WO2021244560A1 - Composés d'aminopyrimidine, leurs procédés de préparation et leurs utilisations - Google Patents

Composés d'aminopyrimidine, leurs procédés de préparation et leurs utilisations Download PDF

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WO2021244560A1
WO2021244560A1 PCT/CN2021/097809 CN2021097809W WO2021244560A1 WO 2021244560 A1 WO2021244560 A1 WO 2021244560A1 CN 2021097809 W CN2021097809 W CN 2021097809W WO 2021244560 A1 WO2021244560 A1 WO 2021244560A1
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optionally substituted
alkyl
compound
pharmaceutically acceptable
acceptable salt
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PCT/CN2021/097809
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English (en)
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Xing DAI
Yaolin Wang
Yueheng Jiang
Yanqin Liu
Haotao NIU
Hong Yang
Zixing HAN
Zhenwu Wang
Liangshan TAO
Zhe SHI
Jifang WENG
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InventisBio Co., Ltd.
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Publication of WO2021244560A1 publication Critical patent/WO2021244560A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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

Definitions

  • the present disclosure generally relates to novel aminopyrimidine compounds, compositions of the same, methods of preparing and methods of using the same, e.g., for treating a number of diseases or disorders, such as lung cancers.
  • Epidermal growth factor receptor is a receptor tyrosine protein kinase, and a transmembrane protein in the ErbB receptor family.
  • EGFR regulates proliferation, survival, adhesion, migration and differentiation of cells, which is hyperactivated or sustained in a variety of tumor cells, such as lung cancer cells, breast cancer cells, prostate cancer cells and the like.
  • Abnormal activation of EGFR plays a key role in tumor transformation and growth.
  • Blocking activation of EGFR has been clinically proven as one of the effective targeted therapies for treating cancer.
  • EGFR has been found to be highly mutated in NSCLC (non-small cell lung cancer) patients, which makes EGFR and its family members candidates for targeted therapy.
  • Gefitinib and erlotinib are the first generation of small molecule inhibitors of EGFR, which are primarily used as drugs for treating advanced NSCLC.
  • EGFR-tyrosine kinase inhibitor such as gefitinib or erlotinib
  • EGFR mutated NSCLC tumors have an in-frame insertion within exon 20 of EGFR (Arcila et al, 2012) .
  • 90%of human epidermal growth factor receptor 2 (HER2) mutations in NSCLC are exon 20 mutations (Mazieres et al, 2013) .
  • EGFR and HER2 kinase inhibitors such as gefitinib, erlotinib, osimertinib, lapatinib, etc. have limited activity in patients with EGFR and/or HER2 exon 20 mutant tumors.
  • the present disclosure provides novel compounds, pharmaceutical compositions, methods of preparing and using the same.
  • the compounds herein are inhibitors of EGFR and/or HER2 mutant proteins, such as those with mutations in the exon 20 domain as described herein.
  • the compounds and compositions herein are useful for treating various diseases or disorders, including cancer associated with EGFR and/or HER2 mutations in the exon 20 domain.
  • the present disclosure provides a compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof:
  • the compounds of Formula I can have a subformulae of I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, or I-2B as defined herein.
  • the compounds of Formula II can have a subformulae of II-1, II-2, II-3, II-1A, II-2A, or II-3A as defined herein.
  • the compounds of Formula III can have a subformulae of III-1 as defined herein.
  • the present disclosure also provides specific compound Nos. 1-94, or a pharmaceutically acceptable salt thereof.
  • Certain embodiments are directed to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more of the compounds of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos. 1-94, or a pharmaceutically acceptable salt thereof) and optionally a pharmaceutically acceptable excipient.
  • the pharmaceutical composition described herein can be formulated for different 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, such as a cancer described herein.
  • 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 I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos.
  • a compound of the present disclosure e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B)
  • Formula II e.
  • a method of treating cancer e.g., a cancer associated with EGFR and/or HER2 mutant protein which has an exon 20 mutation, in a subject in need thereof.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure or a therapeutically effective amount of a pharmaceutical composition described herein.
  • the cancer can be any one or more selected from lung cancer (e.g., non-small cell lung cancer) , breast cancer, stomach cancer, colorectal cancer, pancreatic cancer, prostate cancer, myeloma, head and neck cancer, ovarian cancer, uterine cancer, esophageal cancer, and metastatic cell carcinoma.
  • the cancer is associated with a mutation in the exon 20 domain of EGFR selected from A763insFQEA, V769insASV, D770insSVD, or H773insNPH, or T790M.
  • the cancer is associated with an NPH insertion in the exon 20 domain of EGFR, H773insNPH.
  • the cancer is associated with a T790M mutation in the exon 20 domain of EGFR concurrent with an exon 19 deletion mutation and/or an exon 21 point mutation (e.g., L858R) .
  • the cancer is associated with an YVMA insertion mutation in the exon 20 domain of HER2.
  • the administering 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 chemotherapeutic agent, therapeutic antibody, radiation, cell therapy, or immunotherapy.
  • novel compounds, pharmaceutical compositions, methods of preparation and methods of use are novel compounds, pharmaceutical compositions, methods of preparation and methods of use. It was discovered that the compounds of the present disclosure can have potent inhibition on EGFR mutant proteins with mutations in the exon 20 domain, such as with an insertion mutation. The compounds o the present disclosure can selectively inhibit mutant EGFR with mutations in the exon 20 domain over wild type EGFR.
  • Some embodiments of the present disclosure are directed to novel compounds.
  • the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof:
  • each of J 1 , J 3 , J 4 , and J 9 is independently C or N,
  • J 2 is CR 5 or N
  • each of J 5 , J 6 , J 7 , and J 8 is independently CR 6 or N,
  • bicyclic ring of J 1 -J 9 is a heteroaryl ring
  • R 4 is an optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted amino group;
  • R 5 is hydrogen, halogen, -CN, -OH, an optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl; or when both J 1 and J 3 are N, R 5 can also be an oxo group;
  • R 6 at each occurrence is independently hydrogen, halogen, -CN, -OH, an optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, an optionally substituted C 1-6 alkoxy, an optionally substituted C 3-6 cycloalkoxy, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl; and
  • R 7 is OH, an optionally substituted C 1-6 alkoxy, or an optionally substituted amino group, provided that when J 3 is N, R 7 is not OH;
  • R 2 is hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or an oxygen protecting group;
  • X is O, NR 20 , or an optionally substituted 4 to 7 membered heterocyclic ring, wherein R 20 is hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group;
  • L is absent or an optionally substituted C 1-6 alkylene, optionally substituted C 1-6 heteroalkylene, optionally substituted C 3-6 carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring;
  • R 3 is hydrogen, -NR 21 R 22 , or an optionally substituted 4 to 7 membered heterocyclyl, wherein R 21 and R 22 are independently hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group.
  • a in Formula I is A-1 or A-II,
  • J 1 -J 9 , R 4 , and R 7 can be any of those defined herein in any combination.
  • J 3 is N. In some embodiments, J 3 is C. In some embodiments, J 1 is N. In some embodiments, J 1 is C. In some embodiments, J 2 is N. In some embodiments, J 2 is CR 5 . Typically, J 4 and J 9 are both C. In some embodiments, one of J 4 and J 9 is N and the other of J 4 and J 9 is C.
  • a in Formula I is selected from A-1 to A-18:
  • a in Formula I is A-1. In some embodiments, A in Formula I is A-2. In some embodiments, A in Formula I is A-3. In some embodiments, A in Formula I is A-4. In some embodiments, A in Formula I is A-5. In some embodiments, A in Formula I is A-6. In some embodiments, A in Formula I is A-7. In some embodiments, A in Formula I is A-8. In some embodiments, A in Formula I is A-9. In some embodiments, A in Formula I is A-10. In some embodiments, A in Formula I is A-11. In some embodiments, A in Formula I is A-12.
  • a in Formula I is A-13. In some embodiments, A in Formula I is A-14. In some embodiments, A in Formula I is A-15. In some embodiments, A in Formula I is A-16. In some embodiments, A in Formula I is A-17. In some embodiments, A in Formula I is A-18.
  • a in Formula I comprises a –SO 2 -R 4 group.
  • A is a fused 5, 6-bicyclic heteroaryl group represented by A-I, as defined herein, such as A-1 to A-4 (i.e., A-1, A-2, A-3, or A-4) , or A-9 to A-13 (i.e., A-9, A-10, A-11, A-12, or A-13) .
  • the compound of Formula I can be a compound of Formula I-1:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, and L can be any of those defined herein in any combination.
  • the compound of Formula I can be a compound of Formula I-2:
  • R 1 , R 2 , R 3 , R 4 , R 6 , X, and L can be any of those defined herein in any combination.
  • the compound of Formula I can be a compound of Formula I-1A, I-1B, or I-2A:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, and L can be any of those defined herein in any combination.
  • the compound of Formula I can be a compound of Formula I-1C:
  • R 1 , R 2 , R 3 , R 4 , X, and L can be any of those defined herein in any combination.
  • the compound of Formula I can be a compound of Formula I-1D or 1E:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, and L can be any of those defined herein in any combination.
  • the compound of Formula I can be a compound of Formula I-1F or 1G:
  • R 1 , R 2 , R 3 , R 4 , X, and L can be any of those defined herein in any combination.
  • R 4 in Formula I is an optionally substituted C 1-6 alkyl, such as unsubstituted C 1-6 alkyl (e.g., methyl, ethyl, or isopropyl) or a C 1-6 alkyl substituted with 1-3 substituents independently selected from F, Cl, -CN, C 1-6 alkyl, C 1-6 alkyl substituted with 1-3 fluorine, C 1-6 alkoxy, C 1-6 alkoxy substituted with 1-3 fluorine, -OH, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) (C 1-6 alkyl) , cycl
  • R 4 in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1F, I-1H, or I-2B) or A-1 to A-4 or A-9 to A-13 can be an optionally substituted C 1-4 alkyl, such as an unsubstituted C 1-4 alkyl such as methyl, ethyl, or isopropyl.
  • R 4 in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1F, I-1H, or I-2B) or A-1 to A-4 or A-9 to A-13 can be a C 1-4 alkyl substituted with 1-3 fluorine, such as CF 3 .
  • R 4 in Formula I is an optionally substituted C 3-6 carbocyclic ring, such as unsubstituted C 3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) or C 3- 6 cycloalkyl substituted with 1-3 substituents independently selected from F, Cl, -CN, C 1-6 alkyl, C 1-6 alkyl substituted with 1-3 fluorine, C 1-6 alkoxy, C 1-6 alkoxy substituted with 1-3 fluorine, -OH, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) (C 1-6 alkyl) , cyclopropyl, and cyclobutyl.
  • C 3-6 carbocyclic ring such as unsubstituted C 3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) or C 3- 6 cycloalkyl substituted with 1-3 substitu
  • R 4 in Formula I is a cyclopropyl or cyclobutyl, which is optionally substituted with 1-2 substituents selected from methyl and fluorine.
  • R 4 in Formula I is an optionally substituted phenyl, such as substituted with 1-3 substituents independently selected from F, Cl, -CN, C 1-6 alkyl, C 1-6 alkyl substituted with 1-3 fluorine, C 1-6 alkoxy, C 1-6 alkoxy substituted with 1-3 fluorine, -OH, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) (C 1-6 alkyl) , cyclopropyl, and cyclobutyl.
  • 1-3 substituents independently selected from F, Cl, -CN, C 1-6 alkyl, C 1-6 alkyl substituted with 1-3 fluorine, C 1-6 alkoxy, C 1-6 alkoxy substituted with 1-3 fluorine, -OH, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) (C 1-6 alkyl) , cyclopropyl, and
  • R 4 in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1F, I-1H, or I-2B) or A-1 to A-4 or A-9 to A-13 is an unsubstituted phenyl.
  • R 4 in Formula I is a phenyl substituted with 1-3 substituents independently selected from F, Cl, -CN, C 1-4 alkyl, CF 3 , methoxy, -OH, cyclopropyl, and cyclobutyl.
  • R 4 in Formula I e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1F, I-1H, or I-2B
  • A-1 to A-4 or A-9 to A-13 is an optionally substituted amino group.
  • R 4 in Formula I e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1F, I-1H, or I-2B
  • A-1 to A-4 or A-9 to A-13 is unsubstituted amino group –NH 2 .
  • R 4 in Formula I is a monosubstituted amino group, such as a monoalkylamine, such as -NH (C 1-6 alkyl) , monocycloalkylamine, such as –NH (C 3-6 cycloalkyl) , wherein the C 1-6 alkyl or C 3-6 cycloalkyl can be optionally substituted with a permissible substituent as described herein.
  • a monoalkylamine such as -NH (C 1-6 alkyl)
  • monocycloalkylamine such as –NH (C 3-6 cycloalkyl)
  • C 1-6 alkyl or C 3-6 cycloalkyl can be optionally substituted with a permissible substituent as described herein.
  • R 4 in Formula I is -NH (C 1-4 alkyl) , such as –NH (methyl) , -NH (ethyl) , or -NH (isopropyl) .
  • R 4 in Formula I is a disubstituted amino group, for example, a dialkylamine, such as -N (C 1-6 alkyl) (C 1-6 alkyl) .
  • a dialkylamine such as -N (C 1-6 alkyl) (C 1-6 alkyl)
  • the two C 1-6 alkyl groups are independently selected, which can be the same or different.
  • -N (C 1-6 alkyl) (C 1-6 alkyl) includes without limitation both –N (CH 3 ) 2 and –N (CH 3 ) (C 2 H 5 ) .
  • Other similar expressions should be understood similarly.
  • R 4 in Formula I can be methyl, ethyl, isopropyl, -CF 3 , cyclopropyl, phenyl, -NH 2 , or -NH-CH 3 .
  • a in Formula I is A-I: e.g., A-1 to A-4, or A-11 or A-13, wherein J 2 is CR 5 , and the other variables can be any of those defined herein in any combination.
  • R 5 in Formula I e.g., Formula I-1, I-1B, I-1D, I-1E, or I-1H
  • A-1 to A-4, A-11 or A-13 is hydrogen, halogen, -CN, an optionally substituted C 1-6 alkyl or an optionally substituted C 3-6 cycloalkyl.
  • R 5 in Formula I e.g., Formula I-1, I-1B, I-1D, I-1E, or I-1H
  • A-1 to A-4, A-11 or A-13 is hydrogen.
  • R 5 in Formula I e.g., Formula I-1, I-1B, I-1D, I-1E, or I-1H
  • A-1 to A-4, A-11 or A-13 is a C 1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, C 1-6 alkyl, C 3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C 1-6 heteroalkyl, and –OH.
  • R 5 in Formula I e.g., Formula I-1, I-1B, I-1D, I-1E, or I-1H
  • A-1 to A-4, A-11 or A-13 is an unsubstituted C 1-4 alkyl, such as methyl, ethyl, isopropyl, etc.
  • R 5 in Formula I e.g., Formula I-1, I-1B, I-1D, I-1E, or I-1H
  • A-1 to A-4, A-11 or A-13 is a C 1-4 alkyl substituted with fluorines, such as CF 3 , C 1-4 alkyl substituted with a cyclopropyl, such as cyclopropylmethyl, or hydroxyl-substituted C 1-4 alkyl such as hydroxyethyl, etc.
  • R 5 in Formula I e.g., Formula I-1, I-1B, I-1D, I-1E, or I-1H
  • A-1 to A-4, A-11 or A-13 is a C 3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) optionally substituted with fluorine and/or methyl groups.
  • R 5 in Formula I e.g., Formula I-1, I-1B, I-1D, I-1E, or I-1H
  • A-1 to A-4, A-11 or A-13 can be cyclopropyl or cyclobutyl.
  • Other suitable groups for R 5 include those described herein.
  • a in Formula I is A-I, e.g., A-1 to A-4, or A-9 to A-13, wherein each of J 5 , J 6 , J 7 and J 8 is CR 6 or N as defined herein, and other variables can be any of those defined herein in any combination.
  • R 6 in Formula I e.g., Formula I-1, I-2, I-1A, I-1D, I-1E, I-1H, or I-2B
  • R 6 in Formula I is independently hydrogen, F, Cl, -CN, C 1-6 alkyl optionally substituted with 1-3 fluorine, C 1-6 alkoxy optionally substituted with 1-3 fluorine, C 3-6 cycloalkyl optionally substituted with 1-3 fluorine, C 3-6 cycloalkoxy optionally substituted with 1-3 fluorine.
  • 2, 3, or 4 of the R 6 groups are hydrogen, in other words, at least two of J 5 , J 6 , J 7 and J 8 are CH.
  • a in Formula I comprises a –CO-R 7 group.
  • A is a fused 5, 6-bicyclic heteroaryl group represented by A-II: e.g., A-5 to A-8 (i.e., A-5, A-6, A-7, or A-8) , or A-14 to A-18 (i.e., A-14, A-15, A-16, A-17, or A-18) wherein J 1 -J 9 and R 7 are defined herein.
  • J 3 is N.
  • J 3 is C.
  • J 1 is N.
  • J 1 is C.
  • J 2 is N.
  • J 2 is CR 5 .
  • J 4 and J 9 are both C.
  • one of J 4 and J 9 is N and the other of J 4 and J 9 is C.
  • R 7 is an optionally substituted amino group.
  • R 7 in Formula I e.g., those compounds having A-5 to A-8 or A-14 to A-18 as A
  • R 7 in Formula I is unsubstituted amino group –NH 2 .
  • R 7 in Formula I is a monosubstituted amino group, such as a monoalkylamine, such as -NH (C 1-6 alkyl) , monocycloalkylamine, such as –NH (C 3-6 cycloalkyl) , wherein the C 1-6 alkyl or C 3-6 cycloalkyl can be optionally substituted with a permissible substituents as described herein.
  • a monoalkylamine such as -NH (C 1-6 alkyl)
  • monocycloalkylamine such as –NH (C 3-6 cycloalkyl)
  • R 7 in Formula I is -NH (C 1-4 alkyl) , such as –NH (methyl) , -NH (ethyl) , or -NH (isopropyl) .
  • R 7 in Formula I is a disubstituted amino group, for example, a dialkylamine, such as -N (C 1-6 alkyl) (C 1-6 alkyl) .
  • R 7 can also be an optionally substituted C 1-6 alkoxy group, such as methoxy, ethoxy, isopropoxy group.
  • a in Formula I is A-II: e.g., A-5, A-6, A-7, A-8, A-16 or A-18, wherein J 2 is CR 5 , and the other variables can be any of those defined herein in any combination.
  • R 5 in Formula I e.g., those compounds having A-5, A-6, A-7, A-8, A-16 or A-18 as A
  • R 5 in Formula I is hydrogen, halogen, -CN, an optionally substituted C 1-6 alkyl or an optionally substituted C 3-6 cycloalkyl.
  • R 5 in Formula I e.g., those compounds having A-5, A-6, A-7, A-8, A-16 or A-18 as A
  • R 5 in Formula I is a C 1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, C 1-6 alkyl, C 3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C 1-6 heteroalkyl, and –OH.
  • R 5 in Formula I e.g., those compounds having A-5, A-6, A-7, A-8, A-16 or A-18 as A
  • R 5 in Formula I is an unsubstituted C 1-4 alkyl, such as methyl, ethyl, isopropyl, etc.
  • R 5 in Formula I is a C 1-4 alkyl substituted with fluorines, such as CF 3 , C 1-4 alkyl substituted with a cyclopropyl, such as cyclopropylmethyl, or hydroxyl-substituted C 1-4 alkyl such as hydroxyethyl, etc.
  • R 5 in Formula I is a C 3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) optionally substituted with fluorine and/or methyl groups.
  • R 5 in Formula I e.g., those compounds having A-5, A-6, A-7, A-8, A-16 or A-18 as A
  • R 5 in Formula I can be cyclopropyl or cyclobutyl.
  • Other suitable groups for R 5 include those described herein.
  • a in Formula I is A-II: e.g., A-5, A-6, A-7, A-8, or A-14 to A-18, wherein each of J 5 , J 6 , J 7 and J 8 is CR 6 or N as defined herein, and other variables can be any of those defined herein in any combination.
  • R 6 in Formula I when present, R 6 in Formula I (e.g., those compounds having A-5 to A-8 or A-14 to A-18 as A) or any of A-5 to A-8 or A-14 to A-18, at each occurrence is independently hydrogen, F, Cl, -CN, C 1-6 alkyl optionally substituted with 1-3 fluorine, C 1-6 alkoxy optionally substituted with 1-3 fluorine, C 3-6 cycloalkyl optionally substituted with 1-3 fluorine, C 3-6 cycloalkoxy optionally substituted with 1-3 fluorine.
  • 2, 3, or 4 of the R 6 groups are hydrogen, in other words, at least two of J 5 , J 6 , J 7 and J 8 in A-II are CH.
  • R 1 in Formula I Various groups can be used as R 1 in Formula I.
  • R 1 in Formula I e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1E, I-1G, I-1H, or I-2B
  • R 1 in Formula I is –L 1 -R 10 , wherein L 1 is absent, and R 10 is defined herein.
  • L 1 when L 1 is a 5 or 6 membered heteroarylene, it can link R 10 to the remaining structures via any two available attaching points, which can be through ring nitrogen atoms as valence permits.
  • R 10 is hydrogen.
  • R 10 is an optionally substituted C 1-6 alkyl, such as unsubstituted C 1-6 alkyl, e.g., a C 1-4 alkyl, methyl, ethyl, isopropyl, etc. or a C 1-6 alkyl optionally substituted with 1-3 fluorine, e.g., CF 3 .
  • R 10 is an optionally substituted C 3-6 carbocyclic ring, such as cyclopropyl or cyclobutyl.
  • Other suitable R 10 groups are described herein.
  • R 10 groups can be combined with any of the L 1 groups described herein to form a R 1 group.
  • L 1 is – (CH 2 ) p -, -O-, -O- (CH 2 ) p -, or 5 or 6 membered heteroarylene having 1-4 ring nitrogen atoms
  • R 1 in Formula I can be hydrogen, F, Cl, -CN, C 1-6 alkyl optionally substituted with 1-3 fluorine, C 1-6 alkoxy optionally substituted with 1-3 fluorine, C 3-6 carbocyclic ring optionally substituted with 1-3 substituents independently selected from C 1-6 alkyl and F, 4 to 7 membered heterocyclic ring optionally substituted with 1-3 substituents independently selected from C 1-6 alkyl and F, phenyl optionally substituted with 1-3 substituents independently selected from C 1-6 alkyl optionally substituted with 1-3 fluorine, C 1-6 alkoxy optionally substituted with 1-3 fluorine, F, -CN, and Cl, or 5 or 6 membered heteroaryl having 1-4 ring nitrogen atoms and optionally substituted with 1-3 substituent
  • R 2 in Formula I is typically hydrogen or an optionally substituted C 1-6 alkyl.
  • R 2 in Formula I e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1E, I-1F, or I-1G
  • R 2 in Formula I can be hydrogen, a C 1-4 alkyl (e.g., methyl) , or a C 1-4 alkyl substituted with one or more substituents independently selected from F, –OH, C 1-4 alkoxy, cyclopropyl, and C 1-4 heteroalkyl (such as -O–CH 2 CH 2 -O-CH 3 ) .
  • R 2 in Formula I can also be an oxygen protecting group (e.g., described herein) .
  • R 2 in Formula I e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1E, I-1F, or I-1G
  • R 2 in Formula I is hydrogen or methyl.
  • X in Formula I is O.
  • X in Formula I is NR 20 , wherein R 20 is defined herein.
  • R 20 is hydrogen, a C 1-4 alkyl (e.g., methyl) , or a nitrogen protecting group (e.g., described herein) .
  • R 20 is methyl.
  • X in Formula I is an optionally substituted 4-7 membered monocyclic saturated heterocyclic ring having 1-2 heteroatoms selected from N and O, such as an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH 2 , –NH (C 1-6 alkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) group, etc.
  • N and O such as an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH 2 , –NH (C 1-6 alkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) group, etc.
  • X is an optionally substituted 4-7 membered monocyclic saturated heterocyclic ring having 1-2 heteroatoms selected from N and O, such as
  • L in Formula I can be absent or a C 1-6 alkylene.
  • L in Formula I e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1E, I-1F, or I-1G
  • L in Formula I can be absent, -CH 2 -, or – (CH 2 ) 2 -.
  • R 3 in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1E, I-1F, or I-1G) can be hydrogen.
  • R 3 in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1E, I-1F, or I-1G) can be -NR 21 R 22 , wherein R 21 and R 22 are independently hydrogen, or an optionally substituted C 1-6 alkyl.
  • R 3 in Formula I can be —NH (C 1-6 alkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) , such as –NHCH 3 or -N (CH 3 ) 2 or –NHC 2 H 5 , –N (CH 3 ) (C 2 H 5 ) or -N (C 2 H 5 ) 2 .
  • R 3 in Formula I can be an optionally substituted monocyclic saturated heterocyclic ring having 1-2 heteroatoms selected from N and O, such as an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH 2 , –NH (C 1-6 alkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) group, etc.
  • R 3 in Formula I is e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1E, I-1F, or I-1G
  • X-L-R 3 is In some preferred embodiments, X-L-R 3 is
  • the compound of Formula I can have a Formula I-1H or I-2B:
  • R 1 , R 4 , R 5 , and R 6 can be any of those defined herein in any combination.
  • R 5 is hydrogen.
  • all of R 6 are hydrogen.
  • R 4 is methyl, ethyl, isopropyl, -CF 3 , cyclopropyl, phenyl, -NH 2 , or -NH-CH 3 .
  • R 1 , R 4 , R 5 , and R 6 include any of those described herein in any combination.
  • the present disclosure provides a compound of Formula II, or a pharmaceutically acceptable salt thereof:
  • G 1 is selected from:
  • C 1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, methyl, C 1-6 alkoxy optionally substituted with fluorine, C 3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, and 4-7 membered heterocyclic ring optionally substituted with fluorine and/or methyl groups,
  • Q 1 and Q 4 are independently C or N, Q 2 , Q 3 , and Q 5 are independently CH, N, O, or S, provided that the ring of Q 1 -Q 5 is a 5-membered heteroaryl ring;
  • R 30 and R 31 are independently hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group; or R 30 andR 31 are joined to form an optionally substituted 4-7 membered heterocyclic ring;
  • R 32 is hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring;
  • R 40 is hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring; and
  • R 41 is hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group when applicable;
  • G 2 is an optionally substituted fused bicyclic heteroaryl group, preferably, G 2 is
  • J 1 , J 4 , and J 9 is independently C or N
  • J 2 is CR 5B or N
  • J 3 is CR 5B , N, or NR 5A , as valence permits,
  • each of J 5 , J 6 , J 7 , and J 8 is independently CR 6 or N,
  • bicyclic ring of J 1 -J 9 is a heteroaryl ring
  • R 4 is an optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted amino group; and
  • R 2 is hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or an oxygen protecting group;
  • X is O, NR 20 , or an optionally substituted 4 to 7 membered heterocyclic ring, wherein R 20 is hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group;
  • L is absent or an optionally substituted C 1-6 alkylene, optionally substituted C 1-6 heteroalkylene, optionally substituted C 3-6 carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring;
  • R 3 is hydrogen, -NR 21 R 22 , or an optionally substituted 4 to 7 membered heterocyclyl, wherein R 21 and R 22 are independently hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group.
  • G 1 in Formula II is wherein R 30 and R 31 can be any of those defined herein in any combination.
  • R 30 and R 31 can be any of those defined herein in any combination.
  • one of R 30 and R 31 is hydrogen or C 1-6 alkyl, and the other of R 30 and R 31 is defined above.
  • one of R 30 and R 31 is hydrogen or C 1-6 alkyl, and the other of R 30 and R 31 is C 1-6 alkyl or a C 3-6 cycloalkyl.
  • R 30 and R 31 are joined to form a monocyclic 4-7 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from O, N, and S, with at least one of which being N, for example, an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH 2 , –NH (C 1-6 alkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) group, etc.
  • -NR 30 R 31 is –NH (C 1-6 alkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) , wherein the C 1-6 alkyl can be independently, for example, methyl, ethyl, isopropyl, etc.
  • G 1 in Formula II is wherein R 32 is C 1-6 alkyl or a C 3-6 cycloalkyl.
  • R 32 is C 1-6 alkyl or a C 3-6 cycloalkyl.
  • G 1 in Formula II is –COO (C 1-6 alkyl) , such as –C (O) -O-isopropyl.
  • G 1 in Formula II is wherein R 40 is defined herein.
  • R 40 is C 1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, C 1-6 alkyl, C 3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C 1-6 heteroalkyl, and –OH.
  • R 40 is C 1-6 alkyl such as methyl, ethyl, or isopropyl.
  • R 40 is a C 3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) optionally substituted with fluorine and/or methyl groups.
  • G 1 in Formula II is wherein Q 1 -Q 5 and R 41 can be any of those defined herein in any combination.
  • G 1 can be a 5-membered heteroaryl moiety selected from:
  • R 41 is C 1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, C 1-6 alkyl, C 3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C 1-6 heteroalkyl, and –OH.
  • R 41 is C 1-6 alkyl such as methyl, ethyl, or isopropyl.
  • R 41 is a C 3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) optionally substituted with fluorine and/or methyl groups.
  • G 1 in Formula II is an unsubstituted C 1-6 alkyl, such as methyl, ethyl, isopropyl, etc.
  • G 1 in Formula II is a C 1-6 alkyl substituted with 1-3 substituents independently selected from fluorine, methyl, C 1-6 alkoxy optionally substituted with fluorine, C 3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, and 4-7 membered heterocyclic ring optionally substituted with fluorine and/or methyl groups.
  • G 1 in Formula II is a C 1-6 alkyl substituted with 1-3 fluorine, such as CF 3 .
  • G 1 in Formula II is F, Cl, or CN.
  • G 1 in Formula II is C 1-6 alkoxy optionally substituted with fluorine, such as methoxy, ethoxy, isopropoxy, trifluoromethoxy, etc.
  • G 1 in Formula II is phenyl, which is optionally substituted 1-3 substituents independently selected from F, Cl, -CN, C 1-6 alkyl, C 1-6 alkyl substituted with 1-3 fluorine, C 1-6 alkoxy, C 1-6 alkoxy substituted with 1-3 fluorine, -OH, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) (C 1-6 alkyl) , cyclopropyl, and cyclobutyl.
  • G 1 in Formula II is cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl group.
  • G 1 in Formula II is a 4-7 membered heterocyclic ring, such as a monocyclic 4-7 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from O, N, and S, for example, azetidine, oxetane, pyrrolidine, piperidine, piperazine, morpholine, etc., which is optionally substituted with fluorine and/or methyl groups.
  • G 2 in Formula II is wherein J 1 -J 9 can be any of those defined herein in any combination.
  • G 2 in Formula II is selected from:
  • R 5A , R 5B , and R 6 can be any of those defined herein in any combination.
  • G 2 in Formula II is wherein R 5A , R 5B , and R 6 can be any of those defined herein in any combination.
  • R 5A is hydrogen, -S (O) 2 -R 4 , -C (O) -R 7 , optionally substituted C 1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C 1-6 alkyl, C 3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C 1-6 heteroalkyl, and –OH) , or optionally substituted C 3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups) ; and R 5B is hydrogen, halogen, -CN, optionally substituted C 1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine,
  • G 2 in Formula II can also be any of the A groups (e.g., A-1 to A-8) as defined herein in connection with Formula I.
  • G 1 and G 2 are suitable for Formula II.
  • the compound of Formula II can be characterized as having Formula II-1, II-2, or II-3:
  • R 5A , R 5B , R 6 , R 30 , R 31 , R 40 , R 41 , R 2 , R 3 , X, and L can be any of those defined herein in any combination.
  • one of R 30 and R 31 is hydrogen or C 1-6 alkyl, and the other of R 30 and R 31 is defined above.
  • one of R 30 and R 31 is hydrogen or C 1-6 alkyl, and the other of R 30 and R 31 is C 1-6 alkyl or a C 3-6 cycloalkyl.
  • R 30 and R 31 are joined to form a monocyclic 4-7 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from O, N, and S, with at least one of which being N, for example, an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH 2 , –NH (C 1-6 alkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) group, etc.
  • -NR 30 R 31 is –NH (C 1-6 alkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) , wherein the C 1-6 alkyl can be independently, for example, methyl, ethyl, isopropyl, etc.
  • R 40 is C 1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, C 1-6 alkyl, C 3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C 1-6 heteroalkyl, and –OH.
  • R 40 is C 1-6 alkyl such as methyl, ethyl, or isopropyl.
  • R 40 is a C 3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) optionally substituted with fluorine and/or methyl groups.
  • R 41 is C 1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, C 1-6 alkyl, C 3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C 1-6 heteroalkyl, and –OH. In some embodiments,
  • R 41 is C 1-6 alkyl such as methyl, ethyl, or isopropyl. In some embodiments, R 41 is a C 3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) optionally substituted with fluorine and/or methyl groups.
  • R 5A is hydrogen, -S (O) 2 -R 4 , -C (O) -R 7 , optionally substituted C 1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C 1-6 alkyl, C 3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C 1-6 heteroalkyl, and –OH) , or optionally substituted C 3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups) ; and R 5B is hydrogen, halogen, -CN, optionally substituted C 1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C 1-6 alkyl, C 3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C 1-6 heteroalkyl
  • G 1 in Formula II is C 1-6 alkyl, CF 3 , -CH 2 -O- (C 1-6 alkyl) , cyclopropyl, cyclobutyl, phenyl, F, Cl, CN, C 1-6 alkoxy, and G 2 in Formula II is wherein R 5A , R 5B , and R 6 can be any of those defined herein in any combination.
  • R 5A is hydrogen, -S (O) 2 -R 4 , -C (O) -R 7 , optionally substituted C 1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C 1-6 alkyl, C 3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C 1-6 heteroalkyl, and –OH) , or optionally substituted C 3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups) ; and R 5B is hydrogen, halogen, -CN, optionally substituted C 1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C 1-6 alkyl, C 3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C 1-6 heteroalkyl
  • G 2 in Formula II (e.g., Formula II-1, II-2, or II-3) can be selected from B-1 to B-4:
  • R 5B and R 6 can be any of those defined herein in any combination.
  • R 5B in Formula II e.g., Formula II-1, II-2, or II-3 or Formula II-1A, II-2A, or II-3A as described below
  • B-1 to B-2 moiety can be selected from:
  • a C 1-6 alkyl such as methyl, ethyl, isopropyl, etc.
  • a C 1-6 alkyl substituted with a C 3-6 cycloalkyl e.g., cyclopropyl or cyclobutyl
  • the C 3-6 cycloalkyl is optionally substituted with fluorine and/or methyl groups, such as –CH 2 -cyclopropyl, or
  • substitution with a C 1-6 heteroalkyl can be through any of the attaching point of the C 1-6 heteroalkyl.
  • C 1-6 heteroalkyl can be attached to the remainder of the structure via a terminal heteroatom, terminal carbon atom, internal heteroatom, or internal carbon atom, for example, –O-CH 2 CH 2 -OCH 3 , where the attaching point is via the terminal oxygen atom, HO-CH 2 CH 2 -O-CH 2 -, where the attaching point is via the terminal carbon atom, -N- (CH 3 ) 2 , where the attaching point is via the internal nitrogen atom, -CH (OCH 3 ) (CH 3 ) , where the attaching point is via the internal carbon atom.
  • R 5A in Formula II e.g., Formula II-1, II-2, II-3, II-1A, II-2A, or II-3A
  • R 5A in Formula II can be selected from:
  • a C 1-6 alkyl such as methyl, ethyl, isopropyl, etc.
  • R 4 is defined herein, such as methyl, ethyl, isopropyl, -CF 3 , cyclopropyl, phenyl, -NH 2 , and -NH-CH 3 ,
  • R 7 is defined herein, such as -NH (C 1-6 alkyl) , –NH (C 3-6 cycloalkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) ,
  • a C 1-6 alkyl substituted with a C 3-6 cycloalkyl e.g., cyclopropyl or cyclobutyl
  • the C 3-6 cycloalkyl is optionally substituted with fluorine and/or methyl groups, such as –CH 2 -cyclopropyl, or
  • R 6 in Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, or II-3A) at each occurrence can be independently hydrogen, F, Cl, -CN, C 1-4 alkyl optionally substituted with 1-3 fluorine, C 1-4 alkoxy optionally substituted with 1-3 fluorine, C 3-6 cycloalkyl optionally substituted with 1-3 fluorine, C 3-6 cycloalkoxy optionally substituted with 1-3 fluorine.
  • 2, 3, or 4 of the R 6 groups are hydrogen.
  • G 2 in Formula II e.g., Formula II-1, II-2, II-3, II-1A, II-2A, or II-3A
  • G 2 in Formula II can be selected from:
  • R 2 in Formula II is typically hydrogen or an optionally substituted C 1-6 alkyl.
  • R 2 in Formula II e.g., Formula II-1, II-2, or II-3
  • R 2 in Formula II can be hydrogen, a C 1-4 alkyl (e.g., methyl) , or a C 1-4 alkyl substituted with one or more substituents independently selected from F, –OH, C 1-4 alkoxy, cyclopropyl, and C 1-4 heteroalkyl (such as -O–CH 2 CH 2 -O-CH 3 ) .
  • R 2 in Formula II can also be an oxygen protecting group (e.g., described herein) .
  • R 2 in Formula II (e.g., Formula II-1, II-2, or II-3) is hydrogen or methyl.
  • X in Formula II (e.g., Formula II-1, II-2, or II-3) is O.
  • X in Formula II is NR 20 , wherein R 20 is defined herein.
  • R 20 is hydrogen, a C 1-4 alkyl (e.g., methyl) , or a nitrogen protecting group (e.g., described herein) .
  • R 20 is methyl.
  • X in Formula II is an optionally substituted 4-7 membered monocyclic saturated heterocyclic ring having 1-2 heteroatoms selected from N and O, such as an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH 2 , –NH (C 1-6 alkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) group, etc.
  • X is an optionally substituted 4-7 membered monocyclic saturated heterocyclic ring having 1-2 heteroatoms selected from N and O, such as an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH 2 , –NH (C 1-6 alkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) group, etc.
  • X is
  • L in Formula II can be absent or a C 1-6 alkylene.
  • L in Formula II e.g., Formula II-1, II-2, or II-3 can be absent, -CH 2 -, or – (CH 2 ) 2 -.
  • R 3 in Formula II (e.g., Formula II-1, II-2, or II-3) can be hydrogen.
  • R 3 in Formula II can be -NR 21 R 22 , wherein R 21 and R 22 are independently hydrogen, or an optionally substituted C 1-6 alkyl.
  • R 3 in Formula II e.g., Formula II-1, II-2, or II-3) can be —NH (C 1-6 alkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) , such as –NHCH 3 or -N (CH 3 ) 2 or –NHC 2 H 5 , –N (CH 3 ) (C 2 H 5 ) or -N (C 2 H 5 ) 2 .
  • R 3 in Formula II can be an optionally substituted monocyclic saturated heterocyclic ring having 1-2 heteroatoms selected from N and O, such as an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH 2 , –NH (C 1-6 alkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) group, etc.
  • R 3 in Formula II is
  • any of the X group can be combined with any of the L and any of the R 3 group defined herein for Formula II (e.g., Formula II-1, II-2, or II-3) .
  • X-L-R 3 is In some preferred embodiments, X-L-R 3 is
  • the compound of Formula II can have a Formula II-1A, II-2A, or II-3A:
  • R 5A , R 5B , R 6 , R 30 , R 31 , R 40 , and R 41 can be any of those defined herein in any combination.
  • one of R 30 and R 31 is hydrogen or C 1-6 alkyl, and the other of R 30 and R 31 is defined above.
  • one of R 30 and R 31 is hydrogen or C 1-6 alkyl, and the other of R 30 and R 31 is C 1-6 alkyl or a C 3-6 cycloalkyl.
  • R 30 and R 31 are joined to form a monocyclic 4-7 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from O, N, and S, with at least one of which being N, for example, an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH 2 , –NH (C 1-6 alkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) group, etc.
  • -NR 30 R 31 is –NH (C 1-6 alkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) , wherein the C 1-6 alkyl can be independently, for example, methyl, ethyl, isopropyl, etc.
  • R 40 is C 1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, C 1-6 alkyl, C 3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C 1-6 heteroalkyl, and –OH.
  • R 40 is C 1-6 alkyl such as methyl, ethyl, or isopropyl.
  • R 40 is a C 3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) optionally substituted with fluorine and/or methyl groups.
  • R 41 is C 1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, C 1-6 alkyl, C 3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C 1-6 heteroalkyl, and –OH.
  • R 41 is C 1-6 alkyl such as methyl, ethyl, or isopropyl.
  • R 41 is a C 3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) optionally substituted with fluorine and/or methyl groups.
  • R 5A , R 5B , R 6 can be any of those described herein in any combination.
  • the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt thereof:
  • C 1-6 alkyl e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C 1-6 alkyl, C 3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C 1-6 heteroalkyl, and –OH
  • C 3-6 cycloalkyl e.g., cyclo
  • R 5B is hydrogen, halogen, -CN, optionally substituted C 1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C 1-6 alkyl, C 3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C 1-6 heteroalkyl, and –OH) , or optionally substituted C 3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups) ;
  • R 4 is an optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted amino group; and
  • R 2 is hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or an oxygen protecting group;
  • X is O, NR 20 , or an optionally substituted 4 to 7 membered heterocyclic ring, wherein R 20 is hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group;
  • L is absent or an optionally substituted C 1-6 alkylene, optionally substituted C 1-6 heteroalkylene, optionally substituted C 3-6 carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring;
  • R 3 is hydrogen, -NR 21 R 22 , or an optionally substituted 4 to 7 membered heterocyclyl, wherein R 21 and R 22 are independently hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group.
  • the moiety of in Formula III (e.g., Formula III-1 as described below) can be selected from B-1 to B-4:
  • R 5B and R 6 can be any of those defined herein in any combination.
  • R 5B in Formula III (e.g., Formula III-1) or B-1 to B-2 moiety can be selected from:
  • a C 1-6 alkyl such as methyl, ethyl, isopropyl, etc.
  • a C 1-6 alkyl substituted with a C 3-6 cycloalkyl e.g., cyclopropyl or cyclobutyl
  • the C 3-6 cycloalkyl is optionally substituted with fluorine and/or methyl groups, such as –CH 2 -cyclopropyl, or
  • R 5A in Formula III (e.g., Formula III-1) can be selected from:
  • a C 1-6 alkyl such as methyl, ethyl, isopropyl, etc.
  • R 4 is defined herein, such as methyl, ethyl, isopropyl, -CF 3 , cyclopropyl, phenyl, -NH 2 , and -NH-CH 3 ,
  • R 7 is defined herein, such as -NH (C 1-6 alkyl) , –NH (C 3-6 cycloalkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) ,
  • a C 1-6 alkyl substituted with a C 3-6 cycloalkyl e.g., cyclopropyl or cyclobutyl
  • the C 3-6 cycloalkyl is optionally substituted with fluorine and/or methyl groups, such as –CH 2 -cyclopropyl, or
  • R 6 in Formula III (e.g., Formula III-1) at each occurrence can be independently hydrogen, F, Cl, -CN, C 1-4 alkyl optionally substituted with 1-3 fluorine, C 1-4 alkoxy optionally substituted with 1-3 fluorine, C 3-6 cycloalkyl optionally substituted with 1-3 fluorine, C 3-6 cycloalkoxy optionally substituted with 1-3 fluorine.
  • 2, 3, or 4 of the R 6 groups are hydrogen.
  • the moiety of in Formula III is selected from:
  • the moiety of in Formula III is selected from:
  • R 2 in Formula III is typically hydrogen or an optionally substituted C 1-6 alkyl.
  • R 2 in Formula III can be hydrogen, a C 1-4 alkyl (e.g., methyl) , or a C 1-4 alkyl substituted with one or more substituents independently selected from F, –OH, C 1-4 alkoxy, cyclopropyl, and C 1-4 heteroalkyl (such as -O–CH 2 CH 2 -O-CH 3 ) .
  • R 2 in Formula III can also be an oxygen protecting group (e.g., described herein) .
  • R 2 in Formula III is hydrogen or methyl.
  • X in Formula III is O.
  • X in Formula III is NR 20 , wherein R 20 is defined herein.
  • R 20 is hydrogen, a C 1-4 alkyl (e.g., methyl) , or a nitrogen protecting group (e.g., described herein) .
  • R 20 is methyl.
  • X in Formula III is an optionally substituted 4-7 membered monocyclic saturated heterocyclic ring having 1-2 heteroatoms selected from N and O, such as an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH 2 , –NH (C 1-6 alkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) group, etc.
  • X is an optionally substituted 4-7 membered monocyclic saturated heterocyclic ring having 1-2 heteroatoms selected from N and O, such as an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH 2 , –NH (C 1-6 alkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) group, etc.
  • X is
  • L in Formula III can be absent or a C 1-6 alkylene.
  • L in Formula III can be absent, -CH 2 -, or – (CH 2 ) 2 -.
  • R 3 in Formula III can be hydrogen.
  • R 3 in Formula III can be -NR 21 R 22 , wherein R 21 and R 22 are independently hydrogen, or an optionally substituted C 1-6 alkyl.
  • R 3 in Formula III can be —NH (C 1-6 alkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) , such as –NHCH 3 or -N (CH 3 ) 2 or –NHC 2 H 5 , –N (CH 3 ) (C 2 H 5 ) or -N (C 2 H 5 ) 2 .
  • R 3 in Formula III can be an optionally substituted monocyclic saturated heterocyclic ring having 1-2 heteroatoms selected from N and O, such as an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH 2 , –NH (C 1-6 alkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) group, etc.
  • R 3 in Formula III is an optionally substituted monocyclic saturated heterocyclic ring having 1-2 heteroatoms selected from N and O, such as an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH 2 , –NH (C 1-6 alkyl) or -N (C 1-6 alkyl) (C 1-6 alkyl) group, etc.
  • R 3 in Formula III is
  • X-L-R 3 is In some preferred embodiments, X-L-R 3 is
  • the compound of Formula III can have a Formula III-1:
  • R 5A , R 5B , and R 6 can be any of those defined herein in any combination.
  • the present disclosure also provides a compound selected from any of Compound Nos 1-94, or a pharmaceutically acceptable salt thereof:
  • the genus of compounds in the present disclosure also excludes any of the compounds specifically prepared and disclosed prior to the filing of this disclosure.
  • the present disclosure also provides synthetic methods and synthetic intermediates for preparing the compounds of Formula I, II, or III, as represented by the schemes herein.
  • Compounds of S-6 can be typically prepared from a compound of S-5 by reducing the nitro group, for example, using hydrogenation, such as in the presence of Pd/C.
  • Compounds of S-5 can be typically prepared by reacting S-3 with an agent of S-4, under conditions to replace the Lg 2 with X-L-R 3 .
  • Lg 2 is a halo such as F, Cl, Br, etc.
  • Lg 2 is F.
  • the agent of S-4 is an amine, such as which can react with the compound of S-3 to replace the Lg 2 and form the compound of S-5.
  • Compounds of S-3 can be prepared from reacting S-1 and S-2 under suitable conditions.
  • Lg 1 is a halo such as F, Cl, Br, etc., an oxygen containing leaving group such as mesylate, tosylate, trifluoromethanesulfonate, or a sulfone such as -SO 2 Me.
  • Suitable conditions for carrying out the transformations in Scheme 1 include any of those known in the art for similar transformations. Exemplary suitable conditions are also described herein in the Examples section.
  • the variables X, R 1 , R 2 , R 3 , L, and A in Scheme 1 can be any of those defined herein in any combination.
  • the introduction of the acryloyl group can occur earlier in the synthetic process.
  • compounds of Formula I can be prepared from reacting the analine S-11 with the pyrimidine S-1 under suitable conditions.
  • Lg 1 is a halo such as F, Cl, Br, etc., an oxygen containing leaving group such as mesylate, tosylate, trifluoromethanesulfonate, or a sulfone such as -SO 2 Me.
  • Analine of S-11 can be prepared from S-10 through deprotection of Pg 1 , which can be any nitrogen protecting group (e.g., described herein) , for example, an acid labile protecting group such as Boc (tert-butyloxycarbonyl) .
  • S-9 can be prepared by reducing the nitro precursor S-8, for example, using hydrogenation, such as in the presence of Pd/C.
  • Lg 2 is a halo such as F, Cl, Br, etc. or an oxygen containing leaving group such as mesylate, tosylate, trifluoromethanesulfonate.
  • Lg 2 is F.
  • the agent of S-4 is an amine, such as which can react with the compound of S-7 to replace the Lg 2 and form the compound of S-8.
  • Suitable conditions for carrying out the transformations in Scheme 2 include any of those known in the art for similar transformations. Exemplary suitable conditions are also described herein in the Examples section.
  • the variables X, R 1 , R 2 , R 3 , L, and A in Scheme 2 can be any of those defined herein in any combination.
  • S-1 can be readily prepared by those skilled in the art in view of the present disclosure.
  • S-1 can be prepared from coupling a compound of S-12 with S-13 under suitable conditions.
  • Lg 3 is a halogen such as Cl.
  • G 10 can be hydrogen, a boronic acid or ester, or a metal.
  • the reaction between S-12 and S-13 can be facilitated by a Lewis acid such as AlCl 3 , a suitable base, such as potassium tert-butoxide, or transition metal catalyst such as palladium. Exemplary procedures are also described herein in the Examples section.
  • the variables Lg 1 , Lg 3 , R 1 , R 2 , G 10 , and A in Scheme 3 can be any of those defined herein in any combination.
  • 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 I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos. 1-94, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient.
  • Pharmaceutically acceptable excipients are known in the art.
  • Non-limiting 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. See also Remington's The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro (Lippincott, Williams &Wilkins, Baltimore, Md., 2005; incorporated herein by reference) , which discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof.
  • absorption accelerators such as absorption accelerators, antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extend
  • the pharmaceutical composition can include any one or more of the compounds of the present disclosure.
  • the pharmaceutical composition comprises a compound of Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos. 1-94, or a pharmaceutically acceptable salt thereof) , e.g., in a therapeutically effective amount.
  • the pharmaceutical composition can comprise a therapeutically effective amount of a compound selected from compound Nos. 1-94, 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 I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos. 1-94, or a pharmaceutically acceptable salt thereof) .
  • a compound of the present disclosure e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I
  • 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 an EGFR and/HER2 mutant protein as described herein) , 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 with the compound of the present disclosure, and/or instructions for the treatment of the disease packaged with the medicaments.
  • the instructions may be fixed in any tangible medium, such as printed paper, or a computer readable magnetic or optical medium, or instructions to reference a remote computer data source such as a world wide web page accessible via the internet.
  • Compounds of the present disclosure are useful as therapeutic active substances, for example, for the treatment and/or prophylaxis of diseases or disorders that are associated with an EGFR and/or HER2 exon 20 mutation, such as an insertion mutation.
  • the present disclosure provides a method of inhibiting an EGFR and/or HER2 mutant protein which has an exon 20 mutation, such as one or more insertion, deletion, and/or point mutations in the exon 20 domain of the EGFR and/or HER2, the method comprising contacting a cell with an effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos. 1-94, or a pharmaceutically acceptable salt thereof) .
  • a compound of Formula I e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D
  • the present disclosure provides a method of treating a disease or disorder, e.g., a cancer associated with EGFR and/or HER2 mutant protein which has an exon 20 mutation, 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 I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos. 1-94, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein.
  • a compound of the present disclosure e.g., a compound of Formula I (e.g., Formula I-1
  • a method for treatment of cancer comprising administering to a subject in need thereof an effective amount of any of the compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-2, I- 1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos. 1-94, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising the compound of the present disclosure.
  • a compound of Formula I e.g., Formula I-1, I-2, I- 1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B
  • Formula II e.g., Formula II-1, II-2,
  • Non-limiting examples of cancer include lung cancer, breast cancer, stomach cancer, colorectal cancer, pancreatic cancer, prostate cancer, myeloma, head and neck cancer, ovarian cancer, uterine cancer, esophageal cancer, and metastatic cell carcinoma.
  • the cancer comprises non-small cell lung cancer.
  • the present disclosure provides a method of treating a disease or disorder (e.g., a cancer described herein) in a subject in need thereof, wherein the method comprises determining if the subject has an EGFR and/or HER2 exon 20 mutation, such as an insertion mutation, and if the subject is determined to have EGFR and/or HER2 exon 20 mutation, e.g., an insertion mutation, then administering to the subject a therapeutically effective dose of at least one compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos.
  • a compound of Formula I e.
  • Mutation detection methods are known the art including PCR analyses and nucleic acid sequencing as well as FISH and CGH.
  • the exon 20 mutations are detected by DNA sequencing, such as from a tumor or circulating free DNA from plasma.
  • EGFR and/or HER2 exon 20 mutation include any of those described herein and those described in WO2015/195228, WO2015/175632, WO2020/061470, WO2020/068867, WO2020/068873, WO2020/039060, and references cited therein; see also Vyse, S. and Huang P.H. Signal Transduction and Targeted Therapy (2019) 4: 5; https: //doi. org/10.1038/s41392-019-0038-9.
  • the EGFR exon 20 mutation (s) may comprise one or more point mutations, insertions, and/or deletions of 3-18 nucleotides between amino acids 763-778. In some embodiments, the EGFR exon 20 mutation (s) may be located at one or more residues selected from the group consisting of A763, A767, S768, V769, D770, N771, P772, and H773. In some embodiments, in addition to an EGFR exon 20 mutation, the subject herein may also have one or more EGFR exon 19 mutation such as exon 19 deletion, L858R, and L861Q, etc.
  • the EGFR exon 20 mutation (s) includes an exon 20 insertion such as H773_V774insH, A767_v769ASV, N771_P772insH, D770_N771insG, H779_V774insH, N771delinsHH, S768_D770dupDVD, A767_V769dup ASV, A767_V769dupASV, P772_H773dup, N771_H773dupNPH, S768_D770dupSVD, N771delinsGY, S768_D770delinsSVD, D770_D770delinsGY, A767_V769dupASV, and/or H773dup.
  • an exon 20 insertion such as H773_V774insH, A767_v769ASV, N771_P772insH, D770_N771insG,
  • the EGFR exon 20 mutation (s) comprises A763insFQEA, A767insASV, S768dupSVD, V769insASV, D770insSVD, D770insNPG, H773insNPH, N771del insGY, N771del insFH and/or N771dupNPH.
  • the cancer herein is associated with an insertion mutation in the exon 20 domain of EGFR. In some embodiments, the cancer herein is associated with a mutation in the exon 20 domain of EGFR selected from A763insFQEA, V769insASV, D770insSVD, or H773insNPH, or T790M. In some embodiments, the cancer is associated with an NPH insertion in the exon 20 domain of EGFR, H773insNPH.
  • the cancer is associated with a T790M mutation in the exon 20 domain of EGFR concurrent with an exon 19 deletion mutation and/or an exon 21 point mutation.
  • the HER2 exon 20 mutation may comprise one or more point mutations, insertions, and/or deletions of 3-18 nucleotides between amino acids 770-785.
  • the one or more HER2 exon 20 mutations may be at residue A775, G776, S779, and/or P780.
  • the one or more HER2 exon 20 mutations may be A775insV G776C, A775insYVMA, G776V, G776C V777insV, G776C V777insC, G776del insVV, G776del insVC, and/or P780insGSP.
  • the cancer herein is also associated with a mutation in the exon 20 domain of HER2. In some embodiments, the cancer is associated with an YVMA insertion mutation in the exon 20 domain of HER2.
  • 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 agent, chemotherapeutic agent, therapeutic antibody, radiation, cell therapy, 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 (e.g., a subject having a cancer associated with an EGFR and/HER2 mutation as described herein) .
  • the additional pharmaceutically active compound can be a targeted agent, a chemotherapeutic agent, a therapeutic antibody, etc. Any of the known chemotherapeutics can be used in combination with the compounds of the present disclosure.
  • compounds of the present disclosure can also be used in combination with a radiation therapy, hormone therapy, cell therapy, surgery and immunotherapy, which therapies are well known to those skilled in the art.
  • the chemotherapeutic is selected from the group an antimetabolite, a mitotic inhibitor, alkylating agent, a platinum-based antineoplastic drug, an antibody-drug conjugate consisting of the EGFR monoclonal antibody and toxic payload such as T-DM1, a targeted agent such as c-MET tyrosine kinase inhibitor, immune checkpoint inhibitors such as anti-PD-1/PD-L1 or anti-CTLA4 antibody, an mTOR inhibitor, a VEGF inhibitor, an aromatase inhibitor, a CDK4/6 inhibitor, and any combination thereof.
  • Non-limiting examples of useful additional pharmaceutically active compounds include but not limited to (Imatinib Mesylate) , (carfilzomib) , (bortezomib) , Casodex (bicalutamide) , (gefitinib) , venetoclax, and Adriamycin.
  • Non-limiting examples of useful additional pharmaceutically active compounds also include but not limited to alkylating agents such as thiotepa and cyclosphosphamide (CYTOXANTM) ; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard;
  • Non-limiting examples of useful additional pharmaceutically active compounds also include but not limited to anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen, (NolvadexTM) , raloxifene, aromatase inhibiting 4 (5) -imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston) ; and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16) ; ifosfamide; mitomycin C; mitoxantrone; vincri
  • the compounds or pharmaceutical composition of the present disclosure can be used in combination with commonly prescribed anti-cancer drugs such as ABVD, AVICINE, Abagovomab, Acridine carboxamide, Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins, Antineoplastic, Antitumorigenic herbs, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar, Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy) , Calyculin, cell-cycle nonspecific antineoplastic agents, Dichloroacetic acid, Discodermolide, Elsamitrucin, Enocita
  • the compounds of the present disclosure may also be used in combination with an additional pharmaceutically active compound that disrupts or inhibits RAS-RAF-ERK or PI3K-AKT-TOR signaling pathways.
  • the additional pharmaceutically active compound is a PD-1 and PD-L1 antagonist.
  • the compounds or pharmaceutical compositions of the disclosure can also be used in combination with an amount of one or more substances selected from EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, Mcl-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immune therapies, including monoclonal antibodies, immunomodulatory imides (IMiDs) , anti-PD-1, anti-PDL-1, anti-CTLA4, anti-4-1-BB, anti-LAG1, anti-GITR and anti-OX40 antibodies, CAR-T cells, and BiTEs.
  • IMDs immunomodulatory imides
  • WO 2006/121168 A1 each of which are expressly incorporated by reference herein, include: pembrolizumab nivolumab Yervoy TM (ipilimumab) or Tremelimumab (to CTLA-4) , galiximab (to B7.1) , M7824 (a bifunctional anti-PD-L1/TGF- ⁇ Trap fusion protein) , AMP224 (to B7DC) , BMS-936559 (to B7-H1) , MPDL3280A (to B7-H1) , MEDI-570 (to ICOS) , AMG 404, AMG557 (to B7H2) , MGA271 (to B7H3) , IMP321 (to LAG-3) , BMS-663513 (to CD137) , PF-05082566 (to CD137) , CDX-1127 (to CD27) , anti-OX40 (Providence Health Services) , huMAb
  • Immune therapies also include genetically engineered T-cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTEs) .
  • Non-limiting useful additional agents also include anti-EGFR antibody, anti-EGFR/cMET antibody and anti-EGFR antibodies such as cetuximab (Erbitux) , panitumumab (Vectibix) , zalutumumab, nimotuzumab, matuzumab, and EGFR inhibitors such as gefitinib (Iressa) , erlotinib (Tarceva) , lapatinib (TykerB) , osimertinib (Tagrisso) , etc.
  • Non-limiting useful additional agents also include CDK inhibitors such as CDK4/6 inhibitors, such as palbociclib, abemaciclib, ribociclib, etc.
  • Non-limiting useful additional agents also include MEK inhibitors such as trame
  • 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 , X, L, and A in Formula I can be combined with any of the definitions of the others of X, R 1 , R 2 , R 3 , X, L, and A in Formula I. Such combination is contemplated and within the scope of the present disclosure.
  • 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 skilled 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.
  • a stereochemistry is specifically drawn, it should be understood that with respect to that particular chiral center or axial chirality, the compound exists 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 area, or both, or with a non-detectable amount of the other stereoisomer (s) .
  • the presence and/or amounts of stereoisomers can be determined by those skilled in the art in view of the present disclosure, including through the use of chiral HPLC.
  • 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” refers to any of the compounds described herein according to Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos.
  • Formula I e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B
  • Formula II e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A
  • Formula III e.g., Formula III-1) , any of compound Nos.
  • isotopically labeled compound (s) thereof such as a deuterated analog wherein one 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 including diastereoisomers, enantiomers, and racemic mixtures
  • geometric isomers thereof including diastereoisomers, enantiomers, and racemic mixtures
  • atropisomers thereof including diastereoisomers, enantiomers, and racemic mixtures
  • tautomers 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) .
  • pharmaceutically acceptable salts thereof e.g., acid addition salt such as HCl salt or base addition salt such as Na salt
  • Compounds 1-94 refers to the compounds described herein labeled as integers 1, 2, 3, ..., 94, see for example the title compounds of Examples 1-21 and Table 1. 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.
  • 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 disclosure.
  • 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 group is a C 1-6 alkyl group.
  • the alkyl group is a C 1-4 alkyl groupselected from methyl, ethyl, propyl (n-propyl) , isopropyl, butyl (n-butyl) , sec-butyl, tert-butyl, and iso-butyl.
  • 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.
  • heteroalkyl refers to an alkyl group as defined above, with one or more carbon being replaced with a heteroatom, such as O or N. Those skilled in the art would understand that an O atom will replace a CH 2 unit and an N atom will replace a CH unit.
  • a heteroalkyl can be designated by its number of carbons. For example, a C 1-4 heteroalkyl refers to a heteroalkyl group containing 1-4 carbons.
  • heteroalkyl examples include but not limited to –O-CH 2 CH 2 -OCH 3 , HO-CH 2 CH 2 -O-CH 2 -, -CH 2 CH 2 -N (H) -CH 3 , -N- (CH 3 ) 2 , -CH (CH 3 ) (OCH 3 ) , etc.
  • heteroalkylene as used by itself or as part of another group refers to a divalent radical derived from a heteroalkyl group.
  • 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.
  • haloalkyl as used by itself or as part of another group 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, two, or three fluorine atoms.
  • 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 a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms ( “C 3–10 cycloalkyl” ) . In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ( “C 3–8 cycloalkyl” ) . In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ( “C 3–6 cycloalkyl” ) . In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ( “C 5–6 cycloalkyl” ) . In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ( “C 5–10 cycloalkyl” ) .
  • 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” ) .
  • 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” ) .
  • 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, carbazolyl, 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, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, 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, carbocyclylene, heterocyclylene, arylene, and heteroarylene refer to the corresponding divalent radicals of alkyl, alkenyl, alkynyl, 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 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, 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 heteroatoms independently selected
  • each instance of R ee is, independently, selected from C 1–6 alkyl, C 1–6 haloalkyl, C 2–6 alkenyl, C 2–6 alkynyl, C 3–10 carbocyclyl, C 6–10 aryl, 3–10 membered heterocyclyl, and 3–10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg 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, salicylate, 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, salicylate, 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, methoxylmethyl (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 methane
  • 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- (a different 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.
  • 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. Exemplary embodiments of steps for performing the synthesis of products described herein are described in greater detail infra.
  • Step 2 To a solution of 18-1 (500 mg, 1.58 mmol) in DMF (5 mL) was added NaH (95 mg, 60%, 2.37 mmol) at 0°C. After stirring at 0°C for 10min, methanesulfonyl chloride (272 mg, 2.37 mmol) was added dropwise and the mixture was stirred at room temperature for 2 h. The mixture was poured into water and filtered. The filter cake was washed with water and dried to afford 18-2 which was used directly in the next step without purification.
  • Step 3 A mixture of crude 18-2 (300 mg, 0.76 mmol) , 4-fluoro-2-methoxy-5-nitroaniline (170 mg, 0.91 mmol) , p-TsOH (144 mg, 0.84 mmol) in dioxane (8 mL) was stirred at 100°Cfor 12 h. The mixture was cooled, poured into water and filtered. The filter cake was washed with water and dried to afford 18-3 which was used directly in the next step without purification.
  • Step 5 A mixture of 18-4 (600 mg, 0.96 mmol) and 10%Pd/C (179 mg) in MeOH (60 mL) was stirred at room temperature for 12 h under H 2 atmosphere. The mixture was filtered and concentrated to afford 18-5 which was used directly in the next step without purification.
  • Step 6 Acryloyl chloride (9 mg, 0.1 mmol) was added dropwise to a solution of crude 18-5 (60 mg, 0.1 mmol) and DIEA (26 mg, 0.2 mmol) in dichloromethane (2 mL) at 0°C. After stirring at 0°C for 5 min, the mixture was poured into 10 mL of ice-water and extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by prep-HPLC (acetonitrile with 0.05%of FA in water: 5%to 35%) to afford 18 as a 0.5 FA salt.
  • Step 2 A mixture of N 1 , N 1 , N 2 -trimethylethane-1, 2-diamine (24.5 g, 240.6 mmol) , 71-1 (57.4 g, 200.5 mmol) and DIEA (25.9 g, 200.5 mmol) in dimethylacetamide (800 mL) was stirred at 60°C for 2 h. The mixture was quenched with water and extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous Na 2 SO 4 , filtered and concentrated to afford 71-2 which was used directly in the next step without purification.
  • Step 3 A mixture of crude 71-2 (66.3 g, 179.95 mmol) and 10%Pd/C (600 mg) in ethyl acetate (1000 mL) was stirred at room temperature for 16 h under H 2 atmosphere. The reaction mixture was filtered and concentrated to afford 71-3 which was used directly in the next step without purification.
  • Step 6 A mixture of 2, 4-dichloro-5-iodopyrimidine (2.0 g, 7.3 mmol) and AlCl 3 (1.07 g, 8.45 mmol) in dichloroethane (20 mL) was stirred at 80°C for 0.5 h under N 2 . After cooling to room temperature, indole (811 mg, 6.93 mmol) was added. The resulting mixture was stirred at 80°C for 18 h under N 2 . The mixture was cooled, quenched with ice-water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by flash chromatography (12 g, 0 to 100%of ethyl acetate in petroleum ether) to afford 71-6.
  • Step 7 To a solution of 71-6 (1.0 g, 2.8 mmol) in dry THF (20 mL) was added NaH (60%in oil, 225 mg, 5.6 mmol) at 0°C. The mixture was stirred at 0°C for 1 h. Ethanesulfonyl chloride (542 mg, 4.2 mmol) was added at 0°C and the solution was stirred at room temperature for 2 h. The mixture was quenched with ice water, and extracted with ethyl acetate. The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash chromatography (12 g, 0%to 30%of ethyl acetate in petroleum ether) to afford 71-7.
  • Step 8 A mixture of 71-7 (550 mg, 1.23 mmol) , copper (I) iodide (46.8 mg, 0.25 mmol) and bis (triphenylphosphine) palladium (II) chloride (86 mg, 0.12 mmol) in triethylamine (6 mL) and DMF (0.05 mL) in a sealed tube was stirred at room temperature under nitrogen. 3-methylbut-1-yne (251 mg, 3.69 mmol) was then added via syringe. The mixture was stirred at room temperature for 16 h, and then quenched with ethyl acetate and water. The separated organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by flash chromatography (0%to 20%ethyl acetate in petroleum) to afford 71-8.
  • Step 9 A mixture of 71-8 (424 mg, 1.45 mmol) , 71-5 (421 mg, 1.45 mmol) , Pd 2 (dba) 3 (110 mg, 0.12 mmol) , BINAP (150 mg, 0.24 mmol) and cesium carbonate (1.18 g, 3.63 mmol) in anhydrous 1, 4-dioxane (10 mL) was stirred at 100°C for 16 h under nitrogen. The mixture was cooled, poured into water and extracted with ethyl acetate. The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated.
  • Step 2 A mixture of 3-bromo-1- [ [2- (trimethylsilyl) ethoxy] methyl] indazole (2.0 g, 6.1 mmol) , Pd (dppf) Cl 2 (890 mg, 1.2 mmol) , KOAc (2.4 g, 24.4 mmol) and 4, 4, 5, 5-tetramethyl-2- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (1.86 g, 7.3 mmol) in dioxane (30 mL) was stirred at 0°C under argon atmosphere for 16 h. The mixture was then concentrated to afford crude 74-2 which was used directly in the next step without purification.
  • Step 6 To a solution of 74-5 (100 mg, 0.2 mmol) in pyridine (3 mL) was added methanesulfonyl chloride (69 mg, 0.6 mmol) at 0°C. The resulting mixture was stirred at room temperature for 16 h. The mixture was purified by reverse phase HPLC (acetonitrile with 0.05%of FA in water: 10%to 35%) to afford 74 as a 0.3 FA salt.
  • Step 2 To a solution of 43-1 (2.09 g, 12 mmol) in ethanol (36 mL) was added a solution of sodium sulfide (2.81 g, 36 mmol) in water (4.8 mL) . The mixture was stirred at 50°C for 2 h under N 2 atmosphere. To above mixture was added 2-iodopropane (2.45 g, 14.4 mmol) , and the resulting mixture was stirred for an additional 1 h. After being cooled to room temperature, the mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to afford 43-2 which was used directly in the next step without purification.
  • Step 4 A mixture of 43-3 (446 mg, 2.0 mmol) , 2, 4-dichloropyrimidine (592 mg, 4.0 mmol) and potassium carbonate (828 mg, 6.0 mmol) in acetonitrile (20 mL) was stirred at 50°C for 16 h under N 2 atmosphere. After being cooled to room temperature, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by prep-HPLC (acetonitrile with 0.05%of TFA in water: 15%to 95%) to afford 43-4.
  • Step 5 A mixture of 43-4 (55 mg, 0.17 mmol) , 71-5 (44 mg, 0.15 mmol) , ( ⁇ ) -2, 2'-bis (diphenylphosphino) -1, 1'-binaphthalene (19 mg, 0.03 mmol) , cesium carbonate (98 mg, 0.3 mmol) and tris (dibenzylideneacetone) dipalladium (14 mg, 0.015 mmol) in 1, 4-dioxane (1.5 mL) was stirred at 130°C for 30 min under N 2 atmosphere under microwave conditions.
  • Step 1 A mixture of 3- (methylsulfonyl) -1H-indole (6.9 g, 35 mmol) , potassium carbonate (12.4 g, 90 mmol) and ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate (5.8 g, 25 mmol) in acetonitrile (200 mL) was stirred at 70°C for 16 h. The reaction mixture was filtered, and the filter was concentrated. The residue was triturated with methyl tert-butyl ether to afford 46-1.
  • Step 2 To a mixture of 46-1 (5.5 g, 17.2 mmol) in dichloromethane (250 mL) was added 3-chloroperbenzoic acid (7.7 g. 37.8 mmol) . The reaction was stirred at 20°C for 16 h. The mixture was diluted with dichloromethane. The mixture was washed with saturated sodium bicarbonate solution, 2 M sodium sulfite solution, brine and concentrated to afford crude 46-2.
  • Step 3 A mixture of crude 46-2 (5.9 g, 14.2 mmol) , 4-fluoro-2-methoxy-5-nitroaniline (3.3 g, 18 mmol) and 4-methylbenzenesulfonic acid (3.1 g, 18 mmol) in pentan-2-ol (100 mL) was stirred at 110°C for 4 h. Then the mixture was cooled to 50°C and filtered to afford 46-3.
  • Step 4 A mixture of 46-3 (5.5 g, 10 mmol) , N, N, N'-trimethylethylenediamine (1.4 g, 14 mmol) and N, N-diisopropylethylamine (3.2 g, 25 mmol) in dimethylacetamide (70 mL) was stirred at 70°C for 8 h. The mixture was cooled and filtered to afford 46-4.
  • Step 5 A mixture of 46-4 (6.5 g, 10.6 mmol) and potassium hydroxide (12.0 g, 212 mmol, in 100 mL water) in tetrahydrofuran (100 mL) /water (100 mL) was stirred at 50°C for 24 h, then cooled to room temperature. The solids were collected by filtration to afford 46-5.
  • Step 6 A mixture of 46-5 (583 mg, 1.0 mmol) , O- (7-aza-1H-benzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (456 mg, 1.2 mmol) and N, N-diisopropylethylamine (387 mg, 3.0 mmol) in N, N-dimethylformamide (20 mL) was stirred at 0°C for 0.5 h. Then propan-2-amine (71 mg, 1.2 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water, and solids were collected by filtration to afford 46-6.
  • Step 7 A mixture of 46-6 (300 mg, 0.48 mmol) and 10%Pd/C (40 mg) in methanol (2 mL) and tetrahydrofuran (20 mL) was stirred at room temperature for 5 h under hydrogen atmosphere, then filtered. The filtrate was concentrated to afford crude 46-7.
  • Step 8 To a solution of crude 46-7 (50 mg, 0.08 mmol) and N, N-diisopropylethylamine (22 mg, 0.17 mmol) in dichloromethane (5 mL) was added a solution of acryloyl chloride (7.2 mg, 0.08 mmol) in dichloromethane (2 mL) dropwise at 0°C. After being stirred for 10 min at 0°C, the mixture was concentrated and purified by prep-HPLC (acetonitrile with 0.05%of TFA in water: 15%to 95%) to afford 46.
  • Step 1 Compound 50-1 was prepared following the procedure for the synthesis of 46-1 in example 5.
  • Step 4 To a solution of 50-3 (100 mg, 0.31 mmol) in sec-pentanol (5 mL) was added 71-5 (90 mg, 0.31 mmol) and p-toluenesulfonic acid (106 mg, 0.62 mmol) at room temperature. The reaction was stirred at 120°C for 16 h under N 2 atmosphere. The mixture was filtered, and the filter cake was purified by prep-HPLC (acetonitrile with 0.05%of TFA in water: 5%to 40%) to afford 50.
  • prep-HPLC acetonitrile with 0.05%of TFA in water: 5%to 40%
  • Step 2 Compound 62-2 was prepared following the procedure for the synthesis of 46-1 in example 5.
  • Step 3 Compound 62-3 was prepared following the procedure for the synthesis of 43-3 in example 4.
  • Step 4 Compound 62 was prepared following the procedure for the synthesis of 43 in example 4 as a mono TFA salt.
  • Step 1 To a solution of indole (6.38 g, 54.5 mmol) in tetrahydrofuran (60 mL) was added potassium tert-butoxide (6.72 g, 60 mmol) at room temperature. The mixture was stirred for 30 min under N 2 atmosphere. A solution of triethylborane (1.0 M in tetrahydrofuran, 60 mL, 60 mmol) was then added dropwise, and the reaction was stirred for an additional 30 min. To above mixture was added ethanesulfonyl chloride (7.68 g, 60 mmol) at -15°C over 30 min.
  • Step 2 Compound 72-2 was prepared following the procedure for the synthesis of 46-1 in example 5.
  • Step 3 A mixture of 72-2 (600 mg, 1.5 mmol) , phenylboronic acid (220 mg, 1.8 mmol) , sodium carbonate (318 mg, 3.0 mmol) , and tetrakis (triphenylphosphine) palladium (87 mg, 0.075 mmol) in 1, 4-dioxane (10 mL) /water (1 mL) was stirred for 6 h at 90°C under N 2 atmosphere. The mixture was filtered and concentrated. The residue was purified by prep-HPLC (acetonitrile with 0.05%of TFA in water: 15%to 95%) to afford 72-3.
  • Step 4 72 was prepared following the procedure for the synthesis of 74-4 in example 3 as a mono TFA salt.
  • Step 1 A mixture of 72-1 (448 mg, 2.1 mmol) , 2, 4-dichloro-5-methylpyrimidine (695 mg, 4.3 mmol) and potassium carbonate (886 mg, 6.4 mmol) in acetonitrile (20 mL) was stirred at 50°C for 16 h under N 2 atmosphere. After being cooled to room temperature, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by prep-HPLC (acetonitrile with 0.05%of TFA in water: 15%to 95%) to afford 40-1.
  • Step 2 A mixture of 40-1 (74 mg, 0.22 mmol) , 71-5 (58 mg, 0.2 mmol) , 2, 2'-bis (diphenylphosphino) -1, 1'-binaphthalene (25 mg, 0.04 mmol) , cesium carbonate (130 mg, 0.4 mmol) and tris (dibenzylideneacetone) dipalladium (18 mg, 0.02 mmol) in 1, 4-dioxane (3 mL) was stirred under microwave conditions for 30 min at 130°C under N 2 atmosphere. After being cooled to room temperature, the reaction mixture was filtered and concentrated.
  • Step 1 Compound 4-1 was prepared following the procedure for the synthesis of 71-6 in example 2.
  • Step 2 To a solution of 4-1 (2 g, 6.5 mmol) and Boc 2 O (1.52 g, 7 mmol) in dichloromethane (100 mL) was added 4-dimethylaminopyridine (36.6 mg, 0.03 mmol) . The reaction was stirred at room temperature for 2 h. The reaction was filtered and the filter cake was washed with petroleum ether (10 mL) to afford 4-2.
  • Step 4 To a solution of 4-3 (600 mg, 1.63 mmol) in methanol (15 mL) and tetrahydrofuran (15 mL) was added a solution of potassium carbonate (1.2 g, 8.6 mmol) in water (30 mL) . The reaction mixture was stirred at 65°C overnight. The mixture was cooled, poured into water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na 2 SO 4 and concentrated to afford 4-4.
  • Step 5 Compound 4 was prepared following the procedure for the synthesis of 50 in example 6 as a mono TFA salt.
  • Step 2 Compound 8-2 was prepared following the procedure for the synthesis of 71-6 in example 2.
  • Step 3 Compound 8 was prepared following the procedure for the synthesis of 50 in example 6.
  • Step 1 To a solution of o-toluidine (5.35 g, 50 mmol) and triethylamine (5.56 g, 55 mmol) in dichloromethane (40 mL) was added a solution of isobutyl chloride (5.83 g, 55 mmol) in dichloromethane (10 mL) at 0°C, and the reaction was stirred for 30 min under N 2 atmosphere. The mixture was quenched with water and extracted with dichloromethane. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was triturated with dichloromethane/petroleum ether (1/2) to afford 9-1.
  • Step 3 To a solution of 9-2 (280 mg, 1.76 mmol) in 2-methyl-tetrahydrofuran (4 mL) was added methylmagnesium bromide (3.0 M in 2-methyltetrahydrofuran, 1.76 mL, 5.28 mmol) dropwise at 0°C under N 2 atmosphere. The mixture was stirred for 0.5 h at room temperature. A solution of 2, 4-dichloropyrimidine (521 mg, 3.52 mmol) in 2-methyltetrahydrofuran (2 mL) was then added dropwise at room temperature. The mixture was stirred at reflux overnight.
  • Step 4 Compound 9 was prepared following the procedure for the synthesis of 50 in example 6.
  • Step 1 A solution of 1M lithium hydroxide (48 mL, 48 mmol) was added to ethyl 2- (1H-indol-2-yl) acetate (3.2 g, 16 mmol) in tetrahydrofuran (48 mL) /methanol (48 mL) at room temperature. The mixture was stirred at room temperature for 1 h and concentrated. The residue was quenched with water, and the aqueous layer was washed with diethyl ether, then acidified to about pH 2 with 1M HCl and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford crude 16-1.
  • 1M lithium hydroxide 48 mL, 48 mmol
  • Step 2 To a suspension of crude 16-1 (2.6 g, 15 mmol) in dichloromethane (100 mL) was added 1, 1'-carbonyldiimidazole (2.65 g, 16.3 mmol) followed by addition of 2 M dimethylamine solution in tetrahydrofuran (9 mL) admixed with N, N-diisopropylethylamine (3.9 g, 30 mmol) . The mixture was stirred at room temperature for 2 h and poured into ice water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was triturated with ethyl acetate/tert-butyl methyl ether (1/10) and filtered. The filter cake was dried to afford 16-2.
  • Step 3 Compound 16-3 was prepared following the procedure for the synthesis of 71-6 in example 2.
  • Step 5 Compound 16 was prepared following the procedure for the synthesis of 50 in example 6.
  • Step 1 A mixture of 22-3 (500 mg, 0.9 mmol) , 3, 3-difluoroazetidine hydrochloride (175 mg, 1.35 mmol) , Pd (OAc) 2 (60 mg, 0.27 mmol) , XantPhos (156 mg, 0.27 mmol) and Cs 2 CO 3 (881 mg, 2.7 mmol) in DMSO (8 mL) was stirred at 110°C for 9 h under argon atmosphere. The mixture was cooled and purified by reverse phase flash chromatography to afford 22-4.
  • Step 2 To a solution of isopropyl alcohol (884 mg, 14.7 mmol) in THF (10 mL) was added NaH (423 mg, 17.65 mmol) at 0°C. The mixture was stirred at 0°C for 30 min. The above mixture was added to 2, 4-dichloro-5- (iodomethyl) pyrimidine (4.25 g, 14.7 mmol) in THF (40 mL) dropwise at 0°C. The mixture was stirred at 0°C for an additional 2 h. The reaction was quenched with sat. NH 4 Cl (aq. ) at 0°C and extracted with ethyl acetate.
  • Step 1 To a solution of 1H-indole (6.0 g, 51.2 mmol) in DMF (60 mL) was added NaH (60%wt, 2.46 g, 61.5 mmol) at 0°C. The mixture was stirred at room temperature for 30 min. The above mixture was then added to 1, 4-dibromobutane (33.18 g, 153.7 mmol) in DMF (60 mL) at 0°C. The reaction mixture was stirred at room temperature for 1 h, and quenched with sat. NH 4 Cl (aq. ) at 0°C. The aqueous layer was extracted with ethyl acetate.
  • Step 2 A mixture of 30-1 (33.0 g, 130.9 mmol) and NaI (88.3 g, 588.9 mmol) in acetonitrile (500 mL) was stirred at 80°C overnight, then cooled to room temperature and concentrated. The residue was dissolved in water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford 30-2, which was used directly in the next step without purification.
  • Step 4 A mixture of 30-6 (1.0 g, 1.68 mmol) , 1-isopropyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (0.6 g, 2.5 mmol) , Pd (dppf) Cl 2 (246 mg, 0.34 mmol) and Cs 2 CO 3 (1.1 g, 3.36 mmol) in dioxane/H 2 O (5/1, 20 mL) was stirred at 100°C for 2 h under N 2 atmosphere. The mixture was cooled, quenched with water and extracted with ethyl acetate.
  • Step 1 A mixture of 47-5 (102 mg, 0.18 mmol) and sodium hydroxide (73 mg, 1.83 mmol) in tetrahydrofuran (4 mL) /water (2 mL) was stirred at 50°C for 120 h, and then concentrated to remove the organic solvent. The resulting mixture was acidified with acetic acid and purified by prep-HPLC (acetonitrile with 0.05%of TFA in water: 15%to 95%) to afford 47 as a mono TFA salt.
  • Compound 64-3 was prepared following the procedures for the synthesis of 30-3 in example 18.
  • Compound 64-4 was prepared following the procedure for the synthesis of 18-1 in example 1.
  • Step 1 To a solution of 64-5 (100 mg, 0.17 mmol) in dioxane (2 mL) and H 2 O (2 mL) was added LiOH. H 2 O (57 mg, 1.37 mmol) in portions. The mixture was stirred at room temperature for 3 h. The mixture was concentrated and the residue was purified by prep-HPLC (acetonitrile with 0.05%of formic acid in water: 15%to 95%) to afford 64-6.
  • Step 2 A mixture of 64-6 (35 mg, 0.06 mmol) , HATU (47 mg, 0.12 mmol) and isopropylamine (19 mg, 0.31 mmol) in DMF (7 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated and the residue was purified by prep-HPLC (acetonitrile with 0.05%of TFA in water: 8%to 25%) to afford 64 as a mono TFA salt.
  • Step 3 To a solution of 78-2 (120 mg, 0.57 mmol) in THF (5 mL) was added dropwise a solution of 2.5 M n-BuLi in hexane (0.35 mL, 0.86 mmol) at -78 °C. The mixture was stirred at -78 °C for 2 h. Then ZnCl 2 (194 mg, 1.43 mmol) was added to above solution and the resulting mixture was stirred at -78 °C for 1 h before Pd (PPh 3 ) 4 (66 mg, 0.057 mmol) and 2, 4-dichloro-5-methylpyrimidine (140 mg, 0.86 mmol) were added.
  • Pd (PPh 3 ) 4 66 mg, 0.057 mmol
  • 4-dichloro-5-methylpyrimidine 140 mg, 0.86 mmol
  • Compound 80-3 was prepared following the procedure for the synthesis of 64 in example 21.
  • Compound 80-4 was prepared following the procedure for the synthesis of 71-4 in example 1.
  • Step 3 A mixture of 80-4 (150.00 mg, 273.92 umol) and Raney Ni (20 mg, 273.92 umol) in ethanol (5 mL) were stirred under an atmosphere of H 2 of 1 atm at room temperature for 4 h. The solids were filtered and washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with DCM/MeOH (10/1) to provide 80-5.
  • Step 1 Under nitrogen, to a solution of indole (3 g, 25.61 mmol) , Cu (OAc) 2 (4.65 g, 25.61 mmol) , 2- (2-pyridyl) pyridine (4.00 g, 25.61 mmol) and Na 2 CO 3 (5.43 g, 51.22 mmol) in DMF (20 mL) was added a solution of cyclopropylboronic acid (4.4 g, 51.22 mmol) in 5 mL DMF drop wise. Then the mixture was warmed to 70°C and stirred for 8h. The mixture was filtered and the filtrate was concentrated. The crude product was purified by flash chromatography on a silica gel column with petroleum ether/ethyl acetate (97: 3) to give 82-1.
  • Step 1 To a solution of 1H-indole (3.51 g, 29.96 mmol) in ether (70 mL) , were added potassium tert-butylate (3.93 g, 35.06 mmol) and 18-crown-6 ether (7.92 g, 29.96 mmol) at 0°C. The resulting solution was stirred for 0.3h at 25°C. Then 2, 2, 2-trifluoroethyl trifluoromethanesulfonate (8.14 g, 35.06 mmol) was added in portions over 0.3h. The resulting solution was stirred for 15h at 25°C before H 2 O was added. The organic layer was separated, dried, and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column with petroleum ether/ethyl acetate (10/1) to provide 84-1.
  • Patient-derived xenograft cell line of LU0387 (ADC) with EGFR exon 20 insert mutation at 2319 (H773-V774insNPH) (CrownBio) were grown in DMEM medium supplemented with 10%fetal bovine serum at 37 °C with 5%CO 2 in air. Cells grown in log phase were trypsinized and seeded into a 96-well cell culture plate at the density of 1.5 x 10 4 per well with 90 uL and incubated overnight. The next day, 10 uL of serial diluted compounds for each well were added at a final DMSO concentration of 0.5%. On day 6, 50 uL media solution containing 1x compound was transferred to the assay plate to prevent water evaporation.
  • the IC50 levels are described as I, II, or III, wherein I represents that IC50 value is in the range of less than or equal to 100 nM; II represents that IC50 value is in the range of less than or equal to 1000 nM and more than 100 nM; and III represents that IC50 value is more than 1000 nM.
  • Control A isopropyl 2- ( (5-acrylamido-4- ( (2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate
  • Control B N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ( (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide

Abstract

L'invention concerne de nouveaux composés, par exemple, des composés de formule I ou de formule II, ou un sel pharmaceutiquement acceptable de ceux-ci. L'invention concerne également des procédés de préparation des composés et des procédés d'utilisation des composés, par exemple, pour traiter divers cancers décrits ici, tels que le cancer du poumon (par ex., le cancer du poumon non à petites cellules
PCT/CN2021/097809 2020-06-03 2021-06-02 Composés d'aminopyrimidine, leurs procédés de préparation et leurs utilisations WO2021244560A1 (fr)

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