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WO2025030002A2 - Composés ciblant dgk et leurs utilisations - Google Patents

Composés ciblant dgk et leurs utilisations Download PDF

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Publication number
WO2025030002A2
WO2025030002A2 PCT/US2024/040518 US2024040518W WO2025030002A2 WO 2025030002 A2 WO2025030002 A2 WO 2025030002A2 US 2024040518 W US2024040518 W US 2024040518W WO 2025030002 A2 WO2025030002 A2 WO 2025030002A2
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Prior art keywords
chloro
compound
pyridyl
methyl
alkyl
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WO2025030002A3 (fr
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John P. Caldwell
Jesus Raul Medina
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Arvinas Operations Inc
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Arvinas Operations Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • DGKs Diacylglycerol kinases
  • DGKs are lipid kinases that mediate the conversion of diacylglycerol to phosphatidic acid thereby terminating T-cell functions propagated through the TCR signaling pathway.
  • DGKs serve as intracellular checkpoints, and inhibition of DGKs is expected to enhance T-cell signaling pathways and T-cell activation.
  • Knock-out mouse models of DGK ⁇ have shown a hyper-responsive T-cell phenotype and improved anti- tumor immune activity (Zha Y et al. Nature Immunology, (2006) 12:1343; Olenchock B. A. et al., Nature (2006) 11: 1174–81).
  • the permissible substituents include acyclic and cyclic, branched, and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • the dosage regimen can vary widely, but may be routinely determined using standard methods.
  • the daily dose can be administered in one to four doses divided per day.
  • Other dosing schedules include one dose per week and one dose per two-day cycle.
  • Methods of Treatment The compounds of the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, are useful for the treatment of cancer.
  • the compounds of the invention, or a pharmaceutically acceptable salt thereof can be used in the treatment of diseases or disorders associated with DGK target inhibition in T-cells.
  • the compound of the invention is prepared in combination with one or more additional therapeutic agents for conjoint administration for treating diseases or disorders associated with DGK target inhibition in T- cells.
  • the compounds described herein may be used to treat or prevent viral infections and proliferative diseases such as cancer.
  • disease or conditions that are associated with DGK target inhibition in T cells include viral and other infections (e.g., skin infections, GI infection, urinary tract infections, genito-urinary infections, systemic infections), and proliferative diseases (e.g., cancer).
  • the subject is being treated for cancer.
  • Types of cancers that may be treated with a compound of the invention include, but are not limited to, brain cancers, skin cancers, bladder cancers, ovarian cancers, breast cancers, gastric cancers, pancreatic cancers, prostate cancers, colon cancers, blood cancers, lung cancers and bone cancers.
  • cancer types include neuroblastoma, intestine carcinoma such as rectum carcinoma, colon carcinoma, familiar adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, kidney parenchymal carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphatic leuk
  • B7 family which includes B7-1, B7-2, B7-H1 (PD-L1), B7- DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.
  • agents that can be combined with the compounds of the invention for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells.
  • the compounds of the invention can be combined with antagonists of KIR, such as lirilumab.
  • agents for combination therapies include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (e.g., International Patent Publication Nos.
  • the additional anticancer agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody.
  • Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab), or tremelimumab.
  • the additional anticancer agent is a PD-1 antagonist, such as an antagonistic PD-1 antibody.
  • Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; e.g., International Patent Publication No. WO2012/145493).
  • the additional anticancer agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody.
  • LAG3 antibodies include, for example, BMS-986016 (e.g., International Patent Publication Nos. WO10/19570, WO14/08218), or IMP-731 or IMP-321 (e.g., International Patent Publication Nos. WO08/132601, WO09/44273).
  • the additional anticancer agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody.
  • Suitable CD137 antibodies include, for example, urelumab, and PF-05082566 (e.g., International Patent Publication No. WO12/32433).
  • the additional anticancer agent is a GITR agonist, such as an agonistic GITR antibody.
  • Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX- 518 (e.g., International Patent Publication Nos. WO06/105021, WO09/009116), and MK- 4166 (e.g., International Patent Publication No. WO11/028683).
  • the additional anticancer agent is an IDO antagonist.
  • Suitable IDO antagonists include, for example, INCB-024360 e.g., International Patent Publication Nos. (WO2006/122150, WO07/75598, WO08/36653, WO08/36642), indoximod, BMS-986205, or NLG-919 (e.g., International Patent Publication No. WO09/73620, WO09/1156652, WO11/56652, WO12/142237).
  • the additional anticancer agent is an OX40 agonist, such as an agonistic OX40 antibody.
  • Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.
  • the additional anticancer agent is an OX4OL antagonist, such as an antagonistic OX40 antibody.
  • OX4OL antagonists include, for example, RG-7888 (e.g., International Patent Publication No. WO06/029879).
  • the additional anticancer agent is a CD40 agonist, such as an agonistic CD40 antibody.
  • the anticancer agent is a CD40 antagonist, such as an antagonistic CD40 antibody.
  • Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.
  • the additional anticancer agent agent is a CD27 agonist, such as an agonistic CD27 antibody.
  • Suitable CD27 antibodies include, for example, varlilumab.
  • the additional anticancer agent is MGA271 (to B7H3) (e.g., International Patent Publication No. WO11/109400).
  • Combination therapies, as disclosed herein, are intended to embrace conjoint administration of these therapeutic agents; for example, administration of said therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form having a fixed ratio of each therapeutic agent or in multiple, single dosage forms for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be affected by any appropriate route including, but not limited to, oral routes, parental routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered orally, or both therapeutic agents may be administered by parentally, e.g., by intravenous injection.
  • Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment).
  • the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved.
  • the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
  • One or more additional pharmaceutical agents or treatment methods such as, for example, anti-viral agents, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2 and GM-CSF), and/or tyrosine kinase inhibitors can be optionally used in combination with the compounds of the invention for treatment of DGK ⁇ associated diseases, disorders, or conditions.
  • the agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
  • Suitable additional anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (CYTOXAN®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazene
  • suitable additional agents for use in combination with the compounds of the invention include: dacarbazine (DTIC), optionally, along with other chemotherapy drugs such as carmustine (BCNU) and cisplatin; the “Dartmouth regimen,” which consists of DTIC, BCNU, cisplatin and tamoxifen; a combination of cisplatin, vinblastine, and DTIC, temozolomide or YERVOYTM.
  • DTIC dacarbazine
  • BCNU carmustine
  • cisplatin the “Dartmouth regimen,” which consists of DTIC, BCNU, cisplatin and tamoxifen
  • a combination of cisplatin, vinblastine, and DTIC, temozolomide or YERVOYTM a combination of cisplatin, vinblastine, and DTIC, temozolomide or YERVOYTM.
  • immunotherapy drugs including cytokines such as interferon alpha, interleukin 2, and tumor necrosis
  • the compounds of the invention also can be used in combination with vaccine therapy in the treatment of cancer (e.g., melanoma).
  • Antimelanoma vaccines are, in some ways, similar to the anti-virus vaccines that are used to prevent diseases caused by viruses such as polio, measles, and mumps. Weakened melanoma cells or parts of melanoma cells called antigens may be injected into a patient to stimulate the body’s immune system to destroy melanoma cells.
  • Suitable additional anti-cancer agents also include, for example, anti-metabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6- mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine.
  • anti-metabolites including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • methotrexate including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • methotrexate including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • Suitable additional anti-cancer agents further include, for example, certain natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol), mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN- a), etoposide, and teniposide.
  • certain natural products and their derivatives for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins
  • vinblastine vincristine, vindesine
  • bleomycin dactinomycin
  • daunorubicin daunorubicin
  • cytotoxic agents include navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, and droloxafine.
  • cytotoxic agents such as epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; and haematopoietic growth factors.
  • additional anti-cancer agent(s) include antibody therapeutics such as trastuzumab (HERCEPTIN®), antibodies to costimulatory molecules such as CTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL-10 or TGF- ⁇ ).
  • additional anti-cancer agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR 2 and CCR 4.
  • additional anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T-cell transfer.
  • Additional anti-cancer agents also include anti-cancer vaccines, such as, for example, dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses.
  • the treatment methods of the invention may optionally include conjointly administering at least one signal transduction inhibitor (STI).
  • STI signal transduction inhibitor
  • a “signal transduction inhibitor” is an agent that selectively inhibits one or more vital steps in signaling pathways, in the normal function of cancer cells, thereby leading to apoptosis.
  • Suitable STIs include, but are not limited to: (i) bcr/abl kinase inhibitors such as, for example, STI 571 (GLEEVEC®); (ii) epidermal growth factor (EGF) receptor inhibitors such as, for example, kinase inhibitors ORES SA®, SSI-774) and antibodies (Imclone: C225 [Goldstein et al. Clin.
  • her-2/neu receptor inhibitors such as farnesyl transferase inhibitors (FTI) such as, for example, L-744,832 (Kohl et al. Nat. Med., 1(8):792–97 (1995));
  • FTI farnesyl transferase inhibitors
  • inhibitors of Akt family kinases or the Akt pathway such as, for example, rapamycin
  • cell cycle kinase inhibitors such as, for example, flavopiridol and UCN-01 (see, for example, Sausville Curr. Med. Chem.
  • At least one STI and at least one compound of Formula (I) may be in separate pharmaceutical compositions.
  • at least one compound of the invention and at least one STI may be administered to the patient conjointly.
  • At least one compound of the invention may be administered first or at least one STI may be administered first and the other is administered next; or at least one compound of the invention and at least one STI may be administered at the same time. Additionally, when more than one compound of invention and/or STI is used, the compounds may be administered in any order.
  • pharmaceutical compositions for the treatment of a chronic viral infections in a subject comprising administering a therapeutically effective amount of at least one compound of the invention, optionally, at least one chemotherapeutic drug, and, optionally, at least one antiviral agent, in a pharmaceutically acceptable carrier.
  • one or more compounds of the invention, one or more chemotherapeutic drugs, and/or one or more antiviral agents are administered conjointly.
  • At least one compound of the invention may be administered first or at least one chemotherapeutic agent may be administered first.
  • at least one compound of the invention and the at least one STI may be administered at the same time.
  • the compounds may be administered in any order.
  • any antiviral agent or STI may also be administered at any point in relation to the administration of the compound of the invention.
  • Chronic viral infections that may be treated using the present combinatorial treatment include, but are not limited to, diseases caused by hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV).
  • HCV hepatitis C virus
  • HPV human papilloma virus
  • CMV cytomegalovirus
  • HSV herpes simplex virus
  • EBV Epstein-Barr virus
  • varicella zoster virus coxsackie virus
  • coxsackie virus human immunodeficiency virus
  • HCV hepatitis C virus
  • HCV hepatitis C virus
  • HPV human papilloma virus
  • CMV cytomegalovirus
  • HSV herpes simplex virus
  • EBV Epstein-Barr virus
  • Suitable antiviral agents contemplated for use in combination with the compound of Formula (I) can comprise nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non- nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral drugs.
  • NRTIs nucleoside and nucleotide reverse transcriptase inhibitors
  • NRTIs non- nucleoside reverse transcriptase inhibitors
  • protease inhibitors and other antiviral drugs.
  • NRTIs examples include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(P0M)- PMEA]; lobucavir; BCH-I0652; emitricitabine [(-)-FTC]; beta-L-FD4 (also called beta-L- D4C and named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD, (( ⁇ )-beta-D-2,6-diamino- purine dioxolane); and lodenosine (FddA).
  • ZT zidovudine
  • ddl didanosine
  • ddC zalcitabine
  • d4T stavudine
  • lamivudine lami
  • NNRTIs include nevirapine (BI- RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)- pyrimidinedione); and (+)-calanolide A (NSC-675451) and B.
  • Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir; DMP-450; BMS-2322623; ABT-378; and AG-1549.
  • Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No.11607.
  • kits useful, for example, in the treatment or prevention of DGK ⁇ -associated diseases or disorders referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • Methods of Preparation The compounds of the present invention may be synthesized by many methods available to those skilled in the art in view of the present disclosure.
  • PCT/US2023/012145 filed February 1, 2023, and titled DGK TARGETING COMPOUNDS AND USES THEREOF.
  • the compouinds can be made similar to “4-[(3aR,7aS)-5-[5-(trifluoromethoxy)- 2-pyridyl]-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridin-1-yl]-6-chloro-1-methyl-2-oxo- 1,5-naphthyridine-3-carbonitrile” of PCT/US2023/012145, described below: Exemplary Synthesis of 4-[(3aR,7aS)-5-[5-(trifluoromethoxy)-2-pyridyl]-3,3a,4,6,7,7a- hexahydro-2H-pyrrolo[3,2-c]pyridin-1-yl]-6-chloro-1-methyl-2-oxo-1,
  • Step 2 Preparation of tert-butyl (3aR,7aS)-5-[5-(trifluoromethoxy)-2-pyridyl]- 3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridine-1-carboxylate and tert-butyl (3aS,7aR)-5-[5-(trifluoromethoxy)-2-pyridyl]-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2- c]pyridine-1-carboxylate Racemic tert-butyl (3aR,7aS)-5-[5-(trifluoromethoxy)-2-pyridyl]-3,3a,4,6,7,7a-hexahydro- 2H-pyrrolo[3,2-c]pyridine-1-carboxylate (1.9 g, 4.90 mmol, 1 eq) was purified by SFC (column:
  • Step 3 Preparation of WC-ARV-JM-047-A-2a, (3aR,7aS)-5-[5-(trifluoromethoxy)-2- pyridyl]-1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,2-c]pyridine
  • tert-butyl (3aR,7aS)-5-[5-(trifluoromethoxy)-2-pyridyl]-3,3a,4,6,7,7a- hexahydro-2H-pyrrolo[3,2-c]pyridine-1-carboxylate 500 mg, 1.29 mmol, 1 eq
  • dichloromethane 5 mL
  • trifluoroacetic acid 7.70 g, 67.53 mmol, 5.00 mL, 52.32 eq.
  • Step 4 Preparation of 4-[(3aR,7aS)-5-[5-(trifluoromethoxy)-2-pyridyl]-3,3a,4,6,7,7a- hexahydro-2H-pyrrolo[3,2-c]pyridin-1-yl]-6-chloro-1-methyl-2-oxo-1,5-naphthyridine- 3-carbonitrile
  • 3aR,7aS)-5-[5-(trifluoromethoxy)-2-pyridyl]-1,2,3,3a,4,6,7,7a- octahydropyrrolo[3,2-c]pyridine (517 mg, 1.29 mmol, 1 eq, trifluoroacetic acid) and 4,6- dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (327 mg, 1.29 mmol, 1 eq) in acetonitrile (5 mL) was added
  • Step 2 Preparation of (3aR,7aS)-1-(5-isopropoxy-2-pyridyl)-2,3,3a,4,5,6,7,7a- octahydropyrrolo[3,2-c]pyridine
  • reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by prep-HPLC (column: YMC Triart C18250*50mm*7um; mobile phase: [water(formic acid) in acetonitrile]: 50%-95%, 25min) followed by SFC (column: DAICEL CHIRALCEL OJ(250mm*30mm,10um); mobile phase:40% [0.1% ammonium hydroxide in ethanol] in supercritical carbon dioxide; 40%- 40%,6.0;84min).
  • the material was separated by SFC (condition: column: REGIS(S,S)WHELK- O1(250mm*25mm,10um); mobile phase: 10% [0.1% ammonium hydroxide in ethanol] in supercritical CO 2 : 10%-10%,C6; 160min), then further separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm,10um); mobile phase:10% [0.1% ammonium hydroxide in ethanol] in supercritical CO 2 , 10%-10%,c10; 60min).
  • tert-Butyl (3aR,7aS)-5-[5-(trifluoromethoxy)-2-pyridyl]-3,3a,4,6,7,7a-hexahydro-2H- pyrrolo[3,2-c]pyridine-1-carboxylate (66 mg, 19%) was obtained as a green oil.
  • tert-Butyl (3aS,7aR)-5-[5-(trifluoromethoxy)-2-pyridyl]-3,3a,4,6,7,7a-hexahydro-2H- pyrrolo[3,2-c]pyridine-1-carboxylate 50 mg, 15% was obtained as a green oil.
  • Step 2 Preparation of (3aS,7aR)-5-[5-(trifluoromethoxy)-2-pyridyl]-1,2,3,3a,4,6,7,7a- octahydropyrrolo[3,2-c]pyridine
  • tert-butyl (3aS,7aR)-5-[5-(trifluoromethoxy)-2-pyridyl]-3,3a,4,6,7,7a- hexahydro-2H-pyrrolo[3,2-c]pyridine-1-carboxylate 80 mg, 0.21 mmol, 1 eq
  • dichloromethane 1.5 mL
  • trifluoroacetic acid 1.23 g, 10.80 mmol, 0.8mL, 52.32 eq.
  • the reaction mixture was diluted with water 5 mL and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 0 ⁇ 40% ethyl acetate/petroleum ether gradient @ 60 mL/min) to afford ethyl 6-chloro-4-[4-hydroxy-4- [(1R)-1-[5-(trifluoromethoxy)-2-pyridyl]ethyl]-1-piperidyl]-1-methyl-2-oxo-quinoline-3- carboxylate (272 mg, 96% yield) was obtained as a yellow oil.
  • ISCO® 12 g SepaFlash® Silica Flash Column, eluent of 0 ⁇ 40% ethyl acetate/petroleum ether
  • Step 2 Preparation of tert-butyl 6-chloro-4-hydroxy-1-methyl-2-oxo-1,2- dihydroquinoline-3-carboxylate To a solution of di-tert-butyl malonate (6.35 mL, 1.5 eq) in N,N-dimethylacetamide (40 mL) was added sodium hydride (2.65 g, 60% purity, 3.5 eq) at 0 °C for 0.5 h.
  • Step 3 Preparation of tert-butyl 6-chloro-1-methyl-2-oxo-4- (((trifluoromethyl)sulfonyl)oxy)-1,2-dihydroquinoline-3-carboxylate
  • tert-butyl 6-chloro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxylate (2 g, eq) in dimethylformamide (20 mL) was added sodium hydride (775 mg, 60% purity, 3 eq) at 0 °C.
  • Step 4 Preparation of (5-chloro-2-pyridyl)-phenyl-methanol To a solution of copper iodide (10 g, 1.5 eq) in diethyl ether (50 mL) was added bromo(phenyl)magnesium (3 M, 17.66 mL, 1.5 eq) at -78 °C under nitrogen atmosphere and stirred for 0.5 h.
  • 5-chloropyridine-2-carbaldehyde (5 g, 1 eq) in diethyl ether (50 mL) was added dropwise at -78°C under a nitrogen atmosphere. Then the mixture was stirred at 0°C for another 1h. The mixture was diluted with saturated ammonium chloride (100 mL), extracted with ethyl acetate (3 ⁇ 100 mL), washed with brine (3 ⁇ 100 mL), and dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 8 Preparation of 4-[(S)-(5-chloro-2-pyridyl)-phenyl-methyl]piperidin-4-ol
  • trifluoroacetic acid (0.48 mL) in dichloromethane (0.5 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 25 °C for 0.5 h under nitrogen atmosphere.
  • reaction mixture was quenched by 5 mL saturated sodium sulfate, poured into water (15 mL) extracted with ethyl acetate (3 x 10 mL), the organic layer was washed with brine (2 x 15 mL), dried over anhydrous sodium sulfate, then concentrated under reduced pressure to afford the crude product.
  • the crude product was added slowly to water, and it then saturated triethylamine was added to adjust the pH to 7.
  • Step 12 Preparation of 6-chloro-4-[4-[(R)-(5-chloro-2-pyridyl)-phenyl-methyl]-4- hydroxy-1-piperidyl]-1-methyl-2-oxo-quinoline-3-carboxamide
  • 6-chloro-4-[4-[(R)-(5-chloro-2-pyridyl)-phenyl-methyl]-4-hydroxy-1- piperidyl]-1-methyl-2-oxo-quinoline-3-carboxylic acid 140 mg, 1 eq
  • N,N-dimethyl acetamide (2 mL) was added diisopropylethylamine (0.26 mL, 5 eq), O-(7-azabenzotriazol-1- yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (247mg, 2.5 eq).
  • Boc A mixture of 2-bromo-5-chloro-pyridine (1 g, 1 eq), tert-butyl 4-[(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)methylene]piperidine-1-carboxylate (2.02 g, 1.2 eq), sodium carbonate (2 M, 5.20 mL, 2 eq), tetrakis[triphenylphosphine]palladium(0) (600 mg, 0.1 eq) in dioxane (10 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere.
  • reaction mixture was cooled to 0 °C and sodium hydroxide (4 M, 3.24 mL, 2 eq) was added dropwise. The ice-bath was removed and stirred at 25 °C for 2 h. To the reaction mixture was added water (10 mL), and then extracted with ethyl acetate (15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • sodium hydroxide 4 M, 3.24 mL, 2 eq
  • the resultant residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 10% Ethyl acetate/Petroleum ether gradient @ 60mL/min) then further triturated with acetonitrile (10 mL) at 25 °C to produce tert-butyl 4-[(5-chloro-2-pyridyl)-cyclopropyl-methyl]-4-hydroxy-piperidine-1-carboxylate (800 mg, 2.18 mmol, 47% yield) as a white solid.
  • ISCO® 40 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 10% Ethyl acetate/Petroleum ether gradient @ 60mL/min
  • the mixture was stirred at -78 °C for 1 h under a nitrogen atmosphere.
  • the mixture was diluted with saturated ammonium chloride (150 mL), extracted with ethyl acetate (3 ⁇ 150 mL), washed with brine (500 mL), the combined organic portions were dried over anhydrous sodium sulfate, filtered and concentrated.
  • the resultant residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70 mm, 10 um); mobile phase: [water (formic acid)- acetonitrile], 25%-60%, 26 min) to afford (5-chloro-2-pyridyl)-(4,4-difluorocyclohexyl)methanol (3.4 g, 21% yield) as a yellow oil.
  • the mixture was stirred at -78 °C for 1 h under a nitrogen atmosphere.
  • the mixture was diluted with saturated ammonium chloride (50 mL), extracted with ethyl acetate (3 ⁇ 50 mL), washed with brine (3 ⁇ 50 mL), and the combined organic portions were dried over anhydrous sodium sulfate, filtered, and concentrated.
  • SFC: Rt peak 1 6.124 min.
  • Step 6 Preparation of 6-chloro-4-[4-[(R)-(5-chloro-2-pyridyl)-(4,4- difluorocyclohexyl)methyl]-4-hydroxy-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile and 6-chloro-4-[4-[(S)-(5-chloro-2-pyridyl)-(4,4-difluorocyclohexyl)methyl]- 4-hydroxy-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile
  • Step 1 Preparation of 1-(5-chloro-2-pyridyl)propan-1-ol To a solution of 2-bromo-5-chloro-pyridine (5 g, 1 eq) and propanal (3.78 mL, 2 eq) in tetrahydrofuran (50 mL) was added n-butyllithium (2.5 M, 15.59 mL, 1.5 eq) under a nitrogen atmosphere at -78°C.
  • the resultant residue was purified by reverse- phase HPLC (column: Phenomenex luna C18250*50mm*15um; mobile phase: [water (formic acid) - acetonitrile]; gradient: 37%-67%, over 25 min) to produce tert-butyl 4-[1-(5-chloro-2- pyridyl)propyl]-4-hydroxy-piperidine-1-carboxylate (800 mg, 56% yield) as a yellow solid.
  • Step 2 Preparation of tert-butyl 2-(5-chloro-2-pyridyl)-1-oxa-6-azaspiro[2.5]octane-6- carboxylate.
  • tert-butyl 2-(5-chloro-2-pyridyl)-1-oxa-6-azaspiro[2.5]octane-6- carboxylate To a mixture of 5-methoxy-2-vinyl-pyridine tert-butyl 4-[(5-chloro-2- pyridyl)methylene]piperidine-1-carboxylate (4 g, 1 eq) in dioxane (40 mL) and water (40 mL) was added a solution of N-bromosuccinimide (2.77 g, 1.2 eq) in dioxane (40 mL) and water (40 mL) dropwise and stirred at 20 °C for 2 h under a nitrogen atmosphere.
  • reaction mixture was cooled to 0 °C and sodium hydroxide (4 M, 6.48 mL, 2 eq) was added dropwise and purged with nitrogen three times. The mixture was then stirred at 20 °C for 12 h. The reaction mixture was added slowly to water (100ml), then extracted with ethyl acetate (3 x 100mL), the combined organic layers were dried over sodium sulfate anhydrous, filtered, and concentrated to afford tert-butyl 2-(5-chloro-2-pyridyl)-1-oxa-6-azaspiro[2.5]octane-6- carboxylate (3.29 g, 78% yield) as a colorless oil.
  • Step 5 Preparation of 8-bromo-1-methyl-3, 1-benzoxazine-2, 4-dione
  • a solution of 8-bromo-1H-3, 1-benzoxazine-2, 4-dione (4 g, 1 eq) in N, N- dimethylformamide (40 mL) was added diisopropylethylamine (5.76 mL, 2 eq), and then add iodomethane (3.09 mL, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h.
  • Step 6 Preparation of 8-bromo-4-hydroxy-1-methyl-2-oxo-quinoline-3-carbonitrile
  • ethyl 2-cyanoacetate 2.50 mL, 3 eq
  • triethylamine 8.70 mL, 8 eq
  • 8-bromo-1-methyl-3,1- benzoxazine-2,4-dione 2 g, 1 eq
  • the mixture was stirred at 70 °C for 12 h.
  • Step 7 Preparation of 8-bromo-4-chloro-1-methyl-2-oxo-quinoline-3-carbonitrile To a mixture of 8-bromo-4-hydroxy-1-methyl-2-oxo-quinoline-3-carbonitrile (1.7 g, 1 eq) in acetonitrile (20 mL) was added diisopropylethylamine (6.37 mL, 6 eq) then was added benzyl(triethyl)ammonium chloride (2.77 g, 2 eq) followed by addition of phosphoryl chloride (2.84 mL, 5 eq) in one portion at
  • Step 8 Preparation of 8-bromo-4-[4-[1-(5-chloro-2-pyridyl)ethyl]-4-hydroxy-1- piperidyl]-1-methyl-2-oxo-quinoline-3-carbonitrile
  • N,N-diisopropylethylamine (521 mg, 4.03 mmol, 0.7 mL, 3 eq) in acetonitrile (1 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 40 °C for 12 h under a nitrogen atmosphere.
  • Step 11 Preparation of 4-[4-[(1S)-1-(5-chloro-2-pyridyl)ethyl]-4-hydroxy-1-piperidyl]-1- methyl-8-(oxetan-3-yloxy)-2-oxo-quinoline-3-carbonitrile and 4-[4-[(1R)-1-(5-chloro-2- pyridyl)ethyl]-4-hydroxy-1-piperidyl]-1-methyl-8-(oxetan-3-yloxy)-2-oxo-quinoline-3- carbonitrile
  • the reactant 4-[4-[1-[5-chloro-2-pyridyl)ethyl]-4-hydroxy-1-piperidyl]-1-methyl-8-(oxetan-3- yloxy)-2-oxo-quinoline-3-carbonitrile (50 mg, eq) was purified by SFC (column: DAICEL CHIRALPAK AS (250mm*
  • Step 1 Preparation of 7-bromo-1-methyl-3,1-benzoxazine-2,4-dione
  • N-ethyl-N-isopropyl- propan-2-amine (12.95 mL, 2 eq) in N,N-dimethylformamide (90 mL) was added methyl iodide (6.94 mL, 3 eq) at 0 °C.
  • Step 3 Preparation of 7-bromo-4-chloro-1-methyl-2-oxo-quinoline-3-carbonitrile To a mixture of 7-bromo-4-hydroxy-1-methyl-2-oxo-quinoline-3-carbonitrile (2.77 g, 1 eq) and N-ethyl-N-isopropyl-propan-2-amine (10.37 mL, 6 eq) in acetonitrile (30 mL) was added phosphoryl trichloride (4.63 mL, 5 eq) and benzyl(triethyl)ammonium chloride (4.52 g, 2 eq) in one portion at 0 °C under nitrogen.
  • Step 1 Preparation of (5-chloro-2-pyridyl)-tetrahydropyran-4-yl-methanol
  • 2-bromo-5-chloro-pyridine (27.5 g, 1 eq) tetrahydropyran-4-carbaldehyde (17.94 g, 1.1 eq) in tetrahydrofuran (250 mL) was degassed and purged with N 2 three times, and to the mixture was added n-butyllithium (2.5 M, 114.32 mL, 2 eq) at -70 °C, and then the mixture was stir
  • reaction mixture was quenched by addition ammonium chloride (200 mL) at 0 °C and added water (200 mL) and extracted with ethyl acetate (600 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue which was purified by silica gel column chromatography (10 ⁇ 50% ethyl acetate in petroleum ether) to produce (5-chloro-2-pyridyl)-tetrahydropyran-4-yl-methanol (2.55 g, crude as a yellow oil.
  • reaction mixture was quenched by addition ammonium chloride (30 mL) at 0 °C, added water (20 mL), and extracted with ethyl acetate (150 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue, which was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid)-methanol]; 50%-80%, 30 min).
  • Step 1 Preparation of tert-butyl 1-(5-chloro-2-pyridyl)-3,3,3-trifluoro-propan-1-ol
  • tert-butyl 1-(5-chloro-2-pyridyl)-3,3,3-trifluoro-propan-1-ol A mixture of 3,3,3-trifluoropropanal (10 g, 1.1 eq), 2-bromo-5-chloro-pyridine (15.61 g, 1 eq) in tetrahydrofuran (150 mL) was degassed and purged with nitrogen three times, and the mixture was added n-butyllithium (2.5 M, 64.91 mL, 2 eq) at -70 °C, and then the mixture
  • reaction mixture was quenched by addition ammonium chloride (200 mL) at 0 °C, added water (200 mL), and extracted with ethyl acetate (600 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm, 10 um); mobile phase: [water (formic acid)-acetonitrile]; gradient: 20%-50%, over 22 min) to produce 1-(5-chloro-2-pyridyl)-3,3,3-trifluoro-propan-1-ol (400 mg, 2.19% yield) as a red oil.
  • prep-HPLC columnumn: Phenomenex luna C18 (250*70mm, 10 um)
  • mobile phase [water (formic acid)-acetonitrile]; gradient: 20%-50%, over 22 min
  • Step 3 Preparation of tert-butyl 4-[1-(5-chloro-2-pyridyl)-3,3,3-trifluoro-propyl]-4- hydroxy-piperidine-1-carboxylate A mixture of tert-butyl 4-oxopiperidine-1-carboxylate (138 mg, 1 eq), 2-(1-bromo-3,3,3- trifluoro-propyl)-5-chloro-pyridine (200 mg, 1 eq) in tetrahydrofuran (1.5 mL) and then
  • Step 5 Preparation of 4-[(1S)-1-(5-chloro-2-pyridyl)-3,3,3-trifluoro-propyl]piperidin-4- ol
  • 4-[(1S)-1-(5-chloro-2-pyridyl)-3,3,3-trifluoro-propyl]-4-hydroxy- piperidine-1-carboxylate (80 mg, 1 eq) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL, 68.80 eq). The mixture was stirred at 25 °C for 1hour.
  • Step 6 Preparation of 6-chloro-4-[4-[(1S)-1-(5-chloro-2-pyridyl)-3,3,3-trifluoro-propyl]- 4-hydroxy-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile
  • Step 1 Preparation of 1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethan-1-ol
  • 5-chloropyridine-2-carbaldehyde 10 g, 1 eq
  • tetrahydrofuran 200 mL
  • trimethyl(trifluoromethyl)silane 12.05 g, 1.2 eq
  • tetrabutylammonium fluoride solution (1 M, 5 mL, 0.071 eq) and stirred for 0.5 h at 0°C.
  • the mixture was stirred at -78 °C for 0.5 h.
  • the mixture was diluted with saturated water (30 mL), extracted with ethyl acetate (3 ⁇ 50 mL), washed with brine (2 ⁇ 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • the resultant residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent: 0-20% ethyl acetate/petroleum ether gradient @ 60 mL/min).
  • reaction mixture was concentrated to afford a residue which was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water (formic acid)- acetonitrile]; gradient: 40%-70%, over 30 min) to produce 6-chloro-4-[4-[(1R)-1-(5- chloro-2-pyridyl)-2,2,2-trifluoro-ethyl]-4-hydroxy-1-piperidyl]-1-methyl-2-oxo-1,5- naphthyridine-3-carbonitrile (53.9 mg, 0.1 mmol, 38% yield, 97% purity) as a yellow solid.
  • Examples 92-156 The following compounds were prepared using the requisite halide and amine in an analogous fashion to the compounds above.

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Abstract

La présente invention concerne des composés de formule (I), ou un sel pharmaceutiquement acceptable de ceux-ci, qui inhibent l'activité de la diacylglycérol kinase alpha (DGKα) ou de l'une d'entre elles. Ces composés sont utiles pour le traitement des maladies prolifératives (par exemple, le cancer) et des infections virales.
PCT/US2024/040518 2023-08-02 2024-08-01 Composés ciblant dgk et leurs utilisations Pending WO2025030002A2 (fr)

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