WO2025235331A1 - Composés bifonctionnels contenant des dérivés de pyrazolopyrimidine pour dégrader une certaine kinase dépendante de la cycline par l'intermédiaire d'une voie ubiquitine-protéasome - Google Patents

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

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Publication number
WO2025235331A1
WO2025235331A1 PCT/US2025/027636 US2025027636W WO2025235331A1 WO 2025235331 A1 WO2025235331 A1 WO 2025235331A1 US 2025027636 W US2025027636 W US 2025027636W WO 2025235331 A1 WO2025235331 A1 WO 2025235331A1
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heterocyclylene
alkylene
substituted
compound
hydrogen
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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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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure provides certain bifunctional compounds containing pyrazolopyrimidine 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 diseases mediated by CDK2 and/or CDK4. Also provided are 15 pharmaceutical compositions containing such compounds and processes for preparing such compounds.
  • 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 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT 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 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT NKT-24-004PCT (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.
  • - 3 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT Summary in a first aspect, provided is a compound of Formula (I): 5 wherein R 1 is hydrogen, alkyl, cycloalkyl, bridged cycloalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, cycloalkylalkyl, bridged cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein each of the aforementioned rings, by itself or as part of another group, is substituted with R a1 , R b1 , and R c1 independently selected from 10 hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; R 2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, hal
  • NKT-24-004PCT (b) a group of formula (ii): 5 10 - 5 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref.
  • R gg , R hh , R jj , a kk independently hydrogen, alkyl, or cycloalkyl and each alkylene, itself or as part of another group, is optionally substituted with one 5 or two fluoro;
  • R y , R y1 , and R y2 are independently alkyl, hydroxyalkyl, cycloalkyl, or heterocyclyl wherein
  • NKT-24-004PCT heterocyclylene are substituted with R 11 and R 12 independently selected from hydrogen, alkyl, and halo; provided that at least one of -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 - is not a bond; or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound of 5 Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.
  • 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 10 therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition therefore disclosed herein.
  • the disease is cancer.
  • the disease is cancer selected from lung cancer (e.g., adenocarcinoma, small cell lung cancer, non-small cell lung carcinomas, parvicellular and non- 15 parvicellular carcinoma, bronchial carcinoma, bronchial adenoma, and/or pleuropulmonary blastoma), skin cancer (e.g., melanoma, squamous cell carcinoma, Kaposi sarcoma, and/or Merkel cell skin cancer), bladder cancer, breast cancer, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, head and neck cancer (e.g., cancers of the larynx, hypopharynx, nasopharynx, oropharynx, lips, 20 and/or mouth), liver cancer (e.g., hepatocellular carcinoma and/or cholangiocellular carcinoma), ovarian cancer, prostate cancer, testicular cancer,
  • lung cancer e.g.
  • the 25 cancers are those that are resistant to CDK4/6 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 first aspect (or any of the embodiments thereof 30 described herein), or a pharmaceutically 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.
  • - 9 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT the therapeutically effective amount of a compound of Formulas (I) (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 5 (cisplatin-induced), antibiotic-induced, or age-related hearing loss comprises 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 aspect, (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 10 age-matched control.
  • the hearing loss is prevented when compared to an age-matched control.
  • a compound of (I) 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 any embodiments thereof 15 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 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 20 and/or CDK4 contributes to the pathology and/or symptoms of the disease.
  • the disease is one or more diseases disclosed in the third and fourth aspects 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 25 Formula (I) (or embodiments thereof as disclosed herein, including specific compounds).
  • the CDK2 and/or CDK4 are degraded in vitro. In another embodiment of the seventh aspect, the CDK2 and/or CDK4 are degraded in vivo. In another embodiment of the seventh aspect the CDK2 and/or CDK4 is degraded in a cell of a patient. In an embodiment of any one of above aspects, CDK2 is selectively degraded over CDK1 30 by a compound of Formula (I). In another embodiment of any one of above aspects, CDK2 is selectively degraded over CDK1 and CDK4; or CDK4 is selectively degraded over CDK1 and CDK2 by a compound of Formula (I).
  • both CDK2 and CDK4 are degraded by a compound of Formula (I), includingCDK2 and CDK4 are selectively degraded over CDK1.
  • - 10 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT The ability of compounds of Formula (I) to degrade CDK2 and CDK4 selectively over CDK1 was measured by determining potency of the compounds in inhibiting retinoblastoma protein (Rb) phosphorylation in OVCAR3 (CDK2 dependent cell line), T47D (CDK4 dependent cell line) and KYSE520 (CDK1 dependent cell line) as described in Biological Example 1 below, 5 and then determining the ratio of Rb IC50 from OVCAR3 and KYSE520 and T47D and KYSE520, respectively. Additionally, although the compounds of Formula (I) degrade both CDK2 and CDK4, they can, however, cause degradation of CDK2 to a greater extent than CDK4 or visa-versa.
  • Rb retinoblastoma protein
  • 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 10 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 (I), or a pharmaceutically acceptable salt thereof (or any embodiments thereof 15 disclosed herein) or the pharmaceutical composition of the seventh aspect, in combination with at least one additional anticancer agent.
  • the agents can be 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.
  • Alkenyl means a linear or branched monovalent hydrocarbon radical of two to six 25 carbon atoms containing a double bond e.g., ethenyl, propenyl, 2-propenyl, butenyl, pentenyl, and the like.
  • Alkynyl means a linear or branched monovalent hydrocarbon radical of two to six carbon atoms containing a triple bond e.g., ethynyl, propynyl, 2-propynyl, butynyl, and the like.
  • Alkylene means a linear or branched saturated divalent hydrocarbon radical of one to six 30 carbon atoms unless otherwise stated. When alkylene contains three to six carbon atoms it is also referred to herein as C 3 to C 6 alkylene, Examples include, but are not limited to, e.g., 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 5 to eight carbon atoms containing a triple bond, e.g., , , and the like.
  • Alkoxy means a -OR z radical where R z i s alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.
  • Alkoxyalkyl means alkyl as defined above that is substituted with alkoxy as defined 10 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, cyclopropylcarbonyl, and the like.
  • R z is alkyl
  • acyl is also referred to herein as “alkylcarbonyl.”
  • 20 “Amino” means –NH2.
  • Aminocarbonyl means -C(O)NH 2 .
  • 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 25 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.
  • Aminosulfonyl means -S(O) 2 NH 2 .
  • Alkylsulfinyl means -S(O)R z where R z is alkyl as defined above e.g., methylsulfinyl, ethylsulfinyl, and the like.
  • Alkylsulfonyl means -S(O)2R z where R z is alkyl as defined above e.g., methylsulfonyl, ethylsulfonyl, and the like.
  • R z is alkyl as defined above e.g., methylsulfonyl, ethylsulfonyl, and the like.
  • - 12 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT
  • Alkylaminosulfonyl means -S(O)2NHR z radical where R z is alkyl as defined above e.g., methylaminosulfonyl, ethylaminocarbonyl, propylaminosulfonyl, and the like.
  • Dialkylaminosulfonyl means -S(O)2NR z1 R z radical where R z and R z1 are independently alkyl as defined above e.g., dimethylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl, 5 and the like.
  • Aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.
  • “Aralkyl” means an –(alkylene)-R z radical where R z is aryl as defined above e.g. benzyl.
  • “Arylene” means a divalent aryl (as defined above) radical e.g., phenylene or 10 naphthylene.
  • “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 15 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 20 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, 25 bicyclo[2.2.1]heptyl (in one embodiment bicyclo[2.2.1]hept-2-yl), and the like.
  • “Bridged cycloalkylalkyl” means a –(alkylene)-R z radical where R z is bridged cycloalkyl as defined above e.g., bicyclo[1.1.1]pent-1-ylmethyl, and the like.
  • “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 30 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 - 13 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT 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, including an atom in the bridging group, is replaced by a heteroatom selected from N, O, and 10 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- [3.1.1]heptan-diyl, 2,5-diazabicyclo[2.2.2]octan-diyl, 3,8-diazabicyclo[3.2.1]octan-diyl, 15 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. “Cycloalkyloxy or cycloalkoxy” means a -OR z radical where R z is cycloalkyl as defined 20 above. Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • 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. 25 “Cycloalkylene” means a divalent monocyclic saturated 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)-. “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. - 14 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • 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 5 like.
  • “Deuterium” means refers to 2 H or D.
  • Dialkylamino means a -NR z R z radical where each R z is alkyl as defined above, e.g., dimethylamino, methylethylamino, n-propylmethylamino, 2-propylmethylamino, n-, iso-, or tert-butylmethylamino, and the like.
  • “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, or a five or six membered heteroaryl, each as defined herein, unless stated otherwise.
  • the nitrogen 15 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 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.
  • 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 atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one 30 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- hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl.
  • - 15 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • hydroxyalkyl is 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 5 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
  • the linear portion of the heteroalkylene means the consecutive atoms of the heteroalkylene connecting Z 2 and Z 4 when 15 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 C 5 heteroalkylene.
  • heteroalkylene When the ains only one or two -O-, it can be referred to herein as “oxoalkylene.”
  • heteroalkylene When the heteroalkylene contains only one or two -NR q – and/or -NR q1 -, it can be referred to herein as “aminylalkylene.”
  • aminoalkylene When the heteroalkylene contains only -S-, it can be referred to herein as 20 “sulfanylalkylene.”
  • the heteroalkylene When the heteroalkylene contains only -SO-, it can be referred to herein as “sulfinylalkylene.”
  • sulfonylalkylene When the heteroalkylene contains only -SO2-, it can be referred to herein as “sulfonylalkylene.”
  • Representative examples, of heteroalkylene include, e.g., - 16 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00
  • 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, two, or 5 three), ring atoms are heteroatom selected from N, O, and S, the remaining ring atoms being 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.
  • 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 heteroaryl.
  • 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.
  • 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 ring20 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. - 17 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT “Heterocyclyl” means a saturated, monovalent, 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.
  • heterocyclyl includes, but is not limited to, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, 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.
  • heterocyclylcarbonyl means a -C(O)R radical where R is heterocyclyl as defined herein. More specifically, the term heterocyclyl includes, but is not limited to, piperidinylcarbonyl, piperazinylcarbonyl, pyrrolidinylcarbonyl, azetidinylcarbonyl, and the like.
  • Heterocyclylalkyl means an –(alkylene)-R z radical where R z is heterocyclyl as defined 15 above e.g.
  • 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 20 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.
  • heterocyclylene includes, but is not limited to , piperidin-1,4-diyl, azetidin-1,3-diyl, and the like.
  • P ne means divalent phenyl.
  • phrase “optionally” or “optional” as used herein means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • alkylene optionally substituted with halo is intended to cover alkylene that is unsubstituted and alkylene that is substituted with halo.
  • “Spiro cycloalkylene” means a saturated bicyclic divalent hydrocarbon ring having 6 to 12 ring atoms wherein the rings are connected through only one atom, the connecting atom is also - 18 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT 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.
  • substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano, unless stated otherwise.
  • Representative examples include, but are not limited to, spiro[3,5]nonandiyl e.g., spiro[3.5]nonane-2,7-diyl, and the like.
  • “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 10 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.
  • “11 to 13 membered spiro heterocyclylene” means a saturated bicyclic divalent ring 15 having 11 to 13 ring atoms in which one, two, or three ring atoms are heteroatom(s) 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”).
  • the 11 to 13 membered spiro heterocyclylene is optionally substituted with one or two substituents independently selected from alkyl, halo, 20 alkoxy, hydroxy, and cyano, unless stated otherwise.
  • the present disclosure also includes protected derivatives of compounds of first aspect (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof.
  • compounds of Formula (I) when compounds of Formula (I) contain groups such as hydroxy, carboxy, or any group 30 containing a nitrogen atom(s), these groups can be protected with suitable protecting groups.
  • suitable protecting groups A comprehensive list of suitable protective 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. - 19 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT The present disclosure also includes polymorphic forms and deuterated forms of the compound of first aspect (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 5 compounds Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003).
  • Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under 10 physiological conditions to provide the active compound.
  • Prodrugs are often useful because, in 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 15 compound which is administered as an ester (the “prodrug”), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.
  • a “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such 20 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 25 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
  • NKT-24-004PCT N-methylglucamine, and the like. It is understood that 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. 5
  • the compounds of Formula (I) (and any embodiment thereof disclosed herein including 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 10 materials which contain chiral centers or by preparation of mixtures of enantiomeric products 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 15 scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated.
  • cyclic groups such as aryl
  • it includes all the positional isomers albeit only a 25 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 30 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 - 21 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT 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 can be useful in compound o r substrate tissue distribution assays.
  • Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes can 5 be useful for their ease of preparation and detectability.
  • substitution with (or i sotopically 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 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 15 reagent for a non-isotopically labeled reagent.
  • a “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. 20 “A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient. The term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error.
  • the R aa substituent can replace hydrogen of any CH that is part of the benzo portion of the bicyclic ring that is not already substituted with R bb and X 1 (in the case of R aa ), and similarly with R aa and X 1 (in the case of R bb ), and with R aa and R bb (in the case of X 1 ).
  • 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.
  • the bond on the , : , on the right side of (a), (b), and (c) i.e., X 1 , X 2 , and X 3
  • L is a group of formula: , - 23 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT a nd Degron is a group of formula (a), i.e.
  • the left bond in L i.e., the -NH- group
  • the right han -SO 2 - is attached to an atom of the Hy .
  • “disease” as used herein is intended to be generally synonymous, and is used 5 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 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.
  • the term “combination therapy” means the administration of two or more therapeutic 10 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 manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient.
  • administration also encompasses use of each type of therapeutic agent in a sequential manner.
  • the treatment 15 regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • the term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses.
  • the patient is a human.
  • Treating” or “treatment” of a disease includes: (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; 25 (2) inhibiting the disease, i.e., delaying, arresting, or reducing the development or severity of the disease or its clinical symptoms; or (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 5 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 10 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) can also inhibit CDK2 and/or CDK4.
  • a compound of Formula (I) 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 of 20 a compound disclosed herein in the Summary, Embodiments, and Compound Table 1 disclosed herein as compared to an equivalent sample comprising CDK2 and/or CDK4, respectively, in the absence of said compound.
  • the inhibitory activity of a compound of Formula (I) can be measure using Biological Example 1, by converting a compound of Formula ( (I) to a corresponding compound of Formula (I) that cannot be degraded by the ubiquitin proteosome pathway e.g., by 25 methylating the nitrogen atom i group of ligase ligand (i) or (ii) present in the compound of Formula (I).
  • the term “degrading” 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 CDK1, respectively, over time in a sample containing a compound of Formula (I).
  • 30 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 - 25 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT compound disclosed herein in the Summary, Embodiments, and Compound Table 1 disclosed herein as 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%.
  • 5 the decrease in the concentration of CDK2 is ⁇ 40%.
  • the decrease in the concentration of CDK2 is ⁇ 50%.
  • the decrease in the concentration of CDK2 is ⁇ 60%.
  • the decrease in the concentration of CDK2 ⁇ 70%.
  • the decrease in the concentration of CDK2 is ⁇ 80%.
  • the decrease in the concentration of CDK4 is ⁇ 20%.
  • the decrease in the concentration of CDK4 is ⁇ 40%.
  • the decrease in the concentration of CDK4 is ⁇ 50%.
  • the decrease in the concentration of CDK4 is ⁇ 60%. In another embodiment, the decrease in the concentration of CDK4 ⁇ 70%. In another embodiment, the decrease in the concentration of CDK4 is ⁇ 80%.
  • E3 ubiquitin ligase refers to a family of proteins that operate in conjunction with E1 15 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 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 20 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 the E3 ligase complex VCB, which also consists of elongins B and C, Cul2 and Rbx1.
  • Embodiments in embodiments A1 to A249, the present disclosure includes: A1.
  • A1 provided is a compound of Formula (I) or a pharmaceutically acceptable salt as described in the first aspect of the Summary.
  • the compound of embodiment A1, or a pharmaceutically acceptable salt thereof is wherein R 1 is hydrogen, alkyl, cycloalkyl, bridged cycloalkyl, haloalkyl, alkoxyalkyl, or cyanoalkyl wherein each ring is substituted with R a1 , R b1 , and R c1 .
  • R 1 is hydrogen, alkyl, cycloalkyl, bridged cycloalkyl, haloalkyl, alkoxyalkyl, or cyanoalkyl wherein each ring is substituted with R a1 , R b1 , and R c1 .
  • R 1 is hydrogen, alkyl, cycloalkyl, bridged cycloalkyl, haloalkyl
  • the compound of embodiment A1 or A2, or a pharmaceutically acceptable salt thereof is wherein R 1 is alkyl, haloalkyl, alkoxyalkyl, or cyanoalkyl.
  • R 1 is alkyl, haloalkyl, alkoxyalkyl, or cyanoalkyl.
  • the compound of embodiment A1 or A2, or a pharmaceutically acceptable salt thereof is wherein R 1 is cycloalkyl substituted with R a1 , R b1 , and R c1 .
  • the compound of embodiment A1 or A2, or a pharmaceutically acceptable salt thereof is wherein R 1 is bridged cycloalkyl substituted with R a1 , R b1 , and R c1 . 5 A6.
  • the compound of embodiment A1, A2, A4, and A5, or a pharmaceutically acceptable salt thereof is wherein R 1 is cycloalkyl and bridged cycloalkyl substituted with R a1 , R b1 , and R c1 where R a1 and R b1 are independently hydrogen, methyl, difluoromethyl, trifluoromethyl, fluoro, chloro, and cyano and R c1 is hydrogen.
  • the compound of embodiment A1, A2, A4, and A6, or a 10 pharmaceutically acceptable salt thereof is wherein the cycloalkyl of R 1 is cyclopropyl, cyclopentyl, or cyclohexyl and the bridged cycloalkyl of R 1 is bicyclo[1.1.1]pent-1,3-diyl, bicyclo[1.1.1]pent-1,4-diyl, or bicyclo[2.2.1]hept-1,3-diyl.
  • bridged cycloalkyl of R 1 is bicyclo[2.2.1]hept-2-yl or bicyclo[2.2.1]hept-1,4-diyl.
  • the compound of embodiment A1 to A3, or a pharmaceutically 15 acceptable salt thereof is wherein R 1 is alkyl or haloalkyl.
  • R 1 is alkyl or haloalkyl.
  • the compound of embodiment A1 to A3 and A8, or a pharmaceutically acceptable salt thereof is wherein R 1 is alkyl.
  • R 1 is haloalkyl. 20 A11.
  • the compound of embodiment A1 to A3, or a pharmaceutically acceptable salt thereof, is wherein R 1 is hydrogen or alkoxyalkyl.
  • the compound of embodiments A1 to A3 and A8 to A11, or a pharmaceutically acceptable salt thereof is wherein the R 1 is hydrogen, methyl, ethyl, isopropyl, 2,2-difluoroethyl, 3,3,3-trifluoroethyl, trifluoropropyl, methoxymethyl, methoxyethyl, or 25 methoxypropyl.
  • R 1 is hydrogen, methyl, ethyl, isopropyl, 2,2-difluoroethyl, 3,3,3-trifluoroethyl, trifluoropropyl, methoxymethyl, methoxyethyl, or 25 methoxypropyl.
  • R 2 is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, or cyano.
  • the compound of any one of embodiments A1 to A13, or a 30 pharmaceutically acceptable salt thereof is wherein R 2 is haloalkyl.
  • A15 the compound of any one of embodiments A1 to A13, or a pharmaceutically acceptable salt thereof, is wherein R 2 is alkoxy.
  • A16 the compound of any one of embodiments A1 to A13, or a pharmaceutically acceptable salt thereof, is wherein R 2 is hydrogen or halo. - 27 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT A17.
  • the compound of any one of embodiments A1 to A13, or a pharmaceutically acceptable salt thereof is wherein R 2 is cyano.
  • R 2 is cyano.
  • the compound of any one of embodiments A1 to A13, or a pharmaceutically acceptable salt thereof is wherein R 2 is cycloalkyl. 5
  • the compound of any one of embodiments A1 to A14 and A16, or a pharmaceutically acceptable salt thereof is wherein R 2 is hydrogen, methyl, ethyl, chloro, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy.
  • R 2 is hydrogen, methyl, ethyl, chloro, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy.
  • the compound of any one of embodiments A1 to A14, A16, and A19, or a pharmaceutically acceptable salt thereof is wherein R 2 is hydrogen, methyl, chloro, 10 fluoro, difluoromethyl, or trifluoromethyl.
  • R 2 is hydrogen, methyl, chloro, 10 fluoro, difluoromethyl, or trifluoromethyl.
  • R 2 is alkoxyalkyl A22.
  • R 2 is methoxymethyl.
  • R 3 is hydrogen.
  • the compound of any one of embodiments A1 to A22, or a pharmaceutically acceptable salt thereof is wherein one of R 3 is deuterium.
  • the compound of any one of embodiments A1 to A24, or a 20 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 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 A25, or a 25 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.
  • 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.
  • 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- 30 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.
  • R a and R b are independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxy
  • R c is hydrogen
  • L is attached to the nitrogen atom of the piperidin-1,4-diyl or pyrrolidin-1,3-diyl ring of Hy.
  • the compound of any one of embodiments A1 to A27, or a pharmaceutically acceptable salt thereof is wherein the heterocyclylene of Hy is: - 28 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT where the N atom o diyl rings is attached to L.
  • the compound of any one of embodiments A1 to A28, or a pharmaceutically acceptable salt thereof is wherein the heterocyclylene of Hy is: 5 where the N atom of 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: 10 where the N atom of the piperidin-1, 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. 15 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 , , , and L is attached to 20 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 25 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 5 A34, or a pharmaceutically acceptable salt thereof is wherein the cycloalkylene of Hy is cyclohexylene.
  • A36 is cyclohexylene.
  • 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. 10 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 15 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.
  • 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.
  • Hy is spiro heterocyclylene substituted (such as 2-azaspiro[3.3]heptan-2-
  • 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 20 1,4-phenylene according to structure where denotes bond to NH and denotes bond of L and where R b is hydrogen (in one embodiment R a is methoxy).
  • R a is methoxy
  • the compound of any one of embodiments A1 to A24, or a 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, 25 haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen.
  • R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, 25 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 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.
  • Hy is bicyclic 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 - 30 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT A40A.
  • 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).
  • the compound of any one of embodiments A1 to A40A, or a 5 pharmaceutically acceptable salt thereof is wherein the Degron is an E3 ubiquitin ligase ligand of formula (i): . A41.
  • the compound of any one of embodiments A1 to A40, or a 10 pharmaceutically acceptable salt thereof is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (a): .
  • 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 15 alkyl.
  • 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. 20 A45.
  • 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 25 formula (i) is a group of formula (b): - 31 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT where M is -NR 6 -.
  • the compound of any one of embodiments A1 to A40, and A46, or a pharmaceutically acceptable salt thereof is wherein R 6 is hydrogen. 5 A48.
  • 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 10 formula (i) is: . A50.
  • I , s 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: - 32 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT .
  • I A1 to A50, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: 5 . A .
  • diments A1 to A51, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: - 33 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT i,e, R aa is hydrogen and R dd 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 5 ubiquitin ligase ligand of formula (i) is: . A53.
  • th 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: 10 .
  • th y one of embodiments A1 to A43 and A49 to A52, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: . 15 A55.
  • th e co pou o any one of embodiments A1 to A43 and A49 to A52, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: - 34 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT .
  • A56 t any one of embodiments A1 to A40, 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: 5 . A57.
  • th ny one of embodiments A1 to A40, 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: . 10 A58.
  • th y 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 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. 15 A59.
  • the compound of any one of embodiments A1 to A54, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and cyano.
  • R aa , R bb , R cc , and R dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and cyano.
  • 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 20 independently selected from hydrogen, methyl, methoxy, ethoxy, fluoro, trifluoromethyl, difluoromethyl, and trifluoromethoxy.
  • R aa , R bb , R cc , and R dd are independently selected from hydrogen and methyl. 25 A62.
  • 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 methoxy. - 35 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT A63.
  • 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 fluoro. A64.
  • the compound of any one of embodiments A1 to A54, and 5 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 15 formula (ii): A68.
  • ne of embodiments A1 to A40A and A67, or a pharmaceutically acceptable salt thereof is wherein Y a is CH. 20 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.
  • 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)-. 25 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-, or -NHC(O)-.
  • 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.
  • 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)-.
  • - 36 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT A74.
  • the compound of any one of embodiments A1 to A40A, A67 to A71, and A73, or a pharmaceutically acceptable salt thereof is wherein Z a is -NH-.
  • A74a the compound of any one of embodiments A1 to A40A, A67 to A71, and A73, or a pharmaceutically acceptable salt thereof, is wherein Z a is -NHC(O)-. 5 A75.
  • 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 phenylene substituted with R ee and R ff .
  • 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 10 substituted with R ee and R ff .
  • 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 15 and R ff .
  • 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 . 20 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 .
  • A80 the compound of any one of embodiments A1 to A40A, A67 to A74a, and A77, or a pharmaceutically acceptable salt thereof
  • the compound of any one of embodiments A1 to A40A, A67 25 to A74a, A77, and A79, or a pharmaceutically acceptable salt thereof is wherein ring B is a 9- or 10-membered fused bicyclic heteroarylene containing one or two nitrogen ring atoms and substituted with R ee and R ff .
  • ring B is a 9- or 10-membered fused bicyclic heteroarylene containing one or two nitrogen ring atoms and substituted with R ee and R ff .
  • the compound of any one of embodiments A1 to A40A, and A67 to A80, or a pharmaceutically acceptable salt thereof is wherein the E3 ubiquitin ligase 30 ligand of formula (ii) is: , - 37 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref.
  • 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: - 38 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT , or 5 is cyclylaminylene and R ff is hydrogen when not drawn out in the above 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 . 10 A83.
  • the compou nts A1 to A40A, and A67 to A82, or a pharmaceutically acceptable salt thereof is wherein the E3 ubiquitin ligase ligand of formula (ii) is: - 39 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT , 5 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 .
  • the compou ments A1 to A40A, and 10 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. 15 A86.
  • the compound of any one of embodiments A1 to A40A, and 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.
  • - 40 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.002
  • 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, and isopropyl.
  • R ee and R ff are independently selected from hydrogen, methyl, ethyl, and isopropyl.
  • R ee and R ff are independently selected from hydrogen and methoxy.
  • 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. 10 A90.
  • 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 hydrogen or fluoro and the other of R ee and R ff is selected from hydrogen, trifluoromethyl, 2,2,2- trifluoroethyl, and difluoromethyl.
  • R ee and R ff are independently selected from hydrogen, methyl, ethyl, isopropyl, chloro, and fluoro. 10 A90.
  • 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 e
  • the compound of any one of embodiments A1 to A40A, and 15 A67 to A86, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently selected from hydrogen, difluoromethoxy, and trifluoromethoxy.
  • 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. 25 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.
  • A96 is
  • the compound of any one of embodiments A1 to A40A, A67 to A86, and A90, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are 30 independently trifluoromethyl or 2,2,2-trifluoroethyl.
  • A96a 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).
  • the Degron is an E3 ubiquitin ligase ligand of formula (iii), (iv), (v), or (vi).
  • - 41 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT 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, 5 A96a, and A96b, or a pharmaceutically acceptable salt thereof, is wherein R y , R y1 , and R y2 are 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 10 pharmaceutically acceptable salt thereof, is wherein X 1 , X 2 , X 3 , and X 4 are each a bond.
  • 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.
  • X 1 , X 2 , X 3 , and X 4 are each methylene. 15 A99.
  • the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof is wherein X 1 , X 2 , X 3 , and X 4 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)-. 20 A101.
  • 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-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 25 selected from -(NR gg -alkylene)-.
  • 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 30 pharmaceutically acceptable salt thereof, is wherein X 1 , X 2 , X 3 , and X 4 are each .
  • A105 the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X 1 , X 2 , X 3 , and X 4 are each -NH-.
  • 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 -N(alkyl)-. In a subembodiment of embodiment A106, X 1 , X 2 , X 3 , and X 4 are each independently -N(methyl)- or -N(ethyl)-. 5 A107.
  • 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 15 R kk are each independently hydrogen or alkyl.
  • A110a is
  • 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 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 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 . 25 A113.
  • 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 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 30 X 1 , X 2 , X 3 , and X 4 are as described in any one of embodiments A1 and A98 to A110).
  • the compound for use of any one of embodiments A1 to A96d and A111, or a pharmaceutically acceptable salt thereof is wherein: - 43 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT 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 independently optionally bstituted with one or two fluoro (or X 1 , X 2 su , X 3 , and X 4 are absent in ligands (iii) to (vi));
  • Z 1 is a bond, alkylene, -(CO)NR-, -(O-alkylene) a -, -(alkylene-O) a -, phenylene, or 5 heterocyclylene, where each ring is substituted with R h and R i ;
  • Z 2 is a bond, alkylene, -(O-alkylene) b -, -(
  • 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; Z 2 is a bond, alkylene, cycloalkylene, or heterocyclylene, where each ring is substituted with R j and R k ; 30 Z 3 is a bond, alkylene, -C(O)NR-, -NR’(CO)-, -O-, -NR”-, 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 ; - 44 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client
  • No. NKT-24-004PCT 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 heteroarylene, or heterocycylene, where each ring is 5 substituted with R q and R r ;
  • Z 6 is -S(O) 2 -; and wherein each alkylene in Z 2 , Z 3 , and Z 4 is independently substituted with R s , R t , and R u .
  • the compound of any one of embodiments A1 to A96d, A97, A111, and A115, or a pharmaceutically acceptable salt thereof is wherein: 10 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, 15 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,
  • 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; 25 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; Z 4 is alkylene, -O-, cycloalkylene, monocyclic heteroarylene, heterocyclylene, fused30 heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R o and R p independently selected from hydrogen, deuterium, al
  • NKT-24-004PCT 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 5 wherein alkylene in Z 4 is substituted with substituted with R s , R t , and R u .
  • R q and R r independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy
  • Z 6 is -S(O) 2 -
  • 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 10 substituted with R m and R n independently selected from hydrogen, deuterium, alkyl, alkoxy, 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; 15 Z 5 is phenylene
  • the compound of any one of embodiments A1 to A96d, A97, 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, 25 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; in one embodiment R o
  • NKT-24-004PCT 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; 5 Z 2 is cycloalkylene or heterocyclylene, where each ring is substituted with R j and R k 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
  • 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; 20 Z 2 is heterocyclylene substituted with R j and R k independently selected from hydrogen, 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-; 25 Z 5 is phenylene or monocyclic heteroarylene, each ring substituted with R q and R r 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 independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; - 47 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT 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, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy;
  • 5 Z 5 is phenylene or monocyclic heteroarylene, each ring substituted with R q and R r ; in one embodiment R q and R r are 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 3 is substituted with R s , R t , and R u .
  • 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. 15 A124.
  • 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 20 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- 30 (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-
  • NKT-24-004PCT Z 4 is alkylene, -(alkylene-NR”)-, -(NR”-alkylene)-, -O-, -NR”-, -(O-alkylene)d-, -(alkylene-O) d -, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spiro cyclolalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged 5 heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene, or -spiro heterocyclylene-(
  • the compound of any one of embodiments A1 to A97, A111, 15 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 20 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: 25 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 heterocyclylene, -(alkylene)-spiro heterocyclylene-, or -spiro heterocyclylene-(alkylene), where 30 each ring, by itself or as part of another group,
  • NKT-24-004PCT heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene, or -spiro heterocyclylene-(alkylene)-, 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 5 substituted with R q and R r ; and
  • Z 6 is -S(O) 2 -; and and each alkylene in Z 3 and Z 4 , itself or as part of another group, is independently substituted with R s , R t , and R u .
  • the compound of any one of embodiments A1 to A111, 10 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 heterocyclylene-, where each ring, by itself or as part of another group, is substituted with R o and 15 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 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 heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro 25 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 ; Z 5 is phenylene, monocyclic heteroarylene, heterocycylene, bridged
  • 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; - 50 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT Z 3 is -O-, -NR ” - (where R ” is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic 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, or heteroalkenylene where alkylene and heteroalkylene 5 substituted with R s , R t , and R u and alkenylene is substituted with R v ;
  • 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, 10 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 heterocyclylene, where each ring is substituted with R m and R n ; 15 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 20 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 heterocyclylene, where each ring is substituted with R m and R n ; 25 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 5 - (i.e., Z 5 is phenylene where Z 4 and Z 6 are attached at meta position of the phenyle ne r ng su stituted 30 with R q and R r independently selected from hydrogen, deuterium, alkyl, alkoxy, cyano, halo, haloalkyl, and haloalkoxy.
  • R q and R r independently selected from hydrogen, deuterium, alkyl, alkoxy, cyano, halo, 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 - 51 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT substituted with R q and R r independently selected from hydrogen, deuterium, methyl, ano, fluoro, chloro, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy.
  • R q and R r independently selected from hydrogen, deuterium, methyl, ano, fluoro, chloro, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy.
  • the compound of any one of embodiments A1 to A113, 5 A115 to A134, A135, and A136, or a pharmaceutically acceptable salt thereof is wherein -Z 5 - is . 13, 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 10 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, 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 15 substituted with R q and R r independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy, and trifluoromethoxy.
  • R q and R r independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy, and trifluoromethoxy.
  • 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 20 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.
  • 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 25 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, difluoromethoxy, and trifluoromethoxy.
  • R q and R r independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 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 30 salt thereof is wherein -Z 5 - is azetidinyl, pyrrolidinyl, piperazinyl, or piperidinyl.
  • - 52 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT A143.
  • the compound of any one of embodiments A1 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 and when present, is methylene, ethylene, propylene, or butylene, each substituted with R s , R t , and R u . 5 A144.
  • 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 , 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 , 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 ,10 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 or propylene; as part of –(alkylene-NR”)- and –(
  • the compound of any one of embodiments A1 to A134, 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 25 ethylene; as part of -(alkylene-NR
  • 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 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 A147, or a 5 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 methyl.
  • each R, R’ and R” of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 when present, is methyl.
  • 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 10 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 10 independently selected from cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene.
  • the compound of any one of embodiments A1 to A150, 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 1,2-cyclopropylene, 1,3-cyclopentylene, 1,3-cyclohexylene, and 15 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 15 1,4-cyclohexylene.
  • the compound of any one of embodiments A1 to A134a, 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 20 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 20 when present, is independently selected from imidazoldiyl, pyridindiyl and pyrimid
  • the compound of any one of embodiments A1 to A134a, 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 25 when present, is independently selected from imidazol-2,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, and pyridin-3,5-diyl.
  • 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 25
  • 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 30 present, is independently selected from 1,3-phenylene and 1,4-phenylene.
  • each phenylene of Z 1 , Z 3 , and Z 4 by itself or as part of -(alkylene)-phenylene- and -phenylene-(alkylene)-, and when 30 present, is independently selected from 1,3-phenylene and 1,4-phenylene.
  • 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-, - 54 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • the compound of any one of embodiments A1 to A141 and 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-, 10 -bridged heterocyclylene-(alkylene)-, -(alkylene)-spiro heterocyclylene- and -spiro heterocyclylene-(alkylene)-, respectively, and when present, are independently selected from: , , s stated otherwise in any of the embodiments above.
  • the compound of any one of embodiments A1 to A141 and A143 to A156, or a pharmaceutically acceptable salt thereof is wherein heterocyclylene of Z 1 , Z 2 , - 55 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT Z 3 , Z 4 , and Z 5 by itself or as part of -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)- and when present, is selected from: A1 to A141 and 5 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, i A159.
  • 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 10 wherein -Z 3 -Z 4 -Z 5 -Z 6 - is: , , - 56 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT , ; , 5 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.
  • 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 10 thereof, is wherein -Z 3 -Z 4 -Z 5 -Z 6 - is: , or , halo, 15 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: - 57 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT . 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: 5 . A164.
  • 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 A165.
  • embodiment A16 ne 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: .
  • A166 one of embodiments A1 to A112, 15 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: . A167.
  • p y one of embodiments A1 to A112, A115 to A120, A124 to A128, A130 to A134, A159, A160, or a pharmaceutically acceptable salt 20 thereof, is wherein -Z 3 -Z 4 -Z 5 -Z 6 - is: . - 58 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT A168A.
  • the compound of any 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 A168.
  • one of embodiments A1 to A112, A115 to A136, and A159 to 168A, or a pharmaceutically acceptable salt thereof is wherein the 128, 10 A130, A131, A135 to A154, and A159 to A168, or a pharmaceutically acceptable salt thereof, is wherein Z 4 is –(alkylene)-heterocyclylene-, where heterocyclylene is substituted with R o and R p .
  • A170 is
  • 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 –(CH 2 )-heterocyclylene- where heterocyclylene is substituted with R o and R p . 15 A171.
  • the compound of any one of A1 to A114, A124 to A128, A130, A131, A135 to A154, and A159 to A170, or a pharmaceutically acceptable salt thereof is wherein Z 4 is: o o R o R o R R R o N N N or .
  • -Z 3 -Z 4 -Z 5 -Z 6 - is: - 59 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT o A112, A124 5 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: - 60 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT .
  • 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. 5 A175.
  • 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 Z 4 is C 3 to C 6 alkenylene substituted with R v where R v is fluoro or cyano.
  • Z 4 is C 3 to C 6 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 10 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 s , R t , and R u are hydrogen.
  • Z 4 is C3 to C6 alkylene 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 C3 to C6 alkylene 15 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 g , R h , and R i is halo, in one embodiment the halo is fluoro.
  • 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 or halo, provided at least one of R g , R h , and R i is halo, in one embodiment the halo is fluoro.
  • 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 C3 to C6 alkylene 20 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 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 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 is other than hydrogen and R u is hydrogen.
  • the compound of any one of embodiments A174 to A179, or 5 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. 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. 15 A183.
  • 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 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 20 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 defined therein and R t of linear C3 to C6 alkylene of Z 4 is halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbon
  • the compound of any one of embodiments A178 to A183, or 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. 25 A185.
  • the compound of any one of embodiments A178 to A184, or a pharmaceutically acceptable salt thereof is wherein the heteroaryl, heterocyclyl, and bridged 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 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 30 a pharmaceutically acceptable salt thereof is wherein R s of linear C 3 to C 6 alkylene of Z 4 is as 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, - 62 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref.
  • NKT-24-004PCT pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, or tetrahydrofuranyl, where each ring of R t is substituted with R 7 and R 8 independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino, dimethylamino and cyano, unless stated otherwise. 5 A187.
  • 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 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 A17910 and A187, or a pharmaceutically acceptable salt thereof is wherein Z 4 is branched C 4 to C 6 alkylene substituted as defined therein.
  • the compound of any one of embodiments A176 to A179 30 and A187 to A190, or a pharmaceutically acceptable salt thereof is wherein the R s and R u of 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, - 63 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref.
  • 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 5 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, 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 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. 15 A194.
  • 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 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 20 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 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 cycl
  • the compound of any one of embodiments A178 and 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 C3 to C 6 alkylene and together with the carbon atom to which they are attached can form cycloalkylene25 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 C3 to C 6 alkylene and together with the carbon atom to which they are attached can form cycloalkylene25 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 the same carbon atom of the linear portion of the C 3 to C 6 alkylene and together with the carbon atom to which they are attached can form heterocyclylene 30 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 the same carbon atom of the linear portion of the C 3 to C 6 alkylene and together with the carbon atom to which they are attached can form heterocyclylene 30 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 carbon atoms of the linear portion of the C 3 to C 6 - 64 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT alkylene and together with the carbon atoms to which they are attached can form cycloalkylene 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 carbon atoms of the linear portion of the C 3 to C 6 - 64 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT alkylene and together with the carbon
  • 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 , 5 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 heterocyclylene substituted with R 9 and R 10 .
  • Z 4 is C 3 to C 6 alkylene substituted with R s , R t , 5 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 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 10 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: 15 ent, R 9 is hydrogen, halo, methyl or ethyl and R 10 is hydrogen.
  • R t and R u are attached to the 10 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: 15 ent, R 9 is hydrogen, halo, methyl or ethyl and R 10 is hydrogen.
  • 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 C3 to C6 alkylene and together with the 20 carbon atoms to which they are attached can form cycloalkylene of formula: or heterocyclylene of formula: w ere eac rng s su s u e w an , n one embodiment R 9 is hydrogen, halo, 25 methyl or ethyl and R 10 is hydrogen. - 65 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT A201.
  • 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 C3 to C6 heteroalkylene substituted with R s , R t , and R u .
  • the compound of embodiment A201, or a pharmaceutically 5 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.
  • A203 the compound of embodiment A201, or a pharmaceutically 5 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.
  • the compound of embodiment A201, 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 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. 10 A204.
  • the compound of embodiment A201, or a pharmaceutically acceptable salt thereof is wherein Z 4 is C3 to C6 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 C3 to C6 heteroalkylene, R t and R u together with the carbon atom to which they are attached can form cycloalkylene or 15 heterocyclylene where the cycloalkylene and heterocyclylene are substituted with R 9 and R 10.
  • Z 4 is C3 to C6 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 C3 to C6 heteroalkylene, R t and R u together with the carbon atom to which they
  • 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 C 3 to C 6 heteroalkylene and together with the carbon atom to which they are attached can form cycloalkylene of formula: 20 ent R 9 is hydrogen, halo, methyl or ethyl and R 10 is hydrogen. 25 A206.
  • the compound of embodiment A204, 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 C3 to C6 heteroalkylene and together with the carbon atoms to which they are attached can form cycloalkylene of formula: - 66 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT bodiment, R 9 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 C3 to C6 heteroalkylene and together with the carbon atoms to which they are attached can form cycloalkylene of formula: - 66 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT bodiment, R 9 is hydrogen, halo, 5 methyl or eth
  • 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 to C 6 heteroalkylene substituted with R s , R t , and R u .
  • the C3 to C6 heteroalkylene of Z 4 is linear C3 to C 6 heteroalkylene substituted with R s , R t , and R u .
  • the compound of any one of embodiments A201 to A204,10 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 -, -CH 2CONR q1 CH2-, -CH2SO2NR q1 CH2-, -CH2NR q1 COCH2-, -CH2NR q1 SO2CH2-, -CH 2 CH 2 CH 2 NR q1 CO-, -CH 2 CON
  • the compound of any one of embodiments A201 to A204, A207, and A208, or a pharmaceutically acceptable salt thereof is wherein R q1 is hydrogen, methyl, ethyl, methylcarbonyl, or methylsulfonyl. 20 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 C3 to C6 heteroalkylene of Z 4 is -CH 2 X a CH 2 -, -X a CH 2 CH 2 -, -CH 2 CH 2 X a -, -CH 2 CH 2 CH 2 X a -, -CH2CH(R t )X a -, -X a CH(R t )CH2-, -CH2CONR q1 -, -CH2SO2NR q1 -, -CH2NR q1 CO-, -CH2NR q1 SO2-, -CONR q1 CH 2 -, -SO 2 NR q1 CH 2 -, -NR q1 COCH 2 -, or -NR q1 SO 2 CH 2 - where X a is -S-, -SO 2 -,
  • the compound of any one of embodiments A201 to A204, and A207 to 210, or a pharmaceutically acceptable salt thereof is wherein the linear C3 to C6 heteroalkylene of Z 4 is -CH 2 CH 2 CH 2 X a - or -CH 2 CH 2 X a - substituted with R s , R t , and R u as defined therein.
  • - 67 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT A212.
  • 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, 5 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 10 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 10 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, 15 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, 20 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
  • the compound of any one of embodiments A201 to A215, or a pharmaceutically acceptable salt thereof is wherein X a is -NR q1 -, -O-, -S-, or -SO2-; in one 30 embodiment, X a is -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 a pharmaceutically acceptable salt thereof is wherein X y is -NH- or -NCH 3 -. - 68 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT 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 A204, 5 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 -, 15 -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 -, 15
  • 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, 20 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 25 hydrogen and R t is hydrogen, heteroaryl, alkylaminocarbonyl, or cyano (unless stated otherwise herein above).
  • R s and R u are 25 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, heterocyclyl of branched C4 to C6 heteroalkylene of Z 4 , by itself or as part of heterocyclyloxy, 30 heterocyclylcarbonyl, and bridged heterocyclyl, when present, are five or six membered ring and each ring is substituted as defined therein.
  • the heteroaryl, heterocyclyl of branched C4 to C6 heteroalkylene of Z 4 by itself or as part of heterocyclyloxy, 30 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 C 4 to C 6 heteroalkylene of Z 4 , when present and unless stated otherwise herein above, is hydrogen, - 69 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • 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-, 10 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. 15 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 20 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.
  • the compound of any one of embodiments A227 to A229, or 25 a pharmaceutically acceptable salt thereof is wherein alkynylene of Z 4 is: - 70 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref.
  • No. NKT-24-004PCT . 27, A228, and A230, or a pharmaceutically acceptable salt thereof, is wherein alkynylene of Z 4 is: . 5 ound of any one of embodiments A174 to A226, or a pharmaceutically acceptable salt thereof, is wherein the alkylene, heteroalkylene, and alkenylene of Z 4 are selected from: - 71 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT , respect ve y. 5 A233.
  • the compound of any one of embodiments A174 to A226, and A232, or a pharmaceutically acceptable salt thereof is wherein the alkylene, heteroalkylene, and alkenylene of Z 4 are selected from: - 72 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT - 73 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT 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 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT , ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT res 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: 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 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT A237.
  • the compound of any one of embodiments A174, A176 to A179, A181 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 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: 10 - 77 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref.
  • NKT-24-004PCT 5 96d 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 (i) or (ii)) are independently: - 79 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT MERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT 6d, 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 5 formula (i) or (ii)) are independently: - 81 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT A241.
  • the compound of any one of embodiments A1 to A96d and 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: 5 .
  • 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: 10 , , - 82 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT ; , 5 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 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 10 alkynylene is substituted with R w and R x as defined in the first aspect of the Summary. A243.
  • 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: 15 , or - 83 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • each R m , R n , and R q are independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy and cyano (i.e., R r is hydrogen).
  • R r is hydrogen
  • the compound of embodiment A242 or A243, or a pharmaceutically acceptable salt thereof is wherein: 5 nd nylene is as provided in embodiment 231); and alkylene, alkenylene, and heteroalkylene of Z 4 are those as 10 provided in embodiment A233.
  • alkylene, 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, respectively.
  • alkenylene, and heteroalkylene of Z 4 are those as provided in embodiment A236, respectively.
  • alkenylene, 15 and heteroalkylene of Z 4 are those as provided in embodiment A237, respectively. A245.
  • 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 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: 20 , w p y y g , y , , haloalkyl, haloalkoxy, alkoxy, and cyano; and Z 4 is C 3 to C 6 alkylene substituted with R s , R t , and R u .
  • the compound of embodiment A245, or a pharmaceutically acceptable salt thereof is wherein: where R m and R n are independently selected from hydrogen, methyl methoxy, difluoromethoxy, difluoromethyl, and trifluoromethyl; 5 and Z 4 is propylene, butylene, or pentylene.
  • R m and R n are independently selected from hydrogen, methyl methoxy, difluoromethoxy, difluoromethyl, and trifluoromethyl; 5 and Z 4 is propylene, butylene, or pentylene.
  • the compound of embodiment A245 or A246, or a pharmaceutically acceptable salt thereof is wherein Z 4 is n-propylene.
  • the compound of any one of embodiments A1 to A46, A48 10 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: , , 15 , where R ee is hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl and R is hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or 20 trifluoromethyl.
  • Degron is the E3 ubiquitin ligase ligand selected from: , , 15 , where R ee is hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl and R is hydrogen, methyl
  • 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 pharmaceutically acceptable salt thereof is wherein Degron is the E3 ubiquitin ligase ligand selected from: 5 , , and 10 y g , y, y, y p py, ,, y 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: 15 - 86 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT A251.
  • the compound of embodiment A249, or a pharmaceutically acceptable salt thereof is wherein Degron is the E3 ubiquitin ligase liga where R ee is hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethy f f methyl; and R , when present, is hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, 5 difluoromethoxy, trifluoromethoxy, or trifluoromethyl.
  • the compound of embodiment A250, or a pharmaceutically acceptable salt thereof is wherein Degron is the E3 ubiquitin ligase ligand is .
  • n embodiment includes combination(s) of the embodiment and 10 subembodiment(s) thereof.
  • reference to an embodiment A includes all combinations of embodiments A and subembodiments thereof.
  • the scope of the preceding embodiments control i.e., only those groups that fall within the scope of group(s) recited in a preceding embodiment(s) should be 15 selected from the embodiment referring thereto.
  • Compounds Formula (I) (and any embodiment thereof disclosed herein including specific compounds) can be made by the methods depicted in the reaction schemes shown below.
  • the starting materials and reagents used in preparing these compounds are either available 5 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, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, 10 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).
  • Scheme 1 15 oup such as chlorine, bromine or methylsulfonyl, with an amine of formula 1-2, 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 ZnCl 2 in tert-butanol), provides a compound of formula 1-3.
  • the reaction 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 R 3 is hydrogen, Hy is 1,4- piperidindiyl, Degron is 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 -SO 2 -, can be synthesized as illustrated and described in Scheme 2.
  • An amine compound of formula 2-4 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 10 a suitable leaving group such as halo or methylsulfonyl.
  • 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 10 a suitable leaving group such as halo or methylsulfonyl.
  • piperidin-1,4-d der basic conditions such as in the presence of DIPEA, provides a compound of formula (I).
  • a compound of formula (I) such as where R 3 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 20 Scheme 3. - 97 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref.
  • the compound of Formula (I) (and any embodiment thereof disclosed herein including 5 specific compounds) i.e., compound of this disclosure can cause degradation of CDK2 and/or CDK4 proteins and hence are useful in the treatment of diseases mediated by CDK2 and/or CDK4.
  • Increasing evidence suggests that overactivated CDK2 and/or CDK4 leads to abnormal cell cycle regulation and proliferation in cancer cells. While CDK2/4 mutations are rarely found, 10 the kinase activity of CDK4/Cyclin D, CDK2/Cyclin E or CDK2/Cyclin A complexes is elevated via several mechanisms in human cancers. Aberrations of CDK4/cyclin D regulation have been identified in many human cancers.
  • amplification or overexpression of cyclin D1 has been found in many cancers, including breast invasive ductal carcinoma, invasive breast carcinoma, bladder urothelial carcinoma, breast invasive lobular carcinoma, and lung 15 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, pancreatic adenocarcinoma, esophageal adenocarcinoma, mesothelioma, lung squamous cell 20 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 mutations in FBXW7 or overexpression of USP28 which control the turnover of cyclin E, leads to 25 cyclin E overexpression and CDK2 activation.
  • certain cancer cells express a hyperactive, truncated form of cyclin E or cyclin A.
  • cyclin A amplification and overexpression have also been reported in various cancers such as hepatocellular carcinomas, colorectal and breast cancers.
  • catalytic activity of CDK2 is increased following loss of the expression or alteration of the location of the endogenous CDK2 inhibitor p27 or p21, 30 or overexpression of SKP2, a negative regulator of p27.
  • CDK2 protein phosphatases responsible for the dephosphorylations that activate the CDK2
  • CDK2/cyclin E phosphorylates oncogenic Myc to oppose ras-induced senescence, highlighting the importance of CDK2 in - 99 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT 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 5 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.
  • compounds of Formula (I) can be used in combination with CDK4/6 inhibitors or anti-HER2 therapies for the treatment of cancers that 10 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 15 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), 20 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
  • 20 stomach cancer i.e. gastric cancer
  • lung cancer e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, parvicellular and non
  • kidney cancer including astrocytoma, meningioma and glioblastoma), neuroblastoma, paraganglioma, 25 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.
  • bladder cancer including bladder urothelial carcinoma
  • cervical cancer colorectal cancer (e.g., cancer of the 30 small intestine, colon cancer, rectal cancer, cancer of the anus), head and neck cancer (e.g., cancers of the larynx, hypopharynx, nasopharynx, oropharynx, lips, tongue and mouth), liver cancer (e.g., hepatocellular carcinoma and cholangiocellular carcinoma), prostate cancer, testicular cancer, gall bladder cancer, pancreatic cancer (e.g.
  • exocrine pancreatic carcinoma and neuroendocrine pancreatic cancer thyroid cancer
  • parathyroid cancer fallopian tube cancer
  • fallopian tube cancer - 100 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT 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), 5 lymphoma (e.g. non-Hodgkin lymphoma NHL including mantel cell lymphoma, MCL and Hodgkin lymphoma) and multiple myeloma.
  • leukemia including acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and chronic lymphocytic leukemia
  • 5 lymphoma e.g. non-Hodgkin lymphoma NHL including mantel cell lymphoma, MCL and Hodgkin lymphoma
  • multiple myeloma 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 10 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 15 CCNE1 and/or CCNE2.
  • compounds of Formula (I) 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 disease (CD), gout, 20 uveitis, pemphigus vulgaris, and sepsis, and can also be used as a promising preventive treatment for noise-, cisplatin-, or antibiotic-induced or age-related hearing loss.
  • autoimmune diseases e.g., rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (pSS), multiple sclerosis (MS), Crohn’s disease (CD),
  • a suitable dosage level may be from about 0.1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kg per - 101 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT 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 5 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 10 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 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 15 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 25 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 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 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 - 102 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT 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 including specific compounds) may be formulated for parenteral administration by injection, e.g., 5 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 agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example 10 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.
  • 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) 15 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 oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous 20 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 the preparation of highly concentrated solutions.
  • the compounds of Formula (I) 25 (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 30 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 sparingly soluble 30 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 the active ingredient in a flavored basis such as sucrose and acacia or tragacanth. - 103 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT The compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) 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) (and any embodiment thereof disclosed herein including specific compounds) 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 10 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, 15 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, 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 suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit 30 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. Martin (Mack Publishing Company, 20th ed., 2000).
  • 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 5 herein including specific compounds) based on the total formulation, with the balance being one 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 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 15 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 20 therapies in which the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) and the other active ingredients may be used in lower doses 25 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 30 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 - 105 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT 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).
  • a pharmaceutical composition containing such other drugs in addition to the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) can be used.
  • the pharmaceutical compositions of the present disclosure also include those that also contain one or more other active ingredients, in addition to a 10 compound of Formula (I) (or any embodiment thereof disclosed herein including specific 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.
  • the subject 15 can be treated with a compound of Formula (I) (or any embodiment thereof disclosed herein 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- 20 B3234, PD184352, PD325901, TAK-733, pimasertinib, binimetinib, refametinib, cobimetinib (GDC-0973), AZD8330, BVD
  • RAS/RAF/MEK/ERK MAP kinase pathway
  • NKT-24-004PCT ALK inhibitors PF-2341066 (XALKOPJ ®; crizotinib); 5-chloro-N4-(2- (isopropyl- sulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiper azin-l-yl)piperidin-l- yl)phenyl)pyrimidine- 2,4-diamine; GSK1838705 A; CH5424802; Ceritinib (ZYKADIA); TQ-B3139, TQ-B3101 PI3K inhibitors: 4-[2-(lH-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-l- yl]methyl]thieno[3,2-d]- 5 pyrimidin-4-yl]morholine (also known as GDC 0941 and described in PCT Publication Nos.
  • VEGF receptor inhibitors Bevacizumab (sold under 10 the trademark Avastin® by Genentech/Roche), axitinib, (N-methyl-2-[[3-[(E)-2-pyridin-2- 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- 15 methyl)amino]-3-pyridinecarboxamide, and described in PCT Publication No.
  • WO 02/066470 pasireotide (also known as SOM230, and described in PCT Publication No. WO 02/010192), sorafenib (sold under the tradename Nexavar®); AL-2846 MET inhibitor such as foretinib, carbozantinib, or crizotinib; FLT3 inhibitors - sunitinib malate (sold under the tradename Sutent® by Pfizer); PKC412 20 (midostaurin); tanutinib, sorafenib, lestaurtinib, KW-2449, quizartinib (AC220) and crenolanib; 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
  • 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); - 107 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT HER dimerization inhibitors Pertuzumab (sold under the trademark Omnitarg®, by Genentech); CD20 antibodies: Rituximab (sold under the trademarks Riuxan® and MabThera® by Genentech/Roche), tositumomab (sold under the trademarks Bexxar® by GlaxoSmithKline), 5 ofatumumab (sold under the trademark Arzerra® by GlaxoSmithKline); Tyrosine kinase inhibitors: Erlotinib hydrochloride (sold under the trademark Tarceva® by Genentech/Roche), Linifanib (N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5- methylphenyl)urea, also known as ABT 869, available from Genentech), sunitinib malate (sold under the tradename Sutent® by Pfizer), bosut
  • 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- - 108 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT [(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in PCT Publication No. WO 09/155386); MCl-1 inhibitors: MIK665, S64315, AMG 397, and AZD5991; Aromatase inhibitors: Exemestane (sold under the trademark Aromasin® by Pfizer), 5 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, 10 sold under the tradenames Toposar®, VePe
  • WO 03/064383 everolimus (sold under the tradename Afinitor® by Novartis); Proteasome inhibitor such as carfilzomib, MLN9708, delanzomib, or bortezomib; 20 BET inhibitors such as INCB054329, OTX015, and CPI-0610; LSD1 inhibitors such as GSK2979552, and INCB059872; 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 25 Drug Conjugates: Gemtuzumab ozogamicin (sold under the tradename Mylotarg® by Pfizer/Wyeth); CD22 Antibody Drug Conjugates: Inotuzumab ozogamici
  • NKT-24-004PCT Synthetic erythropoietin: Darbepoetin alfa (sold under the tradename Aranesp® by Amgen); Receptor Activator for Nuclear Factor ⁇ B (RANK) inhibitors: Denosumab (sold under the tradename Prolia® by Amgen); 5 Thrombopoietin mimetic peptibodies: Romiplostim (sold under the tradename Nplate® by Amgen); Cell growth stimulators: Palifermin (sold under the tradename Kepivance® by Amgen); Anti-Insulin-like Growth Factor-1 receptor (IGF-1R) antibodies: Figitumumab (also known as CP-751,871, available from ACC Corp), robatumumab (CAS No.934235-44-6); 10 Anti-CSl antibodies: Elotuzumab (HuLuc63, CAS No.915296-00-3); CD52 antibodies: Alemtuzumab
  • NKT-24-004PCT tradename Cerubidine® daunorubicin liposomal (daunorubicin citrate liposome, sold under the tradename DaunoXome®), mitoxantrone (also known as DHAD, sold under the tradename Novantrone®), epirubicin (sold under the tradename EllenceTM), idarubicin (sold under the tradenames Idamycin®, Idamycin PFS®), mitomycin C (sold under the tradename Mutamycin®); 5 Anti-microtubule agents: Estramustine (sold under the tradename Emcyl®); Cathepsin K inhibitors: Odanacatib (also known as MK-0822, N-(l-cyanocyclopropyl)-4- fluoro-N-2- ⁇ (1S)-2,2,2-trifluoro-l-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl ⁇ -L-
  • Epothilone B analogs Ixabepilone (sold under the tradename 10 Lxempra® by Bristol-Myers Squibb); Heat Shock Protein (HSP) inhibitors: Tanespimycin (17-allylamino-17- demethoxy- 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 15 TpoR agonists: Eltrombopag (sold under the tradenames Promacta® and Revolade® by GlaxoSmithKline); Anti-mitotic agents: Docetaxel (sold under the tradename Taxotere® by Sanofi-Aventis); Adrenal steroid inhibitors: aminoglutethimide (sold under the tradename Cy
  • NKT-24-004PCT butoxy)carbonyl]amino ⁇ -2-hydroxy-3-phenylpropanoate larotaxel ((2 ⁇ ,3 ⁇ ,4 ⁇ ,5 ⁇ ,7 ⁇ ,10 ⁇ ,13 ⁇ )- 4,10-bis(acetyloxy)-13-( ⁇ (2R,3S)-3-[(tert-butoxycarbonyl) amino]-2-hydroxy-3- phenylpropanoyl ⁇ oxy)-l-hydroxy-9-oxo-5,20-epoxy-7,19-cyclotax-l l-en-2-yl benzoate); 5HTla receptor agonists: Xaliproden (also known as SR57746, l-[2-(2-naphthyl)ethyl]-4- 5 [3-(trifluoromethyl)phenyl]-l,2,3,6-tetrahydropyridine, and described in US Patent No.
  • HPC vaccines Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck; Iron 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 10 tradename Purinethol®), pemetrexed (sold under the tradename Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the tradename Cytosar-U®), cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCytTM), decitabine (sold under the tradename Dacogen®), hydroxyurea (sold under the tradenames Hydrea®, Dr
  • NKT-24-004PCT ((8S,9R,10S,l lS,13S,14S,16R,17R)-9-fluoro-l l,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16- trimethyl-6,7,8,9,10,l l,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one), prednisolone (sold under the tradenames Delta-Cortel®, Orapred®, Pediapred® and Prelone®), prednisone (sold under the tradenames Deltasone®, Liquid Red®, Meticorten® and Orasone®), 5 methylprednisolone (also known as 6-Methylprednisolone, Methylprednisolone Acetate, Methylprednisolone Sodium Succinate, sold under the tradenames Duralone®
  • the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, CD137 and STING.
  • the immune checkpoint molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA-4, 30 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, 5 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 10 (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- 15 LAG3 antibody is BMS-986016 or LAG525.
  • the inhibitor of an immune 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 20 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 increasing the immune response to an antigen; to improve immunization, including increasing 25 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 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 adjuvants or adoptive T cell transfer.
  • Compounds of this application may be effective in - 114 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT 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- 5 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). 10 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.
  • NKT-24-004PCT 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- 5 (2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate (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
  • tert-b oisoindolin-4-yl)oxy)- acetate 1.0 g, 2.57 mmol, 1.00 eq.
  • TFA 5.0 mL
  • Step 3 2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(2-(2-(2-hydroxyethoxy) ethoxy)ethyl)acetamide - 116 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT HATU 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 5 mmol, 2.99 eq.) in DMF (6.0 mL) at 0 o C and the mixture was stirred at RT for 1 h. The mixture was diluted with H2O and extracted with DCM.
  • Step 4 2-(2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy) 10 ethoxy)ethyl methanesulfonate MsCl 2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N- (2-(2-(2- hydroxyethoxy)ethoxy)ethyl)acetamide (800 mg, 1.73 mmol, 1.00 eq.) and TEA (524 mg, 5.18 15 mmol, 2.99 eq.) in DCM (8.0 mL) at 0 o C and the mixture was stirred at 0 o C for 1
  • NKT-24-004PCT Step 1 2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(2-(2-hydroxyethoxy)- ethyl) acetamide
  • 2-(2-aminoethoxy)ethan-1-ol 85 mg, 0.81 mmol, 1.50 eq.
  • HATU 308 mg, 0.81 mmol, 1.50 eq.
  • DIPEA 209 mg, 1.62 mmol, 3.00 eq.
  • Step 2 2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy)- ethyl methanesulfonate MsCl ( of 2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N- (2-(2-hydroxyethoxy)ethyl) acetamide 15 (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.
  • NKT-24-004PCT HATU (513 mg, 1.35 mmol, 1.50 eq.) and DIPEA (348 mg, 2.69 mmol, 3.00 eq.) were added to a mixture of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (300 mg, 0.90 mmol, 1.00 eq.) and 2-(2-(2-(2-aminoethoxy)ethoxy)ethan-1-ol (259 mg, 1.34 mmol, 1.49 eq.) in DMF (5.0 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-trioxa-3- azatetradecan-14-yl methanesulfonate 10 6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N- (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.
  • NKT-24-004PCT (6.0 mL) was stirred at 0 o C for 1 h.
  • the reaction mixture was diluted with H2O and extracted with DCM.
  • the combined organic phase was washed with brine, dried over Na 2 SO 4 , concentrated to get crude title compound as a yellow oil, which was used for next step without further purification.
  • Step 2 1-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12,15-tetraoxa-3- azaheptadecan-17-yl methanesulfonate M 2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N- (14-hydroxy-3,6,9,12- 10 tetraoxatetradecyl)acetamide (800 mg, 1.45 mmol, 1.00 eq.) and TEA (479 mg, 4.73 mmol, 326 eq.) in DCM (8.0 mL) at 0 o C.
  • NKT-24-004PCT Step 2 tert-Butyl (1-((4-((1-benzhydrylazetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)- carbamate
  • THF 5.0 5 mL
  • NaH 60%, 251 mg, 6.28 mmol, 1.50 eq.
  • Step 3 tert-Butyl (1-((4-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate
  • a mixture of tert phenyl)sulfonyl) piperidin- 15 4-yl)carbamate (500 mg, 0.87 mmol, 1.00 eq.), Pd(OH)2 (300 mg, 20% on carbon) in THF (20.0 mL) was stirred at 50 o C under H2 (50 psi) overnight. The mixture was cooled, filtrated, concentrated. The residue was purified by silica gel flash column (DCM: MeOH 10:1) to give the title compound as a white solid.
  • Step 4 tert-Butyl (1-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl) 20 oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate A m ridin-4-yl) carbamate (100 mg, 0.24 mmol, 1.00 eq.), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3- dione (74 mg, 0.27 mmol, 1.13 eq.) and DIPEA (94 mg, 0.73 mmol, 3.04 eq.) in NMP (1.5 mL) 25 was stirred at 140 o C 2 h under microwave irradiation.
  • Step 5 5-(3-(4-((4-Aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl) isoindoline-1,3-dione 5
  • a mixt xo-isoindolin-5- yl)- 122 -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 - 122 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT A mixture of tert-butyl (1-((4-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-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 K2CO3 (67 mg, 0.48 mmol, 2.00 eq.) in MeCN (2.0 mL) was stirred at 80 o C overnight.
  • 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 10
  • a mi isoindolin-5-yl) methyl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate 33 mg, 0.048 mmol, 1.00 eq.
  • TFA 1.0 mL
  • DCM 4.0 mL
  • Step 2 4-((2-(2-(2-Aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione 5
  • a mixt soindolin-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 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 eq.) in DCM (2.0 mL) at 0 o C and the mixture was stirred at 0 o C for 3 h. The mixture was diluted 15 with water, and then extracted with DCM.
  • Step 4 tert-Butyl (1-(N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)- ethoxy)ethoxy)ethyl)sulfamoyl)piperidin-4-yl)carbamate 20
  • a ,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.) in DCM (2.0 mL) was added TEA (52.4
  • NKT-24-004PCT 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
  • a mixt dioxoisoindolin-4- 5 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 20
  • DCM dimethylethyl sulfoxide
  • 3-bromoprop-1-yne 3.0 g, 25.22 mmol, 1.59 eq.
  • 40% aqueous NaOH 30.0 mL
  • tetrabutylammonium hydrogen sulfate 270 mg, 0.80 mmol, 0.050 eq.
  • NKT-24-004PCT 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
  • 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 H2 atmosphere.
  • Step 5 2-(2,6-Dioxopiperidin-3-yl)-4-(3-(3-(methylamino)propoxy)propyl)isoindoline-1,3-dione 20
  • the mixture was concentrated and adjusted pH to 9 using aqueous Na2CO3, and then the mixture was extracted with DCM.
  • the organic layer was washed - 126 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT with water, brine, dried over Na2SO4, and then concentrated to give the title compound as a yellow oil.
  • 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 5
  • a mixture oxy)- propyl)isoindoline-1,3-dione 150 mg, 0.39 mmol, 1.00 eq.
  • tert-butyl (1-(chlorosulfonyl)- piperidin-4-yl)carbamate 17.3 mg, 0.58 mmol, 1.49 eq.
  • TEA 118 mg, 1.17 mmol, 3.00 eq.
  • Step 7 4-Amino-N-(3-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)propyl)- N-methylpiperidine-1-sulfonamide 15
  • TFA 0.5 mL
  • NKT-24-004PCT Step 1 tert-Butyl (2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate NaH (1.2 n of tert-butyl (2-(2- hydroxyethoxy)et hyl)carbamate (4.1 g, 19.98 mmol, 1.00 eq.) in THF (50.0 mL) in portions at 0 5 o C and the mixture was stirred for 1h. Then 3-bromoprop-1-yne (2.83 g, 23.79 mmol, 1.19 eq.) was added at 0 o C.
  • 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 ert-Butyl ( 2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate provided the title compound.
  • Step 2 3-((4-Aminopiperidin-1-yl)sulfonyl)phenol 5
  • the solution of b n-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 mixture was cooled and concentrated to give the title compound as a brown oil, which was used for next step without further purification.
  • Step 3 tert-Butyl (1-((3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamate A solution of ( 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. The mixture was stirred at RT for 2 h, 15 diluted with DCM and the organic layer was washed with water, brine, dried over Na 2 SO 4 , and concentrated.
  • Step 4 1-Benzhydrylazetidin-3-yl methanesulfonate 20 To a stirred solution o 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, 2.00eq.) at 0 o C. The mixture was stirred at RT overnight, diluted with DCM and then washed with water.
  • NKT-24-004PCT Step 5 tert-Butyl (1-((3-((1-benzhydrylazetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)- carbamate
  • yl)carbamate 533 mg, 5 1.49 mmol, 1.00 eq.
  • 1-benzhydrylazetidin-3-yl methanesulfonate 570 mg, 1.79 mmol, 1.20 eq.
  • Cs 2 CO 3 (1.46 g, 4.49 mmol, 3.00 eq.
  • Step 6 tert-Butyl (1-((3-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate
  • MeOH a stirred solution idin-3-yl)oxy)phenyl)sulfonyl)- piperidin-4-yl)carbamate (400 mg, 0.69 mmol, 1.00 eq.) in MeOH (15.0 mL) were added Pd(OH)2/C (20 wt. %, 250 mg) and AcOH (0.5 mL) at RT.
  • the resulting mixture was stirred at 50 15 o C under H 2 (50 psi) overnight.
  • the reaction mixture was cooled and filtered, and the filtrate was concentrated.
  • Step 7 tert-Butyl (1-((3-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)- oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate NH Boc B 20 Proceeding an , , 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 ana e, but using tert-butyl 5 (1-((3-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)oxy)phenyl)- sulfonyl)piperidin-4-yl)carbamate provided the title compound.
  • 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 - 131 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT Proceedi t using tert-butyl 4-((4-((3-(1-(2,6 -dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4- yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate provided the title 5 compound.
  • Step 3 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 10 Proceed using 3-(3- methyl-2-oxo-4-(3-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione and tert-butyl(1-(chlorosulfonyl)piperidin-4- yl)carbamate provided the title compound
  • Step 4 3-(4-(3-((1-((1-((4-Aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)piperidin-4-yl)- 15 oxy)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione Proceed 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 20 provided the title compound.
  • Step 2 1-(4-Methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate 15 Trifluoromethanes 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 - 133 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT To a stirred solution of 7-bromo-1-methyl-1H-benzo[d]imidazol-2(3H)-one (1.1 g, 4.84 mmol, 1.23 eq.) in THF (30.0 mL) was added t-BuOK (632 mg, 5.63 mmol, 1.43 eq.) at 0 o C. After stirring at 0 o C for 0.5 h, a solution of 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (1.5 g, 3.93 mmol, 1.00 eq.) in THF (10.0 mL) was added at 0 o C.
  • Step 4 3-(4-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 10
  • a mixture of 3-(4 nzo[d]imidazol-1-yl)-1-(4- 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 and poured into ice water.
  • the resulting mixture was filtered, and the cake was dried to give the title compound as a white solid.
  • Step 5 tert-Butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate NaH (60%, 240 mg, rred 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.). The resulting mixture was stirred 20 at RT for 2 h, quenched with water and then extracted with EtOAc.
  • 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 25 - 134 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT Proceeding analogously as described in Reference 10, Step 3 above, but using 3-(4-bromo- 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione and tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate in DMF provided the title compound.
  • Step 7 3-(3-Methyl-2-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)-2,3-dihydro-1H- 5 benzo[d]imidazol-1-yl)piperidine-2,6-dione Proceeding analog 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 but using 3-(3- methyl-2-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1- 15 yl)piperidine-2,6-dione and tert-butyl (1-(chlorosulfonyl)piperidin-4-yl)carbamate in DMF provided the title compound.
  • 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 20 Proceedi , , using tert-butyl (1-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4- yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate provided the title compound.
  • Step 2 2-(2,6-Dioxopiperidin-3-yl)-4-((4-oxocyclohexyl)amino)isoindoline-1,3-dione
  • 2 -dione (276 mg.1.00 mmol, 1.00 eq.) and 4-aminocyclohexanone hydrochloride (300 mg, 2.00 mmol, 2.00 eq.) in NMP 15 (2.5 mL) was stirred at 140 o C under microwave for 3 h.
  • the reaction mixture was cooled, diluted with DCM and then washed with brine.
  • Step 3 2-(2,6-Dioxopiperidin-3-yl)-4-((4-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione 20
  • lohexyl)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)- cyclohexyl)-N-methylsulfamoyl)piperidin-4-yl)carbamate 5 Proceedi t using 2-(2,6- dioxopiperidin-3-yl)-4-((4-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione and tert-butyl (1-(chlorosulfonyl)piperidin-4-yl)carbamate provided the title compound.
  • Step 5 4-Amino-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexyl)- 10 N-methylpiperidine-1-sulfonamide 2,2,2-trifluoroacetate
  • Pro g tert-butyl (1-(N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexyl)-N- methylsulfamoyl)piperidin-4-yl)carbamate provided the title compound.
  • 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 Proce ng (1-((3-((1-15 ((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-24-004PCT Step 1 tert-Butyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate Proceeding analogou 2 above, but using tert-butyl (2-hydroxyethyl)carbamate a nd 3-bromoprop-1-yne provided the title compound.
  • 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 , but using tert-butyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate provided the title compound.
  • NKT-24-004PCT 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, -dihydro-1H-benzo[d]- 5 imidazole-4-carbaldehyde 360 mg, 1.25 mmol, 1.00 eq.
  • tert-butyl N-methyl (piperidin-4- yl)carbamate (403 mg, 1.88 mmol, 1.50 eq.
  • Step 2 4-(((tert-Butyldimethylsilyl)oxy)methyl)aniline - 140 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT A mixture of (4-aminophenyl)methanol (2.00 g, 16.24 mmol, 1.00 eq.), DMAP (595 mg, 4.87 mmol, 0.30 eq.), TEA (2.00 g, 19.76 mmol, 1.22 eq.) and TBSCl (2.70 g, 17.91 mmol, 1.10 eq.) in DMF (40 mL) was stirred at RT overnight. The reaction mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 , 5 filtered. and then concentrated.
  • Step 3 Dimethyl 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino)phthalate A mixture of 3-iodo-ph 9.37 mmol, 1.00 eq.), 4-(tert- 10 butyl-dimethyl-silanyloxymethyl)-phenylamine (2.67 g, 11.25 mmol, 1.20 eq.), Pd2(dba)3 (436 mg, 0.48 mmol, 0.051 eq.), Cs2CO3 (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.
  • Pd2(dba)3 436 mg, 0.48 mmol, 0.051 eq.
  • Cs2CO3 (6.11 g, 18.75 mmol, 2.00
  • Step 4 Dimethyl 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)(methyl)amino)phthalate A mixture of dimethy y)methyl)phenyl)- amino)phthalate (1.50 g, 3.49 mmol, 1.00 eq.), iodomethane (991 mg, 6.98 mmol, 2.00 eq.), Cs2CO3 (3.41 g, 10.47 mmol, 3.00 eq.) in DMF (30.0 mL) was stirred at 20 o C for 8h under 20 nitrogen atmosphere.
  • Step 5 3-[(4-Hydroxymethyl-phenyl)-methyl-amino]-phthalic acid dimethyl ester 25 - 141 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • Step 6 Dimethyl 3-((4-formylphenyl)(methyl)amino)phthalate A mixture of 3-[(4-y thalic acid dimethyl ester (300 10 mg, 0.91 mmol, 1.00 eq.) and MnO2 (800 mg, 9.20 mmol, 10.11 eq.) in DCM (10.0 mL) was stirred at rt overnight. The reaction mixture was filtered and concentrated to give the title compound as a yellow oil, which was used for next step without further purification.
  • Step 7 Dimethyl 3-((4-(((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl) phenyl)(methyl)amino)phthalate 15
  • a mixture of te (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.
  • NaBH(OAc)3 290 mg, 1.37 mmol, 1.49 eq. was then added and stirred for 4 h.
  • Step 8 3-((4-(((2-((tert-Butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl)phenyl) (methyl)amino)phthalic acid
  • the reaction mixture was concentrated and purified by prep-HPLC to give the title compound as a white solid.
  • 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 5
  • a amino)methyl) phenyl)(methyl)amino)phthalic acid (120 mg, 0.25 mmol, 1.00 eq.) and 3-aminopiperidine-2,6- dione hydrochloride (41 mg, 0.25 mmol, 1.00 eq.) in pyridine (3.0 mL) was stirred at 100 o C overnight. The reaction mixture was cooled and concentrated.
  • NKT-24-004PCT 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
  • a mixture of t oxo-2,3-dihydro-1H- 5 benzo[d]imidazol-4-y l)-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.
  • 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
  • hydro-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 an-19-oic acid (372 mg, 1.06 mmol, 2.00 eq.) in THF (6 mL) was added isobutyl chloroformate (109 mg, 20 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 stir piperidin-1- yl)sulfonyl)phenoxy)azetidin-1-yl)piperidine-1-carboxylate 60 mg, 0.095 mmol, 1.00 eq.
  • 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 nyl)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
  • m roxyethoxybenzoate (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
  • lin-2-yl)piperidine-2,6-dione 500 mg, 1.64 mmol, 1.00 eq.
  • DCM 10.0 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 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 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-24-004PCT 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-24-004PCT 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-24-004PCT Step 4 tert-Butyl (1-((3-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)- carbamate A mixt 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 H 2 (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
  • methyl 2-cyano-4-fluorobenzoate (1.06 g, 5.94 mmol, 1.10 eq.) and DIEA (2.09 g, 16.20 mmol, 3.00 eq.) in DMSO (30.0 mL) was stirred at 120 o C under N 2 for 16 h.
  • 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 mi -1-yl)- sulfonyl)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-cyanobenzoate (1.01g, 1.50 mmol, 1.00 eq.), NaH 2 PO 2 .H 2 O (1.59 g, 15.00 mmol, 10.00 eq.) and Raney Ni (1.60 g) in pyridine (10.0 mL), H2O (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 mix mol, 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 dry D
  • the mixture was stirred at 45 o C under N 2 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 N2 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 Na2SO4, 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-24-004PCT 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 mixtu 0 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 st ndolin-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 : .
  • 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
  • DMF 1.0 mL
  • HCOOH HCOOH
  • Step 2 4-(Dimethoxymethyl)piperidine To a mixture of benzyl -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-24-004PCT 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 com tep 5.
  • Step 2 tert-Butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidine-1-carboxylate
  • a solu g, 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)Cl 2 (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 - 159 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT
  • 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
  • AcOH (3 drops) and benzyl 4-formylpiperidine-1-carboxylate (933 mg, 3.78 mmol, 1.50 eq.) in MeOH (10.0 mL) was stirred at 45 o C for 1 h.
  • the solution cooled to RT and NaBH3CN (475 mg, 7.56 mmol, 3.00 eq.) was added.
  • 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 )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-24-004PCT Step 1: tert-Butyl (1-((3-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)sulfonyl)piperidin-4-yl)- carbamate A mixture rbamate (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 Na 2 SO 4, 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 mixtu enyl)- 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-B amate (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 1.00
  • 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
  • DCM 1.0 mL
  • TFA 0.2 mL
  • 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 - 163 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT 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 4 3-(6-Fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione 5
  • o-1-oxoisoindolin- 5-yl)piperazine-1-carboxylate 95 mg, 0.21 mmol, 1.00 eq.
  • TFA 0.5 mL
  • the reaction mixture was concentrated to give the title compound as a yellow oil.
  • 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 mix ne-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.
  • NKT-24-004PCT Step 1: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1- carboxylate A mixture o .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. The mixture was diluted with water and extracted EA.
  • 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 pipe . , . , . . n 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.
  • 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 mixtu ndoline-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-Buty 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-24-004PCT 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 mix mol, 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 g,
  • Step 2 tert-Butyl 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane- 2-carboxylate tert-but nane-2- 5 carboxylate was converted to the title compound by proceeding analogously as described in Reference 28, Step 6-7.
  • 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 mixtu )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
  • oindoline-1,3- dione 94 mg, 0.26 mmol, 1.00 eq.
  • rac-tert-butyl ((3R,4S)-1-((3-(bromomethyl)phenyl)- sulfonyl)-3-fluoropiperidin-4-yl)carbamate 141 mg, 0.31 mmol, 1.20 eq.) in THF (4.0 mL) was 20 added TEA (131 mg, 1.30 mmol, 5.00 eq.) and the mixture was stirred at
  • Step 2 2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbaldehyde 15
  • 2-(2,6-di e-5-carbonitrile (1.20 g, 4.46 mmol, 1.00 eq.)
  • NaH 2 PO 2 .H 2 O 993 mg, 9.37 mmol, 2.10 eq.
  • Raney-Ni 500 mg
  • H2O AcOH (40.0 mL, 2:2:1) was stirred at 70 o C overnight.
  • NKT-24-004PCT 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.), HCOONH4 ( 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 hyde (100 mg, 0.37 mmol, 1.00 eq.) in THF (3.0 mL) were added tert-butyl (1-((3-(piperidin-4-yloxy)phenyl)- sulfonyl)piperidin-4-yl)carbamate (169 mg, 0.39 mmol, 1.05 eq.) and 1 drop of AcOH.
  • 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 B yl)-piperazin- 1-yl)azetidine-1-carboxylate was converted to the title compound using similar procedure as described in Reference 28, Step 4-7. - 174 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • Step 2 tert-Butyl (1-((3-(3-hydroxyazetidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate A mi mate (5.83 g, 13.95 mmol, 1.00 eq.), K2CO3 (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 yl)- 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 n-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.).
  • NKT-24-004PCT Reference 45 Synthesis of rac-1-(6-(1-(3-(((3R,4S)-4-amino-3-fluoropiperidin-1-yl)sulfonyl)benzyl)piperidin-4- yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 5 0.05 mol, 1.00 eq.) in EtOH (50.0 mL) was added methylhydrazine (57 g, 0.50 mol, 10.00 eq.) and the mixture was stirred at 100 o C 30h in sealed tube. Then the mixture was concentrated, and added water.
  • Step 2 Methyl 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propanoate
  • Methyl acrylate (20 o 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. , . q. on 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 - 177 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT 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.
  • the mixture was concentrated, then diluted with water.
  • the mixture was filtered and solid was washed with water, air dried to give the title compound as 10 pale yellow solid.
  • 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
  • NKT-24-004PCT Step 6 tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)piperidine-1-carboxylate
  • a mixture of t -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
  • 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 mmol,
  • 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
  • a m -1(2H)-yl)-1- methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)phenyl)sulfonyl)-3-fluoropiperidin-4-yl)carbamate 45 mg, 0.07 mmol, 1.00 eq.
  • TFA/DCM 0.5 mL/2.0 mL
  • NKT-24-004PCT 1.50 eq
  • K2CO3 (1.37 g, 9.90 mmol, 2.00 eq)
  • Pd(dppf)Cl2 724 mg, 0.99 mmol, 0.20 eq
  • dioxane/H 2 O 15 mL, 5/1
  • the mixture was filtered and extracted with EA.
  • the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated.
  • the residue was purified by silica flash column PE/EtOAc (10:1) to give product as 5 yellow solid.
  • 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 H2 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.) in DMF (4.0 mL) was stirred at 70°C for overnight.
  • the mixture was diluted with water and extracted with EA.
  • the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and then concentrated.
  • Step 4 3-((4-(Piperidin-4-yl)phenyl)amino)piperidine-2,6-dione TFA (0 . yl 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 mo lution 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 N2. 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 - 182 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT (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
  • 2,6 ioxaborolan-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.)
  • K 3 PO 4 (5.63 10 g, 26.50 mmol, 3.00 eq.)
  • Pd(PPh3)4 510 mg, 0.44 mmol, 0.05 eq.
  • 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.), Pd2(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-24-004PCT Step 6 tert-Butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate
  • a mixture o 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 H 2 . 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) ,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.
  • Step 2 tert-Butyl 4-(1-methyl-1H-indol-6-yl)piperidine-1-carboxylate
  • THF 40 mL
  • 400 mg of 10% w/w Pd/C 40 mg
  • the mixture was hydrogenated at 50 °C for 16 h under hydrogen atmosphere 10 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 15
  • NIS NIS
  • a stirred -carboxylate (2.3 g, 7.3 mmol, 1.00 eq.) in DMF (35 mL) was added NIS (1.64 g, 7.3 mmol, 1.00 eq.) in portions at 0- 5 °C, and the resulting mixture was stirred for 2 h at 0-5 °C.
  • the reaction mixture was diluted with water and extracted with EtOAc.
  • the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced 20 pressure.
  • Step 4 tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indol-6-yl)piperidine-1- carboxylate - 185 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT To a stirred mixture of tert-butyl 4-(3-iodo-1-methylindol-6-yl)piperidine-1-carboxylate (2.5 g, 5.7 mmol, 1.00 eq.) and 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/H2O (10:1, 25 mL) were added K2CO3 (2.38 g, 17.2 mmol, 3.00 eq.) and Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 (462 mg, 0.57 mmol, 0.10 eq.) at room 5 temperature.
  • the resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere.
  • the reaction mixture was diluted with water and extracted with EtOAc.
  • the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluting with PE / EtOAc (0-40%), to afford the crude product.
  • the crude product 10 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
  • EtOH a stirred s -yl)-1-methyl-1H- 15 indol-6-yl)piperidine-1-carboxylate (50 mg, 0.083 mmol, 1.00 eq.) in EtOH (1 mL) was added Pd/C (10% w/w, 50 mg) and 1 drop of AcOH at room temperature.
  • Pd/C 50% w/w, 50 mg
  • the resulting mixture was stirred at room temperature for 3 h under hydrogen atmosphere using a hydrogen balloon.
  • the reaction mixture was filtered and the filtrate was concentrated to afford the title compound.
  • Step 3 tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)benzo[b]thiophen-6-yl)-3,6- 20 dihydropyridine-1(2H)-carboxylate
  • y y p en-3-yl)pyridine 260 mg, 0.57 mmol, 1.00 eq.
  • K3PO4 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 25 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.
  • the resulting mixture was stirred for - 187 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT 3 h at 60 °C under nitrogen atmosphere.
  • the reaction mixture was diluted with EtOAc and the organic layer was 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 EtOAc/PE (0-50%), to afford the title compound as a light 5 brown solid.
  • Step 4 tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)benzo[b]thiophen-6-yl)piperidine-1-carboxylate
  • a stirred -yl)benzo[b]thiophen- 6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (220 mg, 0.36 mmol, 1.00 eq.) in EtOH (3 10 mL) and AcOH (0.3 mL) was added 20 mg of 10% w/w Pd/C.
  • EtOH 3 10 mL
  • AcOH 0.3 mL
  • Step 5 3-(6-(Piperidin-4-yl)benzo[b]thiophen-3-yl)piperidine-2,6-dione hydrochloride 15
  • benzo[b]thiophen-6- yl)piperidine-1-carboxylate 130 mg, 0.30 mmol, 1.00 eq.
  • DCM 1,4- dioxane
  • Step 2 1-(6-(Piperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione 15
  • the title compound was synt 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.
  • Step 2 Benzyl 4-(3-amino-1H-indazol-6-yl)piperazine-1-carboxylate A mixture of xylate (11.00 g, 32.40 15 mmol, 1.00 eq.) and N2H4/H2O (10.14g, 161.99 mmol, 5.00 eq) in BuOH (100.0 mL) was stirred at 100 °C under N 2 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 20
  • a solutio rboxylate (4.00 g, 11.40 mmol, 1.00 eq.) in dry DMF (50.0 mL) at 0 °C was added NaH (0.91 g, 22.80 mmol, 2.00 eq.) under N2, and the mixture was stirred at rt for 30 min.
  • the mixture was cooled to 0 °C, CH3I - 190 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • Step 4 Benzyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)- piperazine-1-carboxylate
  • Step 5 1-(1-Methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • a mixture of dazol-6-yl]piperazine- 15 1-carboxylate (500 mg, 1.08 mmol, 1.00 eq.), 10% Pd/C (400 mg) and ammonium formate (682 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 1 Benzyl 4-(3-amino-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)piperazine-1-carboxylate The title com escribed in 51, with 2,2,2-trifluoroethyl trifluoromethanesulfonate replacing MeI in Step 3.
  • Step 2 3-((6-(4-((Benzyloxy)carbonyl)piperazin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)- amino)propanoic acid
  • Step 3 Benzyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol- 6-yl)piperazine-1-carboxylate 15
  • a mixture of , ,2-trifluoroethyl)-1H- indazol-3-yl)amino)propanoic acid (620 mg, 1.23 mmol, 1.00 eq.) and urea (369 mg, 6.15 mmol, 5.00 eq.) in AcOH (10.0 mL) was stirred at 120 o C under N2 overnight. The mixture was diluted with water and extracted with EtOAc.
  • NKT-24-004PCT 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 -1-(2,2,2- 5 trifluoroethyl)-1H-indazol-6-yl)piperazine-1-carboxylate (280 mg, 0.52 mmol, 1.00 eq.), HCOONH4 (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.
  • NKT-24-004PCT Step 2 tert-Butyl 3,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)- carboxylate Tf 2 O (3.03 g, 10.77 of tert-butyl 3,3-difluoro-4- 5 oxopiperidine-1-carboxyla te (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). The mixture was stirred at -10 o C under N 2 and then stirred at r.t. overnight.
  • Step 3 tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3- 10 difluoro-3,6-dihydropyridine-1(2H)-carboxylate
  • 2-yl)-1H-indazol-3- 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 15 e
  • Step 4 tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3- 20 difluoropiperidine-1-carboxylate
  • a m hyl-1H- 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 25 PSI) overnight.
  • Step 5 1-(6-(3,3-Difluoropiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione 2,2,2-trifluoroacetate 5
  • a mi thyl-1H- indazol-6-yl)-3,3-difluoropiperidine-1-carboxylate (102 mg, 0.22 mmol, 1.00 eq.) in TFA/DCM (0.5 mL/2.0 mL) was stirred at rt for 2h. The mixture was concentrated to give the title compound as brown oil.
  • Step 2 tert-Butyl (1-((3-(bromomethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate 3-(Bromome y y . g, . , . 0 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.), - 195 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT 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. The mixture was quenched with H 2 O and extracted with DCM. The combined organic layer was washed with water, dried over anhydrous Na2SO4, filtered, and then concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (3:1), to afford the 5 title compound as white solid.
  • 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 A mixtur dine-2,4(1H,3H)- 10 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 A )-1-methyl- 20 1H-indazol-6-yl)piperidin-1-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (50 mg, 0.07 mmol, 1.00 eq.) in TFA/DCM (0.5 mL/2.0 mL) was stirred at r.t. for 2h.
  • NKT-24-004PCT Step 2 1-(1-Methyl-6-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione
  • a mixt -1-methyl-1H- 5 indazol-6-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate 200 mg, 0.38 mmol, 1.00 eq.
  • TFA/DCM 0.5 mL/2.0 mL
  • 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 10 tert-But ol, 1.05 eq.) in 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.), TEA (38 mg, 0.38 mmol, 2.00 eq.) in DCM (2.0 mL) at 0 o C, and the mixture was stirred
  • Step 4 1-(6-(1-((1-((4-Aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)piperidin-4-yl)-1- 20 methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-trifluoroacetate
  • a mix , )-yl)-1-methyl- 1H-indazol-6-yl)piperidin-1-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate (27 mg, 0.039 mmol, 1.00 eq.) in TFA/DCM (0.5 mL/2.0 mL) was stirred at rt for 2 h.
  • Step 2 tert-Butyl (1-((3-(4-(hydroxymethyl)piperidin-1-yl)phenyl)sulfonyl)piperidin-4- 15 yl)carbamate
  • NKT-24-004PCT Step 3 tert-Butyl (1-((3-(4-formylpiperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate Dess-Martin (2.5 d solution of tert-butyl (1- ((3-(4-(hydroxymethyl)piperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (1.35 g, 2.98 5 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
  • a mixt iperidin-4- yl)carbamate (264 mg, 0.585 mmol, 1.00 eq.), CH3COOH (1 drops) and 1-(1-methyl-6-(piperidin- 15 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 - 200 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT A mixture of 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 (170 mg, 0.223 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 yellow solid.
  • NKT-24-004PCT 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
  • a mi ethyl-1H- 5 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.
  • Step 2 tert-Butyl ((1r,4r)-4-((3-(hydroxymethyl)phenyl)thio)cyclohexyl)carbamate - 202 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT A mixture of [4-(tert-butoxycarbonylamino)cyclohexyl] 4-methylbenzenesulfonate (2.9 g, 7.85 mmol, 1.0 eq) and (3-mercaptophenyl)methanol (1.1 g, 7.85 mmol, 1.0 eq), potassium carbonate (2.17 g, 15.7 mmol, 2.0 eq) in MeCN (100 mL) was degassed and refilled with N2 and stirred at 80 °C for 16 h. The mixture was filtered through Celite® and the filter cake was washed 5 with MeCN.
  • Step 3 tert-Butyl ((1r,4r)-4-((3-formylphenyl)thio)cyclohexyl)carbamate 10
  • o phenyl) thio)cyclohexyl)- carbamate (260 mg, 0.77 mmol, 1.0 eq) in anhydrous DCM (15 mL) at 0 °C, was added DMP (653.5 mg, 1.54 mmol, 2.0 eq) in portions.
  • 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.
  • the resulting mixture was stirred at rt for 10 min and extracted with DCM, and dried over 15 anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with EA/PE (0-25%) to afford the title compound as a white solid.
  • 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 20
  • To a stirre lohexyl)carbamate (200 mg, 0.6 mmol, 1.0 eq) and 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 25 resulting mixture was stirred for 16
  • 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 5
  • Step 6 1-(6-(1-(3-(((1s,4s)-4-Aminocyclohexyl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-trifluoroacetate
  • iperidin-4-yl 15 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 eq) and the resulting mixture was stirred for 16
  • Step 2 (2S,4R)-4-Hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2- carboxamide
  • a zol-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
  • s yl-3-trityl- 5 sulfanyl-butan oic 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
  • a (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 was diluted with water, extracted with EA. The combined organic layers were washed with brine, 20 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)- butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2-carboxamide 25
  • anoyl]-4-hydroxy- N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (2.1 g, 2.98 mmol) and HATU (2265.4 mg, 5.96 mmol) in DCM (1 mL) was added TEA (1155.0 mg, 8.94 mmol).
  • Step 7 tert-Butyl 4-((((R)-3-(1-fluorocyclopropane-1-carboxamido)-4-((2S,4R)-4-hydroxy-2-15 (((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 (24 2R)-2-[(1- fluorocyclopropanecarbonyl)amino]-3-methyl-3-sulfanyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-20 methylthiazol-5-yl)pheny
  • 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 mixtur )-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 A mixture of amate (5 g, 11.92 mmol), potassium vinyltrifluoroborate (2.4 g, 17.89 mmol), Pd(dppf)Cl2 (872.48 mg, 1.19 mmol) 5 and potassium carbonate (4.9 g, 35.77 mmol) in dioxane/acetonitrile/water (60 mL, 5:5:2, v/v) was purged with argon five times and stirred at 85 °C 6 h.
  • Step 3 tert-Butyl (1-((3-(2-hydroxyethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate
  • borane-tetrahydrofuran complex (16.58 mL, 16.58 mmol) dropwise at 25 °C under argon atmosphere and the mixture was 15 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%).
  • Step 4 tert-Butyl (1-((3-(2-oxoethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate - 210 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT To a stirred solution of tert-butyl (1-((3-(2-hydroxyethyl)phenyl)sulfonyl)piperidin-4-yl)- carbamate (200 mg, 0.52 mmol) in anhydrous dichloromethane (5 mL) was added Dess-Martin Periodinane (441.25 mg, 1.04 mmol) at 0 °C and the mixture was stirred for 1 h. The mixture was diluted with ethyl acetate, washed with sodium sulfite (aq.), sodium bicarbonate (aq.), water, 5 brine, and the organic layer was dried over anhydrous sodium sulfate.
  • Step 5 tert-Butyl (1-((3-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol- 6-yl)piperidin-1-yl)ethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate NHBoc NHBoc N N O 10
  • a mixture pyrimidine- 2,4(1H,3H)-dione hydrochloride 95.13 mg, 0.26 mmol
  • tert-butyl (1-((3-(2-oxoethyl)- phenyl)sulfonyl)piperidin-4-yl)carbamate 100 mg, 0.26 mmol) in anhydrous dichloromethane (2 mL) was stirred at 25 °C for 1 h
  • Step 6 1-(6-(1-(3-((4-Aminopiperidin-1-yl)sulfonyl)phenethyl)piperidin-4-yl)-1-methyl-1H- 20 indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride
  • y ropyrimidin-1(2H)-yl)- 1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate 100 mg, 0.14 mmol
  • dichloromethane 3 mL
  • 4 M hydrogen chloride/1,4-dioxane 1.5 mL
  • the mixture was stirred at 130 °C for 4 h. After cooling the mixture to rt, the mixture was diluted with water and ethyl acetate. After filtration, the mixture was extracted with ethyl acetate and the 15 combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography, eluted with ethyl acetate/petroleum ether (0 ⁇ 21% with 5% dichloromethane) to afford the title compound as an off- white solid.
  • Step 2 tert-Butyl (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol- 20 6-yl)piperidin-1-yl)-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate
  • 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 2H)-yl)- 10 1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)phenyl)sulfonyl) piperidin-4-yl)- 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 5 3-Bromo-4-cya 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, 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.
  • Step 3 tert-Butyl (1-((4-cyano-3-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4- yl)carbamate 15
  • 2-(di-tert-butyl- phosphaneyl)-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
  • NKT-24-004PCT 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 The tit cribed in 5 Reference 61 Step 2-3.
  • Step 2 tert-Butyl (1-((3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamate 25 - 215 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT 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 (9 g, 19.3 mmol, 1 eq.) in ACN (90 mL) was added H 2 O 2 (30%, 45 mL) at rt. The resulting mixture was stirred for 10 min at room temperature. The 5 mixture was quenched with sat. Na2SO3 solution at 0°C and the resulting mixture was extracted with EtOAc.
  • Step 4 tert-Butyl (S)-(1-((3-((1-hydroxypropan-2-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)- carbamate 25
  • THF 16 mL
  • 2 M LiAlH 4 in THF 3.6 mL, 7.2 mmol, 2 eq.
  • the resulting mixture was stirred for 2 h at 0°C.
  • the mixture was quenched with water and 15% NaOH aq.
  • 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 5
  • Step 3 1-(6-(1-(3-(3-((4-Aminopiperidin-1-yl)sulfonyl)phenyl)-2,2-dimethylpropyl) piperidin-4- 15 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)-2,2-dimethylpropyl)phenyl) sulfonyl)piperidin-4- yl)carbamate (280 mg, 0.38 mmol) in dichloromethane (3 mL) was added 4 M hydrogen chloride 20 in dioxane (1.5 mL) at 0 °C and stirred for 1h.
  • NKT-24-004PCT Step 1: 1-(1-Methyl-6-(1-(2-methylbut-3-yn-2-yl)piperidin-4-yl)-1H-indazol-3-yl)dihydro- pyrimidine-2,4(1H,3H)-dione
  • DMSO DMSO
  • 3-chloro-3-methylbut- 1-yne 451 mg, 4.4 mmol, 2.0 eq.
  • CuCl 21 mg, 22 mmol, 10.0 eq.
  • TEA 0.92 mL, 6.6 mmol, 3.0 eq.
  • 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
  • T 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 (8 mg
  • 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 - 219 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT 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 - 220 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT 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 100
  • 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
  • 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 15 (116.26 mg, 0.16 mmol) in DCM (3 mL) was added 4.0M HCl in dioxane (1.5 m
  • Step 2 4-((4-(tert-Butyl)benzyl)thio)-2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzonitrile 15
  • 2-[(tert-butyldimethylsilyl)oxy]ethanol (0.66 g, 3.7 mmol, 1.10 eq.)
  • triphenylphosphine (1.78 g, 6.8 mmol, 2.00 eq.) in THF (25.0 mL) was added diisopropyl azodicarboxylate (1.38 g, 6.8 mmol, 2.00 eq.) slowly at 0 °C.
  • Step 3 3-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-4-cyanobenzenesulfonyl chloride 25
  • ut on o -(( -(tert- uty ) enzy)t o)- -( -((tert- uty methyl- silyl)oxy)ethoxy)benzonitrile (910 mg, 2.00 mmol, 1.00 eq.) in ACN (15.0 mL)/water (2.0 mL) - 222 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT was added AcOH (5.0 mL).1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (786.8 mg, 3.99 mmol, 2.00 eq.) was added at 0 °C and the mixture was stirred at rt for 3h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and the organic layer was dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was 5 concentrated to give the title compound as yellow oil.
  • Step 4 4-((4-Aminopiperidin-1-yl)sulfonyl)-2-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)- 1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethoxy)benzonitrile hydrochloride
  • NKT-24-004PCT Step 2 tert-Butyl (1-((3-((2-methyloxiran-2-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate
  • m-CPBA 834 mg, 4.1 5 mmol, 2.0 eq., 85%
  • Step 3 tert-Butyl (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol- 6-yl)piperidin-1-yl)-2-hydroxy-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate
  • a sti henyl)sulfonyl)-15 650 mg, 1.6 mmol, 1.0 eq.
  • 1-(1-methyl-6-(piperidin-4-yl)-1H- indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (634 mg, 1.76 mmol, 1.1 eq.) in EtOH (6 mL) was added TEA (240 mg, 2.4 mmol, 1.5 eq.) and the mixture
  • Step 4 1-(6-(1-(3-(3-((4-Aminopiperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)- piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride 25 , -1(2H)-yl)- 1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-hydroxy-2-methylpropyl)phenyl)sulfonyl)piperidin-4- - 224 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref.
  • NKT-24-004PCT yl)carbamate 700 mg, 1 mmol, 1.0 eq.
  • DCM 1,4-dioxane
  • 4 M HCl 1,4-dioxane
  • the resulting mixture was concentrated under vacuum to afford the title compound as a light yellow solid.
  • Example 1 5 Synthesis of 1-(6-(1-((1-(3-((4-((3-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: 3-Chloro-1-meth ine 10 To a solution of 3 idine (600 mg, 2.99 mmol) in DMF (8.0 mL) was added NaH (239 mg, 5.97 mmol) at 0 o C.
  • Step 2 3-Chloro-1-methyl-6-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidine 20
  • m-CPBA 145 mg, 0.84 mmol
  • NKT-24-004PCT Step 3: 1-(6-(1-((1-(3-((4-((3-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione 5 To a solu eridin-4- yl)methyl)pipe y y y y py , ,3H)-dione (120 mg, 0.17 mmol) in DMSO (4.0 mL) was added DIEA (110 mg, 0.85 mmol) and 3-chloro-1- methyl-6-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidine (42 mg,
  • NKT-24-004PCT A mixture of copper (II) acetate (353 mg, 1.94 mmol), sodium carbonate (412 mg, 3.88 mmol), 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 1.94 mmol), 2,2'-bipyridine (303 mg, 1.94 mmol) and cyclopropylboronic acid (334 mg, 3.88 mmol) in DCE (20 mL) was stirred at 70 °C for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by 5 silica gel column chromatography, eluted with EtOAc/PE (0-20 %) to afford the title compound as a yellow oil.
  • Step 2 4-((4-((1-Cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)piperidin-1-yl)sulfonyl)- 2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2- methylpropyl)benzonitrile 10
  • 4-[(4-amino-1-piperidyl)sulfonyl]-2-[3-[4-[3-(2,4-dioxohexahydropyrimidin- 1-yl)-1-methyl-indazol-6-yl]-1-piperidyl]-2-methyl-propyl]benzonitrile 66 mg, 0.1mmol
  • Step 2 6-Chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 15 To a solution of 6-chlo e (1.0 g, 3.57 mmol) and potassium carbonate (985.63 mg, 7.13 mmol) in DMF (10 mL) was added iodomethane (0.67 mL, 10.7 mmol), then the resulting mixture was stirred at r.t. for 17 hrs.
  • Step 3 6-Chloro-1-methyl-3-vinyl-1H-pyrazolo[3,4-d]pyrimidine - 229 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT To a solution of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (549.17 mg, 3.57 mmol) and 6-chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (1.00 g, 3.4 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added X-Phos Pd G3 (287.44 mg, 0.34 mmol) under argon atmosphere, then the reaction mixture was stirred at 60 °C for 6 h. The mixture was diluted with 5 water, and the mixture was extracted with EtOAc.
  • Step 4 6-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde 10
  • 1,4-dioxane 5 mL
  • water 5 mL
  • 2,6-dimethylpyridine 161.86 mg, 1.51 mmol
  • potassium osmate (VI) dihydrate 78.39 mg, 0.25 mmol
  • sodium periodate 2154.07 mg, 10.07 mmol
  • Step 5 6-Chloro-3-(difluoromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 20
  • DCM dimethylethyl sulfoxide
  • DAST 122.99 mg, 0.76 mmol
  • the reaction mixture was diluted with water, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over 25 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 6 4-((4-((3-(Difluoromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino) piperidin- 1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)- piperidin-1-yl)-2-methylpropyl)benzonitrile 5 To a soluti tetrahydro- pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl) benzonitrile (50 mg, 0.08 mmol), 6-chloro-3-(difluorone), 4-(4-((3-(Difluoromethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6
  • the reaction mixture was diluted with water, the - 231 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT mixture was 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 2 2-(3-(4-(3-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin- 5 1-yl)-2-methylpropyl)-4-((4-((3-(methoxymethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)amino)piperidin-1-yl)sulfonyl)benzonitrile To a solutio otetrahydro- pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl) benzonitrile (30 10 mg, 0.05 mmol) and 6-chloro-3-(methoxymethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (14.79 mg, 0.07 mmol) in DMSO (1
  • NKT-24-004PCT To a solution of 6-chloro-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine (100 mg, 0.45 mmol) in DMF (1 mL) was added iodomethane (76 mg, 0.54 mmol) and K 2 CO 3 (186 mg, 1.3 mmol), and the resulting mixture was stirred at r.t. for 2 h. The mixture was quenched by water, extracted with DCM, washed with brine, dried over Na 2 SO 4 .
  • Step 2 2-(3-(4-(3-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin- 1-yl)-2-methylpropyl)-4-((4-((1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6- yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 10 To a solu trahydro- pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile (35 mg, 0.05 mmol) in DM
  • NKT-24-004PCT 6-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile
  • idine 100 mg, 0.34 mmol
  • zinc cyanide 59.81 mg, 0.51 mmol
  • DMF dimethyl methoxysulfoxide
  • Pd(PPh 3 ) 4 39.24 mg, 5 0.03 mmol
  • the mixture was stirred at 100 °C under argon atmosphere for 2 h.
  • the 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 resulting mixture was stirred at 100 °C under argon atmosphere for 16 h. The mixture was allowed to cool to r.t. and diluted with water. The resulting mixture was extracted with EtOAc, and the combined organic layer was washed with 10 brine, dried over anhydrous sodium sulphate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (0-50%) to afford the title compound as a white solid.
  • Step 2 tert-Butyl (E)-(1-((4-cyano-3-(3-hydroxy-2-methylprop-1-en-1-yl)phenyl)sulfonyl)- piperidin-4-yl)carbamate 15
  • eridin-1-yl)sulfonyl)- 2-cyanophenyl)-2-methylacrylate 500 mg, 1.08 mmol
  • 1 M LiAlH4 (2.59 mL, 2.59 mmol
  • the resulting mixture was stirred at -78 °C for 4 h.
  • the mixture was diluted with water, 15% NaOH solution, and extracted with EtOAc.
  • Step 3 (E)-3-(5-((4-((tert-Butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)-2-cyanophenyl)-2- methylallyl methanesulfonate 25 - 235 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No.
  • NKT-24-004PCT To a solution of (E)-(1-((4-cyano-3-(3-hydroxy-2-methylprop-1-en-1-yl)phenyl)- sulfonyl)piperidin-4-yl)carbamate (220 mg, 0.505 mmol) and TEA (168.2 mg, 1.52 mmol) in anhydrous DCM (10 mL) was added methanesulfonic anhydride (88 mg, 0.51 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The mixture was diluted with water, and extracted 5 with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4.
  • Step 4 tert-Butyl (E)-(1-((4-cyano-3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl- 1H-indazol-6-yl)piperidin-1-yl)-2-methylprop-1-en-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate 10 To a mixt nyl)-2- cyanophenyl)-2-methylallyl methanesulfonate (100 mg, 0.19 mmol) and 1-(1-methyl-6-(piperidin- 4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (70.8 mg, 0.19 mmol) and sodium iodine
  • NKT-24-004PCT Step 6 6-Chloro-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine
  • sodium hydride (0.48 g, 12 mmol) in anhydrous DMF (15 mL) at 0 °C
  • 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.55 g, 10 mmol) in DMF (15 mL) was added 5 dropwise.
  • the mixture was stirred at 25 °C for 30 mins, followed by addition of 2-iodopropane (2.04 g, 12 mmol) dropwise at 0 °C.
  • the resulting mixture was stirred at 25 °C for 2 h.
  • Step 7 (E)-2-(3-(4-(3-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)piperidin-1-yl)-2-methylprop-1-en-1-yl)-4-((4-((1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)amino)piperidin-1-yl)sulfonyl)benzonitrile 15 To a solution of (E)-4-((4-aminopiperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydro- pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylprop-1-en-1- yl)benzonitrile hydrochloride
  • NKT-24-004PCT Ex.# Structure Procedure Ref.66 replaced (E)-4-((4-aminopiperidin-1- - - - - - - Biological Example 1 Inhibition of CDK2 and CDK4: Phospho-Rb Measurement in Cells 5 Phospho-Rb Measurement in Cells Phosphorylation of RB protein at S807/811 were measured using HTRF phospho-RB cellular kits (Cat# 64RBS807PEG) from Cisbio.
  • OVCAR3 CDK2-dependent cell line
  • T47D CDK4-dependent cells were seeded into 96-well tissue-culture treated plates at 20,000 cells/well in 200 ⁇ L and incubated 10 overnight at 37 °C in CO 2 atmosphere.
  • the cells were treated with test compounds at concentrations from 0.3 to 3,000 nM using HP D300 digital dispenser. Twenty-four hours after compound treatment, cell culture media was removed by flicking the plate and tapping the plate against clean paper towel.30 ⁇ L 1X lysis buffer was supplemented from the kit was added to each well and the plates were then incubated at room temperature on shaker for 30 min.
  • TR-FRET ratio (665 nM/620 nM) was plotted against the compound concentration and - 238 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT normalized to DMSO controls.
  • Half maximal inhibition concentration (IC50) values were calculated with a four-parameter logistic fit using GraphPad Prism (version 9; La Jolla, CA).
  • AA indicates an IC50 of less than 1 nM
  • A indicates an IC50 of greater than or equal to 1 nM but less than or equal to 100 nM
  • B indicates an IC 50 of greater than 100 nM 5 but less than or equal to 500 nM
  • C indicates an IC50 of greater than 500 nM but less than or equal to 2.5 ⁇ M
  • D indicates an IC 50 of greater than 2.5 ⁇ M but less than or equal to 5.0 ⁇ M
  • E indicates an IC50 of greater than 5.0 ⁇ M
  • NT is not determined.
  • cellular CDK level was measured in 96-well format using 15 HTRF total CDK cellular kit (CDK2 Cat# 64CDK2TPEG; CDK4 Cat# 64CDK4TPEG;) from Cisbio/Revvity. - 239 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT
  • 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).
  • Formulation Examples 20 The following are representative pharmaceutical formulations containing a compound of the present disclosure. Tablet Formulation The following ingredients are mixed intimately and pressed into single scored tablets. Ingredient Quantity per tablet (mg) compound Formula (I) 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5 25 - 240 - 1104306605 ⁇ 3 ⁇ AMERICAS Attorney Docket No.119005.00284 Client Ref. No. NKT-24-004PCT Capsule Formulation The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
  • Compound Formula (I) 200 lactose spray dried 148 magnesium stearate 2 5 Injectable Formulation Compound of the disclosure in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL Inhalation Composition
  • 20 mg of a compound 10 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, which is suitable for inhalation administration.
  • Topical Gel Composition 15 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 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. 20 Ophthalmic Solution Composition 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.
  • ophthalmic delivery units such as eye drop containers, which are suitable for ophthalmic administration.
  • 25 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. - 241 - 1104306605 ⁇ 3 ⁇ AMERICAS

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Abstract

La présente invention concerne certains composés bifonctionnels contenant des dérivés de pyrazolopyrimidine qui provoquent la dégradation de la kinase 2 dépendante de la cycline (CDK2) et/ou de la kinase 4 dépendante de la cycline (CDK4) par l'intermédiaire de la voie ubiquitine-protéasome et sont donc utiles pour le traitement de maladies médiées par CDK2 et/ou CDK4. L'invention concerne également des compositions pharmaceutiques contenant de tels composés et des procédés de préparation de tels composés.
PCT/US2025/027636 2024-05-07 2025-05-02 Composés bifonctionnels contenant des dérivés de pyrazolopyrimidine pour dégrader une certaine kinase dépendante de la cycline par l'intermédiaire d'une voie ubiquitine-protéasome Pending WO2025235331A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120015963A1 (en) * 2010-06-11 2012-01-19 Abbott Laboratories NOVEL PYRAZOLO[3,4-d]PYRIMIDINE COMPOUNDS
US20130190292A1 (en) * 2010-08-20 2013-07-25 Cellzome Limited Heterocyclyl pyrazolopyrimidine analogues as selective jak inhibitors
US20210253578A1 (en) * 2008-08-22 2021-08-19 Novartis Ag Pyrrolopyrimidine compounds and their uses
WO2022140472A1 (fr) * 2020-12-22 2022-06-30 Nikang Therapeutics, Inc. Composés pour la dégradation de la kinase 2 dépendante des cyclines par l'intermédiaire d'une voie de l'ubiquitine-protéosome
WO2022174031A1 (fr) * 2021-02-12 2022-08-18 Relay Therapeutics, Inc. Inhibiteurs de cdk et leurs procédés d'utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210253578A1 (en) * 2008-08-22 2021-08-19 Novartis Ag Pyrrolopyrimidine compounds and their uses
US20120015963A1 (en) * 2010-06-11 2012-01-19 Abbott Laboratories NOVEL PYRAZOLO[3,4-d]PYRIMIDINE COMPOUNDS
US20130190292A1 (en) * 2010-08-20 2013-07-25 Cellzome Limited Heterocyclyl pyrazolopyrimidine analogues as selective jak inhibitors
WO2022140472A1 (fr) * 2020-12-22 2022-06-30 Nikang Therapeutics, Inc. Composés pour la dégradation de la kinase 2 dépendante des cyclines par l'intermédiaire d'une voie de l'ubiquitine-protéosome
WO2022174031A1 (fr) * 2021-02-12 2022-08-18 Relay Therapeutics, Inc. Inhibiteurs de cdk et leurs procédés d'utilisation

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