WO2023186060A1 - Kinase inhibitors, preparation methods and uses thereof - Google Patents

Kinase inhibitors, preparation methods and uses thereof Download PDF

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Publication number
WO2023186060A1
WO2023186060A1 PCT/CN2023/085320 CN2023085320W WO2023186060A1 WO 2023186060 A1 WO2023186060 A1 WO 2023186060A1 CN 2023085320 W CN2023085320 W CN 2023085320W WO 2023186060 A1 WO2023186060 A1 WO 2023186060A1
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Prior art keywords
optionally substituted
iii
compound
alkyl
pharmaceutically acceptable
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PCT/CN2023/085320
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English (en)
French (fr)
Inventor
Younong Yu
Xianhai Huang
Yong Luo
Haotao NIU
Hong Yang
Jifang WENG
Yaolin Wang
Xing DAI
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Inventisbio Co Ltd
Inventisbio LLC
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Inventisbio Co Ltd
Inventisbio LLC
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Priority claimed from PCT/CN2022/084377 external-priority patent/WO2023184327A1/en
Application filed by Inventisbio Co Ltd, Inventisbio LLC filed Critical Inventisbio Co Ltd
Priority to US18/852,249 priority Critical patent/US20250223301A1/en
Priority to JP2024557461A priority patent/JP2025510945A/ja
Priority to EP23778425.1A priority patent/EP4499640A4/en
Priority to CN202380028014.1A priority patent/CN118974049A/zh
Publication of WO2023186060A1 publication Critical patent/WO2023186060A1/en
Anticipated expiration legal-status Critical
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—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
    • C07D471/12—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 three hetero rings
    • C07D471/16—Peri-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
    • C07D471/22—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 systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present disclosure generally relates to novel compounds, compositions comprising the same, methods of preparing and methods of using the same, e.g., for inhibiting DGKs and/or for treating a number of diseases or disorders, such as cancers or infections.
  • DGKs Diacylglycerol kinases
  • the present disclosure is based in part on Applicant's discovery of compounds that have activity as inhibitors of one or both of DGKa and DGKz.
  • the present disclosure provides novel compounds, pharmaceutical compositions, methods of preparing and using the same.
  • the compounds herein are DGK inhibitors, such as DGKa and/or DGKz inhibitors.
  • the compounds and compositions herein are useful for treating various diseases or disorders, such as cancer or viral infections.
  • the present disclosure provides a compound of Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, or a pharmaceutically acceptable salt thereof, as defined herein.
  • the compound of Formula III-2 can also be characterized as having a structure according to a subformula of Formula III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b.
  • the compound of Formula III-3 can also be characterized as having a structure according to a subformula of Formula III-3-A.
  • the compound of Formula III-4 can also be characterized as having a structure according to a subformula of Formula III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f.
  • the compound of Formula III-8 can also be characterized as having a structure according to a subformula of Formula III-8-A or III-8-B.
  • the present disclosure also provides a compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides a compound selected from Compound Nos. 1-347 herein, or a pharmaceutically acceptable salt thereof.
  • Certain embodiments of the present disclosure are directed to a pharmaceutical composition comprising one or more of the compounds of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b) , III-3 (e.g., III-3-A) , III-4 (e.g., III-4-A, III-4-B,
  • the pharmaceutical composition described herein can be formulated for various routes of administration, such as oral administration, parenteral administration, or inhalation etc.
  • Certain embodiments are directed to a method of treating a disease or disorder associated with the activity of DGKa, DGKz, or both DGKa and DGKz.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-2
  • Diseases or disorders associated with the activity of DGKa, DGKz, or both DGKa and DGKz suitable to be treated with the method include any of those described herein.
  • a method of treating cancer comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b) , III-3 (e.g., III-3-A) ,
  • the cancer can be cancer of the colon, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia, and/or melanoma.
  • a method of treating viral infection comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III- 2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b) , III-3 (e.g., III-3-A)
  • III-3 e.g., III-3-A
  • the administering in the methods herein is not limited to any particular route of administration.
  • the administering can be orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally.
  • the compounds of the present disclosure can be used as a monotherapy or in a combination therapy.
  • the combination therapy includes treating the subject with a targeted therapeutic agent, chemotherapeutic agent, therapeutic antibody, radiation, cell therapy, and/or immunotherapy.
  • the combination therapy includes treating the subject with an immune-oncology agent herein.
  • the combination therapy includes treating the subject with one or more additional antiviral agents.
  • the present disclosure provides the following exemplary enumerated Embodiments 1-49:
  • Embodiment 1 A compound of Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, or a pharmaceutically acceptable salt thereof:
  • R 1 is hydrogen, halogen (e.g., F, Cl, or Br) , CN, OH, NH 2 , COOH, CONH 2 , R A , OR A , NH (R A ) , N (R A ) 2 , COOR A , CONH (R A ) , CON (R A ) 2 , SR A , SOR A , SO 2 R A , or P (O) (R A ) 2 , wherein R A at each occurrence is independently optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, or optionally substituted 4-7 membered heterocyclyl;
  • halogen e.g., F, Cl, or Br
  • R 2 is hydrogen, halogen (e.g., F, Cl, or Br) , CN, OH, NH 2 , R B , OR B , NH (R B ) , or N (R B ) 2 , wherein R B at each occurrence is independently an optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted 4-7 membered heterocyclyl;
  • halogen e.g., F, Cl, or Br
  • R 3 is hydrogen, optionally substituted C 1-4 alkyl, or optionally substituted 3-7 membered ring, such as optionally substituted C 3-6 cycloalkyl, or optionally substituted 4-7 membered heterocyclyl (such as a saturated 4-7 membered heterocyclyl) ;
  • J is O, CO, SO 2 , NR 15 or optionally substituted methylene
  • W is absent or (W 1 ) p , wherein p is 1, 2, or 3, wherein W 1 at each occurrence is independently, C (O) , NR 15 , SO 2 , O, or optionally substituted methylene, provided that at most one instance of W 1 is C (O) , NR 15 , SO 2 , or O;
  • R 15 at each occurrence is independently hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted 3-6 membered ring, or nitrogen protecting group;
  • X is N or CR 5 , wherein R 5 is hydrogen, halogen, OH, NH 2 , NH (R C ) , N (R C ) 2 , CN, CONH 2 , COOH, CONH (R C ) , CON (R C ) 2 , OR C , or COOR C , wherein R C at each occurrence is independently an optionally substituted C 1-4 alkyl;
  • U is N or CR 6 , wherein R 6 is hydrogen, halogen (e.g., F, Cl, or Br) , CN, OH, NH 2 , R D , OR D , NH (R D ) , N (R D ) 2 , COOH, CONH 2 , COOR D , CONH (R D ) , CON (R D ) 2 , SR D , SOR D , SO 2 R D , or P (O) (R D ) 2 , wherein R D at each occurrence is independently an optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, or optionally substituted 4-7 membered heterocyclyl;
  • R D is hydrogen, halogen (e.g.,
  • Y is N or CR 7 , wherein R 7 is hydrogen, F, Cl, CN, optionally substituted C 1-4 alkyl, or optionally substituted C 1-4 heteroalkyl;
  • Ring C is a 5 or 6 membered ring, preferably, a 5 or 6 membered heteroaryl having 2-3 ring heteroatoms, such as a 5 membered heteroaryl having 2-3 ring nitrogen atoms, for example, imidazole or triazole ring, wherein Ring C shares two ring atoms with the adjacent ring in Formula III-8;
  • L 1 is an optionally substituted 4-12 membered ring, preferably, 4-12 membered heterocyclylene having one or more rings and 1-4 ring heteroatoms each independently O, N, or S, or –N (R E ) -, wherein R E is optionally substituted C 1-4 alkyl or optionally substituted 3-7 membered ring;
  • L 2 is absent, O, NH, –N (R E2 ) -, C (O) , SO 2 , an optionally substituted C 1-4 alkylene, an optionally substituted C 2-4 alkenylene, an optionally substituted C 1-4 alkynylene, optionally substituted C 1-4 heteroalkylene, or an optionally substituted 3-7 membered ring, wherein R E2 is optionally substituted C 1-4 alkyl or optionally substituted 3-7 membered ring;
  • R 30 is hydrogen, an optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted 8-12 membered ring having two or more rings;
  • R 9 at each occurrence is independently halogen, CN, OH, R N , OR N , NHR N , N (R N ) 2 , COOR N , COR N , CONH (R N ) , or CON (R N ) 2 , wherein R N at each occurrence is independently an optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, or optionally substituted 3-7 membered ring, such as optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-7 membered heterocyclyl, or optionally substituted 5 or 6 membered heteroaryl; and
  • n1 is 0, 1, 2, or 3, preferably, n1 is 0 or 1, and R 9 at each occurrence is independently CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , fluorine substituted C 1-3 alkyl (e.g., CF 2 H) , cyclopropyl, cyclobutyl, CH 2 OH, CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 NH 2 , CH 2 N 3 , or CH 2 NHC (O) OCH 3 .
  • fluorine substituted C 1-3 alkyl e.g., CF 2 H
  • cyclopropyl cyclobutyl
  • CH 2 OH, CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 NH 2 , CH 2 N 3 , or CH 2 NHC (O) OCH 3 is independently CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , fluorine substituted C 1-3 alkyl (e.g.,
  • Embodiment 2 The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Y is N.
  • Embodiment 3 The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Y is CH.
  • Embodiment 4 The compound of any of Embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein U is N.
  • Embodiment 5 The compound of any of Embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein U is CR 6 .
  • Embodiment 6 The compound of Embodiment 5, or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.
  • Embodiment 7 The compound of Embodiment 5, or a pharmaceutically acceptable salt thereof, wherein R 6 is C 1-4 alkoxy or
  • Embodiment 8 The compound of any of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein as applicable, R 1 is CN.
  • Embodiment 9 The compound of any of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein as applicable, (i) R 1 is halogen, e.g., F or Cl; (ii) R 1 is (iii) R 1 is an optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, such as an optionally substituted pyrimidinyl or an optionally substituted thiazolyl, for example, R 1 is or (iv) R 1 is SR A1 , wherein R A1 is independently optionally substituted C 1-4 alkyl, for example, R 1 is SCH 3 .
  • R 1 is halogen, e.g., F or Cl
  • R 1 is an optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, such as an optionally substituted pyrimidinyl or an optionally substituted thiazolyl, for example
  • Embodiment 10 The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, or III-4-D-2
  • Embodiment 11 The compound of any of Embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
  • Embodiment 12 The compound of any of Embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein (i) R 3 is an optionally substituted C 1-4 alkyl, such as CH 3 , CD 3 etc; (ii) R 3 is hydrogen; (iii) R 3 is an optionally substituted C 1-4 alkyl, such as CH (CH 3 ) 2 , CH 2 CH 3 , CH 2 CHF 2 etc; or (iv) R 3 is an optionally substituted C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl etc.
  • Embodiment 13 The compound of any of Embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein Z is C (O) .
  • Embodiment 14 The compound of any of Embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein as applicable, R 9 at each occurrence is independently an optionally substituted C 1-4 alkyl or optionally substituted C 3-6 cycloalkyl, preferably, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , fluorine-substituted C 1-3 alkyl (e.g., CF 2 H) , cyclopropyl, cyclobutyl, CH 2 OH, CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 NH 2 , CH 2 N 3 , or CH 2 NHC (O) OCH 3 .
  • R 9 at each occurrence is independently an optionally substituted C 1-4 alkyl or optionally substituted C 3-6 cycloalkyl, preferably, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , fluorine-substituted C 1-3 alkyl (e.g.,
  • Embodiment 15 The compound of any of Embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein as applicable, X is N.
  • Embodiment 16 The compound of any of Embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein as applicable, X is CR 5 , wherein R 5 is CN.
  • Embodiment 17 The compound of any of Embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein as applicable, X is CR 5 , wherein R 5 is CONH 2 , COOH, CONH (R C1 ) , CON (R C1 ) 2 , or COOR C1 , wherein R C1 at each occurrence is independently a C 1-4 alkyl, such as methyl.
  • Embodiment 18 The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein as applicable, L 1 is (either of the two attaching points of the piperidine, N or C, can be attached to L 2 ) ,
  • n 0, 1, 2, 3, or 4
  • R 9A at each occurrence is independently halogen, CN, OH, R N , OR N , NHR N , N (R N ) 2 , COOR N , COR N , CONH (R N ) , or CON (R N ) 2 , wherein R N at each occurrence is independently an optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, or optionally substituted 3-7 membered ring, such as optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-7 membered heterocyclyl, or optionally substituted 5 or 6 membered heteroaryl; or
  • Embodiment 19 The compound of Embodiment 18, or a pharmaceutically acceptable salt thereof, wherein R 9A at each occurrence is independently CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , fluorine- substituted C 1-3 alkyl (e.g., CF 2 H) , cyclopropyl, cyclobutyl, CH 2 OH, CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 NH 2 , CH 2 N 3 , or CH 2 NHC (O) OCH 3 .
  • R 9A at each occurrence is independently CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , fluorine- substituted C 1-3 alkyl (e.g., CF 2 H) , cyclopropyl, cyclobutyl, CH 2 OH, CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 NH 2 , CH 2 N 3 , or CH 2 NHC (O) OCH 3 .
  • Embodiment 20 The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein as applicable, L 1 is selected from the following (the bottom attaching point, N or C, is attached to L 2 ) :
  • Embodiment 21 The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein as applicable, L 1 is selected from the following (the bottom attaching point, N or C, is attached to L 2 ) :
  • Embodiment 22 The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein as applicable, L 1 is an optionally substituted 7-12 membered heterocyclylene having two or more rings and 1-4 ring heteroatoms each independently O, N, or S, when substituted, the substituent (s) can be attached to any one or more of the two or more rings.
  • L 1 is an optionally substituted 7-12 membered heterocyclylene having two or more rings and 1-4 ring heteroatoms each independently O, N, or S, when substituted, the substituent (s) can be attached to any one or more of the two or more rings.
  • Embodiment 23 The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein as applicable, L 1 is selected from the following bicyclic heterocyclylene (the bottom attaching point, N or C, is attached to L 2 ) :
  • each of the two rings can be optionally substituted with 1-3 R 10 , wherein R 10 at each occurrence is independently halogen, OH, NH 2 , oxo (as applicable) , R J , OR J , CN, NH (R J ) , or N (R J ) 2 , wherein R J at each occurrence is independently an optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, or optionally substituted 3-4 membered ring.
  • Embodiment 24 The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein as applicable, L 1 is selected from the following bicyclic heterocyclylene (the bottom attaching point, N or C, is attached to L 2 ) :
  • Embodiment 25 The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein as applicable, L 1 is –N (C 1-4 alkyl) -, such as –N (CH 3 ) -.
  • Embodiment 26 The compound of any of Embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein L 2 is absent.
  • Embodiment 27 The compound of any of Embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein L 2 is an optionally substituted C 1-4 alkylene selected from the following:
  • R 13 is selected from hydrogen, halogen (e.g., F, Cl, or Br) , CN, OH, NH 2 , COOH, CONH 2 , SO 2 NH 2 , COR K , COOR K , CONH (R K ) , CON (R K ) 2 , SO 2 R K , SO 2 NH (R K ) , SO 2 N (R K ) 2 , R K , OR K , NH (R K ) , N (R K ) 2 , SR K , SOR K , SO 2 R K , or P (O) (R K ) 2 , wherein R K at each occurrence is independently optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 1-4 heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 or 6 membered hetero
  • Embodiment 28 The compound of Embodiment 27, or a pharmaceutically acceptable salt thereof, wherein R 13 is hydrogen.
  • Embodiment 29 The compound of Embodiment 27, or a pharmaceutically acceptable salt thereof, wherein R 13 is CN, OH, COOH, CONH 2 , methoxy, ethoxy, cyclopropyl, cyclobutyl, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein, when substituted, the optionally substituted phenyl or 5 or 6 membered heteroaryl is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl) , OH, CN, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc. ) optionally substituted with F and/or methyl.
  • R 13 is
  • Embodiment 30 The compound of any of Embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein L 2 is O or C (O) .
  • Embodiment 31 The compound of any of Embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein L 2 is an optionally substituted 5 or 6 membered heteroarylene, for example,
  • Embodiment 32 The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein as applicable, L 1 is –N (R E ) -, L 2 is an optionally substituted phenylene, e.g., and R 30 is hydrogen.
  • Embodiment 33 The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein as applicable, L 1 , L 2 , and R 30 together are:
  • Embodiment 34 The compound of any of Embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein R 30 is optionally substituted phenyl, such as a phenyl which is substituted with 1-3 (e.g., 1 or 2) R 22 , wherein R 22 at each occurrence is independently halogen (e.g., F, Cl, or Br) , CN, OH, NH 2 , R M , OR M , COOH, CONH 2 , COOR M , CONH (R M ) , CON (R M ) 2 , NHCO (R M ) , N (R M ) CO (R M ) , SO 2 R M , SO 2 NH 2 , S (O) (NH) R M , S (O) (NR M ) R M , SO 2 N (R M ) 2 , NHSO 2 R M , N (R M ) SO 2 R M , P (O) (R M ) 2 , P (O) (
  • Embodiment 35 The compound of Embodiment 34, or a pharmaceutically acceptable salt thereof, wherein R 30 is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R 22 , wherein R 22 at each occurrence is independently halogen (e.g., F, Cl, or Br) , CN, OH, R M1 , OR M1 , SO 2 R M1 , P (O) (R M1 ) 2 , SR M1 , or SF 5 , wherein R M1 at each occurrence is independently an optionally substituted C 1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.
  • R 30 is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R 22 , wherein R 22 at each occurrence is independently halogen (e.g., F, Cl,
  • the optionally substituted C 1-4 alkyl or 3-4 membered ring is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl) , OH, CN, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc. ) optionally substituted with F and/or methyl.
  • halogen preferably F or Cl
  • Embodiment 36 The compound of Embodiment 34, or a pharmaceutically acceptable salt thereof, wherein R 30 is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R 22 , wherein R 22 at each occurrence is independently F, Cl, CN, R M2 , OR M2 , SR M2 , or SF 5 , wherein R M2 at each occurrence is independently a C 1-4 alkyl optionally substituted with 1-3 F, such as CF 3 .
  • 1-3 e.g., 1 or 2
  • R 22 at each occurrence is independently F, Cl, CN, R M2 , OR M2 , SR M2 , or SF 5
  • R M2 at each occurrence is independently a C 1-4 alkyl optionally substituted with 1-3 F, such as CF 3 .
  • Embodiment 37 The compound of any of Embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein R 30 is optionally substituted 5 or 6-membered heteroaryl, such as a pyridyl (e.g., ) or pyrimidinyl (e.g., ) , which is substituted with 1-3 (e.g., 1 or 2) R 22 , wherein R 22 at each occurrence is independently halogen (e.g., F, Cl, or Br) , CN, OH, NH 2 , R M , OR M , COOH, CONH 2 , COOR M , CONH (R M ) , CON (R M ) 2 , NHCO (R M ) , N (R M ) CO (R M ) , SO 2 R M , SO 2 NH 2 , S (O) (NH) R M , S (O) (NR M ) R M , SO 2 N (R M ) 2 , NHSO 2 R
  • Embodiment 38 The compound of Embodiment 37, or a pharmaceutically acceptable salt thereof, wherein R 30 is a 5-membered heteroaryl (e.g., ) or pyridyl (e.g., ) or pyrimidinyl (e.g., ) , which is substituted with 1-3 (e.g., 1 or 2) R 22 , as valency permits, wherein R 22 at each occurrence is independently halogen (e.g., F, Cl, or Br) , CN, OH, R M1 , OR M1 , SO 2 R M1 , P (O) (R M1 ) 2 , SR M1 , or SF 5 , wherein R M1 at each occurrence is independently an optionally substituted C 1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.
  • R 30 is
  • the optionally substituted C 1-4 alkyl or 3-4 membered ring is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl) , OH, CN, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc. ) optionally substituted with F and/or methyl.
  • halogen preferably F or Cl
  • Embodiment 39 The compound of Embodiment 37, or a pharmaceutically acceptable salt thereof, wherein R 30 is a 5-membered heteroaryl (e.g., ) or pyridyl (e.g., ) or pyrimidinyl (e.g., ) , which is substituted with 1-3 (e.g., 1 or 2) R 22 , as valency permits, wherein R 22 at each occurrence is independently F, Cl, CN, R M2 , OR M2 , SR M2 , or SF 5 , wherein R M2 at each occurrence is independently a C 1-4 alkyl optionally substituted with 1-3 F, such as CF 3 .
  • R 30 is a 5-membered heteroaryl (e.g., ) or pyridyl (e.g., ) or pyrimidinyl (e.g., ) , which is substituted with 1-3 (e.g., 1 or 2) R 22 , as val
  • Embodiment 40 The compound of any of Embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein R 30 has a structure according to S-1-A, S-1-B, S-1-C, or S-1-D:
  • R 8 is C 1-4 alkyl optionally substituted with 1-3 F (such as CH 3 , CF 3 , etc. ) , C 1-4 alkoxy optionally substituted with 1-3 F (such as OCH 3 , OCF 3 , etc. ) , SCF 3 , SF 5 , cyclopropyl, cyclobutyl, or
  • Embodiment 41 The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein L 1 , L 2 , and R 30 together (i.e., L 1 -L 2 -R 30 ) are selected from:
  • L 1 -L 2 -R 30 is selected from
  • Embodiment 42 The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein L 1 , L 2 , and R 30 together are selected from:
  • L 1 -L 2 -R 30 is selected from:
  • Embodiment 43 The compound of any of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein L 1 , L 2 , and R 30 together are selected from:
  • L 1 -L 2 -R 30 is selected from:
  • L 1 , L 2 , and R 30 together are selected from:
  • L 1 , L 2 , and R 30 together are selected from:
  • Embodiment 44 The compound of any of Embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein R 30 is selected from the following:
  • R 30 is selected from:
  • R 30 is selected from:
  • R 30 is selected from:
  • Embodiment 45 A compound selected from Compound Nos. 1-347 or any of the compounds disclosed in Table A, or a pharmaceutically acceptable salt thereof.
  • Embodiment 46 A pharmaceutical composition comprising the compound of any of Embodiments 1-45 or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable excipient.
  • Embodiment 47 A method for treating a disease comprising the administration to a subject in need thereof a therapeutically-effective amount of at least one compound according to any one of Embodiments 1 to 45, wherein said disease is cancer or a viral infection.
  • Embodiment 48 The method according to Embodiment 47, wherein said cancer is selected from colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia and melanoma.
  • Embodiment 49 A method of inhibiting activity of at least one of diacylglycerol kinase selected from diacylglycerol kinase alpha (DGKa) and diacylglycerol kinase zeta (DGKz) comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound according to any one of Embodiments 1 to 45.
  • DGKa diacylglycerol kinase alpha
  • DGKz diacylglycerol kinase zeta
  • Figure 1 shows anti-tumor activity of Compound 67 (cpd67) as a single agent and in combination with anti-mouse PD-1 antibody (mPD-1) in MC38 syngeneic tumor model.
  • the present disclosure provides compounds and compositions that are useful for inhibiting DGKs (diacylglycerol kinases) , such as DGKa and/or DGKz, and/or treating or preventing various diseases or disorders described herein, e.g., cancer or infectious diseases such as viral infections.
  • DGKs diacylglycerol kinases
  • the compounds herein typically can be a DGK inhibitor, and useful for treating various diseases or disorders, such as those described herein, e.g., cancer or viral infections.
  • the present disclosure provides a compound of Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, or a pharmaceutically acceptable salt thereof:
  • R 1 is hydrogen, halogen (e.g., F, Cl, or Br) , CN, OH, NH 2 , COOH, CONH 2 , R A , OR A , NH (R A ) , N (R A ) 2 , COOR A , CONH (R A ) , CON (R A ) 2 , SR A , SOR A , SO 2 R A , or P (O) (R A ) 2 , wherein R A at each occurrence is independently optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, or optionally substituted 4-7 membered heterocyclyl;
  • halogen e.g., F, Cl, or Br
  • R 2 is hydrogen, halogen (e.g., F, Cl, or Br) , CN, OH, NH 2 , R B , OR B , NH (R B ) , or N (R B ) 2 , wherein R B at each occurrence is independently an optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted 4-7 membered heterocyclyl;
  • halogen e.g., F, Cl, or Br
  • R 3 is hydrogen, optionally substituted C 1-4 alkyl, or optionally substituted 3-7 membered ring, such as an optionally substituted C 3-6 cycloalkyl, or optionally substituted 4-7 membered heterocyclyl (such as a saturated 4-7 membered heterocyclyl) ;
  • J is O, CO, SO 2 , NR 15 or optionally substituted methylene
  • W is absent or - (W 1 ) p -, wherein p is 1, 2, or 3, wherein W 1 at each occurrence is independently, C (O) , NR 15 , SO 2 , O, or optionally substituted methylene, provided that at most one instance of W 1 is C (O) , NR 15 , SO 2 , or O; to be clear, when W is absent, the ring containing J is a 5-membered ring; when p is 1, the ring containing J and W is a 6-membered ring; when p is 2 or 3, the ring containing J and W is a 7-membered ring or 8-membered ring, respectively;
  • R 15 at each occurrence is independently hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted 3-6 membered ring, or nitrogen protecting group;
  • X is N or CR 5 , wherein R 5 is hydrogen, halogen, OH, NH 2 , NHR C , N (R C ) 2 , CN, CONH 2 , COOH, CONH (R C ) , CON (R C ) 2 , OR C , NO 2 , or COOR C , wherein R C at each occurrence is independently an optionally substituted C 1-4 alkyl;
  • U is N or CR 6 , wherein R 6 is hydrogen, halogen (e.g., F, Cl, or Br) , CN, OH, NH 2 , R D , OR D , NH (R D ) , N (R D ) 2 , COOH, CONH 2 , COOR D , CONH (R D ) , CON (R D ) 2 , SR D , SOR D , SO 2 R D , or P (O) (R D ) 2 , wherein R D at each occurrence is independently an optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, or optionally substituted 4-7 membered heterocyclyl;
  • R D is hydrogen, halogen (e.g.,
  • Y is N or CR 7 , wherein R 7 is hydrogen, F, Cl, CN, optionally substituted C 1-4 alkyl, or optionally substituted C 1-4 heteroalkyl;
  • Ring C is a 5 or 6 membered ring, preferably, a 5 or 6 membered heteroaryl having 2-3 ring heteroatoms, such as a 5 membered heteroaryl having 2-3 ring nitrogen atoms, for example, imidazole or triazole ring, wherein Ring C shares two ring atoms with the adjacent ring in Formula III-8;
  • L 1 is an optionally substituted 4-12 membered ring, preferably, 4-12 membered heterocyclylene having one or more rings and 1-4 ring heteroatoms each independently O, N, or S, or –N (R E ) -, wherein R E is optionally substituted C 1-4 alkyl or optionally substituted 3-7 membered ring;
  • L 2 is absent, O, NH, –N (R E2 ) -, C (O) , SO 2 , an optionally substituted C 1-4 alkylene, an optionally substituted C 2-4 alkenylene, an optionally substituted C 1-4 alkynylene, optionally substituted C 1-4 heteroalkylene, or an optionally substituted 3-7 membered ring, wherein R E2 is optionally substituted C 1-4 alkyl or optionally substituted 3-7 membered ring;
  • R 30 is hydrogen, an optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted 8-12 membered ring having two or more rings;
  • R 9 at each occurrence is independently halogen, CN, OH, R N , OR N , NHR N , N (R N ) 2 , COOR N , COR N , CONH (R N ) , or CON (R N ) 2 , wherein R N at each occurrence is independently an optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, or optionally substituted 3-7 membered ring, such as optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-7 membered heterocyclyl, or optionally substituted 5 or 6 membered heteroaryl; and
  • n1 0, 1, 2, or 3.
  • a "x-y membered ring” should be understood as encompassing any ring structure having the designated number of ring members, for example, such ring can be carbocyclic, heterocyclic, aryl or heteroaryl, which can be monocyclic, bicyclic, or having more than two rings, and each of the ring (s) can be saturated, partially unsaturated, or aromatic, and can optionally contain one or more ring heteroatoms. Further, when applicable, such "x-y membered ring” should be understood as attaching to the remainder of the molecule through one or more ring atoms.
  • substituted or "unsubstituted” used in connection with a variable described herein should be understood as referring to whether the variable is substituted, without considering the required bonding of the variable with the remainder of the molecule.
  • an unsubstituted phenylene should be understood such that other than the two ring atoms of the phenylene that are attached to the remainder of the molecule, the other ring atoms of the phenylene are not substituted, whereas in a substituted phenylene, at least one ring atom, other than the two ring atoms of the phenylene that are attached to the remainder of the molecule, is substituted with a substituent described herein.
  • the compound of Formula III-1 to III-12 can have stereoisomer (s) .
  • the compound of Formula III-1 to III-12 can exist in the form of an individual enantiomer, diastereomer, atropisomer, and/or geometric isomer, as applicable, or a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.
  • the compound of Formula III-1 to III-12 when applicable, can exist as a mixture of a pair of enantiomers in any ratio, including a racemic mixture with a ratio of 1: 1.
  • the compound of Formula III-1 to III-12 can exist as an isolated or enriched individual enantiomer substantially free (e.g., with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount) of the other enantiomer.
  • the present disclosure provides a compound having a structure according to Formula III-1, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein.
  • the present disclosure provides a compound having a structure according to Formula III-2, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein.
  • the present disclosure provides a compound having a structure according to Formula III-3, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein.
  • the present disclosure provides a compound having a structure according to Formula III-4, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein.
  • the present disclosure provides a compound having a structure according to Formula III-5, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein. In some embodiments, the present disclosure provides a compound having a structure according to Formula III-6, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein. In some embodiments, the present disclosure provides a compound having a structure according to Formula III-7, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein. In some embodiments, the present disclosure provides a compound having a structure according to Formula III-8, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein. In some embodiments, the compound of Formula III-8 can be characterized as having a structure according to Formula III-8-A or Formula III-8-B:
  • the present disclosure provides a compound having a structure according to Formula III-9, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein.
  • the present disclosure provides a compound having a structure according to Formula III-10, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein.
  • the present disclosure provides a compound having a structure according to Formula III-11, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein.
  • the present disclosure provides a compound having a structure according to Formula III-12, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein.
  • variable (s) in any of Formula III-1 to III-12 are also applicable for the respective variable (s) in any of its respective subformulae, unless specifically defined in such subformulae or otherwise contradictory.
  • variable (s) in Formula III-2 are also applicable to the respective variable (s) in a subformula herein, such as Formula III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b, unless specifically defined in such subformula or otherwise contradictory.
  • variable (s) in Formula III-4 are also applicable to the respective variable (s) in a subformula herein, such as III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f, unless specifically defined in such subformula or otherwise contradictory.
  • Y is N.
  • Y is CR 7 , wherein R 7 is hydrogen, F, Cl, CN, optionally substituted C 1-4 alkyl, or optionally substituted C 1-4 heteroalkyl.
  • R 7 is hydrogen, F, Cl, CN, optionally substituted C 1-4 alkyl, or optionally substituted C 1-4 heteroalkyl.
  • Y is CH.
  • U in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12 is CR 6 , wherein R 6 is hydrogen, halogen (e.g., F, Cl, or Br) , CN, OH, NH 2 , R D , OR D , NH (R D ) , N (R D ) 2 , COOH, CONH 2 , COOR D , CONH (R D ) , CON (R D ) 2 , SR D , SOR D , SO 2 R D , or P (O) (R D ) 2 , wherein R D at each occurrence is independently an optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected
  • R 6 is hydrogen, i.e., U is CH.
  • R 6 can also be halogen, such as F or Cl.
  • R 6 can also be OR D , wherein R D is defined herein.
  • R 6 can be OR D1 , wherein R D1 is optionally substituted C 1-4 alkyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted 4-7 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from O, N, and S; wherein, when substituted, the optionally substituted C 1-4 alkyl, C 3-6 cycloalkyl, or 4-7 membered heterocyclyl can be substituted with one or more (e.g., 1-3) substituents, for example, each substituent can be independently selected from halogen (e.g., F) , OH, CN, C 1-4 alkyl or C 1-4 alkoxy.
  • R 6 can be C 1-4 alkoxy.
  • R 6 can be In some specific embodiments, R 6 can be In some specific embodiments, R 6 can be In some specific embodiments, R 6 can be
  • R 1 can be OH, COOH, CONH 2 , NH 2 , R A , OR A , COOR A , NH (R A ) , N (R A ) 2 , CONH (R A ) , CON (R A ) 2 , SR A , SOR A , SO 2 R A , or P (O) (R A ) 2 , wherein R A is defined herein.
  • R A at each occurrence can be optionally substituted C 1-4 alkyl.
  • R 1 is CN.
  • R 1 in Formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12 is halogen, preferably F or Cl.
  • R 1 in Formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12 is a C 2-3 alkynyl, such as
  • R 1 in in Formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12 is optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N.
  • R 1 can be an optionally substituted pyrimidinyl or an optionally substituted thiazolyl, for example, R 1 is
  • R 1 in Formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12 is SR A , wherein R A is defined herein.
  • R 1 can be SR A1 , wherein R A1 is independently optionally substituted C 1-4 alkyl, for example, R 1 is SCH 3 .
  • Other suitable R 1 are described herein.
  • R 1 in Formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12 can be characterized in that (i) R 1 is halogen, e.g., F or Cl; (ii) R 1 is (iii) R 1 is an optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, such as an optionally substituted pyrimidinyl or an optionally substituted thiazolyl, for example, R 1 is or (iv) R 1 is SR A1 , wherein R A1 is independently optionally substituted C 1-4 alkyl, for example, R 1 is SCH 3 .
  • R 1 is halogen, e.g., F or Cl
  • R 1 is an optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, such as an optionally substituted pyrimidinyl or an
  • R 2 in Formula III-1, III-2, III-3, III-4, III-6, III-7, or III-8 is hydrogen.
  • R 2 can be halogen (e.g., F, Cl, or Br) , CN, OH, NH 2 , R B , OR B , NH (R B ) , or N (R B ) 2 , wherein R B is defined herein.
  • R B can be an optionally substituted C 1-4 alkyl or optionally substituted 3-4 membered cycloalkyl.
  • R 3 in Formula III-1, III-3, III-4, III-6, or III-7 is an optionally substituted C 1-4 alkyl, such as CH 3 , CD 3 etc.
  • R 3 is CH 3 .
  • R 3 is CD 3 .
  • R 3 is CH 2 CH 3 .
  • R 3 is CH (CH 3 ) 2 .
  • R 3 is CH 2 CHF 2 .
  • R 3 can also be an optionally substituted C 3-6 cycloalkyl.
  • R 3 is cyclopropyl.
  • R 3 is cyclobutyl.
  • R 3 is hydrogen.
  • Z in Formula III-1, III-3, III-4, III-5, III-6, III-7, III-9, III-11, or III-12 is C (O) .
  • Z in Formula III-1, III-3, III-4, III-5, III-6, III-7, III-9, III-11, or III-12 can also be S (O) 2 .
  • X in Formula III-1, III-2, III-5, III-6, III-7, III-8, or III-9 is N.
  • X in Formula III-1, III-2, III-5, III-8, or III-9 is CR 5 , wherein R 5 is defined herein.
  • X is CR 5 , wherein R 5 is CN.
  • X is CR 5 , wherein R 5 is CONH 2 , COOH, CONH (R C1 ) , CON (R C1 ) 2 , or COOR C1 , wherein R C1 at each occurrence is independently a C 1-4 alkyl, such as methyl.
  • n1 is 0. In some embodiments, n1 is 1. In some embodiments, R 9 at each occurrence is independently CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , fluorine-substituted C 1-3 alkyl (e.g., CF 2 H) , cyclopropyl, or cyclobutyl, CH 2 OH, CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 NH 2 , CH 2 N 3 , or CH 2 NHC (O) OCH 3 .
  • C 1-3 alkyl e.g., CF 2 H
  • J is NR 15 , wherein R 15 is defined herein.
  • J is N (C 1-4 alkyl) , such as NCH 3 .
  • J is an optionally substituted methylene.
  • J is CH 2 .
  • J is CF 2 , CHCH 3 , C (CH 3 ) 2 , CHOH, etc.
  • J is O. In some embodiments, in Formula III-6 or III-7, J is NH or NCH 3 .
  • W is absent.
  • the ring containing J is a 5 membered ring.
  • W is W 1 , wherein W 1 is defined herein.
  • W 1 is C (O) , SO 2 , CH 2 , CF 2 , CHCH 3 , C (CH 3 ) 2 , CHOH, etc.
  • the ring containing J and W is a 6-membered ring.
  • each W 1 is independently C (O) , SO 2 , CH 2 , CF 2 , CHCH 3 , C (CH 3 ) 2 , CHOH, etc.
  • both W 1 can be CH 2 .
  • one W 1 is O
  • the other W 1 is CH 2 .
  • one W 1 is C (O)
  • the other W 1 is O, NH, NCH 3 , or CH 2 .
  • the ring containing J and W is a 7-membered ring.
  • L 1 is an optionally substituted 4-12 membered heterocyclylene herein.
  • L 1 in Formula III-1, III-2, III-5, III-8, or III-9 is an optionally substituted 4-12 membered heterocyclylene having one or more rings and 1-4 ring heteroatoms each independently O, N, or S.
  • L 1 in Formula III-1, III-2, III-5, III-8, or III-9 can be –N (R E ) -, wherein R E is optionally substituted C 1-4 alkyl or optionally substituted 3-7 membered ring.
  • L 1 is –N (C 1-4 alkyl) -, such as –N (CH 3 ) -.
  • L 1 in Formula III-1, III-2, III-5, III-8, or III-9 is an optionally substituted 4-7 membered monocyclic heterocyclylene having 1 or 2 ring heteroatoms each independently O, N, or S.
  • the 4-7 membered monocyclic heterocyclylene is a saturated heterocyclylene having 1 or 2 ring heteroatoms, such as 1 or 2 ring nitrogen atoms, such as a piperazine or piperidine ring.
  • the heterocyclylene is typically attached to the remainder of the molecule through two ring nitrogen atoms or one ring nitrogen and one ring carbon atom.
  • L 1 can be (either of the two attaching points of the piperidine, N or C, can be attached to L 2 ) ,
  • n 0, 1, 2, 3, or 4
  • R 9A at each occurrence is independently halogen, CN, OH, R N , OR N , NHR N , N (R N ) 2 , COOR N , COR N , CONH (R N ) , or CON (R N ) 2 , wherein R N at each occurrence is independently an optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted 3-7 membered ring, such as optionally substituted C 3-6 cycloalkyl, optionally substituted 4-7 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl; or
  • R 9A at each occurrence is independently R N .
  • R 9A at each occurrence is independently an optionally substituted C 1-4 alkyl, and when substituted, the substituents can be independently selected from F, OH, C 1-4 heteroalkyl having 1 or 2 heteroatoms, which is optionally substituted with F, or 3-4 membered ring (e.g., cyclopropyl or cyclobutyl, etc. ) .
  • R 9A at each occurrence is independently CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , fluorine-substituted C 1-3 alkyl (e.g., CF 2 H) , cyclopropyl, or cyclobutyl, CH 2 OH, CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 NH 2 , CH 2 N 3 , or CH 2 NHC (O) OCH 3 .
  • R 9A at each occurrence is independently CH 3 , CH 2 CH 3 , or CH 2 CH 2 CH 3 , more preferably, R 9A at each occurrence is CH 2 CH 3 .
  • n is 0, 1, or 2.
  • L 1 can be selected from:
  • L 1 in Formula III-1, III-2, III-5, III-8, or III-9, L 1 can be selected from the following (the bottom attaching point, N or C, is attached to L 2 ) :
  • L 1 in Formula III-1, III-2, III-5, III-8, or III-9, L 1 can be selected from the following (the bottom attaching point, N or C, is attached to L 2 ) :
  • L 1 in Formula III-1, III-2, III-5, III-8, or III-9 can also be an optionally substituted 7-12 membered heterocyclylene having two or more rings and 1-4 ring heteroatoms each independently O, N, or S, when substituted, the substituent (s) can be attached to any one or more of the two or more rings.
  • L 1 can be an optionally substituted 8-12 membered fused, spiro, or bridged bicyclic heterocyclylene having 1-4 ring heteroatoms each independent O, N, or S, wherein each ring of the bicyclic heterocyclylene can be saturated, partially unsaturated, or aromatic, and each ring of the bicyclic heterocyclylene can have 0, 1, 2, or 3 ring heteroatoms, provided that the bicyclic heterocyclylene as a whole is not fully aromatic and the total number of heteroatoms in the bicyclic heterocyclylene does not exceed 4.
  • L 1 can be an optionally substituted 8-11 membered fused bicyclic heterocyclylene having 1-3 ring heteroatoms each independent O, N, or S, wherein (1) one of the two fused rings is phenyl or 5 or 6 membered heteroaryl, and (2) the other of the two fused rings is a 5-7 membered heterocycle having one or two ring heteroatoms each independently O, N, or S, preferably, the 5-7 membered heterocycle has at least one ring nitrogen atom.
  • L 1 can be an optionally substituted 8-11 (e.g., 8, 9, or 10) membered spiro bicyclic heterocyclylene having 1-4 ring heteroatoms each independent O, N, or S, wherein (1) one of the two spiro rings is a 5-7 membered heterocycle having one or two ring heteroatoms each independently O, N, or S, preferably, the 5-7 membered heterocycle has one ring nitrogen atom , and (2) the other of the two spiro rings is a 4-6 membered heterocycle having 1-3 ring heteroatoms each independently O, N, or S, for example, one of the two spiro rings is a pyrrolidine, piperidine, azepane ring and the other of the two spiro rings is azetidine, pyrrolidine, pyrrolidinone, piperidinone, oxazoline, isoxazoline, thiazoline, isothiazoline, etc.
  • 8-11 e.g., 8,
  • L 1 in Formula III-1, III-2, III-5, III-8, or III-9 can be selected from the following (the bottom attaching point, N or C, is attached to L 2 ) :
  • each of the two rings can be optionally substituted with 1-3 R 10 , wherein R 10 at each occurrence is independently halogen, OH, NH 2 , oxo (as applicable) , R J , OR J , CN, NH (R J ) , or N (R J ) 2 , wherein R J at each occurrence is independently an optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, or optionally substituted 3-4 membered ring.
  • L 1 in Formula III-1, III-2, III-5, III-8, or III-9 can be selected from the following (the bottom attaching point, N or C, is attached to L 2 ) :
  • L 1 in Formula III-1, III-2, III-5, III-8, or III-9 can also be -N (C 1-4 alkyl) -, such as -N (CH 3 ) -.
  • L 2 in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, L 2 can be absent.
  • L 2 in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12 can be an optionally substituted C 1-4 alkylene, such as those substituted with one or more R 13 groups defined herein.
  • R 13 at each occurrence is independently selected from halogen (e.g., F, Cl, or Br) , CN, OH, NH 2 , COOH, CONH 2 , SO 2 NH 2 , COR K , COOR K , CONH (R K ) , CON (R K ) 2 , SO 2 R K , SO 2 NH (R K ) , SO 2 N (R K ) 2 , R K , OR K , NH (R K ) , N (R K ) 2 , SR K , SOR K , SO 2 R K , or P (O) (R K ) 2 , wherein R K at each occurrence is independently optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 1-4 heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted
  • L 2 in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12 can be an unsubstituted C 1-4 alkylene such as CH 2 , CH (CH 3 ) , CH (C 2 H 5 ) , CH (C 3 H 7 ) , etc.
  • L 2 in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12 can be an unsubstituted C 1-4 alkylene selected from: CH 2 , or
  • L 2 in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12 can be an optionally substituted C 1-4 alkylene selected from:
  • R 13 is selected from hydrogen, halogen (e.g., F, Cl, or Br) , CN, OH, NH 2 , COOH, CONH 2 , SO 2 NH 2 , COR K , COOR K , CONH (R K ) , CON (R K ) 2 , SO 2 R K , SO 2 NH (R K ) , SO 2 N (R K ) 2 , R K , OR K , NH (R K ) , N (R K ) 2 , SR K , SOR K , SO 2 R K , or P (O) (R K ) 2 , wherein R K at each occurrence is independently optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 1-4 heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 or 6 membered hetero
  • R 13 is hydrogen.
  • R 13 is a C 1-4 alkyl, such as methyl, ethyl, isopropyl, etc.
  • R 13 is methyl.
  • R 13 is isopropyl.
  • R 13 is R K as defined herein.
  • R 13 is OH or OR K , wherein R K is defined herein, such as a C 1-4 alkyl.
  • R 13 is CN, OH, COOH, CONH 2 , methoxy, ethoxy, cyclopropyl, cyclobutyl, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein, when substituted, the optionally substituted phenyl or 5 or 6 membered heteroaryl is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl) , OH, CN, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.
  • halogen preferably F or Cl
  • R 13 is a 3-4 membered ring, such as cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc., which is optionally substituted, such as with F and/or methyl.
  • R 13 is cyclopropyl.
  • R 13 is an optionally substituted phenyl or optionally substituted 5 or 6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, such as an optionally substituted phenyl or thiazole, which is optionally substituted with 1-3 substituents independently selected from halogen (preferably F or Cl) , OH, CN, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc. ) optionally substituted with F and/or methyl.
  • R 13 is In some embodiments, R 13 is OH, methoxy, cyclopropyl, phenyl,
  • L 2 in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, L 2 can be C (O) . In some embodiments, in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, L 2 can be O, preferably, in Formula III-4, L 2 is not O.
  • L 2 in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, L 2 can be an optionally substituted phenylene, e.g.,
  • L 2 in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, L 2 can be an optionally substituted 5 or 6 membered heteroarylene, for example,
  • L 1 in Formula III-1, III-2, III-5, III-8, or III-9, L 1 can be –N (R E ) -, L 2 is an optionally substituted phenylene, e.g., and R 30 is hydrogen.
  • L 1 , L 2 , and R 30 together are:
  • R 30 is optionally substituted phenyl, such as a phenyl which is substituted with 1-3 (e.g., 1 or 2) R 22 , wherein R 22 at each occurrence is independently halogen (e.g., F, Cl, or Br) , CN, OH, NH 2 , R M , OR M , COOH, CONH 2 , COOR M , CONH (R M ) , CON (R M ) 2 , NHCO (R M ) , N (R M ) CO (R M ) , SO 2 R M , SO 2 NH 2 , S (O) (NH) R M , S (O) (NR M ) R M , SO 2 N (R M ) 2 , NHSO 2 R M , N (R M ) SO 2 R M , P (
  • halogen e.g., F, Cl, or Br
  • one instance of R 22 is halogen, such as F, Cl, or Br, and the remaining instance (s) of R 22 , if any, are defined herein.
  • two or three instances of R 22 are halogen, each independently F, Cl, or Br, and the remaining instance (s) of R 22 , if any, are defined herein.
  • one instance of R 22 is CN, and the remaining instance (s) of R 22 , if any, are defined herein.
  • one instance of R 22 is R M , OR M , SR M , SF 5 , or SO 2 R M , wherein R M is defined herein, such as a C 1-3 alkyl optionally substituted with F (e.g., CF 3 , CF 2 CH 3 , CHF 2 , etc. ) or cyclopropyl, and the remaining instance (s) of R 22 , if any, are defined herein.
  • R M is defined herein, such as a C 1-3 alkyl optionally substituted with F (e.g., CF 3 , CF 2 CH 3 , CHF 2 , etc. ) or cyclopropyl, and the remaining instance (s) of R 22 , if any, are defined herein.
  • R 30 is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R 22 , wherein R 22 at each occurrence is independently halogen (e.g., F, Cl, or Br) , CN, OH, R M1 , OR M1 , SO 2 R M1 , P (O) (R M1 ) 2 , SR M1 , or SF 5 , wherein R M1 at each occurrence is independently an optionally substituted C 1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.
  • halogen e.g., F, Cl, or Br
  • the optionally substituted C 1-4 alkyl or 3-4 membered ring is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl) , OH, CN, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc. ) optionally substituted with F and/or methyl.
  • halogen preferably F or Cl
  • R 30 is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R 22 , wherein R 22 at each occurrence is independently F, Cl, CN, R M2 , OR M2 , SR M2 , or SF 5 , wherein R M2 at each occurrence is independently a C 1-4 alkyl optionally substituted with 1-3 F, such as CF 3 .
  • R 22 at each occurrence can be independently halogen, CN, C 1-4 alkyl optionally substituted with 1-3 F (such as CH 3 , CF 3 , etc. ) , C 1-4 alkoxy optionally substituted with 1-3 F (such as OCH 3 , OCF 3 , etc.
  • R 22 at each occurrence is independently F, Cl, Br, CF 3 , OCF 3 , SCF 3 , SF 5 , OMe, CN, methyl, CHF 2 , CF 2 CH 3 , cyclopropyl, CH 3 SO 2 , and OCH 2 - (cyclopropyl) .
  • R 30 is optionally substituted 5 or 6-membered heteroaryl, such as a pyridyl (e.g., ) or pyrimidinyl (e.g., ) , which is substituted with 1-3 (e.g., 1 or 2) R 22 , wherein R 22 at each occurrence is independently halogen (e.g., F, Cl, or Br) , CN, OH, NH 2 , R M , OR M , COOH, CONH 2 , COOR M , CONH (R M ) , CON (R M ) 2 , NHCO (R M ) , N (R M ) CO (R M ) , SO 2 R M , SO 2 NH 2 , S (O) (NH) R M , S (O) (NR M ) R M ,
  • a pyridyl e.g., ) or pyrimidinyl (e.g., )
  • R 22 at each occurrence is independently
  • one instance of R 22 is halogen, such as F, Cl, or Br, and the remaining instance (s) of R 22 , if any, are defined herein.
  • two or three instances of R 22 are halogen, each independently F, Cl, or Br, and the remaining instance (s) of R 22 , if any, are defined herein.
  • one instance of R 22 is CN, and the remaining instance (s) of R 22 , if any, are defined herein.
  • one instance of R 22 is R M , OR M , SR M , SF 5 , or SO 2 R M , wherein R M is defined herein, such as a C 1-3 alkyl optionally substituted with F (e.g., CF 3 , CF 2 CH 3 , CHF 2 , etc. ) or cyclopropyl, and the remaining instance (s) of R 22 , if any, are defined herein.
  • R M is defined herein, such as a C 1-3 alkyl optionally substituted with F (e.g., CF 3 , CF 2 CH 3 , CHF 2 , etc. ) or cyclopropyl, and the remaining instance (s) of R 22 , if any, are defined herein.
  • R 30 is a 5-membered heteroaryl (e.g., ) or pyridyl (e.g., ) or pyrimidinyl (e.g., ) , which is substituted with 1-3 (e.g., 1 or 2) R 22 , as valency permits, wherein R 22 at each occurrence is independently halogen (e.g., F, Cl, or Br) , CN, OH, R M1 , OR M1 , SO 2 R M1 , P (O) (R M1 ) 2 , SR M1 , or SF 5 , wherein R M1 at each occurrence is independently an optionally substituted C 1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.
  • R 22 at each occurrence is independently halogen (e.g., F, Cl, or Br) , CN
  • the optionally substituted C 1-4 alkyl or 3-4 membered ring is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl) , OH, CN, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc. ) optionally substituted with F and/or methyl.
  • halogen preferably F or Cl
  • R 30 is a 5-membered heteroaryl (e.g., ) or pyridyl (e.g., ) or pyrimidinyl (e.g., ) , which is substituted with 1-3 (e.g., 1 or 2) R 22 , as valency permits, wherein R 22 at each occurrence is independently F, Cl, CN, R M2 , OR M2 , SR M2 , or SF 5 , wherein R M2 at each occurrence is independently a C 1-4 alkyl optionally substituted with 1-3 F, such as CF 3 .
  • 1-3 e.g., 1 or 2
  • R 22 at each occurrence can be independently halogen, CN, C 1-4 alkyl optionally substituted with 1-3 F (such as CH 3 , CF 3 , etc. ) , C 1-4 alkoxy optionally substituted with 1-3 F (such as OCH 3 , OCF 3 , etc.
  • R 22 at each occurrence is independently F, Cl, Br, CF 3 , OCF 3 , SCF 3 , SF 5 , OMe, CN, methyl, CHF 2 , CF 2 CH 3 , cyclopropyl, CH 3 SO 2 , and OCH 2 - (cyclopropyl) .
  • R 30 can have a structure of formula S-1, S-2, S-3, or S-4 below:
  • Ring B is attached to L 2 ,
  • Ring B is a 5-7 membered ring containing 0, 1, or 2 ring heteroatoms, and is optionally substituted with 1-3 R G , wherein R G at each occurrence is independently halogen, OH, oxo, NH 2 , NH (C 1-4 alkyl) , N (C 1-4 alkyl) (C 1-4 alkyl) , an optionally substituted C 1-4 alkyl, or optionally substituted C 1-4 alkoxy;
  • q is an integer ranging from 0-3 as valency permits, preferably, 1 or 2,
  • R 8 at each occurrence is independently halogen (e.g., F, Cl, or Br) , CN, OH, NH 2 , R H , OR H , NH (R H ) , N (R H ) 2 , SR H , SF 5 , or optionally substituted 5-8 membered carbocyclic having two or more rings, wherein R H at each occurrence is independently optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted 4-7 membered heterocyclyl;
  • R H at each occurrence is independently optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted 4-7 membered heterocyclyl;
  • each substituent can be independently selected from halogen (e.g., F) , OH, CN, C 1-4 alkyl or C 1-4 alkoxy.
  • Ring B in S-1, S-2, S-3, or S-4 contains no ring heteroatoms. In some embodiments, Ring B in S-1, S-2, S-3, or S-4 contains one ring heteroatom, such as O, N, or S. In some embodiments, Ring B in S-1, S-2, S-3, or S-4 contains no ring heteroatoms and is not substituted.
  • Ring B in S-1, S-2, S-3, or S-4 contains no ring heteroatoms and is optionally substituted with one or more substituents described herein, for example, in some embodiments, Ring B is optionally substituted with 1-3 R G1 , wherein R G1 at each occurrence is independently F, OH, C 1-4 alkyl optionally substituted with 1-3 F, or C 1-4 alkoxy optionally substituted with 1-3 F.
  • the phenyl, pyridyl, or pyrimidyl portion of S-1, S-2, S-3, or S-4 is typically substituted with 1 R 8 , i.e., q is 1, wherein R 8 is defined herein.
  • the phenyl, pyridyl, or pyrimidyl portion of S-1, S-2, S-3, or S-4 can be substituted with 2 R 8 , wherein R 8 is defined herein.
  • R 8 at each occurrence is independently R H1 , OR H1 , SR H1 , SF 5 , or optionally substituted 5-8 membered carbocyclic having two or more rings, wherein R H1 is C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 alkoxy optionally substituted with 1-3 F, or C 3-6 cycloalkyl optionally substituted with 1-3 substituents independently selected from F, OH, methyl, and methoxy, and wherein when substituted, the optionally substituted 5-8 membered carbocyclic is substituted with 1-3 substituents each independently selected from halogen (e.g., F) , OH, CN, C 1-4 alkyl and C 1-4 alkoxy.
  • halogen e.g., F
  • R 8 can be optionally substituted 5-8 membered carbocyclic having two or more rings, such as a bicyclic carbocyclic ring.
  • R 8 can be a 5-8 membered bicyclic carbocyclic, such as a bridged bicyclic carbocyclic, such as which is optionally substituted, wherein, when substituted, the bicyclic carbocyclic can be substituted with one or more (e.g., 1-3) substituents, for example, each substituent can be independently selected from halogen (e.g., F) , OH, CN, C 1-4 alkyl or C 1-4 alkoxy.
  • halogen e.g., F
  • R 8 can be In some embodiments, R 8 at each occurrence can be independently a C 1-4 alkyl optionally substituted with 1-3 F (such as CH 3 , CF 3 , etc. ) , C 1-4 alkoxy optionally substituted with 1-3 F (such as OCH 3 , OCF 3 , etc. ) , SCF 3 , SF 5 , cyclopropyl, cyclobutyl, or
  • R 30 can have a structure according to S-1-A, S-1-B, S-1-C, or S-1-D:
  • R 8 is C 1-4 alkyl optionally substituted with 1-3 F (such as CH 3 , CF 3 , etc. ) , C 1-4 alkoxy optionally substituted with 1-3 F (such as OCH 3 , OCF 3 , etc. ) , SCF 3 , SF 5 , cyclopropyl, cyclobutyl, or
  • R 30 in Formula III-1 to III-12 can be selected from the following:
  • R 30 in Formula III-1 to III-12 can be selected from the following:
  • R 30 in Formula III-1 to III-12 can be selected from the following:
  • R 30 in Formula III-1 to III-12 can be selected from the following:
  • R 30 in Formula III-1 to III-12 can be selected from the following:
  • R 30 in Formula III-1 to III-12 can be selected from the following:
  • R 30 in Formula III-1 to III-12 can be selected from the following:
  • R 30 in Formula III-1 to III-12 can be selected from the following:
  • R 30 in Formula III-1 to III-12 is not selected from the following:
  • R 30 in Formula III-1 to III-12 can be selected from the following:
  • -L 2 -R 30 can be:
  • -L 2 -R 30 can be selected from:
  • -L 2 -R 30 can be selected from:
  • -L 2 -R 30 can be selected from:
  • -L 2 -R 30 can be selected from:
  • -L 2 -R 30 can be:
  • L 1 , L 2 , and R 30 i.e., L 1 -L 2 -R 30 ) together can be selected from:
  • L 1 , L 2 , and R 30 together can be selected from:
  • L 1 , L 2 , and R 30 together can be selected from:
  • L 1 -L 2 -R 30 is selected from the following:
  • L 1 , L 2 , and R 30 together can be selected from:
  • L 1 , L 2 , and R 30 together can be selected from:
  • L 1 , L 2 , and R 30 together can be selected from:
  • the present disclosure provides the following enumerated exemplified Embodiments A1-A38:
  • Embodiment A1 A compound of Formula III-2, or a pharmaceutically acceptable salt thereof,
  • Embodiment A2 The compound of Embodiment A1, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-2-A:
  • Embodiment A3 The compound of Embodiment A1, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-2-B:
  • Embodiment A4 The compound of any of Embodiments A1-A3, or a pharmaceutically acceptable salt thereof, wherein (i) R 1 is CN; (ii) R 1 is halogen, e.g., F or Cl; (iii) R 1 is (iv) R 1 is an optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, such as an optionally substituted pyrimidinyl or an optionally substituted thiazolyl, for example, R 1 is or (v) R 1 is SR A1 , wherein R A1 is independently optionally substituted C 1-4 alkyl, for example, R 1 is SCH 3 .
  • Embodiment A5 The compound of any of Embodiments A1-A4, or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from the following (the bottom attaching point, N or C, is attached to L 2 ) :
  • Embodiment A6 The compound of any of Embodiments A1-A4, or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from the following (the bottom attaching point, N or C, is attached to L 2 ) :
  • Embodiment A7 The compound of any of Embodiments A1-A4, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-2-C:
  • n 0, 1, 2, or 3
  • R 9A is defined herein.
  • Embodiment A8 The compound of Embodiment A7, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-2-C-1, III-2-C-2, III-2-C-3, or III-2-C-4:
  • Embodiment A9 The compound of Embodiment A7 or A8, wherein R 9A at each occurrence is independently CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , fluorine-substituted C 1-3 alkyl (e.g., CF 2 H) , cyclopropyl, cyclobutyl, CH 2 OH, CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 NH 2 , CH 2 N 3 , or CH 2 NHC (O) OCH 3 .
  • C 1-3 alkyl e.g., CF 2 H
  • Embodiment A10 The compound of any of Embodiments A1-A4, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-2-D:
  • n 0, 1, 2, or 3
  • R 9A is defined herein.
  • Embodiment A11 The compound of Embodiment A10, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-2-D-1, III-2-D-2, III-2-D-3, or III-2-D-4:
  • Embodiment A12 The compound of Embodiment A10 or A11, or a pharmaceutically acceptable salt thereof, wherein R 9A at each occurrence is independently CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , fluorine-substituted C 1-3 alkyl (e.g., CF 2 H) , cyclopropyl, cyclobutyl, CH 2 OH, CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 NH 2 , CH 2 N 3 , or CH 2 NHC (O) OCH 3 .
  • R 9A at each occurrence is independently CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , fluorine-substituted C 1-3 alkyl (e.g., CF 2 H) , cyclopropyl, cyclobutyl, CH 2 OH, CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 NH 2 , CH 2 N 3 , or CH 2
  • Embodiment A13 The compound of any of Embodiments A1-A12, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-2-E-1, III-2-E-2, or III-2-E-3:
  • R 13 is defined herein.
  • Embodiment A14 The compound of any of Embodiments A1-A12, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, or III-2-E-3b:
  • R 13 is defined herein.
  • Embodiment A15 The compound of Embodiment A13, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b:
  • R 9A at each occurrence is independently CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , fluorine-substituted C 1-3 alkyl (e.g., CF 2 H) , cyclopropyl, cyclobutyl, CH 2 OH, CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 NH 2 , CH 2 N 3 , or CH 2 NHC (O) OCH 3 , preferably, R 9A at each occurrence is independently CH 3 , CH 2 CH 3 , or CH 2 CH 2 CH 3 , more preferably, R 9A at each occurrence is CH 2 CH 3 .
  • Embodiment A16 The compound of any of Embodiments A13-A15, or a pharmaceutically acceptable salt thereof, wherein R 13 is hydrogen, C 1-4 alkyl, e.g., methyl, isopropyl, etc., CN, OH, COOH, CONH 2 , methoxy, ethoxy, cyclopropyl, cyclobutyl, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein, when substituted, the optionally substituted phenyl or 5 or 6 membered heteroaryl is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl) , OH, CN, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxe
  • Embodiment A17 The compound of any of Embodiments A1-A12, or a pharmaceutically acceptable salt thereof, wherein L 2 is absent, O, or C (O) .
  • Embodiment A18 The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R 30 is an optionally substituted phenyl or 5 or 6-membered heteroaryl (e.g., such as oxadiazolyl (e.g., ) , pyridyl (e.g., ) or pyrimidinyl (e.g., ) , for example, when substituted, the phenyl or 5 or 6-membered heteroaryl can be substituted with 1-3 (e.g., 1 or 2) R 22 , wherein R 22 at each occurrence is halogen (e.g., F, Cl, or Br) , CN, C 1-4 alkyl optionally substituted with 1-3 F (such as CH 3 , CF 3 , etc. ) , C 1-4 alkoxy optionally substituted with 1-3 F (such as OCH 3 , OCF 3 , etc. ) , SCF 3 , SF
  • Embodiment A19 The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R 30 is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R 22 , wherein R 22 at each occurrence is independently halogen (e.g., F, Cl, or Br) , CN, OH, R M1 , OR M1 , SO 2 R M1 , P (O) (R M1 ) 2 , SR M1 , or SF 5 , wherein R M1 at each occurrence is independently an optionally substituted C 1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.
  • R 30 is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R 22 , wherein R 22 at each occurrence is independently halogen (e.
  • the optionally substituted C 1-4 alkyl or 3-4 membered ring is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl) , OH, CN, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.
  • R 22 at each occurrence is independently F, Cl, Br, CF 3 , OCF 3 , SCF 3 , SF 5 , OMe, CN, methyl, CHF 2 , CF 2 CH 3 , cyclopropyl, CH 3 SO 2 , and OCH 2 - (cyclopropyl) .
  • Embodiment A20 The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R 30 is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R 22 , wherein R 22 at each occurrence is independently F, Cl, CN, R M2 , OR M2 , SR M2 , or SF 5 , wherein R M2 at each occurrence is independently a C 1-4 alkyl optionally substituted with 1-3 F, such as CF 3 .
  • 1-3 e.g., 1 or 2
  • R 22 at each occurrence is independently F, Cl, CN, R M2 , OR M2 , SR M2 , or SF 5
  • R M2 at each occurrence is independently a C 1-4 alkyl optionally substituted with 1-3 F, such as CF 3 .
  • Embodiment A21 The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R 30 is a 5-membered heteroaryl (e.g., ) or pyridyl (e.g., ) or pyrimidinyl (e.g., ) , which is substituted with 1-3 (e.g., 1 or 2) R 22 , as valency permits, wherein R 22 at each occurrence is independently halogen (e.g., F, Cl, or Br) , CN, OH, R M1 , OR M1 , SO 2 R M1 , P (O) (R M1 ) 2 , SR M1 , or SF 5 , wherein R M1 at each occurrence is independently an optionally substituted C 1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl,
  • the optionally substituted C 1-4 alkyl or 3-4 membered ring is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl) , OH, CN, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.
  • R 22 at each occurrence is independently F, Cl, Br, CF 3 , OCF 3 , SCF 3 , SF 5 , OMe, CN, methyl, CHF 2 , CF 2 CH 3 , cyclopropyl, CH 3 SO 2 , and OCH 2 - (cyclopropyl) .
  • Embodiment A22 The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R 30 is a 5-membered heteroaryl (e.g., ) or pyridyl (e.g., ) or pyrimidinyl (e.g., ) , which is substituted with 1-3 (e.g., 1 or 2) R 22 , as valency permits, wherein R 22 at each occurrence is independently F, Cl, CN, R M2 , OR M2 , SR M2 , or SF 5 , wherein R M2 at each occurrence is independently a C 1-4 alkyl optionally substituted with 1-3 F, such as CF 3 .
  • R 30 is a 5-membered heteroaryl (e.g., ) or pyridyl (e.g., ) or pyrimidinyl (e.g., ) , which is substituted with 1-3 (e.g., 1 or 2)
  • Embodiment A23 The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R 30 has a structure according to S-1-A, S-1-B, S-1-C, or S-1-D:
  • R 8 is C 1-4 alkyl optionally substituted with 1-3 F (such as CH 3 , CF 3 , etc. ) , C 1-4 alkoxy optionally substituted with 1-3 F (such as OCH 3 , OCF 3 , etc. ) , SCF 3 , SF 5 , cyclopropyl, cyclobutyl, or
  • Embodiment A24 The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R 30 is selected from:
  • Embodiment A25 The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R 30 is selected from:
  • Embodiment A26 The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, R 30 is selected from the following:
  • Embodiment A27 The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R 30 is selected from:
  • Embodiment A28 The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R 30 is selected from:
  • Embodiment A29 The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R 30 is selected from:
  • Embodiment A30 The compound of any of Embodiments A1-A17, or a pharmaceutically acceptable salt thereof, wherein R 30 is selected from:
  • Embodiment A31 The compound of any of Embodiments A1-A4, or a pharmaceutically acceptable salt thereof, wherein L 1 -L 2 -R 30 is selected from the following:
  • Embodiment A32 The compound of any of Embodiments A1-A4, or a pharmaceutically acceptable salt thereof, wherein L 1 -L 2 -R 30 is selected from the following:
  • Embodiment A33 The compound of any of Embodiments A1-A4, or a pharmaceutically acceptable salt thereof, wherein L 1 -L 2 -R 30 is selected from the following:
  • Embodiment A34 The compound of any of Embodiments A1-A4, or a pharmaceutically acceptable salt thereof, wherein L 1 -L 2 -R 30 is selected from the following:
  • L 1 -L 2 -R 30 is selected from the following:
  • L 1 -L 2 -R 30 is selected from the following:
  • Embodiment A35 The compound of any of Embodiments A1-A12, or a pharmaceutically acceptable salt thereof, wherein L 2 -R 30 is selected from:
  • Embodiment A36 The compound of any of Embodiments A1-A12, or a pharmaceutically acceptable salt thereof, wherein L 2 -R 30 is selected from:
  • Embodiment A37 A compound of Formula III-8, or a pharmaceutically acceptable salt thereof, wherein Ring C is an imidazole or triazole ring, and wherein the variables X, Y, U, R 1 , R 2 , L 1 , L 2 , and R 30 are defined herein, including any of those shown in Embodiments A2-A36 as defined in connection with Formula III-2.
  • Embodiment A38 The compound of Embodiment A37, or a pharmaceutically acceptable salt thereof, characterized as having a formula according to III-8-A or III-8-B:
  • Embodiments B1-B45 the present disclosure provides the following enumerated exemplified Embodiments B1-B45:
  • Embodiments B1-B45 are identical to Embodiments B1-B45.
  • Embodiment B A compound of Formula III-3, or a pharmaceutically acceptable salt thereof,
  • Embodiment B2 The compound of Embodiment B1, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-3-A:
  • Embodiment B3 A compound of Formula III-4, or a pharmaceutically acceptable salt thereof,
  • Embodiment B4 The compound of Embodiment B3, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-A:
  • Embodiment B5 The compound of Embodiment B3, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-B:
  • Embodiment B6 The compound of Embodiment B5, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-C or III-4-D:
  • Embodiment B7 The compound of Embodiment B6, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, or III-4-D-2:
  • Embodiment B8 The compound of any of Embodiments B1-B7, or a pharmaceutically acceptable salt thereof, wherein (i) R 3 is an optionally substituted C 1-4 alkyl, such as CH 3 , CD 3 , ethyl, isopropyl, CH 2 CHF 2 , etc. or R 3 is an optionally substituted 3-4 membered ring, such as cyclopropyl or cyclobutyl, etc., when substituted, the C 1-4 alkyl or 3-4 membered ring is typically substituted with 1-3 substituents independently deuterium, F, or methyl, preferably, R 3 is methyl or CD 3 ; (ii) R 3 is hydrogen.
  • R 3 is an optionally substituted C 1-4 alkyl, such as CH 3 , CD 3 , ethyl, isopropyl, CH 2 CHF 2 , etc.
  • R 3 is an optionally substituted 3-4 membered ring, such as cyclopropyl or
  • Embodiment B9 The compound of any of Embodiments B1-B8, or a pharmaceutically acceptable salt thereof, wherein (i) R 1 is CN; (ii) R 1 is halogen, e.g., F or Cl; (iii) R 1 is (iv) R 1 is an optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, S, and N, such as an optionally substituted pyrimidinyl or an optionally substituted thiazolyl, for example, R 1 is or (v) R 1 is SR A1 , wherein R A1 is independently optionally substituted C 1-4 alkyl, for example, R 1 is SCH 3 .
  • Embodiment B10 The compound of any of Embodiments B1-B9, or a pharmaceutically acceptable salt thereof, wherein R 9 at each occurrence is independently CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , fluorine-substituted C 1-3 alkyl (e.g., CF 2 H) , cyclopropyl, cyclobutyl, CH 2 OH, CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 NH 2 , CH 2 N 3 , or CH 2 NHC (O) OCH 3 , preferably, R 9 at each occurrence is independently CH 3 , CH 2 CH 3 , or CH 2 CH 2 CH 3 , more preferably, R 9 at each occurrence is CH 2 CH 3 .
  • R 9 at each occurrence is independently CH 3 , CH 2 CH 3 , or CH 2 CH 2 CH 3 , more preferably, R 9 at each occurrence is CH 2 CH 3 .
  • Embodiment B11 The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein L 2 is an optionally substituted C 1-4 alkylene.
  • Embodiment B12 The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein L 2 is selected from the following:
  • R 13 is defined herein.
  • Embodiment B13 The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f:
  • R 13 is defined herein.
  • Embodiment B14 The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-C-4a:
  • R 13 is defined herein.
  • Embodiment B15 The compound of Embodiment B14, or a pharmaceutically acceptable salt thereof, which is substantially stereoisomerically pure, for example, with an enantiomeric excess ( "ee” ) of 80%or above, such as with 90%ee, 95%ee, 98%ee, 99%ee, or above, and is substantially free of the corresponding stereoisomer according to Formula III-4-C-4b,
  • Embodiment B16 The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-C-4c:
  • R 13 is defined herein.
  • Embodiment B17 The compound of Embodiment B16, or a pharmaceutically acceptable salt thereof, which is substantially stereoisomerically pure, for example, with an enantiomeric excess ( "ee” ) of 80%or above, such as with 90%ee, 95%ee, 98%ee, 99%ee, or above, and is substantially free of the corresponding stereoisomer according to Formula III-4-C-4d,
  • Embodiment B18 The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-4-C-4e:
  • R 13 is defined herein.
  • Embodiment B19 The compound of Embodiment B18, or a pharmaceutically acceptable salt thereof, which is substantially stereoisomerically pure, for example, with an enantiomeric excess ( "ee” ) of 80%or above, such as with 90%ee, 95%ee, 98%ee, 99%ee, or above, and is substantially free of the corresponding stereoisomer according to Formula III-4-C-4f,
  • f for example, with less than 5%, such as with less than 2%, less than 1%, less than 0.5%, or less than 0.1%, of the corresponding stereoisomer according to Formula III-4-C-4f, as determined by HPLC or SFC area%and/or by weight.
  • Embodiment B20 The compound of any of Embodiments B12-B19, or a pharmaceutically acceptable salt thereof, wherein R 13 is hydrogen, CN, OH, COOH, CONH 2 , methoxy, ethoxy, cyclopropyl, cyclobutyl, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein, when substituted, the optionally substituted phenyl or 5 or 6 membered heteroaryl is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl) , OH, CN, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc. ) optionally substituted with F and/
  • Embodiment B21 The compound of any of Embodiments B12-B19, or a pharmaceutically acceptable salt thereof, wherein R 13 is a C 1-4 alkyl optionally substituted with one or more substituents independently selected from F, OH, or C 1-4 alkoxy, for example, R 13 is methyl, ethyl, isopropyl, CH 2 OH, CH 2 OMe, etc.
  • Embodiment B22 The compound of any of Embodiments B12-B19, or a pharmaceutically acceptable salt thereof, wherein R 13 is phenyl, which is optionally substituted with 1-3 substituents independently selected from halogen (preferably F or Cl) , OH, CN, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc. ) optionally substituted with F and/or methyl, for example, R 13 is phenyl, which is optionally substituted with 1-3 substituents independently selected from halogen (preferably F or Cl) , OH, CN, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclo
  • Embodiment B23 The compound of any of Embodiments B12-B19, or a pharmaceutically acceptable salt thereof, wherein R 13 is a 5 or 6 membered heteroaryl, such as which is optionally substituted with 1-3 substituents independently selected from halogen (preferably F or Cl) , OH, CN, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc. ) optionally substituted with F and/or methyl, for example, R 13 is a 5 or 6 membered heteroaryl, such as which is optionally substituted with 1-3 substituents independently selected from halogen (preferably F or Cl) , OH, CN, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 heteroalkyl optionally substituted with 1-3 F, and 3
  • Embodiment B24 The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein L 2 is absent, O, or C (O) .
  • Embodiment B25 The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R 30 is an optionally substituted phenyl or 5 or 6-membered heteroaryl (e.g., such as oxadiazolyl (e.g., ) , pyridyl (e.g., ) or pyrimidinyl (e.g., ) , for example, when substituted, the phenyl or 5 or 6-membered heteroaryl can be substituted with 1-3 (e.g., 1 or 2) R 22 , wherein R 22 at each occurrence is halogen (e.g., F, Cl, or Br) , CN, C 1-4 alkyl optionally substituted with 1-3 F (such as CH 3 , CF 3 , etc. ) , C 1-4 alkoxy optionally substituted with 1-3 F (such as OCH 3 , OCF 3 , etc. ) , SCF 3 , SF
  • Embodiment B26 The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R 30 is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R 22 , wherein R 22 at each occurrence is independently halogen (e.g., F, Cl, or Br) , CN, OH, R M1 , OR M1 , SO 2 R M1 , P (O) (R M1 ) 2 , SR M1 , or SF 5 , wherein R M1 at each occurrence is independently an optionally substituted C 1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.
  • R 30 is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R 22 , wherein R 22 at each occurrence is independently halogen (e.
  • the optionally substituted C 1-4 alkyl or 3-4 membered ring is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl) , OH, CN, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.
  • R 22 at each occurrence is independently F, Cl, Br, CF 3 , OCF 3 , SCF 3 , SF 5 , OMe, CN, methyl, CHF 2 , CF 2 CH 3 , cyclopropyl, CH 3 SO 2 , and OCH 2 - (cyclopropyl) .
  • Embodiment B27 The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R 30 is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R 22 , wherein R 22 at each occurrence is independently F, Cl, CN, R M2 , OR M2 , SR M2 , or SF 5 , wherein R M2 at each occurrence is independently a C 1-4 alkyl optionally substituted with 1-3 F, such as CF 3 .
  • 1-3 e.g., 1 or 2
  • R 22 at each occurrence is independently F, Cl, CN, R M2 , OR M2 , SR M2 , or SF 5
  • R M2 at each occurrence is independently a C 1-4 alkyl optionally substituted with 1-3 F, such as CF 3 .
  • Embodiment B28 The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R 30 is a 5-membered heteroaryl (e.g., ) or pyridyl (e.g., ) or pyrimidinyl (e.g., ) , which is substituted with 1-3 (e.g., 1 or 2) R 22 , as valency permits, wherein R 22 at each occurrence is independently halogen (e.g., F, Cl, or Br) , CN, OH, R M1 , OR M1 , SO 2 R M1 , P (O) (R M1 ) 2 , SR M1 , or SF 5 , wherein R M1 at each occurrence is independently an optionally substituted C 1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl,
  • the optionally substituted C 1-4 alkyl or 3-4 membered ring is substituted with 1-3 substituents independently selected from halogen (preferably F or Cl) , OH, CN, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 heteroalkyl optionally substituted with 1-3 F, and 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.
  • R 22 at each occurrence is independently F, Cl, Br, CF 3 , OCF 3 , SCF 3 , SF 5 , OMe, CN, methyl, CHF 2 , CF 2 CH 3 , cyclopropyl, CH 3 SO 2 , and OCH 2 - (cyclopropyl) .
  • Embodiment B29 The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R 30 is a 5-membered heteroaryl (e.g., ) or pyridyl (e.g., ) or pyrimidinyl (e.g., ) , which is substituted with 1-3 (e.g., 1 or 2) R 22 , as valency permits, wherein R 22 at each occurrence is independently F, Cl, CN, R M2 , OR M2 , SR M2 , or SF 5 , wherein R M2 at each occurrence is independently a C 1-4 alkyl optionally substituted with 1-3 F, such as CF 3 .
  • R 30 is a 5-membered heteroaryl (e.g., ) or pyridyl (e.g., ) or pyrimidinyl (e.g., ) , which is substituted with 1-3 (e.g., 1 or 2)
  • Embodiment B30 The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R 30 has a structure according to S-1-A, S-1-B, S-1-C, or S-1-D:
  • R 8 is C 1-4 alkyl optionally substituted with 1-3 F (such as CH 3 , CF 3 , etc. ) , C 1-4 alkoxy optionally substituted with 1-3 F (such as OCH 3 , OCF 3 , etc. ) , SCF 3 , SF 5 , cyclopropyl, cyclobutyl, or
  • Embodiment B31 The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R 30 is selected from:
  • Embodiment B32 The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R 30 is selected from:
  • Embodiment B33 The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R 30 is selected from:
  • Embodiment B34 The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R 30 is selected from:
  • Embodiment B35 The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R 30 is selected from:
  • Embodiment B36 The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R 30 is selected from:
  • Embodiment B37 The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R 30 is selected from:
  • Embodiment B38 The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein L 2 -R 30 is selected from:
  • Embodiment B39 The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein L 2 -R 30 is selected from:
  • Embodiment B40 The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein L 2 -R 30 is selected from:
  • Embodiment B41 The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein L 2 -R 30 is selected from:
  • Embodiment B42 The compound of any of Embodiments B1-B24, or a pharmaceutically acceptable salt thereof, wherein R 30 is selected from:
  • Embodiment B43 The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein L 2 -R 30 is selected from:
  • Embodiment B44 The compound of any of Embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein L 2 -R 30 is selected from:
  • Embodiment B45 A compound of Formula III-6 or III-7, or a pharmaceutically acceptable salt thereof, wherein –J-W-represents -CH 2 -O-CH 2 , -O-CH 2 -CH 2 -, -N (CH 3 ) -C (O) -, -NH-C (O) -, -N (CH 3 ) -CH 2 , or -NH-CH 2 , (from left to right, i.e., J is the first group from left, such as CH 2 , O, NH, or NCH 3 ) , and wherein the variables Z, Y, U, R 1 , R 2 , R 3 , n1, R 9 , L 2 , and R 30 are defined herein, including any of those shown in Embodiments B1-B44 as defined in connection with Formula III-3 or III-4.
  • the present disclosure also provides a compound selected from Compound Nos. 1-347, or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides a compound selected from the compounds shown in Table A below, or a pharmaceutically acceptable salt thereof:
  • the compounds may be prepared in a racemic form, with respect to one or more of the chiral centers, which can be separated into two enantiomers, including the as-drawn enantiomer, or be prepared through chiral synthesis, in view of the present disclosure.
  • the genus of compounds in the present disclosure also excludes any of the compounds specifically prepared and disclosed prior to this disclosure.
  • the genus of compounds in the present disclosure can optionally have a negative limitation to exclude one or more applicable compound (s) selected from any of the compounds specifically prepared prior to this disclosure.
  • the genus of compounds in the present disclosure includes any of those shown in original claims 1-63 herein, Embodiments 1-49, Embodiments A1-A38, and Embodiments B1-B45.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in “Protective Groups in Organic Synthesis” , 4 th ed. P.G.M. Wuts; T.W. Greene, John Wiley, 2007, and references cited therein.
  • the reagents for the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) , Sigma (St.
  • Certain embodiments are directed to a pharmaceutical composition comprising one or more of the compounds of the present disclosure.
  • the pharmaceutical composition can optionally contain a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises a compound of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b) , III-3 (e.g., III-3-A) , III-4 (e.g., III-4-A, III-4
  • any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient are known in the art.
  • suitable excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.
  • the pharmaceutical composition can include any one or more of the compounds of the present disclosure.
  • the pharmaceutical composition comprises a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b) , III-3 (e.g., III-3-A) , III-4 (e.g., III-4-A, III-4-B, III-4-C
  • the pharmaceutical composition can comprise a therapeutically effective amount of a compound selected from Compound Nos. 1-347, or a pharmaceutically acceptable salt thereof. In any of the embodiments described herein, the pharmaceutical composition can comprise a therapeutically effective amount of a compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition can also be formulated for delivery via any of the known routes of delivery, which include but are not limited to oral, parenteral, inhalation, etc.
  • the pharmaceutical composition can be formulated for oral administration.
  • the oral formulations can be presented in discrete units, such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • Excipients for the preparation of compositions for oral administration are known in the art.
  • Non-limiting suitable excipients include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1, 3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl
  • the pharmaceutical composition is formulated for parenteral administration (such as intravenous injection or infusion, subcutaneous or intramuscular injection) .
  • the parenteral formulations can be, for example, an aqueous solution, a suspension, or an emulsion.
  • Excipients for the preparation of parenteral formulations are known in the art. Non-limiting suitable excipients include, for example, 1, 3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water and mixtures thereof.
  • the pharmaceutical composition is formulated for inhalation.
  • the inhalable formulations can be, for example, formulated as a nasal spray, dry powder, or an aerosol administrable through a metered-dose inhaler.
  • Excipients for preparing formulations for inhalation are known in the art. Non-limiting suitable excipients include, for example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, and mixtures of these substances.
  • Sprays can additionally contain propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • the pharmaceutical composition can include various amounts of the compounds of the present disclosure, depending on various factors such as the intended use and potency and selectivity of the compounds.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b) , III-3 (
  • the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present disclosure and a pharmaceutically acceptable excipient.
  • a therapeutically effective amount of a compound of the present disclosure is an amount effective to treat a disease or disorder as described herein, which can depend on the recipient of the treatment, the disease or disorder being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency (e.g., for inhibiting DGKa and/or DGKz) , its rate of clearance and whether or not another drug is co-administered.
  • a compound of the present disclosure can be administered as a suitably acceptable formulation in accordance with normal veterinary practice.
  • the veterinarian can readily determine the dosing regimen and route of administration that is most appropriate for a particular animal.
  • kits for use in the therapeutic intervention of the disease comprising a packaged set of medicaments that include the compound disclosed herein as well as buffers and other components for preparing deliverable forms of said medicaments, and/or devices for delivering such medicaments, and/or any agents that are used in combination therapy (e.g., any of those described herein, such as an immuno-oncology agent described herein, including for example an antagonist of a protein that inhibits T cell activation, an agonist of a protein that stimulates T cell activation, etc., in particular, one or more antibodies selected from anti-PD-1, anti-PD-L1, anti-CTLA-4, and combinations thereof) with the compound of the present disclosure, and/or instructions for the treatment of the disease packaged with the
  • Compounds of the present disclosure are useful as therapeutic active substances for the treatment and/or prophylaxis of diseases or disorders that are associated with the activity of DGKa, DGKz, or both DGKa and DGKz, such as DGK target inhibition in T cells.
  • diseases or disorders 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 present disclosure provides a method of inhibiting the activity of diacylglycerol kinase alpha and/or zeta (DGKa/z) in a cell comprising contacting a cell with an effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a,
  • the term "cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo.
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • contacting the DGKa and DGKz enzyme with a compound of the present disclosure includes the administration of a compound of the present disclosure to a subject, such as a human, having DGKa and DGKz, as well as, for example, introducing a compound of the present disclosure into a sample containing a cellular or purified preparation containing DGKa and DGKz enzyme.
  • DGK inhibitor such as a DGKa and/or DGKz inhibitor refers to an agent capable of inhibiting the activity of diacylglycerol kinase alpha and/or diacylglycerol kinase zeta (DGKa and/or DGKz) , such as in T cells resulting in T cell stimulation.
  • DGKa and/or DGKz diacylglycerol kinase alpha and/or diacylglycerol kinase zeta
  • the present disclosure provides a method of treating a disease associated with activity or expression, including abnormal activity and/or overexpression, of DGKa and/or DGKz in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-2a, III
  • diseases can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of DGKa and/or DGKz enzyme, such as over expression or abnormal activity.
  • a DGKa and/or DGKz-associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating DGKa and/or DGKz enzyme activity.
  • DGKa and/or DGKz associated diseases include cancer and viral infections such as HIV infection, hepatitis B, and hepatitis C.
  • cancer include cancer of the colon, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia, and/or melanoma.
  • the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b) , III-3 (e.g., III-3-A) , III-3 (e.
  • the cancer is cancer of the colon, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia, and/or melanoma.
  • Types of cancers that may be treated with the compound of the present disclosure 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
  • the present disclosure provides a method of treating viral infection in a subject, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b) , III-3 (e.g., III-3-A) ,
  • Viral infections that may be treated 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 varicella zoster virus
  • coxsackie virus human immunodeficiency virus
  • the present disclosure provides a method of treating a disease or disorder, e.g., a cancer associated with DGKa and/or DGKz in a subject in need thereof.
  • the method comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-2a,
  • the cancer is cancer of the colon, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia, and/or melanoma.
  • Other types of cancer suitable to be treated by the method include those described herein.
  • Compounds of the present disclosure can be used as a monotherapy or in a combination therapy.
  • the combination therapy includes treating the subject with a targeted therapeutic agent, chemotherapeutic agent, therapeutic antibody, radiation, cell therapy, and/or immunotherapy.
  • compounds of the present disclosure can also be co-administered with an additional pharmaceutically active compound, either concurrently or sequentially in any order, to a subject in need thereof.
  • the combination therapy includes treating the subject with one or more additional therapies such as 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.
  • additional therapies such as 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.
  • compounds of the present disclosure can be administered concurrently or sequentially in any order with an immuno-oncology agent.
  • Immuno-oncology agents include, for example, a small molecule drug, antibody, or other biologic or small molecule.
  • biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines.
  • the immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co-inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses (often referred to as immune checkpoint regulators) .
  • Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF) .
  • IgSF immunoglobulin super family
  • One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the 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.
  • TNF family of molecules that bind to cognate TNF receptor family members which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB) , TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTbR, LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, Lymphotoxin a/TNFb, TNFR2, TNFa, LTbR, Lymphotoxin a 1b
  • T cell responses can be stimulated by a combination of a compound of the present disclosure and one or more of (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137) , 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.
  • an antagonist of a protein that inhibits T cell activation e.g., immune
  • agents that can be combined with compounds of the present disclosure for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells.
  • a compound of the present disclosure can be combined with antagonists of KIR, such as lirilumab.
  • Other 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 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357) .
  • a compound of the present disclosure can be used with one or more of agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1/PD-1 interactions) , deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion) , inhibit metabolic enzymes such as IDO, or reverse/prevent T cell anergy or exhaustion) and agents that trigger innate immune activation and/or inflammation at tumor sites.
  • agonistic agents that ligate positive costimulatory receptors e.g., blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents
  • the immuno-oncology 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 immuno-oncology 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; WO2012/145493) .
  • the immuno-oncology agent may also include pidilizumab (CT-011) , though its specificity for PD-1 binding has been questioned.
  • CT-011 pidilizumab
  • Another approach to target the PD-1 receptor is the recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, called AMP-224.
  • the immuno-oncology agent is a PD-L1 antagonist, such as an antagonistic PD-L1 antibody.
  • Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010/077634) , durvalumab (MEDI4736) , BMS-936559 (WO2007/005874) , and MSB0010718C (WO2013/79174) .
  • the immuno-oncology agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody.
  • Suitable LAG3 antibodies include, for example, BMS-986016 (WO10/19570, WO14/08218) , or IMP-731 or IMP-321 (WO08/132601, WO09/44273) .
  • the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody.
  • Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12/32433) .
  • the immuno-oncology agent is a GITR agonist, such as an agonistic GITR antibody.
  • Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06/105021, WO09/009116) and MK-4166 (WO11/028683) .
  • the immuno-oncology agent is an IDO antagonist.
  • Suitable IDO antagonists include, for example, INCB-024360 (WO2006/122150, WO07/75598, WO08/36653, WO08/36642) , indoximod, BMS-986205, or NLG-919 (WO09/73620, WO09/1156652, WO11/56652, WO12/142237) .
  • the immuno-oncology agent is an OX40 agonist, such as an agonistic OX40 antibody.
  • Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.
  • the immuno-oncology agent is an OX40L antagonist, such as an antagonistic OX40 antibody.
  • Suitable OX40L antagonists include, for example, RG-7888 (WO06/029879) .
  • the immuno-oncology agent is a CD40 agonist, such as an agonistic CD40 antibody.
  • the immuno-oncology agent is a CD40 antagonist, such as an antagonistic CD40 antibody.
  • Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.
  • the immuno-oncology agent is a CD27 agonist, such as an agonistic CD27 antibody.
  • Suitable CD27 antibodies include, for example, varlilumab.
  • the immuno-oncology agent is MGA271 (to B7H3) (WO11/109400) .
  • Combination therapy also can include the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and/or non-drug therapies (e.g., surgery or radiation treatment. )
  • Suitable antiviral agents contemplated for use in combination with the compound of the present disclosure 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.
  • Suitable NRTIs include zidovudine (AZT) ; didanosine (ddl) ; zalcitabine (ddC) ; stavudine (d4T) ; lamivudine (3TC) ; abacavir (1592U89) ; adefovir dipivoxil [bis (POM) -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
  • Typical suitable 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.
  • Additional combination therapies such as additional immune-oncology agents also include any of those described as suitable for combination with DGK inhibitors in any of the following published patent applications: WO2019005883; WO2020006016; WO2020006018; WO2021041588; WO2021105115; WO2021105116; WO2021105117; WO2021127554; WO2021130638; WO2021132422; WO2021133748; WO2021133749; WO2021133750; WO2021133751; WO2021133752; WO2021214019; or WO2021214020.
  • the administering herein is not limited to any particular route of administration.
  • the administering can be orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally.
  • the administering is orally.
  • Dosing regimen including doses can vary and can be adjusted, which can depend on the recipient of the treatment, the disease or disorder being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered.
  • variable moiety herein can be the same or different as another specific embodiment having the same identifier.
  • Suitable atoms or groups for the variables herein are independently selected.
  • the definitions of the variables can be combined.
  • any of the definitions of one of R 1 , R 2 , R 3 , R 9 , R 30 , U, Y, Z, n1, and L 2 , in Formula III-4 can be combined with any of the definitions of the others of R 1 , R 2 , R 3 , R 9 , R 30 , U, Y, Z, n1, and L 2 , in Formula III-4.
  • Such combination is contemplated and within the scope of the present disclosure.
  • Non-limiting useful groups for the variables in compounds of Formula III-1 to III-12, or a subformula thereof, as applicable include any of the respective groups, individually or in any combination, as shown in the Examples or in the specific compounds described in Table A herein.
  • variable (s) that is defined in connection with the broader formula
  • such variable (s) for the sub-formula can have the same definition as any of those defined for the broader formula
  • the preferred definition of such variable (s) for the sub-formula can also include the same preferred definition as any of those described for the broader formula, unless obviously contrary from context.
  • variable (s) that is defined in connection with the sub-formula
  • such variable (s) for the broader formula or a different sub-formula of the broader formula can have the same definition as any of those defined for the sub-formula, unless obviously contrary from context.
  • the symbol when displayed perpendicular to (or otherwise crossing) a bond, indicates the point at which the displayed moiety is attached to the remainder of the molecule.
  • the immediately connected group or groups or appropriate variable (s) shown in a formula maybe shown in the divalent structure (or multivalent structure) beyond the symbol, to indicate direction of attachment.
  • the immediately connected group (s) or variable is not shown for either of the two attaching points of a divalent structure, it should mean that either direction of attachment to the remainder of the molecule is allowed, unless otherwise specified or obviously contrary from context.
  • Compounds of the present disclosure can comprise one or more asymmetric centers and/or axial chirality, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer, atropisomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those having ordinary skill in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981) ; Wilen et al., Tetrahedron 33: 2725 (1977) ; Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962) ; and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ.
  • the disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers including racemic mixtures.
  • the compound can exist predominantly as the as-drawn stereoisomer, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount of the other stereoisomer (s) , for example, the compound can be characterized as having an enantiomeric excess ( "ee" ) of greater than 60%, such as greater than 80%ee, greater than 90%ee, greater than 95%ee, greater than 98%ee, or greater than 99%ee.
  • stereoisomers can be determined by those having ordinary skill in the art in view of the present disclosure, including through the use of chiral HPLC or SFC.
  • stereochemistry of a chiral center is not specifically drawn, it should be understood that the structure or a fragment thereof is intended to encompass all possible stereoisomers with respect to that particular chiral center.
  • C 1–6 is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1–6 , C 1–5 , C 1–4 , C 1–3 , C 1–2 , C 2–6 , C 2–5 , C 2–4 , C 2–3 , C 3–6 , C 3–5 , C 3–4 , C 4–6 , C 4–5 , and C 5–6 .
  • the term “compound (s) of the present disclosure” or “compound (s) of the present invention” refers to any of the compounds described herein according to III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b) , III-3 (e.g., III-3-A) , III-4 (e.g., III-4-A, III
  • any compound selected from the compounds shown in Table A herein isotopically labeled compound (s) thereof (such as a deuterated analog wherein one or more of the hydrogen atoms is substituted with a deuterium atom with an abundance above its natural abundance) , possible stereoisomers thereof (including diastereoisomers, enantiomers, and racemic mixtures) , geometric isomers thereof, atropisomers thereof, tautomers thereof, conformational isomers thereof, and/or pharmaceutically acceptable salts thereof (e.g., acid addition salt such as HCl salt or base addition salt such as Na salt) .
  • salts e.g., acid addition salt such as HCl salt or base addition salt such as Na salt
  • Compounds 1-347 refers to the compounds described herein labeled as integers 1, 2, 3, ..., 347, see for example the title compounds of Examples and Table 1.
  • synthetic starting materials or intermediates may be labeled with an integer (compound number) followed by a "-" and additional numeric values, such as 2-1, 2-2, etc., see examples for details.
  • the labeling of such synthetic starting materials or intermediates should not be confused with the compounds labeled with an integer only without the "-" and additional numeric value. Hydrates and solvates of the compounds of the present disclosure are considered compositions of the present disclosure, wherein the compound (s) is in association with water or solvent, respectively.
  • the compound of the present disclosure can be any of those defined in original claims 1-63 herein. In some embodiments, the compound of the present disclosure can be any of those defined in Embodiments 1-49 herein. In some embodiments, the compound of the present disclosure can be any of those defined in any of the enumerated embodiments A1-A38 and B1-B45.
  • Isotopes can be radioactive or non-radioactive isotopes.
  • Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl, and 125 I.
  • Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention.
  • administering means providing the compound or a prodrug of the compound to the individual in need of treatment.
  • alkyl refers to a straight-or branched-chain aliphatic saturated hydrocarbon.
  • the alkyl which can include one to twelve carbon atoms (i.e., C 1-12 alkyl) or the number of carbon atoms designated (i.e., a C 1 alkyl such as methyl, a C 2 alkyl such as ethyl, a C 3 alkyl such as propyl or isopropyl, etc. ) .
  • the alkyl group is a straight chain C 1-10 alkyl group.
  • the alkyl group is a branched chain C 3-10 alkyl group.
  • the alkyl group is a straight chain C 1-6 alkyl group. In another embodiment, the alkyl group is a branched chain C 3-6 alkyl group. In another embodiment, the alkyl group is a straight chain C 1-4 alkyl group. In one embodiment, the alkyl group is a C 1-4 alkyl group selected from methyl, ethyl, propyl (n-propyl) , isopropyl, butyl (n-butyl) , sec-butyl, tert-butyl, and iso-butyl.
  • the term "alkylene" as used by itself or as part of another group refers to a divalent radical derived from an alkyl group.
  • non-limiting straight chain alkylene groups include -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -, and the like.
  • alkenyl refers to a straight-or branched-chain aliphatic hydrocarbon containing one or more, such as one, two or three carbon-to-carbon double bonds.
  • the alkenyl group is a C 2-6 alkenyl group.
  • the alkenyl group is a C 2-4 alkenyl group.
  • Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.
  • alkynyl refers to a straight-or branched-chain aliphatic hydrocarbon containing one or more, such as one to three carbon-to-carbon triple bonds. In one embodiment, the alkynyl has one carbon-carbon triple bond. In one embodiment, the alkynyl group is a C 2-6 alkynyl group. In another embodiment, the alkynyl group is a C 2-4 alkynyl group.
  • Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.
  • alkoxy as used by itself or as part of another group refers to a radical of the formula OR a1 , wherein R a1 is an alkyl.
  • cycloalkoxy as used by itself or as part of another group refers to a radical of the formula OR a1 , wherein R a1 is a cycloalkyl.
  • haloalkyl refers to an alkyl substituted with one or more fluorine, chlorine, bromine and/or iodine atoms.
  • the haloalkyl is an alkyl group substituted with one or more fluorine atoms, alternatively referred to herein as fluorine-substituted alkyl, such as with one, two, or three fluorine atoms.
  • the haloalkyl group is a C 1-4 haloalkyl group.
  • the haloalkyl group is a fluorine-substituted C 1-4 alkyl group.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched-chain alkyl group, e.g., having from 2 to 14 carbons, such as 2 to 10 carbons in the chain, one or more of the carbons has been replaced by a heteroatom selected from S, O , P and N, and wherein the nitrogen, phosphine, and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized.
  • the heteroatom (s) S, O , P and N may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • the substituent (s) can replace one or more hydrogen atoms attached to the carbon atom (s) and/or the heteroatom (s) of the heteroalkyl.
  • the heteroalkyl is a C 1-4 heteroalkyl, which refers to the heteroalkyl defined herein having 1-4 carbon atoms.
  • C 1-4 heteroalkyl examples include, but are not limited to, C 4 heteroalkyl such as -CH 2 -CH 2 -N (CH 3 ) -CH 3 , C 3 heteroalkyl such as -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -S-CH 2 -CH 3 , -CH 2 -CH 2 -S (O) -CH 3 , -CH 2 -CH 2 -S (O) 2 -CH 3 , C 2 heteroalkyl such as -CH 2 -CH 2 -OH, -CH 2 -CH 2 -NH 2 , -CH 2 -NH (CH 3 ) , -O-CH 2 -CH 3 and C 1 heteroalkyl such as, -CH 2 -OH, -CH 2 -NH 2 , -O-CH 3 .
  • C 4 heteroalkyl such as -CH 2 -CH
  • the C 1-4 heteroalkyl (or C 1-4 heteroalkylene) herein contains 1 or 2 heteroatoms, such as one oxygen, one nitrogen, two oxygens, two nitrogens, or one oxygen and one nitrogen.
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -O-CH 2 -CH 2 -and –O-CH 2 -CH 2 -NH-CH 2 -.
  • heteroalkylene groups heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like) . Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R” or the like, it will be understood that the terms heteroalkyl and -NR'R” are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R” or the like.
  • Carbocyclyl or “carbocyclic” as used by itself or as part of another group refers to a radical of a non–aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ( “C 3– 10 carbocyclyl” ) and zero heteroatoms in the non–aromatic ring system.
  • the carbocyclyl group can be either monocyclic ( “monocyclic carbocyclyl” ) or contain a fused, bridged or spiro ring system such as a bicyclic system ( “bicyclic carbocyclyl” ) and can be saturated or can be partially unsaturated.
  • Carbocyclyl also includes ring systems wherein the carbocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclic ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • Non-limiting exemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl.
  • “carbocyclyl” is fully saturated, which is also referred to as cycloalkyl.
  • the cycloalkyl can have from 3 to 10 ring carbon atoms ( “C 3– 10 cycloalkyl” ) .
  • the cycloalkyl is a monocyclic ring.
  • Heterocyclyl or “heterocyclic” as used by itself or as part of another group refers to a radical of a 3–to 10–membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ( “3–10 membered heterocyclyl” ) .
  • Heterocyclyl or heterocyclic ring that has a ring size different from the 3-10 membered heterocyclyl is specified with a different ring size designation when applicable.
  • heterocyclyl is also a non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon.
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic ( “monocyclic heterocyclyl” ) or a fused, bridged, or spiro ring system, such as a bicyclic system ( “bicyclic heterocyclyl” ) , and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • “Heterocyclyl” also includes ring systems wherein the heterocyclic ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclic ring, or ring systems wherein the heterocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclic ring system.
  • Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiiranyl.
  • Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl–2, 5–dione.
  • Exemplary 5–membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C 6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • Aryl as used by itself or as part of another group refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ( “C 6–14 aryl” ) .
  • an aryl group has six ring carbon atoms ( “C 6 aryl” ; e.g., phenyl) .
  • an aryl group has ten ring carbon atoms ( “C 10 aryl” ; e.g., naphthyl such as 1–naphthyl and 2–naphthyl) . In some embodiments, an aryl group has fourteen ring carbon atoms ( “C 14 aryl” ; e.g., anthracyl) .
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • Alkyl as used by itself or as part of another group refers to an alkyl substituted with one or more aryl groups, preferably, substituted with one aryl group. Examples of aralkyl include benzyl, phenethyl, etc. When an aralkyl is said to be optionally substituted, either the alkyl portion or the aryl portion of the aralkyl can be optionally substituted.
  • Heteroaryl as used by itself or as part of another group refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ( “5–10 membered heteroaryl” ) .
  • Heteroaryl that has a ring size different from the 5-10 membered heteroaryl is specified with a different ring size designation when applicable.
  • heteroaryl is also a 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl) .
  • Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl.
  • Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5–membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5–membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6–membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6–membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7–membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5, 6–bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6, 6–bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Heteroaralkyl as used by itself or as part of another group refers to an alkyl substituted with one or more heteroaryl groups, preferably, substituted with one heteroaryl group. When a heteroaralkyl is said to be optionally substituted, either the alkyl portion or the heteroaryl portion of the heteroaralkyl can be optionally substituted.
  • alkylene, alkenylene, alkynylene, heteroalkylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene refer to the corresponding divalent radicals of alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, respectively.
  • an “optionally substituted” group such as an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl groups, refers to the respective group that is unsubstituted or substituted.
  • substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent can be the same or different at each position.
  • the optionally substituted groups herein can be substituted with 1-5 substituents.
  • Substituents can be a carbon atom substituent, a nitrogen atom substituent, an oxygen atom substituent or a sulfur atom substituent, as applicable.
  • a “stable” compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject) .
  • the “optionally substituted” alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclic, cycloalkyl, alkoxy, cycloalkoxy, or heterocyclic group herein can be unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, -OH, protected hydroxyl, oxo (as applicable) , NH 2 , protected amino, NH (C 1-4 alkyl) or a protected derivative thereof, N (C 1-4 alkyl ( (C 1-4 alkyl) , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, 3-7 membered heterocyclyl containing 1 or 2 ring
  • each instance of R aa is, independently, selected from C 1–10 alkyl, C 1–10 haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl, C 3–10 carbocyclyl, 3–14 membered heterocyclyl, C 6–14 aryl, and 5–14 membered heteroaryl, or two R aa groups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R ff is, independently, selected from hydrogen, C 1–6 alkyl, C 1–6 haloalkyl, C 2–6 alkenyl, C 2–6 alkynyl, C 3–10 carbocyclyl, 3–10 membered heterocyclyl, C 6–10 aryl and 5–10 membered heteroaryl, or two R ff groups are joined to form a 3–14 membered heterocyclyl or 5– 14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; and
  • a “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
  • An anionic counterion may be monovalent (i.e., including one formal negative charge) .
  • An anionic counterion may also be multivalent (i.e., including more than one formal negative charge) , such as divalent or trivalent.
  • Exemplary counterions include halide ions (e.g., F – , Cl – , Br – , I – ) , NO 3 – , ClO 4 – , OH – , H 2 PO 4 – , HSO 4 – , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like) , carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like)
  • Exemplary counterions which may be multivalent include CO 3 2- , HPO 4 2- , PO 4 3- , B 4 O 7 2- , SO 4 2- , S 2 O 3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, Sali cylate, phthalates, aspartate, glutamate, and the like) , and carboranes.
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, Sali cylate, phthalates, aspartate, glutamate, and the like
  • Halo or “halogen” refers to fluorine (fluoro, –F) , chlorine (chloro, –Cl) , bromine (bromo, –Br) , or iodine (iodo, –I) .
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group) .
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley &Sons, 1999, incorporated by reference herein.
  • Exemplary nitrogen protecting groups include, but not limited to, those forming carbamates, such as Carbobenzyloxy (Cbz) group, p-Methoxybenzyl carbonyl (Moz or MeOZ) group, tert-Butyloxycarbonyl (BOC) group, Troc, 9-Fluorenylmethyloxycarbonyl (Fmoc) group, etc., those forming an amide, such as acetyl, benzoyl, etc., those forming a benzylic amine, such as benzyl, p-methoxybenzyl, 3, 4-dimethoxybenzyl, etc., those forming a sulfonamide, such as tosyl, Nosyl, etc., and others such as p-methoxyphenyl.
  • carbamates such as Carbobenzyloxy (Cbz) group, p-Methoxybenzyl carbonyl (Moz or MeOZ) group, tert
  • the oxygen atom substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group) .
  • Oxygen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley &Sons, 1999, incorporated herein by reference.
  • oxygen protecting groups include, but are not limited to, alkyl ethers or substituted alkyl ethers such as methyl, allyl, benzyl, substituted benzyls such as 4-methoxybenzyl, methoxymethyl (MOM) , benzyloxymethyl (BOM) , 2–methoxyethoxymethyl (MEM) , etc., silyl ethers such as trymethylsilyl (TMS) , triethylsilyl (TES) , triisopropylsilyl (TIPS) , t-butyldimethylsilyl (TBDMS) , etc., acetals or ketals, such as tetrahydropyranyl (THP) , esters such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, etc., carbonates, sulfonates such as methanes,
  • leaving group is given its ordinary meaning in the art of synthetic organic chemistry, for example, it can refer to an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502) .
  • Suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine) ) , alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy) , arylcarbonyloxy, aryloxy, methoxy, N, O-dimethylhydroxylamino, pixyl, and haloformates.
  • halogen such as F, Cl, Br, or I (iodine)
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art.
  • tautomers or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa) .
  • the exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base.
  • Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to- (adifferent enamine) tautomerizations.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • the terms “treat, “ “treating, “ “treatment, “ and the like refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated.
  • the terms “treat, “ “treating, “ “treatment, “ and the like may include “prophylactic treatment, “ which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition.
  • the term “treat” and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.
  • Headings and subheadings are used for convenience and/or formal compliance only, do not limit the subject technology, and are not referred to in connection with the interpretation of the description of the subject technology.
  • Features described under one heading or one subheading of the subject disclosure may be combined, in various embodiments, with features described under other headings or subheadings. Further it is not necessarily the case that all features under a single heading or a single subheading are used together in embodiments.
  • the various starting materials, intermediates, and compounds of the preferred embodiments can be isolated and purified where appropriate using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds can be performed using conventional methods such as by melting point, mass spectrum, nuclear magnetic resonance, and various other spectroscopic analyses.
  • the examples are illustrative only and do not limit the claimed invention in any way.
  • Step 4 To a solution of 2-cyanoacetic acid (16.6 g, 195.2 mmol) in DMF (400 mL) were added HATU (1.39 g, 3.7 mmol) and triethylamine (45.2 mL, 325.4 mmol) at room temperature. The mixture was stirred at room temperature for 15 minutes. Then 1-5 (31.9 g, 130.2 mmol) was added. The mixture was stirred at room temperature for 12 h. Water was added to the reaction mixture. The solid was collected by filtration to afford 1-6.
  • Step 5 To a solution of 1-6 (21.5 g, 68.9 mmol) in THF (300 mL) was added KHMDS (1M in THF, 89.6 mL, 89.6 mmol) at room temperature. The mixture was stirred at room temperature for 12 h. HCl (1 N) was added until the pH was 4. The solid was collected by filtration to afford 1-7.
  • Step 6 To a solution of 1-7 (15.8 g, 59.4 mmol) in DMF (200 mL) was added NaH (9.5 g, 60%, 237.6 mmol) in portions at 0 °C. The mixture was stirred at 0 °C for 30 minutes. CH 3 I (14.8 mL, 237.6 mmol) was added. The reaction was stirred at room temperature for 12 h, then quenched with H 2 O. The pH of the reaction mixture was adjusted to 3 with HCl (1 N) . The solid was collected by filtration to afford 1-8.
  • Step 9 To a solution of 1-10 (210 mg, 0.37 mmol) in NMP (8 mL) were added Zn (CN) 2 (87.7 mg, 0.75 mmol) , Zn (4.9 mg, 0.075 mmol) , Pd 2 (dba) 3 (34.2 mg, 0.037 mmol) and dppf (12.6 mg, 0.022 mmol) under N 2 .
  • the reaction mixture was stirred at 80 °C for 1 h.
  • the reaction was quenched by H 2 O.
  • the aqueous layer was extracted with ethyl acetate.
  • the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated.
  • Step 2 To a solution of 2-2 (22.1 g, 61.2 mmol) in dichloromethane (20 mL) was added a solution of HCl in dioxane (4M, 61.2 mL, 244.8 mmol) at 20 °C. The mixture was stirred at 20 °C for 16 h. The mixture was concentrated under reduced pressure to afford 2-3.
  • Step 5 To a mixture of 2-5 (250 mg, 0.46 mmol) , Zn (6.0 mg, 0.09 mmol) and Zn (CN) 2 (108.5 mg, 0.92 mmol) in NMP (4 mL) were added Pd 2 (dba) 3 (42.3 mg, 0.046 mmol) and dppf (12.8 mg, 0.023 mmol) at room temperature. Then the mixture was stirred at 90 °C for 1 h. The reaction mixture was quenched with H 2 O and extracted with ethyl acetate. The combined organic layers were dried over Na 2 SO 4 , filtered and the filtrate was concentrated.
  • Step 1 3-1 (10 g, 81.2 mmol) and piperidine-4-carboxylic acid (10.5 g, 81.2 mmol) were added to PPA (53.4 g, 81.2 mmol) and the mixture was stirred at 180 °C for 2 h. The reaction mixture was cooled to 90 °C, then H 2 O was added to quench the reaction. The pH of the mixture was adjusted to 12 with 50%KOH. The mixture was extracted with CH 2 Cl 2 . The organic layer was dried over Na 2 SO 4 , filtered and concentrated to afford 3-2.
  • Step 2 Compound 3-3 was prepared from compound 3-2 following the procedure for the synthesis of compound 1-10 in example 1.
  • Step 3 Compound 3 was prepared from compound 3-3 following the procedure for the synthesis of compound 1 in example 1.
  • Step 2 To a solution of 4-2 (2.9 g, 7.8 mmol) in dichloromethane (20 mL) was added TFA (5 mL, 805.6 mmol) . Then the reaction mixture was stirred at 25 °C for 3 h. The pH was adjusted to 6 by aqueous solution of NaHCO 3 and the mixture was extracted with ethyl acetate. The organic layer was dried over Na 2 SO 4 , filtered and concentrated to afford 4-3.
  • Step 3 Compound 4-4 was prepared from compound 4-3 following the procedure for the synthesis of compound 1-10 in example 1.
  • Step 4 Compound 4 was prepared as a 0.33 eq of TFA salt from compound 4-4 following the procedure for the synthesis of compound 1 in example 1.
  • Step 1 To a solution of 5-1 (46 g, 250.6 mmol) in con. HCl (170 mL) and EtOH (510 mL) was added Fe powder (42.0 g, 751.8 mmol) at 40 °C in portions. Then the mixture was stirred at 80 °C for 1 h. The mixture was filtered and the filtrate was concentrated. The pH of the mixture was adjusted to 8 with ammonia. Then the mixture was filtered and the filtrate was extracted with ethyl acetate. The combined organic layers were dried over Na 2 SO 4 , filtered and the filtrate was concentrated to afford 5-2.
  • Step 5 To a solution of 5-5 (27 g, 87.3 mmol) in DMF (300 mL) was added NaH (60%, 7.0 g, 174.6 mmol) at 0 °C in portions. After the mixture was stirred at 0 °C for 1 h, CDI (21.2 g, 130.9 mmol) was added to the reaction mixture. Then the mixture was stirred at 70 °C for 2 h. The solid was collected by filtration and washed with ethyl acetate and methanol to afford 5-6.
  • Step 6 To a solution of 5-6 (1.5 g, 7.09 mmol) in toluene (15 mL) were added POCl 3 (5.27 mL, 56.71 mmol) and DIPEA (2.93 mL, 17.72 mmol) at room temperature. Then the mixture was stirred at 110 °C for 12 h. The mixture was concentrated to afford 5-7 which was used for the next step directly without further purification.
  • Step 8 To a solution of 5-8 (98 mg, 0.22 mmol) in NMP (6 mL) were added dppf (11.9 mg, 0.022 mmol) , Zn (5.6 mg, 0.088 mmol) , Zn (CN) 2 (50.6 mg, 0.43 mmol) and Pd 2 (dba) 3 (19.7 mg, 0.022 mmol) at room temperature. Then the mixture was stirred at 90 °C for 3 h. The mixture was quenched with H 2 O and extracted with ethyl acetate. The combined organic layers were dried over Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum.
  • Step 2 To a solution of tert-butyl 4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2, 3, 6-tetrahydropyridine-1-carboxylate (4.7 g, 15.2 mmol) in dioxane (60 mL) was added 12-2 (3 g, 12.7 mmol) and K 2 CO 3 (5.2 g, 38 mmol) . The reaction mixture was degassed with nitrogen 3 times, then Pd (dppf) Cl 2 (0.9 g, 1.27 mmol) and H 2 O (20 mL) were added to the reaction mixture. The reaction mixture was stirred for 14 h at 80 °C.
  • Step 4 To a solution of 12-4 (826 mg, 2.4 mmol) in dichloromethane (5 mL) was added HCl in ethyl acetate (4M, 5 mL, 20 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to afford 12-5 which was used for the next step directly without further purification.
  • Step 3 To a solution of 16-5 (923 mg, 2.37 mmol) in dichloromethane (5 mL) was added HCl in ethyl acetate (4M, 2.37 mL, 9.5 mmol) at 25 °C. The mixture was stirred at 25 °Cfor 3 h. The mixture was concentrated to afford 16-6 which was used for the next step directly without further purification.
  • Step 4 Compound 16-7 was prepared from compound 16-6 following the procedure for the synthesis of compound 5 in example 5.
  • Step 1 Compound 21-1 was prepared from compound 2-3 following the procedure for the synthesis of compound 5-8 in example 5.
  • Step 3 To a solution of 21-2 (310 mg, 0.56 mmol) in methanol (5 mL) was added HCl in ethyl acetate (4M, 3 mL) at room temperature. Then the mixture was stirred at room temperature for 0.5 h. The mixture was concentrated to afford 21-3.
  • Step 2 To a solution of 12-2 (1.0 g, 4.22 mmol) , 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (1.39 g, 5.48 mmol) in dioxane (20 mL) was added KOAc (0.8 g, 8.44 mmol) and Pd (dppf) Cl 2 (0.3 g, 0.42 mmol) . The mixture was stirred at 100 °C for 16 h under N 2 atmosphere. The mixture was quenched with H 2 O and extracted with ethyl acetate.
  • Step 4 To a solution of 23-4 (310 mg, 0.84 mmol) in methanol (10 mL) was added 10%Pd/C (179.5 mg) . The mixture was degassed with H 2 several times. Then the mixture was stirred at 25 °C under H 2 atmosphere (1 atm) for 16 h. The mixture was filtered and the filtrate was concentrated to afford 23-5 which was used for the next step directly without further purification.
  • Step 5 To a solution of 23-5 (240 mg, crude) in dichloromethane (4 mL) was added TFA (1 mL) . The mixture was stirred at 25 °C for 1 h. The mixture was concentrated to afford 23-6 which was used for the next step directly without further purification.
  • Step 6 Compound 23-7 was prepared from compound 23-6 following the procedure for the synthesis of compound 5 in example 5.
  • Step 1 To a mixture of 26-1 (10 g, 46.29 mmol) and potassium trifluoro (vinyl) borate (7.44 g, 55.55 mmol) in THF (160 mL) and H 2 O (40 mL) was added 1, 1'-bis (di-t-butylphosphino) ferrocene palladium dichloride (3.0 g, 4.63 mmol) and K 3 PO 4 (24.6 g, 115.73 mmol) under N 2 . Then the mixture was stirred at room temperature for 16 h. The mixture quenched by addition of water. The aqueous layer was extracted with ethyl acetate.
  • Step 2 To a mixture of methyl 26-2 (7.8 g, 47.8 mmol) in AcOH (100 mL) was added PtO 2 (2.2 g, 9.56 mmol) . The mixture was degassed with H 2 several times, then the mixture was stirred at 80 °C for 16 h under H 2 (1 atm) atmosphere. The mixture was filtered and the filtrate was concentrated to afford 26-3 which was used for the next step directly without further purification.
  • Step 4 To a mixture of 26-4 (9.6 g, 35.38 mmol) in THF (60 mL) and H 2 O (60 mL) was added LiOH (7.4 g, 176.89 mmol) . Then the mixture was stirred at room temperature for 16 h. The pH of mixture was adjusted to 4 with 1N HCl and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to afford 26-5 which was used for the next step directly without further purification.
  • Step 5 A mixture of 26-5 (4.55 g, crude) and PPA (100 mL) was stirred at 180 °C for 2 h. After being cooled to 90 °C, the reaction was quenched by water. The filtrate was adjusted pH to about 12 with 50%potassium hydroxide aqueous solution and then extracted with methylene chloride. The organic layer was dried by Na 2 SO 4 , filtered and concentrated to afford 26-6 which was used for the next step directly without further purification.
  • Step 6 Compound 26-7 was prepared from compound 26-6 following the procedure for the synthesis of compound 5 in example 5.
  • Step 7 26-7 (150 mg, 0.35 mmol) was separated by reverse phase HPLC (acetonitrile/H 2 O, 5-95%) to afford 26 (24.47 mg) and 27 (54.71 mg) .
  • 26 Analytical HPLC: retention time: 1.85 min; column: Waters ACQUITY BEH C18 2.1*50mm, 1.7um; Mobile phase A: H 2 O (0.05%TFA) ; Mobile phase B: Acetonitrile (0.05%TFA) ; flow rate: 1.0 mL/min; Run time: 5 min; 95 to 5%Ain 3min, 5%Afor 2 min.
  • Step 2 To a solution of 28-2 (1 g, 3.81 mmol) in dichloromethane (10 mL) at 0°C was added DMF (0.029 mL, 0.38 mmol) and SOCl 2 (0.42 mL, 5.72 mmol) . The reaction was stirred at room temperature for 18 h. The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel (petroleum ether) to afford 28-3.
  • Step 3 To a stirred solution of 28-4 (100 g, 651 mmol) in dry CH 2 Cl 2 (1.5 L) were added benzaldehyde (67.5 mL, 664 mmol) , K 2 CO 3 (90.0 g, 651 mmol) and Na 2 SO 4 (92.5 g, 651 mmol) . The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled with an ice water bath and NaBH (OAc) 3 (207.0 g, 976 mmol) was added in portions over 30 minutes. Then the mixture was stirred at room temperature for 16 h. The solid was filtered and the filtration was concentrated.
  • benzaldehyde 67.5 mL, 664 mmol
  • K 2 CO 3 90.0 g, 651 mmol
  • Na 2 SO 4 92.5 g, 651 mmol
  • Step 4 To a solution of (2R) -2- ⁇ [ (tert-butoxy) carbonyl] amino ⁇ butanoic acid (124 g, crude) in DMF (1 L) were added DIPEA (137 mL, 832 mmol) and HATU (253 g, 666 mmol) . The reaction was stirred at 0 °C for 10 minutes, then 28-5 (115 g, 555 mmol) was added to the mixture. The resulting mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous Na 2 SO 4 , filtered and evaporated to afford 28-6 which was used for next step directly without further purification.
  • Step 5 To a solution of 28-6 (300 g, crude) in dichloromethane (1 L) was added TFA (500 mL, 764 mmol) , the reaction was stirred at room temperature for 16 h. The solvent was removed to afford 28-7 which was used for next step directly without further purification.
  • Step 6 28-7 (500 g, crude) was dissolved in methanol (1.5 L) and the reaction mixture was heated at 70 °C for 16 h. The solvent was removed, the residue was dissolved in dichloromethane and washed with saturated aqueous NaHCO 3 solution. The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was dissolved in propan-2-ol (500 mL) and heated at 70 °C for 1 h. The mixture was filtered, the solution was cooled to -10 °C, the solid was filtered and dried to afford 28-8.
  • Step 7 To a stirred solution of 28-8 (20 g, 76.82 mmol) in dry THF (500 mL) was slowly added BH 3 . THF (1M, 768 mL, 768 mmol) at 0 °C. The reaction mixture heated at 70 °C for 16 h. The reaction was quenched with methanol and 1.5 N HCl. The solvent was removed, the residue was dissolved in dichloromethane and washed with saturated aqueous NaHCO 3 solution. The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated to afford 28-9 which was used in the next step directly.
  • Step 12 To a solution of 28-13 (570 mg, 1.34 mmol) in dichloromethane (5 mL) was added TFA (2 mL, 1.34 mmol) at room temperature. Then the mixture was stirred at room temperature for 1 h. The mixture was concentrated to 28-14 which was used in the next step directly without further purification.
  • Step 13 The mixture of 28-14 (220 mg, 0.67 mmol) , 28-3 (283.8 mg, 1.01 mmol) , DIPEA (1.11 mL, 6.74 mmol) and NaI (151.5 mg, 1.01 mmol) in acetonitrile (10 mL) was stirred at 90 °C for 24 h. The solvent was removed, and the residue was purified by Reverse phase HPLC (acetonitrile with 0.05%of TFA in water: 10%to 70%) to afford 28-15.
  • Step 1 To a solution of 30-1 (5 g, 26.3 mmol) and NaOH (1.6 g, 39.5 mmol) in EtOH (30 mL) and H 2 O (15 mL) was added hydroxylamine hydrochloride (2.2 g, 31.6 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h. Ice was added to the reaction mixture, the solid was filtered, the filter cake was washed with H 2 O and dried to afford 30-2.
  • Step 2 A solution of 30-2 (1.6 g, 7.8 mmol) and NCS (1.1 g, 8.6 mmol) in DMF (15 mL) was stirred at 25 °C for 16 h. The mixture was concentrated, the residue was diluted with ethyl acetate, washed with H 2 O. The organic layer was dried over Na 2 SO 4 , filtered and concentrated to afford 30-3.
  • Step 4 To a solution of 30-4 (300 mg, 0.78 mmol) in dichloromethane (5 mL) was added HCl (4 M in ethyl acetate, 2.0 mL) at 25°C. The mixture was stirred at 25°C for 2 h. The mixture was concentrated to afford 30-5.
  • Step 5 Compound 30 was prepared from compound 30-5 following the procedure for the synthesis of compound 5 in example 5.
  • 1 H NMR (400 MHz, DMSO-d 6 , ppm) ⁇ 8.33 -8.20 (m, 1H) , 8.06 -7.94 (m, 1H) , 7.88 -7.76 (m, 2H) , 7.55 -7.43 (m, 2H) , 4.69 –4.49 (m, 1H) , 4.44 –4.19 (m, 1H) , 4.12 –3.93 (m, 1H) , 3.90 –3.68 (m, 2H) , 3.64 –3.52 (m, 1H) , 3.46 (s, 3H) , 2.45 -2.15 (m, 2H) .
  • 19 F NMR (376 MHz, DMSO-d 6 , ppm) ⁇ -56.74 (3
  • Step 1 To a solution of 32-1 (15 g, 99.25 mmol) in acetonitrile (100 mL) was added CH 3 NH 2 (200 mL, 3.56 mmol, 40%in H 2 O) . Then the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with H 2 O. The mixture was extracted with ethyl acetate. The combined organic layers were washed with H 2 O. The organic layer was dried over Na 2 SO 4 , filtered and concentrated to afford 32-2.
  • Step 3 To a solution of 32-3 (5.0 g, 25.43 mmol) in DMSO (60 mL) were added K 2 CO 3 (5.3 g, 38.14 mmol) and H 2 O 2 (17.3 g, 30%, 152.6 mmol) . Then the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with H 2 O. The mixture was extracted with ethyl acetate. The combined organic layers were washed with H 2 O. The organic layer was dried over Na 2 SO 4 , filtered and the filtrate was concentrated to afford 32-4.
  • Step 4 To a stirred 0 °C solution of 32-4 (5 g, 23.29 mmol) in DMF (70 mL) was in portions added NaH (1.9 g, 46.59 mmol) . After stirred at 0 °C for 0.5 h, CDI (5.7 g, 34.94 mmol) was added to the mixture, then the mixture was stirred at 60 °C for 16 h. The reaction mixture was quenched with H 2 O. The mixture was extracted with ethyl acetate. The combined organic layer was washed with H 2 O. The organic layer was dried by Na 2 SO 4 , filtered and the filtrate was concentrated to afford 32-5.
  • Step 5 To a solution of 32-5 (1 g, 4.16 mmol) in toluene (10 mL) was added DIPEA (1.2 g, 9.14 mmol) and POCl 3 (3.2 g, 20.78 mmol) . The mixture was stirred at 90 °C for 3h. The reaction mixture was concentrated to afford 32-6.
  • Step 6 A mixture of 32-6 (1.0 g, 3.86 mmol) , 3-2 (1.00 g, 4.63 mmol) and DIPEA (7.5 g, 57.9 mmol) in propan-2-ol (15 mL) was stirred at 90 °C for 5 h. The mixture was cooled to room temperature. The precipitate was collected by filtration to afford 32-7.
  • Step 7 To a solution of 32-7 (1.0 g, 2.28 mmol) in dichloromethane (10 mL) under N 2 at -78 °C was added dropwise BBr 3 (5.7 g, 22.8 mmol) . After the addition was completed, the mixture was stirred at room temperature for 16 h. Ice water was added to the reaction mixture and the precipitate was collected by filtration, washed with H 2 O and dried to afford 32-8.
  • Step 8 To a mixture of 32-8 (300 mg, 0.71 mmol) in DMF (10 mL) were added Cs 2 CO 3 (690 mg, 2.12 mmol) and 3-bromooxolane (213.2 mg, 1.41 mmol) . Then the mixture was stirred at 85 °C for 1 h. The solvent was removed under vacuum. The residue was purified by reverse phase HPLC (acetonitrile/H 2 O: 5% ⁇ 42%) to afford 32-9.
  • Step 9 32-9 (100 mg) was purified by SFC (column: ETOH (+0.1%7.0mol/l Ammonia in methanol) to afford 32 (14.80 mg) and 33 (15.23 mg) respectively.
  • Step 1 Compound 34-2 was prepared from compound 34-1 following the procedure for the synthesis of compound 28-3 in example 11.
  • Step 3 To a stirred solution of 34-3 (450 mg, 1.1 mmol) in isopropanol (10 mL) was added Pd/C (10%, 45 mg) at 25 °C. The mixture was degassed several times with H 2 , then the mixture was stirred at 25 °C under H 2 for 21 h. The reaction mixture was filtered and the filtrate was concentrated to afford 34-4.
  • Step 5 To a solution of 34-5 (5.0 g, 29.2 mmol) in NMP (100 mL) were added Zn (0.4 g, 5.84 mmol) , Zn (CN) 2 (6.9 g, 58.4 mmol) , dppf (1.0 g, 1.75 mmol) and Pd 2 (dba) 3 (2.7 g, 2.92 mmol) under N 2 .
  • the reaction mixture was stirred at 120 °C for 2 h.
  • the reaction mixture was diluted with water and extracted with ethyl acetate.
  • the combined organic layers were washed with water and brine, dried and concentrated under reduced pressure.
  • Step 6 To a solution of 34-6 (0.5 g, 3.08 mmol) in dioxane (20 mL) was added triphosgene (457.5 mg, 1.54 mmol) under N 2 . The reaction mixture was stirred at 100 °Cfor 3 h. The resulting mixture was cooled to room temperature, filtered and dried to afford 34-7.
  • Step 7 To a solution of 34-7 (255 mg, 1.36 mmol) in toluene (10 mL) were added POCl 3 (1.26 mL, 13.6 mmol) and DIPEA (0.67 mL, 4.06 mmol) . The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated to afford 34-8 which was used for the next step directly without further purification.
  • Step 10 To a solution of 34-10 (240 mg, 0.39 mmol) in dichloromethane (6 mL) was added TFA (3 mL) . The reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated to afford 34-11 which was used in the next step directly without further purification.
  • LCMS (ESI, m/z) : [M+H] + 523.5.
  • Step 1 A mixture of LiAlH 4 (0.30 g, 8.2 mmol) in THF (20 mL) was stirred at 0°C under N 2 for 0.5 h. Then 36-1 (1 g, 4.1 mmol) was added and the mixture was stirred at 25°C for 16 h. The mixture was diluted with THF, quenched with saturated Na 2 SO 4 (1.5 mL) and filtered. The filtrate was concentrated to afford 36-2 which was used for the next step directly without further purification.
  • Step 4 To a solution of 36-4 (588 mg, 1.47 mmol) in dichloromethane (6 mL) was added HCl in ethyl acetate (4M, 2.5 mL) at 20 °C. The mixture was stirred at 20 °C for 1.5 h. The mixture was concentrated under reduced pressure to afford 36-5.
  • Step 6 A solution of 37 (100 mg, 0.20 mmol) , dppf (22.5 mg, 0.040 mmol) , Zn (13.2 mg, 0.20 mmol) , Zn (CN) 2 (47.6 mg, 0.41 mmol) and Pd 2 (dba) 3 (18.5 mg, 0.02 mmol) in NMP (8 mL) was stirred at 90°C for 16 h under N 2 . The mixture was diluted with H 2 O and extracted with ethyl acetate. The organic phase was washed with H 2 O and concentrated. The residue was purified by reverse phase HPLC (acetonitrile/H 2 O: 5%-80%) to afford 36.
  • NMP 8 mL
  • Step 2 To a solution of 5-7 (583 mg, 2.53 mmol) in acetonitrile (5 mL) were added 39-2 (500 mg, 2.53 mmol) and DIPEA (983 mg, 7.6 mmol) . The reaction was stirred at room temperature for 3 h under N 2 . The reaction mixture was concentrated, the residue was purified by reverse phase HPLC (acetonitrile/H 2 O, 5% ⁇ 50%) to afford 39.
  • Step 3 To a solution of 39 (140 mg, 0.36 mmol) in DMF (1.5 mL) were added Zn (CN) 2 (420 mg, 3.58 mmol) and Pd (PPh 3 ) 4 (206.8 mg, 0.18 mmol) . Then the reaction mixture was stirred at 110 °C for 1 h under N 2 . The reaction mixture was concentrated, the residue was purified by reverse phase HPLC (acetonitrile/H 2 O: 5% ⁇ 50%) to afford 42.
  • Zn (CN) 2 420 mg, 3.58 mmol
  • Pd (PPh 3 ) 4 206.8 mg, 0.18 mmol
  • Step 1 To a solution of N1, N1, N2, N2-tetramethylethane-1, 2-diamine (5.8 g, 56.28 mmol) in THF (80 mL) was added n-BuLi (40 mL, 64 mmol, 1.6 mol/L in THF) dropwise at -40 °C under N 2 . The reaction was stirred at -40 °C for 40 minutes. Then 44-1 (7 g, 40.2 mmol) was added to the mixture over 5 minutes. The mixture was stirred at -40 °C for 30 minutes.
  • the pH of the mixture was adjusted to 6 with HCl (6M) .
  • the reaction mixture was filtered and the filter cake was washed with ethyl acetate.
  • the mixture was extracted with ethyl acetate.
  • the combined organic layer was washed with brine.
  • the combine organic layer was concentrated.
  • Step 4 To a solution of 44-4 (1.36 g, 5.96 mmol) in EtOH (25 mL) was added 10%Pd/C (0.1 g) . The suspension was degassed under vacuum and purged with H 2 3 times, then the mixture was stirred at 25 °C for 1 h under H 2 . The suspension was filtered, and the filter cake was washed with EtOH (20 mL) . The combined filtrates were concentrated to afford 44-5.
  • Step 7 44-7 (150 mg, 0.28 mmol) was purified by reverse phase HPLC (acetonitrile/0.1%TFA in water: 75%) to afford 44 (10.43 mg) and 45 (4.01mg) .
  • Step 2 Compound 50 was prepared from 50-2 following the procedure for the synthesis of compound 30 in example 12.
  • Step 1 To a stirred solution of 57-1 (45 g, 276 mmol) in EtOH (450 mL) was added thiourea (22.06 g, 290 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 15 h under N 2 . The solvent was removed under reduced pressure. The residue was diluted with H 2 O and neutralized with NaHCO 3 until the pH is 8-9, then dichloromethane was added to the mixture. The mixture was extracted with dichloromethane. The combined organic layers were washed with saturated NaHCO 3 and brine, dried over anhydrous Na 2 SO 4 and concentrated to afford 57-2.
  • Step 3 To a stirred solution of 57-3 (1.0 g, 4.9 mmol) in THF (20 mL) was added n-BuLi (2.55 mL, 6.37 mmol) below -60 °C under N 2 . The resulting mixture was stirred at this temperature for 1 h. A solution of 4- ( (trifluoromethyl) thio) benzaldehyde (1313.4 mg, 6.37 mmol) in THF (20 mL) was added into the above reaction mixture below -60 °C. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with saturated NH 4 Cl and diluted with H 2 O. The mixture was extracted with ethyl acetate.
  • Step 4 To a stirred solution of 57-4 (450 mg, 1.36 mmol) in dichloromethane (6 mL) was added SOCl 2 (0.15 mL, 2.04 mmol) at 25 °C. The resulting mixture was stirred at 25 °C for 15 h. The reaction mixture was concentrated to afford 57-5 which was used for the next step directly without further purification.
  • Step 5 To a stirred solution of 57-5 (1.15 g, 2.63 mmol) and 28-14 (0.86 g, 2.63 mmol) in acetonitrile (10 mL) was added DIPEA (1.83 mL, 10.52 mmol) at 25 °C. The resulting mixture was stirred at 90 °C for 15 h. The reaction mixture was concentrated. The residue was purified by reverse phase HPLC (acetonitrile/0.05%TFA in H 2 O, 0-60%) to afford 57 (11.65 mg) and 58 (6.24 mg) .
  • Step 1 Compound 59-2 was prepared from 59-1 following the procedure for the synthesis of compound 30-5 in example 12.
  • Step 4 To a solution of 59-5 (2.6 g, 14.09 mmol) in THF (20 mL) was added BH 3 ⁇ THF (1M, 65 mL, 65 mmol) at room temperature. Then the mixture was stirred at 80 °C for 2 h. The mixture was quenched with methanol and stirred at 80°C for 30 minutes. Then the mixture was concentrated to afford 59-6 which was used for the next step directly without further purification.
  • Step 8 To a solution of 59-9 (620 mg, 2.1 mmol) and K 2 CO 3 (870 mg, 6.29 mmol) in DMSO (10 mL) was added H 2 O 2 (30%, 713.0 mg, 6.29 mmol) at 0 °C. Then the mixture was stirred at room temperature for 1 h. The solid was collected by filtration and washed with dichloromethane. The solid was suspended in H 2 O, then conc. HCl was added until the pH was 4-5. The solid was collected by filtration to afford 59-10.
  • Step 9 Compound 59 was prepared from 59-10 following the procedure for the synthesis of compound 5 in example 5.
  • 1 H NMR (400 MHz, DMSO-d 6 , ppm) ⁇ 7.89 (s, 1H) , 7.84 –7.76 (m, 2H) , 7.53 –7.44 (m, 2H) , 5.06 -4.58 (m, 1H) , 4.55 –4.46 (m, 2H) , 4.48 –4.06 (m, 2H) , 4.05 -3.68 (m, 3H) , 3.35 (s, 2H) , 2.06 -1.82 (m, 4H) .
  • 19 F NMR (376 MHz, DMSO-d 6 , ppm) ⁇ -56.75 (3F) .
  • Step 2 To a mixture of 64-2 (500 mg, 1.17 mmol) and 28-14 (421.05 mg, 1.29 mmol) in acetonitrile (15 mL) was added DIPEA (0.97 mL, 5.86 mmol) and NaI (351.6 mg, 2.35 mmol) . Then the mixture was stirred at 85 °C for 3 h. The mixture was extracted with ethyl acetate. The organic layer was washed with H 2 O and brine (20 mL) , dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by reverse phase HPLC (acetonitrile/0.05%TFA in water: 0-60%) to afford 64-3 and 64-4.
  • DIPEA 0.97 mL, 5.86 mmol
  • NaI 351.6 mg, 2.35 mmol
  • Step 3 To a mixture of 64-3 (75 mg, 0.13 mmol) and N- [azanylidene (cyclopropyl) methyl] hydroxylamine (14.08 mg, 0.14 mmol) in DMSO (2 mL) was added DIPEA (58.3 mg, 0.15 mmol) and HATU (58.3 mg, 0.15 mmol) . The mixture was stirred at room temperature for 30 minutes, then the mixture was heated to 90 °C and stirred for 30 minutes. The mixture was cooled and extracted with ethyl acetate. The organic layer was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 and concentrated.
  • DIPEA 58.3 mg, 0.15 mmol
  • HATU 58.3 mg, 0.15 mmol
  • Step 1 To a stirred solution of 67-1 (25 g, 150.4 mmol) in acetonitrile (250 mL) was added NBS (28.1 g, 158 mmol) in portions at 25-40 °C. The reaction mixture was stirred at 25-40 °C for 2 h. The precipitate was filtered and the cake was washed with acetonitrile. The cake was collected and dried to afford 67-2.
  • Step 2 To a stirred solution of 67-2 (20 g, 81.6 mmol) in THF (100 mL) was added dropwise acetyl acetate (24.14 mL, 257.06 mmol) at 25 °C. The reaction mixture was stirred at 75 °C for 19 h. The reaction mixture was concentrated. The residue was diluted with H 2 O and extracted with ethyl acetate. The organic layer was combined, dried over anhydrous Na 2 SO 4 and concentrated to afford 67-3.
  • Step 4 KHMDS in THF (1M, 54.6 mL, 54.6 mmol) was added to THF (200 mL) at -10 °C under N 2 , then 67-4 (13.7 g, 45.5 mmol) in THF (400 mL) was added to the solution at -60 °C to -50 °C under N 2 . Then the reaction mixture was stirred at 20 °C for 1.5 h. The reaction was quenched with H 2 O, and the mixture was extracted with ethyl acetate. The aqueous layer was acidified with HCl (2 N) to change the pH to 3-4. The precipitate was filtered, washed with H 2 O and dried to afford 67-5.
  • Step 5 To a stirred solution of 67-5 (2 g, 7.84 mmol) in AcOH (20 mL) was added HNO 3 (1.3 mL, 31.74 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 15 h. The reaction mixture was cooled to 25 °C and diluted with H 2 O. The mixture was stirred for 10 minutes and the precipitation was filtered and dried to afford 67-6.
  • Step 6 To a stirred solution of 67-6 (1.4 g, 4.67 mmol) in toluene (28 mL) was added DIPEA (4.06 mL, 23.33 mmol) and POCl 3 (2.17 mL, 23.33 mmol) at 25 °C. The reaction mixture was stirred at 110 °C for 3 h under N 2 . The reaction mixture was concentrated to afford 67-7 which was used for the next step directly without further purification.
  • Step 7 To a stirred solution of 67-8 (34.9 g, 292.99 mmol) in methanol (250 mL) was added triethylamine (42.76 mL, 307.63 mmol) and benzaldehyde (31.27 mL, 307.63 mmol) at 5-10 °C. The reaction mixture was stirred at this temperature for 3 h. Then the reaction mixture was cooled to 0 °C and NaBH 4 (22.2 g, 585.964 mmol) was added into the reaction mixture in portions. The reaction mixture was stirred at 0-20 °C for 2.5 h. The reaction mixture was quenched with HCl (3 N) and extracted with ethyl acetate.
  • Step 8 To a solution of 67-9 (32.86 g, 157.04 mmol) and (2R) -2- ⁇ [ (tert-butoxy) carbonyl] amino ⁇ butanoic acid (31.92 g, 157.04 mmol) in DMF (350 mL) was added dropwise DIPEA (82.06 mL, 471.11 mmol) at 25 °C, then HATU (89.6 g, 235.56 mmol) was added to the solution at 5-15 °C. The reaction mixture was stirred at 25 °C for 48 h. The reaction mixture was diluted with H 2 O and extracted with ethyl acetate.
  • Step 9 To a stirred solution of 67-10 (28.9 g, 73.26 mmol) in methanol (280 mL) was added HCl in ethyl acetate (4M, 50 mL) at 25-35 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to afford 67-11.
  • BH 3 ⁇ THF 1M in THF, 22.9 mL, 22.9 mmol
  • Step 13 To a stirred solution of 67-14 (5 g, 14.95 mmol) in methanol (30 mL) was added HCl in ethyl acetate (4M, 30 mL) at 25 °C, the reaction mixture was stirred at 25 °C for 15 h. The reaction mixture was concentrated to afford 67-15 which was used for the next step directly without further purification.
  • Step 15 To a stirred solution of 67-16 (1.93 g, 4.59 mmol) in isopropanol (60 mL) was added Pd/C (5%, 450 mg) at 25 °C. The reaction mixture was degassed with H 2 several times, then the mixture was stirred at 60 °C for 15 h under H 2 . The reaction mixture was filtered and the filtrate was concentrated to afford 67-18.
  • Analytical HPLC retention time: 1.69 min; column: Waters ACQUITY BEH C18 2.1*50mm, 1.7um; Mobile phase A: H 2 O (0.05%TFA) ; Mobile phase B: Acetonitrile (0.05%TFA) ; flow rate: 1.0 mL/min; Run time: 5 min; 95 to 5%Ain 3min, 5%Afor 2 min.
  • Step 1 To a mixture of methyl 72-1 (500 mg, 2.31 mmol) in 2-methoxyethyl ether (10 mL) was added 2, 2'-bipyridine (542 mg, 3.47 mmol) , AgSCF 3 (725.4 mg, 3.47 mmol) and CuI (661 mg, 3.47 mmol) . Then the mixture was stirred at 130°C for 24 h under N 2 . The mixture was quenched by addition of water, the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na 2 SO 4 , the mixture was concentrated. The residue was purified by reverse phase HPLC (MeCN/H 2 O (0.05%TFA) , 5-95%) to afford 72-2.
  • 2, 2'-bipyridine 542 mg, 3.47 mmol
  • AgSCF 3 725.4 mg, 3.47 mmol
  • CuI 661 mg, 3.47 mmol
  • Step 5 To a solution of 72-5 (580 mg, 1.91 mmol) in DCM (12 mL) were added DMF (0.01 mL, 0.13 mmol) and SOCl 2 (378 mg, 3.82 mmol) at 0°C, then the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo to afford 72-6 which was used for the next step directly without further purification.
  • Step 2 To a mixture of 77 (50 mg, 0.087 mmol) in THF (2 mL) was added NaH (7.0 mg, 0.17 mmol) and iodomethane (37.0 mg, 0.26 mmol) . Then the mixture was stirred at 0°C for 3 h. The reaction mixture was quenched by water, the aqueous layer was extracted with ethyl acetate. The organic layer was combined and washed with brine, dried over anhydrous Na 2 SO 4 . The solvent was concentrated. The residue was purified by reverse phase HPLC (MeCN /water from 1/0 to 2/3) to afford 78.
  • Step 3 84-2 (3.6 g, 8.44 mmol) was dissolved in trimethoxymethane (30 mL) , the mixture was stirred at 100°C under N 2 for 16 h. The mixture concentrated under reduced pressure to afford product 84-3.
  • Step 4 To a solution of 84-3 (3.65 g, 8.36 mmol) in DCM (30 mL) was added TFA (10 mL) at room temperature and stirred for 5 h. The mixture was concentrated under reduced pressure, the residue was dissolved in DCM and washed with saturated NaHCO 3 . The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated to afford 84-4.
  • Step 1 To a solution of 91-1 (15 g, 99.25 mmol) in MeCN (100 mL) was added CH 3 NH 2 (200 mL, 3.56 mmol, 40%in H 2 O) . Then the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with H 2 O. The mixture was extracted with ethyl acetate. The combined organic layers were washed with H 2 O. The organic layer was dried over Na 2 SO 4 , filtered and concentrated to afford 91-2.
  • Step 3 Compound 91-4 and 91-5 was prepared from compound 91-3 following the procedure for the synthesis of compound 5-8 in example 5, the product was obtained by reverse phase HPLC (MeCN/water, 55%-65%) .
  • Step 4 91-4 (1.2 g) was purified by SFC (column: REGIS (S, S) WHELK-O1, 250 ⁇ 25mm I.D., 10 ⁇ m, A for CO 2 and B for Ethanol) to afford 91-6 (200 mg) and 91-7 (250 mg) respectively.
  • 91-6 SFC analysis: 100.00%ee; retention time: 5.932 min; column: ChiralPak AD, 250 ⁇ 30mm I. D., 10 ⁇ m, A for CO 2 and B for Ethanol, 40%; pressure: 100 bar; flow rate: 70 mL/min.
  • 91-7 SFC analysis: 98.76%ee; retention time: 7.760 min; column: ChiralPak AD, 250 ⁇ 30mm I. D., 10 ⁇ m, A for CO 2 and B for Ethanol, 40%; pressure: 100 bar; flow rate: 70 mL/min.
  • Step 5 To a solution of 91-6 (180 mg, 0.39 mmol) in DCM (1 mL) under N 2 at -78°C was added dropwise BBr 3 (3.86 mL, 3.86 mmol) . After the addition was completed, the mixture was stirred at room temperature for 16 h. Ice water was added to the mixture to quench the reaction and the precipitation was collected by filtration, washed with H 2 O and dried to afford 91-8.
  • Step 6 The mixture of 91-8 (160 mg, 0.35 mmol) , 3-bromotetrahydrofuran (67.84 mg, 0.45 mmol) and Cs 2 CO 3 (266.2 mg, 0.82 mmol) in DMF (5 mL) was stirred at 100°C for 6 h. Then the mixture was washed with water and extracted with ethyl acetate. The organic layer was dried over Na 2 SO 4 , filtered and concentrated to afford 91-9.
  • Step 7 91-9 (110 mg) was purified by SFC (column: ChiralPak AD, 250 ⁇ 30mm I. D., 10 ⁇ m, A for CO2 and B for Ethanol) to afford 91 (26 mg) and 92 (15 mg) respectively.
  • 91 SFC analysis: 100.00%ee; retention time: 2.519 min; column: ChiralPak AD, 250 ⁇ 30mm I. D., 10 ⁇ m, A for CO2 and B for Ethanol, 35%; pressure: 100 bar; flow rate: 80 mL/min.
  • Step 1 Compound 98-1 was prepared from compound 28-12 following the procedure for the synthesis of compound 28-14 in example 11.
  • Step 6 To a solution of 98-6 (200 mg, 0.59 mmol) in MeCN (4 mL) were added 98-1 (265.5 mg, 0.59 mmol) , DIPEA (380 mg, 2.94 mmol) and NaI (105.8 mg, 0.71 mmol) . Then the reaction was stirred at 90°C for 2 h. The solvent was removed under vacuum, and the residue was purified by reverse phase HPLC (MeCN/H 2 O, 5-80%) to afford 98-7.
  • Step 7 To a solution of 98-7 (110 mg, 0.19 mmol) in THF (4 mL) was added Lawesson's reagent (74.83 mg, 0.19 mmol) . Then the reaction mixture was stirred at 50°C for 30 h. The solvent was removed under vacuum, and the residue was purified by reverse phase HPLC (MeCN/H 2 O, 5-80%) to afford 98-8.
  • Step 9 To a mixture of 98-9 (20 mg, 0.03 mmol) in DMF (1 mL) was added Zn (CN) 2 (10.6 mg, 0.09 mmol) and Pd (PPh 3 ) 4 (3.5 mg, 0.003 mmol) . Then the mixture was stirred at 130°C for 2 h under microwave. The reaction mixture was purified by reverse phase HPLC (MeCN/H 2 O (0.05%TFA) , 5-80%) to afford 98 (5 mg) and 99 (7 mg) .
  • Step 3 To a solution of 102-3 (345 mg, 0.86 mmol) in DCM (5 mL) was added ethyl acetate/HCl (0.43 mL) and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness to afford 102-4 which was used for the next step directly without further purification.
  • Step 4 Compound 102 was prepared from compound 102-4 following the procedure for the synthesis of compound 84-3 in example 25.
  • Step 2 To a mixture of 103-2 (12 g, 25.71 mmol) and CoCl 2 ⁇ 6H 2 O (0.6 g, 2.57 mmol) in MeOH (360 mL) and THF (180 mL) was added NaBH 4 (5.8 g, 154.23 mmol) in portions at 0°C. Then the mixture was stirred at room temperature for 1 h. H 2 O was added to the reaction mixture. This mixture was extracted with ethyl acetate. The combined organic layers were dried over Na 2 SO 4 , filtered and the filtrate was concentrated under vacuo. The residue was purified by column chromatography on silica gel (DCM) to afford 103-3.
  • DCM silica gel
  • Step 3 103-3 (7.6 g, 23.12 mmol) in HCl/ethyl acetate (100 mL) was stirred at room temperature for 1 h. The mixture was concentrated under vacuo to afford 103-4.
  • Step 4 Compound 103 was prepared from compound 103-4 following the procedure for the synthesis of compound 59 in example 20.
  • 1 H NMR 400 MHz, DMSO-d 6 , ppm) : ⁇ 8.07 (s, 1H) , 7.82 –7.77 (m, 2H) , 7.49-7.47 (m, 2H) , 4.92-4.17 (m, 4H) , 3.91 –3.83 (m, 2H) , 3.35 (s, 2H) , 2.96 -2.89 (m, 2H) , 2.02 -1.90 (m, 6H) .
  • 19 F NMR (376 MHz, DMSO-d 6 , ppm) : ⁇ -56.75 (3F) .
  • Step 1 The mixture of 104-1 (5.0 g, 44.59 mmol) , 1- (pyridin-3-yl) propan-1-one (7.23 g, 53.51 mmol) , AgNO 3 (2.27 g, 13.38 mmol) , H 2 SO 4 (9.75 g, 89.18 mmol) and ammonium persulfate (10.17g, 44.59 mmol) in H 2 O (70 mL) and DCM (70 mL) was flushed with N 2 for 0.5 min, then the mixture was stirred at 25°C for 18 h. The mixture quenched by addition of saturated NaHCO 3 solution, the aqueous layer was extracted with DCM.
  • Step 2 To a solution of 104-2 (560 mg, 2.78 mmol) in MeOH (10 mL) was added NaBH 4 (12.3 mg, 3.34 mmol) at 0°C, the reaction mixture was stirred at room temperature for 2 h. The mixture was quenched by addition of H 2 O, and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to afford 104-3.
  • Step 3 To a solution of 104-3 (580 mg, 2.85 mmol) in DCM (15 mL) were added DMF (21.0 mg, 0.29 mmol) and SOCl 2 (509 mg, 4.28 mmol) at 0°C, the reaction mixture was stirred at room temperature for 3 hr. The solvent was removed under reduced pressure to afford 104-4 which was used for next step directly without further purification.
  • Step 4 The mixture of 28-9 (100 mg, 0.43 mmol) , 104-4 (239 mg, 1.08 mmol) , DIPEA (0.29 mL, 1.72 mmol) and NaI (129 mg, 0.86 mmol) in MeCN (2 mL) was stirred at 85°C for 18 h. The mixture was filtered and concentrated, the residue was purified by reverse phase HPLC (0.05%NH 4 HCO 3 in water/MeCN, 5-95%) to afford 104-5.
  • Step 5 To a solution of 104-5 (80 mg, 0.19 mmol) in 1, 2-dichloroethane (1 mL) was added 1-chloroethyl chloromethanoate (274.5 mg, 1.92 mmol) , the reaction was stirred at 110°Cfor 96 h. The mixture was concentrated in vacuo, the residue was diluted with THF and H 2 O. Then the mixture was stirred at 70°C for 3 h. The solvent was removed under reduced pressure to afford 104-6 which was used for next step directly without further purification.
  • Step 1 To a stirred solution of 107-1 (500 g, 3.27 mol) in dry DCM (5000 mL) was added benzaldehyde (352 g, 3.32 mol) , K 2 CO 3 (494.9 g, 3.58 mol) and Na 2 SO 4 (462 g, 3.25 mol) . The reaction mixture was stirred at room temperature for 6 h. Then sodium triacetoxyborohydride (1030 g, 4.86 mol) was added in portion wise over 30 minutes to the mixture at ice-bath. The mixture was stirred at room temperature for 16 h. The solid was removed by filtration and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and HCl (1N) .
  • the mixture was extracted with ethyl acetate.
  • the pH of the aqueous layer was adjusted to 8.0 with NaHCO 3 (aq) and the milky aqueous layer was extracted immediately with ethyl acetate.
  • the combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford 107-2.
  • Step 2 To a solution of 107-2 in DMF (3500 mL) were added DIPEA (885 mL, 5.08mol) and HATU (966 g, 2.54 mol) , the reaction mixture was stirred at 0°C for 10 minutes, then methyl (2R) -2- (benzylamino) butanoate (351 g, 1, 69 mol) was added to the reaction mixture. The result mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure to afford 107-3.
  • DIPEA 885 mL, 5.08mol
  • HATU 966 g, 2.54 mol
  • Step 3 Compound 107-4 was prepared from compound 107-3 following the procedure for the synthesis of compound 67-14 in example 22.
  • Step 4 To a stirred solution of 107-4 (4.8 g, 11.31 mmol) in isopropanol (150 mL) was added Pd/C (10%, 0.96 g, 9.02mmol) at room temperature, the resulting mixture was stirred at 80°C under H 2 balloon for 15 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated to afford 107-5.
  • Step 6 To a stirred solution of 107-6 (4.57 g, 10.09 mmol) in MeOH (20 mL) was added dropwise HCl in ethyl acetate (4M, 9.1 mL) at room temperature, the resulting mixture was stirred at 25°C for 15 h. The reaction mixture was concentrated under reduced pressure to afford 107-7.
  • Step 7 Compound 107-8 was prepared from compound 107-7 following the procedure for the synthesis of compound 67-20 in example 22.
  • Step 8 To a stirred solution of 107-8 (350 mg, 0.63 mmol) in DMF (10 mL) was added CsF (285.5 mg, 1.88 mmol) at 15°C, the resulting mixture was stirred at 110°C for 15 h. The reaction mixture was diluted with H 2 O and extracted with ethyl acetate. The organic layer was combined, washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 and concentrated.
  • Step 2 To a solution of 109-1 (660 mg, 1.1 mmol) in DCM (8 mL) was added HCl/ethyl acetate (6 mL) . The mixture was stirred at 30 °C for 12 h. The mixture was concentrated to afford 109-2.
  • Step 3 A solution of 109-2 (611 mg, 1.23 mmol) , 2-chloroacetaldehyde (5 mL, 0.49 mmol) and AcOH (0.070 mL, 1.23 mmol) in EtOH (12 mL) was stirred at 80 °C for 16 h. The mixture was concentrated. The residue was purified by reverse phase HPLC (MeCN/water (0.5%FA) : 5%-80%) to afford 109-3.
  • Step 1 To a solution of 28-11 (3.0 g, 12.38 mmol) in DCM (30 mL) was added DIPEA (5.12 mL, 30.95 mmol) and benzyl carbonochloridate (3.49 mL, 24.76 mmol) , then the reaction mixture was stirred at 20°C for 18 h. The reaction was concentrated in vacuo. The residue was diluted with ethyl acetate and water. The mixture was extracted with ethyl acetate.
  • Step 2 To a solution of 113-1 (4.5 g, 11.98 mmol) in DCM (30 mL) was added TFA (6 mL, 11.98 mmol) and the reaction was stirred at 20°C for 18 h. The reaction mixture was concentrated under vacuo, the residue was dilute with DCM and neutralized by NaHCO 3 aqueous. The mixture was extracted with DCM. The combined organic layer was concentrated to afford 113-2.
  • Step 4 To a solution of 113-4 (280 mg, 0.57 mmol) in MeOH (10 mL) was added Pd/C 10%(6.1 mg, 0.057 mmol) under N 2 . The then the reaction was stirred at 25°C for 18 h at H 2 atmosphere. The mixture was filtered and the filtrate was concentrated to afford 113-4.
  • Step 5 Compound 113-5 was prepared from compound 113-4 following the procedure for the synthesis of compound 84-3 in example 25.
  • 113 SFC analysis: 95%ee; retention time: 5.52 min; column: ChiralPak IG, 100 ⁇ 4.6mm I. D., 3 ⁇ m, MeOH (0.05%DEA) in CO2, 5%to 40%; pressure: 100 bar; flow rate: 2.5 mL/min.
  • Step 3 To a solution of 119-2 (3.0 g, 8.76 mmol) in THF (30 mL) and H 2 O (20 mL) was added LiOH (0.6 g, 13.14 mmol) at room temperature. Then the mixture was stirred at 30°C for 12 h. NaOH (1.1 g, 26.28 mmol) was added to the reaction mixture. The mixture was heated at 80°C for 12 h. The solvent was removed under vacuo. The pH of the residue was adjusted to 3 with HCl (6N) . The mixture was extracted with DCM. The combined organic layers were dried over Na 2 SO 4 , filtered and the filtrate was concentrated to afford 119-3.
  • Step 5 To a solution of 119-4 (400 mg, 1.02 mmol) in DCM (4 mL) was added TFA (4 mL) at room temperature. Then the mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuo to afford 119-5 which was used for the next step directly without further purification.
  • Step 6 Compound 119-6 was prepared from compound 119-5 following the procedure for the synthesis of compound 84-3 in example 25.
  • Step 2 To a solution of 121-2 (2 g, 4.97 mmol) in DCM (12 mL) was added HCl/ethyl acetate (6 mL) at 15 °C. The mixture was stirred at 15 °C for 2 h. The mixture was concentrated to afford 121-3.
  • Step 3 Compound 121-4 was prepared from compound 121-3 following the procedure for the synthesis of compound 67-20 in example 22.
  • Step 5 To a solution of 121-5 (130 mg, 0.26 mmol) in THF (6 mL) was added triethyl amine (0.072 mL, 0.52 mmol) and TFAA (0.14 mL, 1.04 mmol) at 0 °C. The mixture was stirred at 15 °C for 48 h. The mixture was diluted with H 2 O, extracted with ethyl acetate. The organic phase was concentrated. The residue was purified by reverse phase HPLC (0.5%TFA in water/MeCN, 5-70%) to afford 121-6.
  • 121 SFC analysis: 100%ee; retention time: 2.69 min; column: ChiralCel OD, 150 ⁇ 4.6mm I. D., 3 ⁇ m, 40%of ethanol (0.05%DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min.
  • LCMS (ESI, m/z) : [M+H] + 484.4.
  • Step 1 To a stirred solution of 67-14 (2 g, 5.98 mmol) in isopropanol (35 mL) was added Pd/C (10%, 0.5 g, 0.470 mmol) at 25 °C, the resulting mixture was stirred at 50 °C under H 2 balloon for 15 h. The reaction mixture was filtered and the filtrate was concentrated to afford 123-1.
  • Step 2 Compound 123-2 was prepared from compound 123-1 following the procedure for the synthesis of compound 67-20 in example 22.
  • Step 2 To a solution of 154-2 (13.7 g, 40.98 mmol) in DMF (300 mL) was added C 2 H 5 OH (2.5 mL, 42.82 mmol) and NaH (3.8 g, 94.26 mmol) , the mixture was stirred at room temperature for 18 h. Then the reaction mixture was heated to 100°C for 2 h. The reaction mixture was cooled to room temperature, quenched with HCl. The mixture was concentrated in vacuo. The residue was diluted with ethyl acetate and water. The organic layer was separated and washed with NaCl aqueous.
  • Step 5 Compound 154 was prepared from compound 154-6 following the procedure for the synthesis of compound 44-7 in example 17. The product was obtained by reverse phase HPLC (acetonitrile/H 2 O: 5% ⁇ 95%) to afford 154.
  • Step 2 Compound 192-4 was prepared from compound 192-3 following the procedure for the synthesis of compound 67-14 in example 22.
  • Step 3 To a stirred solution of 192-4 (3.6 g, 10.76 mmol) in isopropanol (50 mL) was added Pd/C (10%, 0.72 g) at 25 °C, the resulting mixture was stirred at 50 °C under H 2 balloon for 15 h. The reaction mixture was filtered and the filtrate was concentrated to afford 192-5.
  • DCM/methanol 1/0 to 5/1
  • Step 6 Compound 192 was prepared from compound 192-7 following the procedure for the synthesis of compound 84-3 in example 25. The product was obtained by reverse phase HPLC (0-60%acetonitrile in water) to afford 192 (77 mg) .
  • Step 2 NaIO 4 (9.9 g, 46.3 mmol) was dissolved in water (50 mL) and CH 3 CN/dimethyl carbonate (40 ml, 1: 1) , then Ruthenium (III) chloride trihydrate (60.5 mg, 0.23 mmol) was added to the mixture, followed by a solution of 198-1 (8.76 g, 23.15 mmol) in CH 3 CN /dimethyl carbonate (60 ml, 1: 1) at 0°C over 1 minutes. The solution was stirred at 25°C for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organics were washed with brine and dried over Na 2 SO 4 . The mixture was filtered and concentrated.
  • Step 4 To a stirred solution of 198-3 (5.76 g, 14.17 mmol) in propan-2-ol (50 mL) was added Pd/C (10%, 0.8 g) . The reaction mixture was stirred at 25°C under H 2 for 18 h. The reaction mixture was filtered, washed with propan-2-ol, evaporated under reduced pressure to afford 198-4.
  • Step 7 The mixture of 198-6 (300 mg, 0.61 mmol) , K 2 CO 3 (168.4 mg, 1.22 mmol) , and CH 3 I (864.8 mg, 6.09 mmol) in CH 3 CN (5 mL) was stirred at 70°C for 18 h. The solvent was removed under reduced pressure, the residue was purified by C18 reverse phase column (CH 3 CN/H 2 O (0.05%TFA) , 5-95%) to afford 198-7.
  • Step 8 Compound 198 and 199 was prepared from compound 198-7 following the procedure for the synthesis of compound 28 and 29 in example 11.
  • 198: LCMS (ESI, m/z) : [M+H] + 539.4; SFC analysis: 100%ee; retention time: 1.341 min; column: ChiralPak AD, 150 ⁇ 4.6mm, 3 ⁇ m, 40%EtOH (0.05%DEA) in CO 2 ; pressure: 100 bar; flow rate: 2.5 mL/min.
  • Step 1 To a stirred solution of 210-1 (10 g, 66.16 mmol) in AcOH (60 mL) and H2O (120 mL) was added iodine (16.8 g, 66.16 mmol) over a period of 10 minutes. The reaction mixture was stirred at room temperature for 48h. The reaction mixture was filtered and the solid was collected and dried under vacuum to afford 210-2.
  • Step 2 To a stirred solution of 210-2 (12.1 g, 43.67 mmol) in dioxane (120 mL) was added triphosgene (7.1 g, 24.02 mmol) at 25°C, the resulting mixture was stirred at 100°C for 15 h. The reaction mixture was concentrated under reduced pressure to afford 210-3 which was used for the next step directly.
  • Step 3 NaH (1.8 g, 45.89 mmol) was added to a mixture of diethyl malonate (27.28 mL, 180.56 mmol) and DMF (240 mL) with stirring at room temperature. A mixture of 210-3 (12 g, 37.62 mmol) and DMF (240 mL) was added dropwise to this solution, the mixture was stirred at 120°C for 4 h. The mixture was filtered and the solid was added to H 2 O (1L) and HCl (30%, 200 mL) , the mixture was stirred and filtered. The solid was collected and dried to afford 210-4.
  • Step 4 A solution of ethyl 210-4 (12 g, 32.16 mmol) in TFA (95 mL) and HCl (95 mL) was stirred at 100°C for 16 h. The reaction mixture was diluted with H 2 O and filtered. The cake was washed with a large amount of H 2 O and dried under reduced pressure to afford 210-5.
  • Step 5 To a stirred solution of 210-5 (3 g, 9.96 mmol) in AcOH (26 mL) was added HNO 3 (1.6 mL, 2.46 mmol) at 25°C, the resulting mixture was stirred at 80°C for 1.5 h. The reaction mixture was cooled to 25 °C and diluted with H 2 O, after stirred for 10 minutes, the resulting solid was filtered and dried to afford 210-6.
  • Step 6 To a stirred solution of 210-6 (2.7 g, 7.80 mmol) and Zn (CN) 2 (2.7 g, 23.41 mmol) in DMF (40 mL) was added Pd (PPh 3 ) 4 (0.9 g, 0.78 mmol) at room temperature, the resulting mixture was stirred at 110°C for 36 h under N 2 . The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (0-20%CH 3 CN in H 2 O (0.5%FA) ) to afford 210-7.
  • Step 9 To a stirred solution of 210-9 (320 mg, 0.57 mmol) in NMP (9 mL) was added t-BuOK (193.2 mg, 1.72 mmol) in one portion at room temperature, the resulting mixture was stirred at 120°C for 18 h. The reaction mixture was diluted with H 2 O and extracted with ethyl acetate. The organic layer was combined, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated.
  • Step 5 To a solution of 219-6 (2.26 g, 5.48 mmol) in dioxane (10 mL) was added HCl/dioxane (40 mL) at room temperature. Then the mixture was stirred at room temperature for 1 h. This mixture was concentrated under vacuo to afford 219-7.
  • Step 7 To a solution of 219-8 (1.0 g, 3.81 mmol) in THF (8 mL) was added borane tetrahydrofuran (22.87 mL, 22.87 mmol) at room temperature. Then the mixture was heated at 80°C for 1 h. The mixture was quenched with methanol and HCl. This mixture was concentrated under vacuo to afford 219-9.
  • Step 9 Compound 219-11 was prepared from compound 219-10 following the procedure for the synthesis of compound 192-7 in example 40.
  • Step 10 Compound 219 (26 mg) was prepared from compound 219-11 following the procedure for the synthesis of compound 5 in example 5.
  • Step 2 To a stirred solution of 220-1 (3.79 g, 7.2 mmol) in ethyl acetate (40 mL) was added 5%Pt/C (0.7 g, 3.6mmol) . The reaction mixture was stirred at 25°C under H 2 for 18 h. The reaction mixture was filtered, washed with ethyl acetate, evaporated under reduced pressure to afford 220-2.
  • Step 3 To a solution of 220-2 (3.57 g, 7.19 mmol) and triethylamine (4 mL, 28.77 mmol) in CH 2 Cl 2 (30 mL) was added MsCl (1.6 g, 14.38 mmol) at 0°C. Then the reaction mixture was stirred at 25°C for 1 h, the solvent was removed under reduced pressure to afford 220-3 which was used for next step directly.
  • Step 4 To a solution of 220-3 (4.13 g, crude) in DMF (30 mL) was added DIPEA (1.9 g, 14.38 mmol) . Then the reaction was stirred at 120°C for 5 h. The reaction was purified by C18 reverse phase column (MeCN/H 2 O (0.05%TFA) , 5-95%) to afford 220-4.
  • Step 5 To a solution of 220-4 (1.0 g, 2.09 mmol) in anhydrous THF (10 mL) was added NaH (334.5 mg, 8.36 mmol) at 0°C, the mixture further stirred at 0°C under N 2 for 30 mins. Then CH 3 I (890.1 mg, 6.27 mmol) in THF (10 mL) was added dropwise and the mixture stirred at 25°C for 1 h. The reaction was quenched with H 2 O at 0°C. The mixture was partitioned between ethyl acetate and H 2 O, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine. The organic phase was separated, dried over Na 2 SO 4 , filtered and concentrated to afford 220-5.
  • Step 6 Compounds 220 and 221were prepared from compound 220-5 following the procedure for the synthesis of compound 28-15 in example 11.
  • 220: LCMS (ESI, m/z) : [M+H] + 525.3.
  • Step 1 A mixture of 67-5 (50 g, 196.08 mmol) , aniline (50 g, 537.63 mmol) , and trimethyl orthoformate (56.3 g, 530.53 mmol. ) in ethyleneglycol (400 mL) was heated to 70 °C under stirring. The temperature was increased to 170 °C, then kept at 170 °C for 2 h. After cooling the solid was collected with filtration and washed with EtOH, dried at 55 ⁇ 60 °C to afford 227-1.
  • Step 2 To a solution of 227-1 (63 g, 175.88 mmol) in anhydrous DMF (400 mL) was slowly added POCl 3 (42 g, 273.94 mmol) and the mixture was stirred at room temperature for 20 h. The mixture was poured into ice water (3.2 L) , and the precipitate was collected with filtration and dried at 55 ⁇ 60 °C to afford 227-2.
  • Step 3 To a solution of 67-18 (150 mg, 0.45 mmol) in DCM (10 mL) were added 1H-imidazole (494.5 mg, 7.26 mmol) , DMAP (5.5 mg, 0.045 mmol) and TBSCl (136.9 mg, 0.91 mmol) . The reaction mixture was stirred at 25°C for 4 h under N 2 . The reaction was partitioned between DCM and H 2 O. The separated organic layer was washed with brine and dried over anhydrous Na 2 SO 4 . Evaporation of the solvent under reduced pressure afford 227-3.
  • Step 5 To a solution of 227-4 (200 mg, 0.28 mmol) and TMSOTf (62.6 mg, 0.28 mmol) in DCM (25 mL) was added Et 3 SiH (65.5 mg, 0.56 mmol) at -78°C. The mixture was stirred at 25°C for 3 h. The reaction was quenched by addition of H 2 O, and the aqueous layer was extracted with DCM. The organic extracts were combined, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to afford 227-5.
  • Step 6 To a solution of 227-5 (250 mg, 0.43 mmol) in DMF (5 mL) were added Zn (CN) 2 (152.0 mg, 1.29 mmol) , Zn (8.5 mg, 0.13 mmol) and palladium (0) bis [tris (2-methylprop-2-yl) phosphane] (22.0 mg, 0.043 mmol) . The reaction mixture was stirred at 85°C for 3 h under N 2 . The reaction was concentrated to give a residue. The residue was purified by C18 reverse phase column (MeCN/H 2 O (0.05%NH 3 . H 2 O) , 5-95%) to afford 227 (53 mg) .
  • Step 1 To a solution of 235-1 (5 g, 24.49 mmol) in CCl 4 (50 mL) was added NBS (4.8 g, 26.94 mmol) and AIBN (0.4 g, 2.45 mmol) . The reaction mixture was stirred at room temperature for 2 h. The reaction was diluted with ethyl acetate and water. The organic layer was separated, washed with saturated NaCl and concentrated in vacuo. The residue was purified by C18 column and was eluted with (Acetonitrile in water (0.1%FA) , 0-70 %, keep in 50%25 min) to afford 235-2.
  • NBS 4.8 g, 26.94 mmol
  • AIBN 0.4 g, 2.45 mmol
  • Step 3 Compound 235-4 was prepared from compound 235-3 and 123-3 following the procedure for the synthesis of compound 28-15 in example 11.
  • Step 4 To a solution of 235-4 (300 mg, 0.55 mmol) in THF (3 mL) and water (0.5 mL) was added LiOH (232.5 mg, 5.54 mmol) The reaction mixture was stirred at 0°C at N 2 overnight. The crude product was purified by reverse HPLC (0.1%TFA in water/MeCN, 0-70%) to afford 235-5.
  • 235-6 SFC analysis: 100%ee; retention time: 6.129 min; column: ChiralCel OD, 100 ⁇ 4.6mm I. D., 3 ⁇ m, 40%of Ethanol (0.05%DEA) in CO 2 ; pressure: 100 bar; flow rate: 2.5 mL/min.
  • 235-7 SFC analysis: 100%ee; retention time: 8.821 min; column: ChiralCel OD, 100 ⁇ 4.6mm I. D., 3 ⁇ m, 40%of Ethanol (0.05%DEA) in CO 2 ; pressure: 100 bar; flow rate: 2.5 mL/min.
  • Step 6 To a solution of 235-6 (20 mg, 0.038 mmol) in THF (2 mL) was added CDI (15.4 mg, 0.095 mmol) , the reaction mixture stirred at 60°C for 18 h. NaBH 4 (3.6 mg, 0.095 mmol) was added in and stirred at room temperature for 2 h. This reaction mixture was diluted with ethyl acetate and saturated NaCl. The organic layer was separated, washed with saturated NaCl and concentrated in vacuo. The residue was purified by reverse HPLC (MeCN in water (0.1%NH 4 HCO 3 ) , keep in 50%) to afford 235 (3 mg) .
  • Step 2 To a stirred solution of 241-2 (9.4 g, 38.82 mmol) in DCM (100 mL) was added oxalyl Chloride (3.94 mL, 46.59 mmol) . The mixture was warmed up to room temperature and stirred for 1 h, then FeCl 3 (12.6 g, 77.65 mmol) was added, and stirred at room temperature for 24 h. The reaction was quenched with 1M HCl. The mixture was extracted with DCM. The organic layers were combined and dried over Na 2 SO 4 , filtered and concentrated to afford 241-3 which was used for the next step directly.
  • Step 3 To a solution of 241-3 (10 g, crude) in MeOH (100 mL) was added H 2 SO 4 (25 mL) . The reaction mixture was stirred at 65°C for 4 h. After cooling to room temperature, the reaction mixture was quenched with NH 3. H 2 O. The mixture was extracted with DCM. The organic layers were dried over Na 2 SO 4 , filtered and concentrated to afford 241-4 which was used for the next step directly.
  • Step 4 To a solution of 241-4 (5.5 g, crude) in EtOH (20 mL) was in portions added NaBH 4 (0.84 g, 22.10 mmol) . After stirred at 0°C for 2 h, HCl (15 mL, 5M) was added and the mixture was stirred at room temperature for 16 h. The solvent was removed and EtOH was added to the residue, followed by NH 3 H 2 O at 0°C to quench the reaction. The mixture was extracted with DCM. The organic layers were dried over Na 2 SO 4 , filtered and concentrated to afford 241-5 which was used for the next step directly.
  • Step 7 To a solution of 241-7 (2.6 g, 6.64 mmol) in DCM (21 mL) was added TFA (7 mL) . Then the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to afford 241-8 which was used for the next step directly.
  • Step 8 Compound 241-9 was prepared from compound 241-8 following the procedure for the synthesis of compound 5 in example 5.
  • 241 SFC analysis: 100%ee; retention time: 1.637 min; column: Chiralpak AD 150 ⁇ 4.6mm I. D., 3um, 40%EtOH (0.05%DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min.
  • LCMS (ESI, m/z) : [M+H] + 476.4.
  • Step 1 Compound 252-1 was prepared from compound 67-3 following the procedure for the synthesis of compound 67-7 in example 22.
  • Step 2 Compound 252-2 was prepared from compound 252-1 following the procedure for the synthesis of compound 67 in example 22.
  • Step 3 To a stirred solution of 252-2 (5 mg, 0.008 mmol) in TFA (1.5 mL) was stirred at 70°C under N 2 for 18 h. The reaction mixture was concentrated. The residue was purified by C18 reverse phase column (MeCN/H 2 O (0.05%NH 3 . H 2 O) , 5-95%) to afford 252 (3 mg) .
  • LCMS (ESI, m/z) : [M+H] + 498.2.
  • Step 2 To a solution of 261-2 (1.7 g, 6.0 mmol) in THF (30 mL) was added Boc 2 O (5.51 mL, 24.0 mmol) , DMAP (0.1 g, 1.20 mmol) and triethylamine (2.50 mL, 18.0 mmol) at room temperature. Then the mixture was stirred at room temperature for 2h. This mixture was washed with H 2 O, extracted with ethyl acetate, dried and concentrated to afford 261-3 which was used for the next step directly.
  • Boc 2 O 5.51 mL, 24.0 mmol
  • DMAP 0.1 g, 1.20 mmol
  • triethylamine 2.50 mL, 18.0 mmol
  • Step 3 To a solution of 261-3 (2.8 g, crude) in THF (30 mL) and H 2 O (10 mL) was added KOH (9.7 g, 172.88 mmol) . Then the mixture was stirred at room temperature for 3 h. The mixture was concentrated under vacuo. The residue was purified by reverse-HPLC (57%MeCN in H 2 O) to afford 261-4.
  • Step 4 A solution of LiAlH 4 (161.6 mg, 4.26 mmol) in THF (15 mL) was stirred at 0°Cunder N 2 for 0.5 h. Then 261-4 (550 mg, 2.13 mmol) was added and stirred at 25 °C for 16 h. The mixture was diluted with THF, quenched with saturated Na 2 SO 4 , filtered and the filtrate was concentrated to afford 261-5 which was used for the next step directly.
  • Step 5 Compound 261 and 262 was prepared from compound 261-5 following the procedure for the synthesis of compound 36 in example 15.
  • the product was purified by reverse-HPLC (80%ACN in H 2 O) and SFC (Column: ChiralPak IG, 250 ⁇ 30mm I. D., 10 ⁇ m; 30%Ethanol in CO 2 , Flow rate: 150 mL /min, Back pressure: 100 bar) to afford 261 (8 mg) and 262 (8 mg) .
  • 261 SFC analysis: 100%ee; retention time: 2.666 min; column: ChiralPak IG, 100 ⁇ 4.6mm I. D., 3 ⁇ m, 40%EtOH (0.05%DEA) in CO2, pressure: 100 bar; flow rate: 2.5 mL/min.
  • Step 1 A solution of 264-1 (3 g, 17.09 mmol) and cyclopropanamine (7.5 mL, 108.23 mmol) in dioxane (9 mL) was stirred at 85°C for 10 h in a sealed tube. The mixture was concentrated. The residue was dissolved in ethyl acetate and H 2 O. The mixture was adjusted pH to 5 by 2M HCl, the mixture was extracted with ethyl acetate. The organic phases were dried over Na 2 SO 4 , filtered and concentrated to afford 264-2.
  • Step 4 Compound 264-5 was prepared from compound 264-4 following the procedure for the synthesis of compound 67-7 in example 22.
  • Step 5 Compound 264 (29 mg) was prepared from compound 264-5 following the procedure for the synthesis of compound 67 in example 22.
  • Step 3 To a solution of 272-2 (450 mg, 0.86 mmol) in THF (4.5 mL) were added IrCl (CO) (PPh 3 ) 3 (67.4 mg, 0.086 mmol) at room temperature under N 2 . Then the reaction mixture was cooled to -78°C, 1, 1, 3, 3-Tetramethyldisiloxane (101.1 mg, 0.130 mmol) was added into the mixture, the mixture was stirred at -78°C for 1.5 h, then bromo (prop-2-yl) magnesium (2.59 mL, 2.59 mmol) was added into the reaction, the mixture was stirred for another 18 h at room temperature under N 2 .
  • IrCl (CO) (PPh 3 ) 3 67.4 mg, 0.086 mmol
  • Step 5 Compound 272-5 was prepared from compound 272-4 following the procedure for the synthesis of compound 5 in example 5.
  • 272 SFC analysis: 100%ee; retention time: 2.185 min; column: ChiralPak AD, 150 ⁇ 4.6mm I. D., 3 ⁇ m, 5-40%of ethanol (0.05%DEA) in CO2; pressure: 100 bar; flow rate: 2.5 mL/min.
  • Step 1 To a solution of 278-1 (2 g, 11.39 mmol) and DMF (0.088 mL, 1.14 mmol) in DCM (40 mL) was dropwise added oxalyl dichloride (1.45 mL, 17.09 mmol) at 0°Cand stirred for 12 h at room temperature. The reaction mixture was concentrated to dryness afford 278-2 which was used for next step directly.
  • Step 2 To a solution of 1H-1, 2, 4-triazol-5-amine (800 mg, 9.52 mmol) in DMF (30 mL) was added DIPEAe (7.86 mL, 47.57 mmol) , then 278-2 (2214.9 mg, 11.42 mmol) in DMF (10 mL) was added to the mixture at 0°C. The resulting mixture was stirred at room temperature for 12 h. The reaction mixture used for the next step directly.
  • Step 3 K 2 CO 3 (3.8 g, 27.32 mmol) was added to the reaction mixture from step 2, stirred at 100°C under N 2 for 16 h. The reaction was quenched with HCl (2 N) until the pH to 4. The solid was collected with filtration to afford 278-4.
  • Step 1 To a solution of 235-5 (153 mg, 0.29 mmol) in THF (5 mL) was added CDI (70.5 mg, 0.44 mmol) and the reaction was stirred at room temperature overnight. NaBH 4 (11.0 mg, 0.29 mmol) was added to this mixture and stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine and concentrated in vacuo. The residue was by reverse HPLC (MeCN in water (0.1%FA) , 0-70%) to afford 282-1.
  • DCM/ethyl acetate 1/0 to 1/3
  • Step 1 To a solution of 220-1 (10 g, 19.0 mmol) in DMF (100 mL) was added Zn (CN) 2 (6.69 g, 57 mmol) , Zn (372.6 mg, 5.7 mmol) and palladium (0) bis [tris (2-methylprop-2-yl) phosphane] (970.9 mg, 1.90 mmol) .
  • the reaction mixture was stirred at 85°C for 3 h under N 2 .
  • Step 2 To a stirred solution of 300-1 (5.5 g, 11.64 mmol) in EtOH (60 mL) and H 2 O (15 mL) at room temperature was added Fe (3.2 g, 58.20 mmol) and NH 4 Cl (6.2 g, 116.40 mmol) . The reaction mixture was stirred at 80°C for 1 h. The hot reaction mixture was filtered and the filter cake was washed with EtOH. The filtrate was concentrated to dryness. The residue was purified by C18 reverse phase HPLC (MeCN/H 2 O (0.05%TFA) , 5-95%, 50 min) to afford 300-2.
  • Step 3 Compound 300-3 was prepared from compound 300-2 following the procedure for the synthesis of compound 220-4 in example 44.
  • Step 4 Compound 300-4 was prepared from compound 300-3 following the procedure for the synthesis of compound 28-15 in example 11.

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US12077538B2 (en) 2022-03-01 2024-09-03 Insilico Medicine Ip Limited Diacylglycerol kinase (DGK) alpha inhibitors and uses thereof

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