 15
  • Step 3 tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1- carboxylate - 161 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT tert-Butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate was converted to the title compound by proceeding analogously as described in Reference 28, Step 6-7.
  • 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 A mixtu dine-2,6-dione (74 mg, 0.33 mmol, 1.00 eq.), tert-butyl (1-((3-(bromomethyl)phenyl)sulfonyl)piperidin-4- 15 yl)carbamate (138 mg, 0.32 mmol, 1.50 eq.), TEA (127 mg, 1.26 mmol, 6.00 eq.) in THF (5.0 mL) was stirred at 55 o C overnight.
  • Step 1 tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1- carboxylate A mixture of , 1.00 eq.) and 2-(2,6- 5 dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (1.50 g, 5.10 mmol, 1.00 eq.), DIEA (1.97 g, 15.30 mmol, 3.00 eq.) in NMP (15.0 mL) was stirred at 110 o C overnight.
  • Step 2 2-(2,6-Dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione
  • DCM 4.0 mL
  • TFA 1.0 mL
  • Step 4 tert-Butyl (1-((3-(bromomethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate tert-Butyl piper in THF (20.00 mL) was 25 added to a stirred solution of 3-(bromomethyl)benzenesulfonyl chloride (3.79 g, 18.95 mol, 0.90 eq.) in THF (40.00 mL) and TEA (4.25 g, 42.10 mmol, 2.00 eq.) at 0 o C.
  • the resulting mixture - 163 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • 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
  • a mixture oindoline-1,3-dione (509 mg, 1.41 mmol, 1.00 eq.)
  • tert-butyl (1-((3-(bromomethyl)phenyl)sulfonyl)-piperidin-4- 10 yl)carbamate (916 mg, 2.12 mmol, 1.50 eq.)
  • TEA (854 mg, 8.46 mmol, 6.00 eq.
  • Step 2 tert-Butyl (1-((3-((8-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3,8- 5 diazabicyclo[3.2.1]octan-3-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate tert-Butyl n-5-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate was converted to the title compound proceeding analogously as described in Reference 36, Step 2-5.
  • NKT-24-003PCT Step 2 tert-Butyl 4-(3-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate
  • Step 3 tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate 10 A mixtu mmol, 1.20 eq.) DIEA (4.03 g, 31.22 mmol, 2.42 eq.), AcOH (10.63 g, 188.76 mmol, 13.78 eq.) and tert-butyl 4-(3-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (4.50 g, 12.90 mmol, 1.00 eq.) in DCM (50.0 mL) was stirred at 35 o C for 4 h and then NaBH(OAc)3 (8.20
  • Step 4 3-(1-Oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione 20 To a soluti dolin-5-yl)piperazine- 1-carboxylate (72 mg, 0.17 mmol, 1.00 eq.) in DCM (4.0 mL) was added TFA (1.0 mL).
  • NKT-24-003PCT Step 2 tert-Butyl 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane- 2-carboxylate tert-buty nonane-2- 5 carboxylate was converted to the title compound by proceeding analogously as described in Reference 28, Step 6-7.
  • Step 3 3-(1-Oxo-5-(2,7-diazaspiro[3.5]nonan-7-yl)isoindolin-2-yl)piperidine-2,6-dione
  • TFA 0.5 mL
  • 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 15 A mixtur l)piperidine-2,6- dione (173 mg, 0.47 mmol, 1.00 eq.) and tert-butyl (1-((3-(bromomethyl)phenyl)sulfonyl)- piperidin-4-yl)carbamate (264 mg, 0.61 mmol, 1.30 eq.) TEA (285 mg, 2.82 mmol, 6.00 eq.) in THF (5.0 mL) was stirred at 55 o C overnight.
  • Step 2 rac-tert-Butyl ((3R,4S)-1-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3- 15 dioxoisoindolin-5-yl)piperazin-1-yl)methyl)phenyl)sulfonyl)-3-fluoropiperidin-4-yl)carbamate
  • Step 2 2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbaldehyde 15
  • NKT-24-003PCT Step 3 Benzyl 4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenoxy)piperidine- 1-carboxylate
  • benzyl 4-((methylsulfonyl)oxy)piperidine-1- carboxylate (7.52 g, 24 mmol, 1.50 eq.) and Cs 2 CO 3 (10.4 g, 32 mmol, 2.00 eq.) in DMSO (70.0 mL) was stirred at 90 o C for 4 h and then extracted with EtOAc.
  • Step 4 tert-Butyl (1-((3-(piperidin-4-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate 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 eq.), HCOONH 4 ( 3.3 g, 52.35 mmol, 15 5.00 eq.), and Pd(OH)2 (1.2 g) in EtOH (60.0 mL) was stirred at 70 o C for 4 h.
  • 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 20
  • T dehyde 100 mg, 0.37 mmol, 1.00 eq.
  • THF 3.0 mL
  • tert-butyl (1-((3-(piperidin-4-yloxy)phenyl)- sulfonyl)piperidin-4-yl)carbamate 169 mg, 0.39 mmol, 1.05 eq.
  • 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 20 Ben enyl)-piperazin- 1-yl)azetidine-1-carboxylate was converted to the title compound using similar procedure as described in Reference 28, Step 4-7. - 172 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • Step 2 tert-Butyl (1-((3-(3-hydroxyazetidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate A mixt amate (5.83 g, 13.95 mmol, 1.00 eq.), K 2 CO 3 (6.74 g, 48.83 mmol, 3.50 eq.), CuI (0.53 g, 2.79 mmol, 0.20 eq.), 15 L-PRO (481 mg, 4.19 mmol, 0.30 eq.) and 3-hydroxyazetidine (2.28 g, 20.92 mmol, 1.50 eq.) in DMSO (50.00 mL) was stirred at 90 o C for 12 h.
  • Step 3 tert-Butyl (1-((3-(3-oxoazetidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate 20 T nyl)- piperidin-4-yl)carbamate (0.50 g, 1.22 mmol, 1.00 eq.) in DCM (5.00 mL) was added Dess-Martin (1.03 g, 2.44 mmol, 2.00 eq.) and the mixture was stirred at 0 o C for 3 h.
  • Step 4 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 5
  • To din-4- yl)carbamate (40.00 mg, 0.10mmol, 1.00 eq.) in THF(1.00 mL) and DMF (0.50 mL) were 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 eq.).
  • Step 2 Methyl 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propanoate Methyl acrylate (209 to a solution of 6-bromo-1- methyl-1H-indazol-3-amine (55.00 g, 0.24 mol, 1.00 eq.), DBU (55.00 g, 0.36 mol, 1.50 eq.), 15 lactic acid (33.00 g, 0.36 mol, 1.50 eq.) at 0 o C, and the mixture was stirred at 90 o C 20 h under N 2 .
  • Step 3 Methyl 3-(1-(6-bromo-1-methyl-1H-indazol-3-yl)ureido)propanoate 20 NaOCN (26.00 g, 0.3 ion of methyl 3-((6-bromo-1- methyl-1H-indazol-3-yl)amino)propanoate (50.00 g, 0.16 mol, 1.00 eq.) in AcOH (500.0 mL), and - 175 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT the mixture was stirred at 80 o C 20 h under N2. The mixture was diluted with water and extracted with EA, and the organic layer was washed with sat. NaHCO 3 aq., water, brine, dried over Na2SO4, concentrated to give the title compound as yellow solid.
  • Step 4 1-(6-Bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 5
  • MeCN MeCN
  • Tirton-B 7.90 g, 0.05 mol, 0.30 eq.
  • Step 5 tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-5,6- dihydropyridine-1(2H)-carboxylate
  • 1,4-dioxane/H2O 10 mL/1 mL
  • 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 eq.
  • K3PO4 (2.20 g, 10.22 mmol, 3.00 eq.
  • X-Phos-Pd G3 289 mg, 0.34 mmol, 0.
  • NKT-24-003PCT Step 6 tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)piperidine-1-carboxylate
  • a mixture of te )-yl)-1-methyl-1H- 5 indazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate 300 mg, 0.71 mmol, 1.00 eq.
  • Pd/C 150mg, 50% wt
  • Pd(OH)2 150mg, 50% wt
  • THF 20.0 mL
  • Step 7 1-(1-Methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 10 2,2,2-trifluoroacetate
  • Step 8 rac-tert-Butyl ((3R,4S)-1-((3-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl- 1H-indazol-6-yl)piperidin-1-yl)methyl)phenyl)sulfonyl)-3-fluoropiperidin-4-yl)carbamate A m dine- 20 2,4(1H,3H)-dione (82 mg, 0.25 mmol, 1.00 eq.), rac-tert-butyl ((3R,4S)-1-((3- (bromomethyl)phenyl)sulfonyl)-3-fluoropiperidin-4-yl)carbamate (115 mg, 0.25 mmol, 1.00 eq.) in DCM (4.0 mL), and TEA (76 mg, 0.75 m
  • Step 9 rac-1-(6-(1-(3-(((3R,4S)-4-amino-3-fluoropiperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)- 1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 5
  • Step 2 tert-Butyl 4-(4-aminophenyl)piperidine-1-carboxylate A mixture of tert- -1(2H)-carboxylate (1.20 g, 3.95 mmol, 1.00 eq), Pd/C (360 mg) in MeOH/THF (30 mL, 1:1) was stirred at 45 °C under H 2 10 overnight. The mixture was filtered and concentrated, and the residue was purified by silica flash column PE/EtOAc (3:1) to give product as yellow solid.
  • Step 3 tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate
  • 3-bromopiperidine-2,6-dione (242 mg, 1.26 mmol, 1.05 eq.)
  • NaHCO3 (302 mg, 3.60 mmol, 3.00 eq.)
  • DMF 4.0 mL
  • Step 4 3-((4-(Piperidin-4-yl)phenyl)amino)piperidine-2,6-dione TFA (0. tyl 4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidine-1-carboxylate (100 mg, 0.26 mmol, 1.00 eq.) in DCM (2.0 mL) and the mixture was stirred at rt for 2 h. The solution was concentrated to give the title compound as a 25 yellow solid.
  • Step 2 2,6-Bis(benzyloxy)-3-bromopyridine NBS (8.70 g, 0.05 mol olution 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 o C 15 for 4 h under N 2 . The mixture was diluted with water and extracted with EA. The combined organic layers was washed with brine, dried over Na2SO4, concentrated to give the title compound as yellow solid.
  • Step 3 2,6-Bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 20
  • KOAc - 180 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT (10.00 g, 0.10 mol, 2.00 eq.), and Pd(dppf)Cl2 (3.7 g, 5.00 mmol, 0.10 eq.) in 1,4-dioxane (200.0 mL) was stirred at 100 o C for 25 h under N 2 .
  • the mixture was diluted with water and extracted with EA, and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated.
  • Step 4 2,6-Bis(benzyloxy)-3-(4-bromophenyl)pyridine
  • a mixture of 2,6- dioxaborolan-2-yl)pyridine (4.42 g, 10.60 mmol, 1.20 eq.), 1-bromo-4-iodobenzene (2.50 g, 8.83 mol, 1.00 eq.), K3PO4 (5.63 10 g, 26.50 mmol, 3.00 eq.), and Pd(PPh 3 ) 4 (510 mg, 0.44 mmol, 0.05 eq.) in 1,4-dioxane/H 2 O 10:1 (40.0 mL) was stirred at 100 o C for 16 h under N2.
  • Step 5 tert-Butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carboxylate A mixture of mg, 1.12 mmol, 1.00 eq.), tert-butyl piperazine-1-carboxylate (417 mg, 2.24 mmol, 2.00 eq.), Cs2CO3 (730 mg, 2.24 mmol, 2.00 eq.), Pd 2 (dba) 3 (51 mg, 0.06 mmol, 0.05 eq.), and Ruphos (52 mg, 0.11 mmol, 0.10 20 eq.) in toluene (15.0 mL) was stirred at 110 o C for 20 h under N2.
  • NKT-24-003PCT Step 6 tert-Butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate
  • a mixture of l)piperazine-1- carboxylate (260 mg, 0.47 mmol, 1.00 eq.), 10% Pd/C (260 mg) in EA (5.0 mL) and 1,4-dioxane 5 (5.0 mL) was stirred at r.t for 20 h under H2. The mixture was filtered and the filtrate was concentrated to give the title compound as yellow oil.
  • Step 7 3-(4-(Piperazin-1-yl)phenyl)piperidine-2,6-dione TFA (0.5 mL) 2,6-dioxopiperidin-3- 10 yl)phenyl)piperazine-1-carboxylate (160 mg, 0.43 mmol, 1.00 eq.) in DCM (2.0 mL) and the mixture was stirred at r.t for 2 h under N2. The mixture was concentrated to give the title compound as its TFA salt as yellow oil.
  • NKT-24-003PCT Step 2 N-(piperidin-4-yl)-5-(trifluoromethyl)thiazol-2-amine hydrochloride A mixture of tert-butyl 4-(( yl)amino)piperidine-1-carboxylate (200 mg, 0.57 mmol, 1.00 eq.) and 2.0 M HCl in EtOAc (2.0 mL) was stirred at r.t. under N 2 for 2 5 h. The mixture was concentrated to give the title compound as off-white solid.
  • the following references were prepared by proceeding analogously as described in Reference 48.
  • NKT-24-003PCT NaH (2.10 g, 52.83 mmol, 2.00 eq.) was added to a stirred solution of 6-bromo-1H- indazol-3-amine (5.60 g, 26.42 mmol, 1.00 eq.) in DMF (20.0 mL) at 0 o C and the mixture was stirred at 0 o C for 1h.2,2,2-Trifluoroethyl trifluoromethanesulfonate (6.7 g, 29.06 mmol, 1.10 eq.) was added and the mixture was stirred at r.t. for 3 h under N 2 . The mixture was poured into cold 5 water and filtered.
  • Step 2 1-(6-(Piperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione 10
  • the title compound was synt g analogously as described in Reference 45, Steps 2-7 with 6-bromo-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine replacing 6-bromo-1- methyl-1H-indazol-3-amine.
  • NKT-24-003PCT Step 2 Benzyl 4-(3-amino-1H-indazol-6-yl)piperazine-1-carboxylate A mixture of b boxylate (11.00 g, 32.40 mmol, 1.00 eq.) and N2H4/H2O (10.14g, 161.99 mmol, 5.00 eq) in BuOH (100.0 mL) was stirred 5 at 100 °C under N2 for 16 h. The mixture was concentrated and purified by flash chromatography to give the title compound as yellow solid.
  • Step 3 Benzyl 4-(3-amino-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate
  • arboxylate 4.00 g, 10 11.40 mmol, 1.00 eq.
  • dry DMF 50.0 mL
  • NaH 0.91 g, 22.80 mmol, 2.00 eq.
  • N 2 N 2
  • CH 3 I 1.78 g, 12.54 mmol, 1.10 eq.
  • Step 4 Benzyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)- piperazine-1-carboxylate 20
  • - 185 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT Step 5: 1-(1-Methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • a mixture of b indazol-6-yl]piperazine- 1-carboxylate (500 mg, 1.08 mmol, 1.00 eq.), 10% Pd/C (400 mg) and ammonium formate (682 5 mg, 10.81 mmol, 10.00 eq.) in MeOH (20.0 mL) was stirred at 60 °C under N2 for 16 h. The mixture was filtered and the filtrate was concentrated to give the title compound as white solid.
  • Step 2 3-((6-(4-((Benzyloxy)carbonyl)piperazin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)- amino)propanoic acid - 186 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • Step 3 Benzyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol- 6-yl)piperazine-1-carboxylate
  • 2,2-trifluoroethyl)-1H- 10 indazol-3-yl)amino)propanoic acid 620 mg, 1.23 mmol, 1.00 eq.
  • urea 369 mg, 6.15 mmol, 5.00 eq.
  • Step 4 1-(6-(Piperazin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione
  • a mixture of b l)-1-(2,2,2- trifluoroethyl)-1H-indazol-6-yl)piperazine-1-carboxylate (280 mg, 0.52 mmol, 1.00 eq.), 20 HCOONH 4 (312 mg, 5.20 mmol, 10.0 eq.) and 10% Pd/C (100 mg) in THF/MeOH (5.0 mL/5.0 mL) was stirred at 60 o C under N2 overnight.
  • Step 2 tert-Butyl 3,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)- 15 carboxylate Tf2O (3.03 g, 10.77 of tert-butyl 3,3-difluoro-4- oxopiperidine-1-carboxylate (1.68 g, 7.18 mmol, 1.00 eq.) and DIEA (5.56 g, 43.08 mmol, 6.00 eq.) in DCM (20.0 mL).
  • NKT-24-003PCT Step 3 tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3- difluoro-3,6-dihydropyridine-1(2H)-carboxylate F O F F Boc F N A mixture of n-2-yl)-1H-indazol-3- 5 yl)dihydropyrimidine-2,4(1H,3H)-dione (800 mg, 2.00 mmol, 1.00 eq.), tert-butyl 3,3-difluoro-4- (((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (1.10 g, 3.00 mmol, 1.50 eq.), Na2CO3 (636 mg, 6.00 mmol, 3.00 eq.), P
  • Step 4 tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3- difluoropiperidine-1-carboxylate
  • a mi ethyl-1H- 15 indazol-6-yl)-3,3-difluoro-3,6-dihydropyridine-1(2H)-carboxylate (940 mg, 2.00 mmol, 1.00 eq.), 10% Pd/C (900mg) and Pd(OH) 2 (900mg) in MeOH (10.0 mL) was stirred at 50 o C under H 2 (50 PSI) overnight.
  • Step 2 tert-Butyl (1-((3-(bromomethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate 15 3-(Bromomet 00 eq.) in THF (20.0 mL) was added to a stirred solution of tert-butyl piperidin-4-ylcarbamate (3.83 g, 19.13 mol, 0.90 eq.), TEA (4.30 g, 42.50 mmol, 2.00 eq.) in THF (40.0 mL) at 0 o C and the mixture was stirred at RT for 12h.
  • Step 3 tert-Butyl (1-((3-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)piperidin-1-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate 25 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT A mixture of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)- dione 2,2,2-trifluoroacetate (50 mg, 0.15 mmol, 1.00 eq.) and tert-butyl (1-((3-(bromomethyl)- phenyl)sulfonyl)piperidin-4-yl)carbamate (99 mg, 0.23 mmol, 1.50 eq.), TEA (45 mg, 0.45 mmol, 3.00 eq.) in THF (5.0 mL) was stirred at 55 o C overnight.
  • Step 4 1-(6-(1-(3-((4-Aminopiperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-indazol- 3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-trifluoroacetate 10
  • Step 2 1-(1-Methyl-6-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione
  • a mixtu l)-1-methyl-1H- 20 indazol-6-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (200 mg, 0.38 mmol, 1.00 eq.) in TFA/DCM (0.5 mL/2.0 mL) was stirred at rt for 2 h. The mixture was concentrated to give the title compound as brown oil.
  • Step 3 tert-Butyl (1-((4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)piperidin-1-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate tert-Buty mol, 1.05 eq.) in 5 DCM (2.0 mL) was added to a mixture of 1-(1-methyl-6-(1-(piperidin-4-ylmethyl)piperidin-4-yl)- 1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (80 mg, 0.19 mmol, 1.00 eq.), TE
  • Step 4 1-(6-(1-((1-((4-Aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)piperidin-4-yl)-1- methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-trifluoroacetate 15
  • NKT-24-003PCT Step 1 tert-Butyl (1-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate 3-Bromobenze .) in THF (50.0 mL) was added to a stirred solution of tert-butyl piperidin-4-ylcarbamate (4.12 g, 20.55 mmol, 1.05 eq.) in 5 THF (50 mL) and TEA (2.18 g, 21.53 mmol, 1.10 eq.) dropwise at -10 °C, and the mixture was stirred at rt for 2 h.
  • Step 2 tert-Butyl (1-((3-(4-(hydroxymethyl)piperidin-1-yl)phenyl)sulfonyl)piperidin-4- 10 yl)carbamate
  • Step 3 tert-Butyl (1-((3-(4-formylpiperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate 20 Dess-Martin (2.53 ed solution of tert-butyl (1- ((3-(4-(hydroxymethyl)piperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (1.35 g, 2.98 mmol, 1.00 eq.) in DCM (15.0 mL) at 0 o C, and the mixture was stirred at RT for 2 h. The mixture was quenched with H 2 O and then extracted with DCM.
  • Step 4 tert-Butyl (1-((3-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol- 6-yl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate 5
  • a mixtur piperidin-4- yl)carbamate (264 mg, 0.585 mmol, 1.00 eq.), CH3COOH (1 drops) and 1-(1-methyl-6-(piperidin- 4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (191.5 mg, 0.585 mmol,1.00 eq.) in THF (2.0 mL)/DMF (2.0 mL) was stirred at 45 o C for 0.5 h.
  • Step 5 1-(6-(1-((1-(3-((4-Aminopiperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4- yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-trifluoroacetate
  • Step 2 1-(1-Methyl-6-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione 2,2,2-trifluoroacetate 20 - 196 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT A mixture of tert-butyl 6-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (90 mg, 0.204 mmol, 1.00 eq.) in TFA/DCM (0.5 mL/2 mL) was stirred at rt for 2 h. The mixture was concentrated to give the title compound as brown oil.
  • the suspension was allowed to cool to rt and stirred overnight before being quenched at 0 °C by the slow addition of water, 1N aq. NaOH and water.
  • the solid 15 was removed by filtration.
  • the solid was dissolved in 1N aq. HCl and the resulting solution was extracted with EA.
  • the combined organic extracts were concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography to afford the title compound as a yellow oil.
  • Step 2 tert-Butyl ((1r,4r)-4-((3-(hydroxymethyl)phenyl)thio)cyclohexyl)carbamate 20
  • Step 3 tert-Butyl ((1r,4r)-4-((3-formylphenyl)thio)cyclohexyl)carbamate 5
  • yl)phenyl) thio)cyclohexyl)- carbamate 260 mg, 0.77 mmol, 1.0 eq
  • DMP 653.5 mg, 1.54 mmol, 2.0 eq
  • the resulting mixture was stirred for 2 h at 25 °C.
  • the resulting mixture was diluted with water, quenched with saturated Na 2 S 2 O 3 and saturated NaHCO 3 at 0 °C.
  • Step 4 tert-Butyl ((1r,4r)-4-((3-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperidin-1-yl)methyl)phenyl)thio)cyclohexyl)carbamate 15
  • clohexyl)carbamate 200 mg, 0.6 mmol, 1.0 eq
  • 1-[1-methyl-6-(4-piperidyl)indazol-3-yl]hexahydropyrimidine- 2,4-dione (hydrochloride salt, 216.9 mg, 0.6 mmol, 1.0 eq) in anhydrous DCE (20 mL) at 0 °C was added sodium triacetoxyborohydride (379.1 mg, 1.8 mmol, 1.0 eq) in portions and the 20 resulting mixture was stirred for 16
  • NKT-24-003PCT Step 5: 1-(6-(1-(3-(((1r,4r)-4-Aminocyclohexyl)thio)benzyl)piperidin-4-yl)-1-methyl-1H-indazol- 3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-trifluoroacetate
  • Step 6 1-(6-(1-(3-(((1s,4s)-4-Aminocyclohexyl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H- 10 indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-trifluoroacetate
  • a )piperidin-4-yl)- 1-methyl-1H-indazol-3-yl)dihydro pyrimidine-2,4(1H,3H)-dione 2,2,2-trifluoroacetate (0.15 mmol, 1.0 eq) in anhydrous DCM (10 mL) at 0 °C was added m-CPBA (78.4 mg, 0.45 mmol, 3.0 15 eq) and the resulting mixture was stirred
  • Step 2 (2S,4R)-4-Hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2- carboxamide iazol-5-yl)- phenyl]ethyl]carbamoyl]pyrrolidine-1-carboxylate (3.77 g, 8.74 mmol) in DCM (20 mL) was 20 added 4M HCl-dioxane (20 mL, 80 mmol) and the reaction mixture was stirred at room temperature for 1 h.
  • Step 3 (9H-Fluoren-9-yl)methyl ((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxo-3-(tritylthio)butan-2-yl)carbamate
  • a sol hyl-3-trityl- 5 sulfanyl-butanoic acid 1576.6 mg, 2.57 mmol
  • reaction mixture was diluted with water, extracted with EA. The combined organic layers were washed with brine, dried over anhydrous 10 sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to afford the title compound.
  • Step 4 (2S,4R)-1-((R)-2-Amino-3-methyl-3-(tritylthio)butanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 15
  • To a solution of 9H-fluoren-9-ylmethyl N-[(1R)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4- methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-2-tritylsulfanyl- propyl]carbamate (1360 mg, 1.47 mmol) in DCM (10 mL) was added piperidine (0.29 mL, 2.93 mmol) at room temperature, and the solution was stirred at 25 °C for 3 h.
  • reaction mixture 20 was diluted with water, extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to afford the title compound.
  • Step 5 (2S,4R)-1-((R)-2-(1-Fluorocyclopropane-1-carboxamido)-3-methyl-3-(tritylthio)- 25 butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2-carboxamide
  • a solut tanoyl]-4-hydroxy- N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (2.1 g, 2.98 mmol) - 201 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref.
  • Step 6 (2S,4R)-1-((R)-2-(1-fluorocyclopropane-1-carboxamido)-3-mercapto-3-methylbutanoyl)- 4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2-carboxamide
  • TFA 10 mL, 129.8 mmol
  • triisopropylsilane (1.03 mL, 5.01 mmol).
  • Step 7 tert-Butyl 4-((((R)-3-(1-fluorocyclopropane-1-carboxamido)-4-((2S,4R)-4-hydroxy-2- (((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-2-methyl-4-oxobutan-2- yl)thio)methyl)piperidine-1-carboxylate DBU (243 [(2R)-2-[(1- 20 fluorocyclopropanecarbonyl)amino]-3-methyl-3-sulfanyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4- methylthiazol-5-y
  • Step 9 tert-Butyl (1-((3-((4-((((R)-3-(1-fluorocyclopropane-1-carboxamido)-4-((2S,4R)-4- hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl) pyrrolidin-1-yl)-2-methyl-4- oxobutan-2-yl)thio)methyl)piperidin-1-yl)methyl)phenyl) sulfonyl)piperidin-4-yl)carbamate 5 A mixture o)-3-methyl-3- ((piperidin-4-ylmethyl)thio)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)- ethyl
  • Step 2 tert-Butyl (1-((3-vinylphenyl)sulfonyl)piperidin-4-yl)carbamate 5
  • t rbamate 5 g, 11.92 mmol
  • potassium vinyltrifluoroborate 2.4 g, 17.89 mmol
  • Pd(dppf)Cl2 872.48 mg, 1.19 mmol
  • potassium carbonate 4.9 g, 35.77 mmol
  • Step 3 tert-Butyl (1-((3-(2-hydroxyethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate
  • a yl)carbamate 15 (4.05 g, 11.05 mmol) in anhydrous tetrahydrofuran (40 mL) was added borane-tetrahydrofuran complex (16.58 mL, 16.58 mmol) dropwise at 25 °C under argon atmosphere and the mixture was stirred for 2.5 h.10% sodium hydroxide aq (8840.86 mg, 22.1 mmol) was added slowly, followed by hydrogen peroxide (2.26 mL, 22.1 mmol, 30%).
  • NKT-24-003PCT Step 4 tert-Butyl (1-((3-(2-oxoethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate
  • a stirred soluti yl)sulfonyl) piperidin-4-yl)- carbamate 200 mg, 0.52 mmol
  • Dess-Martin 5 Periodinane 441.25 mg, 1.04 mmol
  • the mixture was diluted with ethyl acetate, washed with sodium sulfite (aq.), sodium bicarbonate (aq.), water, brine, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound as a white solid.
  • Step 5 tert-Butyl (1-((3-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol- 10 6-yl)piperidin-1-yl)ethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate
  • Step 2 tert-Butyl (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol- 6-yl)piperidin-1-yl)-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate 5
  • Step 3 1-(6-(1-(3-(3-((4-Aminopiperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl) piperidin-4-yl)- 1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride 1(2H)-yl)- 1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)phenyl)sulfonyl) piperidin-4-yl)- 20 carbamate (62 mg, 0.086 mmol) in dichloromethane (2 mL) was added 4 M hydrogen chloride in dioxane (1.0 mL) at 0 °C and the mixture was stirred for 1 h.
  • Step 2 tert-Butyl (1-((3-bromo-4-cyanophenyl)sulfonyl)piperidin-4-yl)carbamate 3-Bromo-4-cyan l, 1.00 eq.) in DCM (5.0 mL) was added to a stirred solution of tert-butyl piperidin-4-ylcarbamate (359.2 mg, 1.79 mmol, 20 1.00 eq.) and TEA (542.4 mg, 5.37 mmol, 3.00 eq.) in DCM (5.0 mL) dropwise at 0 °C. The mixture was stirred at rt for 2h. The mixture was poured into water and extracted with DCM.
  • NKT-24-003PCT Step 3 tert-Butyl (1-((4-cyano-3-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4- yl)carbamate
  • 2-(di-tert- butylphosphaneyl)-1-phenyl-1H-indole (20 mg, 0.06 mmol, 0.06 eq.)
  • N-cyclohexyl-N- methylcyclohexanamine (194.4 mg, 1.17 mmol, 1.1 eq.)
  • 2-methylprop-2-en-1-ol 130 mg, 1.8 mmol, 2.00 eq.
  • Pd 2 (dba) 3 (16.8 mg, 0.02 mmol, 0.02 eq.).
  • Step 4 4-((4-Aminopiperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)- 1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile hydrochloride NHBoc HCl NH 2 N N O O N S O 15 O The title escribed in Reference 61 Step 2-3.
  • NKT-24-003PCT Step 1 tert-Butyl(1-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperidin-4- yl)carbamate
  • o tert- uty ( -(( - romop eny )su ony )piperidin-4-yl)carbamate 5 5 g, 11.92 mmol, 1 eq.) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.03 g, 11.92 mmol, 1 eq.) in 1,4-dioxane (50 mL) was added Pd(dppf)Cl2 (0.87 g, 1.19 mmol, 0.1 eq.) and AcOK (3.51 g
  • Step 2 tert-Butyl (1-((3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamate 15
  • a stirred solu , , , ,2-dioxaborolan-2- yl)phenyl)sulfonyl)piperidin-4-yl) carbamate (9 g, 19.3 mmol, 1 eq.) in ACN (90 mL) was added H2O2 (30%, 45 mL) at rt.
  • the resulting mixture was stirred for 10 min at room temperature.
  • the mixture was quenched with sat. Na 2 SO 3 solution at 0°C and the resulting mixture was extracted 20 with EtOAc.
  • NKT-24-003PCT Step 3 Methyl (S)-2-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1- yl)sulfonyl)phenoxy)propanoate
  • m xture o tert- uty ( -(( - y roxyp eny )su ony)piperidin-4-yl)carbamate 5 (2 g, 5.6 mmol, 1.0 eq.
  • PPh 3 2.2 g, 8.4 mmol, 1.5 eq.
  • methyl (2S)-2-hydroxypropanoate 600 mg, 5.78 mmol, 1.03 eq.
  • THF 20 mL
  • Step 4 tert-Butyl (S)-(1-((3-((1-hydroxypropan-2-yl)oxy)phenyl)sulfonyl)piperidin-4- yl)carbamate 15
  • THF 16 mL
  • 2 M LiAlH4 in THF 3.6 mL, 7.2 mmol, 2 eq.
  • Step 5 (S)-1-(6-(1-(2-(3-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1- methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride - 212 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT The title reference compound was synthesized by proceeding analogous as described in Reference 60, Step 4-5.
  • Reference 62 Synthesis of 1-(6-(1-(3-(3-((4-Aminopiperidin-1-yl)sulfonyl)phenyl)-2,2-dimethylpropyl) 5 piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride
  • Step 1 tert-Butyl (1-((3-(2,2- nyl)piperidin-4-yl)carbamate A mixture of iperidyl]carbamate (1.0 10 g, 2.31 mmol), 2-methylpropanal (416 mg, 5.77 mmol), tetrabutylammonium iodide (85.24 mg, 0.23 mmol) and sodium hydroxide (323.06 mg, 8.08 mmol)
  • Step 2 tert-Butyl (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol- 6-yl)piperidin-1-yl)-2,2-dimethylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate 20 Tita ure of tert- butyl (1-((3-(2,2-dimethyl-3-oxopropyl)phenyl)sulfonyl) piperidin-4-yl)carbamate (530 mg, 1.25 mmol) and 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (408.7 mg, 1.25 mmol) in anhydrous N-methyl-2-pyrrolidone (5.3
  • Step 3 1-(6-(1-(3-(3-((4-Aminopiperidin-1-yl)sulfonyl)phenyl)-2,2-dimethylpropyl) piperidin-4- 5 yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride T in-1(2H)-yl)- 1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2,2-dimethylpropyl)phenyl) sulfonyl)piperidin-4- yl)carbamate (280 mg, 0.38 mmol) in dichloromethane (3 mL) was added 4 M hydrogen chloride 10 in dioxane (1.5 mL) at 0 °C and stirred for 1 h.
  • NKT-24-003PCT Step 2 tert-Butyl 4-(1-methyl-1H-indol-6-yl)piperidine-1-carboxylate
  • ydropyridine-1(2H)- carboxylate 4.0 g, 12.8 mmol, 1.00 eq.
  • THF 40 mL
  • 400 mg of 10% w/w Pd/C at 5 room temperature.
  • the mixture was hydrogenated at 50 °C for 16 h under hydrogen atmosphere using a hydrogen balloon.
  • the reaction mixture was filtered and the filtrate was concentrated.
  • the residue was purified by silica gel column chromatography, eluted with EtOAc/PE (0-20%), to afford the title compound as a yellow oil.
  • Step 3 tert-Butyl 4-(3-iodo-1-methyl-1H-indol-6-yl)piperidine-1-carboxylate 10
  • NIS NIS
  • Step 4 tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indol-6-yl)piperidine-1- carboxylate 20
  • dine-1-carboxylate 2.5 g, 5.7 mmol, 1.00 eq.
  • 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (2.51 g, 6.0 mmol, 1.05 eq.) in 1,4-dioxane/H 2 O (10:1, 25 mL) were added K 2 CO 3 (2.38 g, 17.2 mmol, 3.00 eq.) and Pd(dppf)Cl2 ⁇ CH2Cl2 (462
  • the resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere.
  • the - 215 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (0-40%), to afford the crude product.
  • the crude product 5 was purified by prep-HPLC to afford the title compound as a light yellow solid.
  • Step 5 tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indol-6-yl) piperidine-1- carboxylate
  • 3-yl)-1-methyl-1H- 10 indol-6-yl)piperidine-1-carboxylate 50 mg, 0.083 mmol, 1.00 eq.
  • EtOH 1 mL
  • Pd/C 10% w/w, 50 mg
  • the reaction mixture was filtered and the filtrate was concentrated to afford the title compound.
  • Step 2 2,6-Bis(benzyloxy)-3-(6-chlorobenzo[b]thiophen-3-yl)pyridine S Cl S Cl 5
  • a stirred solutio 370 mg, 1.49 mmol, 1.00 eq.
  • 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 624 mg, 1.50 mmol, 1.00 eq.
  • dioxane 4 mL
  • water 1 mL
  • Cs2CO3 1.5 g, 4.60 mmol, 3.09 eq.
  • Pd(dppf)Cl2 ⁇ CH2Cl2 243.5 mg, 0.33 mmol, 0.22 eq.
  • Step 3 tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)benzo[b]thiophen-6-yl)-3,6- 15 dihydropyridine-1(2H)-carboxylate
  • K 3 PO 4 362 mg, 1.71 mmol, 3.00 eq.
  • tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (175 mg, 0.57 20 mmol, 1.00 eq.) in dioxane and H2O (2.6 mL, 10:1) was added X-Phos Pd G3 (48 mg, 0.06 mmol, 0.10 eq.) at room temperature under nitrogen atmosphere.
  • NKT-24-003PCT Step 4 tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)benzo[b]thiophen-6-yl)piperidine-1-carboxylate To a stirred so -3-yl)benzo[b]thiophen- 6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (220 mg, 0.36 mmol, 1.00 eq.) in EtOH (3 5 mL) and AcOH (0.3 mL) was added 20 mg of 10% w/w Pd/C. The resulting mixture was stirred at room temperature for 3 h under hydrogen atmosphere using a hydrogen balloon.
  • Step 5 3-(6-(Piperidin-4-yl)benzo[b]thiophen-3-yl)piperidine-2,6-dione hydrochloride 10
  • enzo[b]thiophen-6- yl)piperidine-1-carboxylate 130 mg, 0.30 mmol, 1.00 eq.
  • DCM 1,4- dioxane
  • NKT-24-003PCT Step 1: 1-(1-Methyl-6-(1-(2-methylbut-3-yn-2-yl)piperidin-4-yl)-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione
  • DMSO dimethyl sulfoxide
  • 3-chloro-3-methylbut- 1-yne 451 mg, 4.4 mmol, 2.0 eq.
  • CuCl 21 mg, 22 mmol, 10.0 eq.
  • TEA TEA
  • Step 2 tert-Butyl (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol- 6-yl)piperidin-1-yl)-3-methylbut-1-yn-1-yl)phenyl) sulfonyl) piperidin-4-yl)carbamate
  • a te 211 mg,15 0.5 mmol, 1.1 eq.
  • DMF 1-(1-methyl-6-(1-(2-methylbut-3-yn-2-yl)piperidin- 4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (180 mg, 0.46 mmol, 1.0 eq.), Pd(dppf)Cl2 (37 mg, 0.05 mmol, 0.1 eq.) and CuI
  • Step 3 1-(6-(1-(4-(3-((4-Aminopiperidin-1-yl)sulfonyl)phenyl)-2-methylbut-3-yn-2-yl)piperidin- 4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride HCl O N N c HN O N N N Bo NH 2 N N H N O S O O O - 219 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT A mixture of tert-butyl (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperidin-1-yl)-3-methylbut-1-yn-1-yl)phenyl) sulfonyl)piperidin-4-yl)carbamate (300 mg, 0.41 mmol) in ethyl acetate (1 mL) and HCl/EtOAc (4 M, 1 mL) was stirred at r.t. for 2 hrs. The mixture was concentrated under reduced pressure to afford the title compound.
  • Step 2 tert-Butyl (1-((4-cyano-3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperidin-1-yl)but-1-yn-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate - - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT To a solution of 1-(6-(1-(but-3-yn-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (175 mg, 0.46 mmol, 1.0 eq.), CuI (7.98 mg, 0.04 mmol, 0.1 eq.), tert-butyl(1-((3-bromo-4-cyanophenyl)sulfonyl)piperidin-4-yl)carbamate (225.41 mg, 0.51 mmol, 1.1 eq.) and triethylamine (212.12 mg, 2.1 mmol, 4.0 eq.) in DMF (3 mL) was added 5 Pd(dppf)2Cl2 (30.68 mg, 0.04 mmol, 0.1 eq.) under argon atmosphere, then the resulting mixture was stirred at
  • reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title compound.
  • Step 3 4-((4-Aminopiperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)- 1-methyl-1H-indazol-6-yl)piperidin-1-yl)but-1-yn-1-yl)benzonitrile hydrochloride
  • a sol idin-1(2H)-yl)- 1-methyl-1H-indazol-6-yl)piperidin-1-yl)but-1-yn-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate 15 (116.26 mg, 0.16 mmol) in DCM (3 mL) was added 4.0M HCl in dioxane (1.5 mL, 6 mmol), then the resulting mixture was stirred at r.t for 1 h.
  • NKT-24-003PCT Step 1 (1-(3-Nitrophenyl)piperidin-4-yl)methanol A mixture o q.), piperidin-4- ylmethanol (16.33 g, 141.74 mmol, 2.00 eq.) and K 2 CO 3 (29.38 g, 212.61 mmol, 3.00 eq.) in 5 DMSO (80.0 ml) was stirred at 110 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, and the organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 2 (1-(3-Aminophenyl)piperidin-4-yl)methanol HO HO N NO N NH2 A mixt mol, 1.00 eq.) and Pd/C (600 mg) in MeOH (40.0 mL) was stirred 16 h under H 2 atmosphere. The mixture was filtered and concentrated to afford the crude title compound as a brown solid.
  • Step 3 3-(4-(Hydroxymethyl)piperidin-1-yl)benzenesulfonyl chloride To a mixtu 10.03 mmol, 1.00 eq.) and conc.
  • NKT-24-003PCT Step 4 (1-(3-((4-((5-Ethylthiazol-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4- yl)methanol
  • ne hydrochloride 5 109 mg, 0.35 mmol, 1.00 eq.
  • 3-(4-(hydroxymethyl)piperidin-1-yl)benzenesulfonyl chloride 100 mg, 0.35 mmol, 1.00 eq.
  • TEA 105 mg, 1.04 mmol, 3.00 eq.
  • NKT-24-003PCT yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (100 mg, 0.28 mmol, 1.20 eq.) in DCM (2.0 mL) was added TEA (70 mg, 0.69 mmol, 3.00 eq.) and NaBH(OAc) 3 (146 mg, 0.69 mmol, 3.00 eq.) at r.t. and the resulting mixture was stirred for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers was washed with 5 water, brine, and the organic layer was dried over anhydrous Na2SO4.
  • NKT-24-003PCT To a mixture of 1,4-dioxa-8-azaspiro[4.5]decane (5.00 g, 34.90 mmol, 1.00 eq.) in DCM (50.0 mL) was added 3-bromobenzenesulfonyl chloride (8.92 g, 34.90 mmol, 1.00 eq.) and TEA (10.59 g, 104.70 mmol, 3.00 eq.) at 0 o C, and the resulting mixture was stirred at r.t. for 2 h. The mixture was quenched by addition of water, and the mixture was extracted with DCM. The 5 combined organic layers was washed with brine, dried over Na2SO4.
  • Step 2 (1-(3-((1,4-Dioxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)phenyl)piperidin-4-yl)methanol 10
  • Copper (I) iodide (323 mg, 1.70 mmol, 0.05 eq.)
  • L-proline 391 mg, 3.40 mmol, 0.10 eq
  • K2CO3 (2.58 g, 18.68 mmol, 0.55 eq) in DMSO (120.0 mL)
  • Step 3 1-(3-((1,4-Dioxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)phenyl)piperidine-4-carbaldehyde 20
  • Step 5 1-(1-Methyl-6-(1-((1-(3-((4-oxopiperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)- 15 piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydro-pyrimidine- 2,4(1H,3H)-dione (2.26 g, 3.20 mmol) and 4 M 1,4-dioxane/ HCl (30.0 mL) was stirred at r.t.
  • Step 6 1-(1-Methyl-6-(1-((1-(3-((4-((5-(trifluoromethyl)thiazol-2-yl)amino)piperidin-1-yl)- sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione O N N O N N N N H CF 3 O 5 T l)- phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)- di
  • Step 2 N-(1-((3-(Bromomethyl)-4-fluorophenyl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)- 5 thiazol-2-amine
  • TEA 107 mg, 1.05 mmol, 3.00 eq.
  • DCM 1.0 10 mL
  • Step 3 1-(6-(1-(2-Fluoro-5-((4-((5-(trifluoromethyl)thiazol-2-yl)amino)piperidin-1-yl)sulfonyl)- 15 benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • TEA 61 mg, 0.60 mmol, 3.00 eq.
  • Step 2 2-(4-(Hydroxymethyl)piperidin-1-yl)-4-((4-((5-(trifluoromethyl)thiazol-2-yl)amino)- piperidin-1-yl)sulfonyl)benzonitrile 20
  • DIEA 569 mg, 4.41 mmol, 5.00 eq.
  • piperidin-4-ylmethanol 508 mg, 4.41 mmol, 5.00 eq.
  • Step 3 2-(4-Formylpiperidin-1-yl)-4-((4-((5-(trifluoromethyl)thiazol-2-yl)amino)piperidin-1- yl)sulfonyl)benzonitrile
  • a solution of -(trifluoromethyl)thiazol-2- 10 yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 160 mg, 0.30 mmol, 1.00 eq.
  • DCM 5.0 mL
  • Dess-Martin periodinane (257 mg, 0.60 mmol, 2.00 eq.) at 0 o C, and the resulting mixture was stirred 2 h.
  • Step 4 2-(4-((4-(3-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-15 1-yl)methyl)piperidin-1-yl)-4-((4-((5-(trifluoromethyl)thiazol-2-yl)amino)piperidin-1-yl)- sulfonyl)benzonitrile
  • TEA 91 mg, 0.9120 mmol, 3.00 eq.
  • Step 2 1-(1-Methyl-6-(1-(4-((4-((5-(trifluoromethyl)thiazol-2-yl)amino)piperidin-1-yl)sulfonyl)- benzyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione - 231 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref.
  • NKT-24-003PCT To a stirred solution of 1-[1-methyl-6-(piperidin-4-yl)indazol-3-yl]-1,3-diazinane-2,4-dione hydrochloride (64 mg, 0.18 mmol, 1.00 eq.) in THF (2.0 mL) was added DMF (1.0 mL), TEA (53 mg, 0.53 mmol, 3.00 eq.) and N-(1-((4-(bromomethyl)phenyl)sulfonyl)piperidin-4-yl)-5- (trifluoromethyl)thiazol-2-amine (85 mg, 0.18 mmol, 1.00 eq.), and the resulting mixture was 5 stirred 12 h at 55 °C.
  • Step 2 tert-Butyl (1-((4-cyano-3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperidin-1-yl)butyl)phenyl)sulfonyl)piperidin-4-yl)carbamate
  • nyl)piperidin-4- 10 yl)carbamate 200 mg, 0.46 mmol, 1.00 eq.) in MeOH(1.5 ml) and THF (1.5 ml) was added 1-(1- methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (250 mg, 0.69 mmol, 1.50 eq.), trimethoxymethane (73 mg, 0.69 mmol, 1.50 eq.),
  • Step 3 4-((4-Aminopiperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)- 1-methyl-1H-indazol-6-yl)piperidin-1-yl)butyl)benzonitrile hydrochloride 20 1(2H)-yl)- 1-methyl-1H-indazol-6-yl)piperidin-1-yl)butyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (100 mg, 0.14 mmol, 1.00 eq.) and 4 M HCl in EtOAc (3.0 mL) was stirred for 2 h.
  • NKT-24-003PCT dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butyl)benzonitrile hydrochloride (86 mg, 0.14 mmol, 1.00 eq.) in NMP (3.0 mL) was added 2-bromo-5- 5 (trifluoromethyl)thiazole (34 mg, 0.14 mmol, 1.00 eq.) and DIEA (52 mg, 0.41 mmol, 3.00 eq.), and the resulting mixture was stirred 12 h at 140 o C. The mixture was diluted with water and extracted with EtOAc.
  • NKT-24-003PCT Step 1 tert-Butyl (1-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate
  • te g, 205.47mmol, 1.00 eq. triethylamine
  • tetrahydrofuran 500 mL
  • 3- 5 bromobenzenesulfonyl chloride 50 g, 195.69 mmol, 0.95 eq.
  • Step 2 tert-Butyl (1-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl) piperidin- 4-yl)carbamate
  • t peridin-4-yl)carbamate 70 15 g, 166.93 mmol, 1.00 eq.
  • 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) 63.59 g, 250.4 mmol, 1.5 eq.
  • potassium acetate 49.15 g, 500.8 mmol, 3.00 eq.
  • 1,4-dioxane 500 mL
  • Pd(dppf)Cl 2 3.66 g, 5.01 mmol, 0.03 eq.
  • Step 3 tert-Butyl (1-((3-(5-(hydroxymethyl)pyrimidin-2-yl)phenyl)sulfonyl)piperidin-4- yl)carbamate 25 - 235 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT To a stirred solution of tert-butyl (1-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (68 g, 145.8 mmol, 1.0 eq.), (2-chloro pyrimidin-5- yl)methanol (25.29 g, 174.96 mmol, 1.2 eq.) and potassium carbonate (60.45 g, 437.39 mmol, 3.0 eq.) in 1,4-dioxane (500 mL)/water (100 mL) was added Pd(dppf)Cl 2 (3.2 g, 4.37 mmol, 0.03 eq.) 5 at 25 °C under argon atmosphere.
  • Step 4 (2-(3-((4-Aminopiperidin-1-yl)sulfonyl)phenyl)pyrimidin-5-yl)methanol hydrochloride
  • m phenyl)- sulfonyl)piperidin-4-yl)carbamate 65 g 144.91 mmol
  • dichloromethane 650 mL
  • HCl/dioxane 220 mL, 4.0 M
  • Step 5 (2-(3-((4-((5-(Trifluoromethyl)thiazol-2-yl)amino)piperidin-1-yl)sulfonyl) phenyl)pyrimidin-5-yl)methanol 20
  • NMP NMP
  • NKT-24-003PCT Step 6 2-(3-((4-((5-(Trifluoromethyl)thiazol-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl) pyrimidine-5-carbaldehyde
  • DIPEA 357.04 mg, 2.76 mmol, 6.0 eq.
  • pyridine sulfur trioxide 219.85 mg, 1.38 mmol, 3.0 eq.
  • DMSO 2 mL
  • Step 7 1-(1-Methyl-6-(1-((2-(3-((4-((5-(trifluoromethyl)thiazol-2-yl)amino)piperidin-1- yl)sulfonyl)phenyl)pyrimidin-5-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione 15 To a solutio in-1-yl)sulfonyl)- phenyl)pyrimidine-5-carbaldehyde (50.0 mg, 0.1 mmol, 1.00 eq.) and 1-(1-methyl-6-(piperidin-4- yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (36.37 mg, 0.1 mmol, 1.00 eq.) in DMA (2 mL) was added tri
  • OVCAR3 CDK2-dependent cell line
  • T47D CDK4-dependent cells
  • IC50 Half maximal inhibition concentration
  • NKT-24-003PCT than or equal to 500 nM; C indicates a IC50 of greater than 500 nM but less than or equal to 2.5 ⁇ M; D indicates a IC 50 of greater than 2.5 ⁇ M but less than or equal to 5.0 ⁇ M; E indicates a IC 50 of greater than 5.0 ⁇ M; NT is not determined.
  • cellular CDK level was measured in 96-well format using HTRF total CDK cellular kit (CDK2 Cat# 64CDK2TPEG; CDK4 Cat# 64CDK4TPEG;) from Cisbio/Revvity. - 239 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT
  • cells were seeded into 96-well tissue-culture treated plates at 20,000 cells/well in 200 ⁇ L and incubated overnight at 37°C in CO 2 atmosphere.
  • d2 conjugated-CDK antibody and Eu-cryptate conjugated CDK antibody were diluted into detection buffer following manufacturer’s instruction.
  • Detection plates were incubated overnight at room temperature and read on ClarioStar (BMG Labtech) in TR-FRET mode (665 nM and 620 nM).
  • TR-FRET ratio (665 nM/620 nM) was normalized to DMSO controls (0% degradation) and lysis buffer controls (100% degradation) to calculate the relative 15 CDK level (%CDK relative to DMSO), which was then plotted against the compound concentration.
  • Half maximal degradation concentration (DC 50 ) and maximal degradation (Dmax) values were calculated with a four-parameter logistic fit using GraphPad Prism (version 9; La Jolla, CA).
  • AA indicates a IC50 of less than 1 nM
  • A indicates a DC50 of greater 20 than or equal to 1 nM but less than or equal to 10 nM
  • B indicates a DC 50 of greater than 10 nM but less than or equal to 100 nM
  • C indicates a DC50 of greater than 100 nM but less than or equal to 1 ⁇ M
  • D indicates a DC 50 of greater than 1 ⁇ M nM but less than or equal to 5 ⁇ M.
  • NT means not tested.
  • NKT-24-003PCT Formulation Examples The following are representative pharmaceutical formulations containing a compound of the present disclosure. 5 Tablet Formulation The following ingredients are mixed intimately and pressed into single scored tablets. Ingredient Quantity per tablet (mg) compound Formula (I) or (IB) 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5 Capsule Formulation 10 The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule. Ingredient Quantity per capsule (mg) Compound Formula (I) or (IB) 200 lactose spray dried 148 magnesium stearate 2 Injectable Formulation Compound of the disclosure in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, 15 q.s.
  • Inhalation Composition To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound disclosed herein is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, 20 which is suitable for inhalation administration.
  • Topical Gel Composition To prepare a pharmaceutical topical gel composition, 100 mg of a compound disclosed herein is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of - 241 - 1104266430 ⁇ 4 ⁇ AMERICAS Attorney Docket No.119005.00283 Client Ref. No.
  • NKT-24-003PCT isopropyl myristate and 100 mL of purified alcohol USP.
  • the resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.
  • Ophthalmic Solution Composition 5 To prepare a pharmaceutical ophthalmic solution composition, 100 mg of a compound disclosed herein is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter.
  • the resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.
  • 10 Nasal spray solution To prepare a pharmaceutical nasal spray solution, 10 g of a compound disclosed herein is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 ⁇ L of spray for each application. - 242 - 1104266430 ⁇ 4 ⁇ AMERICAS

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Abstract

La présente divulgation concerne certains composés bifonctionnels contenant des dérivés de thiazolyle qui provoquent la dégradation de la kinase dépendante de la cycline 2 (CDK2) et de la kinase dépendante de la cycline 4 (CDK4) par l'intermédiaire de la voie ubiquitine-protéasome et sont donc utiles pour le traitement de maladies médiées par CDK2 et/ou CDK4. La divulgation concerne également des compositions pharmaceutiques contenant de tels composés et des procédés de préparation de tels composés.
PCT/US2025/027391 2024-05-07 2025-05-01 Composés bifonctionnels contenant des dérivés thiazolyle pour dégrader une certaine kinase dépendante de la cycline par l'intermédiaire d'une voie ubiquitine-protéasome Pending WO2025235298A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017185036A1 (fr) * 2016-04-22 2017-10-26 Dana Farber Cancer Institute, Inc. Molécules bifonctionnelles pour la dégradation du egfr et méthodes d'utilisation
US20180179183A1 (en) * 2016-12-23 2018-06-28 Arvinas, Inc. Compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides
WO2023096995A1 (fr) * 2021-11-23 2023-06-01 St. Jude Children's Research Hospital, Inc. Compositions et procédés comprenant des analogues de n-(2-chloro-6-méthylphényl)-2-((6-(hétérocycloalkyle à 6 chaînons)-2-méthylpyrimidin-4-yl)amino)thiazole-5-carboxamide substitués

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017185036A1 (fr) * 2016-04-22 2017-10-26 Dana Farber Cancer Institute, Inc. Molécules bifonctionnelles pour la dégradation du egfr et méthodes d'utilisation
US20180179183A1 (en) * 2016-12-23 2018-06-28 Arvinas, Inc. Compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides
WO2023096995A1 (fr) * 2021-11-23 2023-06-01 St. Jude Children's Research Hospital, Inc. Compositions et procédés comprenant des analogues de n-(2-chloro-6-méthylphényl)-2-((6-(hétérocycloalkyle à 6 chaînons)-2-méthylpyrimidin-4-yl)amino)thiazole-5-carboxamide substitués

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