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WO2025067468A1 - Inhibiteurs de cbl-b et leurs méthodes d'utilisation - Google Patents

Inhibiteurs de cbl-b et leurs méthodes d'utilisation Download PDF

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Publication number
WO2025067468A1
WO2025067468A1 PCT/CN2024/121873 CN2024121873W WO2025067468A1 WO 2025067468 A1 WO2025067468 A1 WO 2025067468A1 CN 2024121873 W CN2024121873 W CN 2024121873W WO 2025067468 A1 WO2025067468 A1 WO 2025067468A1
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compound
alkyl
cycloalkyl
pharmaceutically acceptable
ring
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Inventor
Xiao DING
Jinxin LIU
Fanye MENG
Feng Ren
Yazhou WANG
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InSilico Medicine IP Ltd
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InSilico Medicine IP Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Definitions

  • the present disclosure provides compounds useful as Casitas B-lineage lymphoma (Cbl) inhibitors, pharmaceutical compositions comprising them, and their use in treating a disease or condition associated with Cbl-b activity.
  • Cbl Casitas B-lineage lymphoma
  • n is 1, and both R 2 and R 3 are hydrogen.
  • R c is C 3-9 cycloalkyl, C 3-8 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyl, or C 3-4 cycloalkyl. In some embodiments, R c is C 9 cycloalkyl, C 8 cycloalkyl, C 7 cycloalkyl, C 6 cycloalkyl, C 5 cycloalkyl, C 4 cycloalkyl or C 3 cycloalkyl. In some embodiments, R c is monocyclic cycloalkyl.
  • R 6 is independently -OR a .
  • R a is alkyl or haloalkyl, each independently optionally substituted with one or more R.
  • each R is independently halogen, cyano, oxo, or -OH.
  • R 6 is independently -OR a , and R a is alkyl.
  • R a is independently C 1 -C 6 alkyl, C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl or C 1 -C 2 alkyl, each independently optionally substituted with one or more R.
  • R a is independently C 6 alkyl, C 5 alkyl, C 4 alkyl, C 3 alkyl, C 2 alkyl or C 1 alkyl, each independently optionally substituted with one or more R.
  • each R is independently halogen, cyano, oxo, or -OH.
  • j is 1, and R 6 is -OCH 3 .
  • one or more of R 6 is independently C 1 -C 6 alkyl, C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl or C 1 -C 2 alkyl, each independently optionally substituted with one or more R.
  • one or more of R 6 is independently C 6 alkyl, C 5 alkyl, C 4 alkyl, C 3 alkyl, C 2 alkyl or C 1 alkyl, each independently optionally substituted with one or more R.
  • each R is independently halogen, cyano, oxo, or -OH.
  • j is 1, and R 6 is -CH 3 .
  • one or more of R 6 is independently C 1 -C 6 haloalkyl, C 1 -C 5 haloalkyl, C 1 -C 4 haloalkyl, C 1 -C 3 haloalkyl or C 1 -C 2 haloalkyl, each independently optionally substituted with one or more R.
  • one or more of R 6 is independently C 6 haloalkyl, C 5 haloalkyl, C 4 haloalkyl, C 3 haloalkyl, C 2 haloalkyl or C 1 haloalkyl, each independently optionally substituted with one or more R.
  • each R is independently halogen, cyano, oxo, or -OH.
  • j is 1, and R 6 is C 1 -C 6 haloalkyl, C 1 -C 5 haloalkyl, C 1 -C 4 haloalkyl, C 1 -C 3 haloalkyl or C 1 -C 2 haloalkyl.
  • j is 1, and R 6 is C 1 haloalkyl.
  • j is 1, and R 6 is -CF 3 or -CHF 2 .
  • each R 6A , R 6B , R 6C and R 6D is independently selected from hydrogen or R 6 , and *end of Ring D indicates the attachment point of Ring D to Ring C.
  • R 6A is hydrogen
  • R 6B is hydrogen, halogen, cyano, -OR a , -SR a , -NR b R c , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, cycloalkyl, or heterocyclyl wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R.
  • R 6B is hydrogen, halogen, cyano, -OR a , -SR a , -NR b R c , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 2-6 heteroalkenyl, C 2-6 heteroalkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more R.
  • R 6B is hydrogen, halogen, -OR a , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl wherein the alkyl, haloalkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more R.
  • R 6B is hydrogen, halogen, CF 3 , CH 3 , OCH 3 , CHF 2 , or cyclopropyl.
  • R 6C is hydrogen, halogen, cyano, -OR a , -SR a , -NR b R c , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, cycloalkyl, or heterocyclyl wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R.
  • R 6C is hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl wherein the alkyl, and haloalkyl are optionally substituted with one or more R.
  • R 6B is hydrogen, F, Cl, Br, I or CH 3 .
  • R 6D is hydrogen
  • Ring D is wherein *end of Ring D indicates the attachment point of Ring D to Ring C.
  • Ring D is wherein *end of Ring D indicates the attachment point of Ring D to Ring C, and i is 1.
  • Ring D is W is N, and Y is C (O) , and *end of Ring D indicates the attachment point of Ring D to Ring C.
  • i is 1.
  • Ring D is wherein Ring E is a 6-membered heteroaryl, and *end of Ring D indicates the attachment point of Ring D to Ring C.
  • i is 1.
  • Ring D is X is C, and T is C, and *end of Ring D indicates the attachment point of Ring D to Ring C. In some embodiments, i is 1.
  • Ring D is wherein *end of Ring D indicates the attachment point of Ring D to Ring C.
  • Ring D is Ring G is cycloalkyl, heterocyclyl or heteroaryl, and *end of Ring D indicates the attachment point of Ring D to Ring C.
  • i is 1.
  • Ring G is cycloalkyl. In some embodiments, Ring G is C 5-11 cycloalkyl, C 5-10 cycloalkyl, C 5-9 cycloalkyl, C 5-8 cycloalkyl, C 5-7 cycloalkyl, or C 5-6 cycloalkyl. In some embodiments, Ring G is C 11 cycloalkyl, C 10 cycloalkyl, C 9 cycloalkyl, C 8 cycloalkyl, C 7 cycloalkyl, C 6 cycloalkyl or C 5 cycloalkyl. In some embodiments, Ring G is monocyclic cycloalkyl.
  • Ring G is heterocyclyl.
  • Ring G is 5-to 10-membered heterocyclyl, 5-to 9-membered heterocyclyl, 5-to 8-membered heterocyclyl, 5-to 7-membered heterocyclyl, or 5-to 6-membered heterocyclyl.
  • Ring G is 10-membered heterocyclyl, 9-membered heterocyclyl, 8-membered heterocyclyl, 7-membered heterocyclyl, 6-membered heterocyclyl, or 5-membered heterocyclyl.
  • Ring G is monocyclic heterocyclyl.
  • Ring G is 5-to 7-membered monocyclic heterocyclyl. In some embodiments, Ring G is 5-to 6-membered monocyclic heterocyclyl. In some embodiments, Ring G is 5-membered monocyclic heterocyclyl. In some embodiments, Ring G is 6-membered monocyclic heterocyclyl.
  • Ring G is heteroaryl.
  • Ring G is 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, 5-to 8-membered heteroaryl, 5-to 7-membered heteroaryl, or 5-to 6-membered heteroaryl.
  • Ring G is 10-membered heteroaryl, 9-membered heteroaryl, 8-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl, or 5-membered heteroaryl.
  • Ring G is monocyclic heteroaryl.
  • Ring G is polycyclic heteroaryl.
  • Ring G is bicyclic heteroaryl.
  • Ring G is 5-to 7-membered monocyclic heteroaryl. In some embodiments, Ring G is 5-to 6-membered monocyclic heteroaryl. In some embodiments, Ring G is 5-membered monocyclic heteroaryl. In some embodiments, Ring G is 6-membered monocyclic heteroaryl.
  • j is 0, 1 or 2
  • each R 6 is independently halogen, alkyl or haloalkyl.
  • each R 6 is independently halogen. In some embodiments, each R 6 is independently fluoro or chloro.
  • Ring D is wherein *end of Ring D indicates the attachment point of Ring D to Ring C.
  • Ring D is wherein *end of Ring D indicates the attachment point of Ring D to Ring C, and i is 1.
  • Ring D is W is -N-, Y is -C (O) -, and *end of Ring D indicates the attachment point of Ring D to Ring C.
  • i is 1.
  • Ring D is Ring E is a 6-membered heteroaryl
  • *end of Ring D indicates the attachment point of Ring D to Ring C.
  • i is 1.
  • Ring D is J is CH, X is C, T is C, and *end of Ring D indicates the attachment point of Ring D to Ring C.
  • i is 1.
  • Ring D is wherein *end of Ring D indicates the attachment point of Ring D to Ring C.
  • Ring G is cycloalkyl. In some embodiments, Ring G is C 5-11 cycloalkyl, C 5-10 cycloalkyl, C 5-9 cycloalkyl, C 5-8 cycloalkyl, C 5-7 cycloalkyl, or C 5-6 cycloalkyl. In some embodiments, Ring G is C 11 cycloalkyl, C 10 cycloalkyl, C 9 cycloalkyl, C 8 cycloalkyl, C 7 cycloalkyl, C 6 cycloalkyl or C 5 cycloalkyl. In some embodiments, Ring G is monocyclic cycloalkyl.
  • Ring G is heterocyclyl.
  • Ring G is 5-to 10-membered heterocyclyl, 5-to 9-membered heterocyclyl, 5-to 8-membered heterocyclyl, 5-to 7-membered heterocyclyl, or 5-to 6-membered heterocyclyl.
  • Ring G is 10-membered heterocyclyl, 9-membered heterocyclyl, 8-membered heterocyclyl, 7-membered heterocyclyl, 6-membered heterocyclyl, or 5-membered heterocyclyl.
  • Ring G is monocyclic heterocyclyl.
  • Ring G is 5-to 7-membered monocyclic heterocyclyl. In some embodiments, Ring G is 5-to 6-membered monocyclic heterocyclyl. In some embodiments, Ring G is 5-membered monocyclic heterocyclyl. In some embodiments, Ring G is 6-membered monocyclic heterocyclyl.
  • Ring G is heteroaryl.
  • Ring G is 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, 5-to 8-membered heteroaryl, 5-to 7-membered heteroaryl, or 5-to 6-membered heteroaryl.
  • Ring G is 10-membered heteroaryl, 9-membered heteroaryl, 8-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl, or 5-membered heteroaryl.
  • Ring G is monocyclic heteroaryl.
  • Ring G is polycyclic heteroaryl.
  • Ring G is bicyclic heteroaryl.
  • Ring G is 5-to 7-membered monocyclic heteroaryl. In some embodiments, Ring G is 5-to 6-membered monocyclic heteroaryl. In some embodiments, Ring G is 5-membered monocyclic heteroaryl. In some embodiments, Ring G is 6-membered monocyclic heteroaryl.
  • each of R 6a and R 6b is independently R 6 ;
  • j1 is 0, 1, or 2;
  • j2 is 0, 1, 2, 3 or 4.
  • both j1 and j2 are 0.
  • R 6a is alkyl.
  • R 6a is C 1 -C 6 alkyl, C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl or C 1 -C 2 alkyl.
  • R 6 is independently C 6 alkyl, C 5 alkyl, C 4 alkyl, C 3 alkyl, C 2 alkyl or C 1 alkyl.
  • j1 is 1, j2 is 0, and R 6a is -CH 3 .
  • k is 0.
  • k is 1, and each of R 7 and R 8 is independently selected from hydrogen or alkyl.
  • k is 1, and both R 7 and R 8 are hydrogen.
  • k is 1, R 7 is hydrogen, and R 8 is alkyl.
  • R 8 is C 1 -C 6 alkyl, C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl or C 1 -C 2 alkyl.
  • R 8 is C 6 alkyl, C 5 alkyl, C 4 alkyl, C 3 alkyl, C 2 alkyl or C 1 alkyl.
  • k is 1, R 7 is hydrogen, and R 8 is -CH 3 .
  • k is 1, and both R 7 and R 8 are alkyl.
  • R 7 and R 8 are independently C 1 -C 6 alkyl, C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl or C 1 -C 2 alkyl.
  • R 7 and R 8 are independently C 6 alkyl, C 5 alkyl, C 4 alkyl, C 3 alkyl, C 2 alkyl or C 1 alkyl.
  • k is 1, and both R 7 and R 8 are -CH 3 .
  • V is N.
  • V is N
  • R 9 is hydrogen
  • R 10 is cycloalkylalkyl or cycloalkyl, each optionally substituted with one or more R, and each R is independently selected from halogen, alkyl or haloalkyl.
  • V is N
  • R 9 is hydrogen
  • R 10 is cycloalkylalkyl optionally substituted with one or more R, and each R is independently selected from halogen, alkyl or haloalkyl.
  • R 10 is -C 1 -C 3 alkyl-C 3-9 cycloalkyl, -C 1 -C 3 alkyl-C 3-8 cycloalkyl, -C 1 -C 3 alkyl-C 3-7 cycloalkyl, -C 1 -C 3 alkyl-C 3-6 cycloalkyl, -C 1 -C 3 alkyl-C 3-5 cycloalkyl, or -C 1 -C 3 alkyl-C 3-4 cycloalkyl, each independently optionally substituted with one or more R.
  • R 5 is -C 1 -C 3 alkyl-C 9 cycloalkyl, -C 1 -C 3 alkyl-C 8 cycloalkyl, -C 1 -C 3 alkyl-C 7 cycloalkyl, -C 1 -C 3 alkyl-C 6 cycloalkyl, -C 1 -C 3 alkyl-C 5 cycloalkyl, -C 1 -C 3 alkyl-C 4 cycloalkyl or -C 1 -C 3 alkyl-C 3 cycloalkyl, each independently optionally substituted with one or more R.
  • each R is independently halogen, alkyl or haloalkyl.
  • V is N
  • R 9 is hydrogen
  • R 10 is
  • V is N
  • R 9 is hydrogen
  • R 10 is cycloalkyl optionally substituted with one or more R, and each R is independently selected from halogen, alkyl or haloalkyl.
  • R 10 is -C 3-9 cycloalkyl, -C 3-8 cycloalkyl, -C 3-7 cycloalkyl, -C 3-6 cycloalkyl, -C 3-5 cycloalkyl, or -C 3-4 cycloalkyl, each independently optionally substituted with one or more R.
  • R 5 is -C 9 cycloalkyl, -C 8 cycloalkyl, -C 7 cycloalkyl, -C 6 cycloalkyl, -C 5 cycloalkyl, -C 4 cycloalkyl or -C 3 cycloalkyl, each independently optionally substituted with one or more R.
  • each R is independently halogen, alkyl or haloalkyl.
  • V is N
  • R 9 is hydrogen
  • R 10 is
  • V is N, and R 9 and R 10 together with the atom to which they are attached form a heterocyclyl optionally substituted with one or more R, and each R is independently selected from halogen, alkyl or haloalkyl.
  • V is N, and R 9 and R 10 together with the atom to which they are attached form a 5-to 10-membered heterocyclyl, 5-to 9-membered heterocyclyl, 5-to 8-membered heterocyclyl, 5-to 7-membered heterocyclyl, or 5-to 6-membered heterocyclyl, each independently optionally substituted with one or more R.
  • R 9 and R 10 together with the atom to which they are attached form a 10-membered heterocyclyl, 9-membered heterocyclyl, 8-membered heterocyclyl, 7-membered heterocyclyl, 6-membered heterocyclyl, or 5-membered heterocyclyl, each independently optionally substituted with one or more R.
  • R 9 and R 10 together with the atom to which they are attached form a 5-to 7-membered monocyclic heterocyclyl optionally substituted with one or more R.
  • R 9 and R 10 together with the atom to which they are attached form a 5-to 6-membered monocyclic heterocyclyl optionally substituted with one or more R.
  • R 9 and R 10 together with the atom to which they are attached form a 5-membered monocyclic heterocyclyl optionally substituted with one or more R. In some embodiments, R 9 and R 10 together with the atom to which they are attached form a 6-membered monocyclic heterocyclyl optionally substituted with one or more R. In some embodiments, each R is independently selected from halogen, alkyl or haloalkyl.
  • V is N, and R 9 and R 10 together with the atom to which they are attached form a piperidine optionally substituted with one or more R.
  • V is N, and R 9 and R 10 together with the atom to which they are attached form a piperidine substituted with one -CH 3 .
  • Ring E1 is a 5-or 6-membered heteroaryl or a 5-or 6-membered heterocyclyl. In some embodiments, Ring E1 is a 6-membered heteroaryl or a 6-membered heterocyclyl. In some embodiments, Ring E1 is a 5-membered heteroaryl or a 5-membered heterocyclyl.
  • Ring D1 is
  • Ring D1 is selected from the group consisting of:
  • g is 0, 1, or 2.
  • each R 600a1 , R 600a2 , R 600a3 , and R 600a4 is independently selected from hydrogen or R 600 .
  • each R 600 is independently selected from halogen, cyano, heterocyclyl, -SR a , -NH 2 , -N (alkyl) 2 , -NH (cycloalkyl) , -C (O) NH 2 , -C (O) NH (alkyl) , unsubstituted alkyl, alkenyl, alkynyl, alkoxyl, haloalkyl, hydroxylalkyl, haloalkoxyl, -alkynyl-N (alkyl) 2 , haloalkynyl, -alkynyl-heterocyclyl, or cycloalkyl, wherein the heterocyclyl and cycloalkyl are optionally substituted with one or more
  • each R 600 is independently selected from halogen, cyano, piperazinyl, -SR a , -NH 2 , -N (alkyl) 2 , -NH (cycloalkyl) , -C (O) NH 2 , -C (O) NH (alkyl) , unsubstituted alkyl, alkenyl, alkynyl, alkoxyl, haloalkyl, hydroxylalkyl, haloalkoxyl, -alkynyl-N (alkyl) 2 , haloalkynyl, -alkynyl-heterocyclyl, or cycloalkyl.
  • each R 600 is independently selected from halogen, cyano, heterocyclyl, -C (O) NH 2 , unsubstituted alkyl, alkynyl, haloalkyl, hydroxylalkyl, haloalkoxyl, -alkynyl- N(alkyl) 2 , haloalkynyl, -alkynyl-heterocyclyl or cycloalkyl, wherein the heterocyclyl and cycloalkyl are optionally substituted with one or more R’ .
  • each R 600 is independently selected from halogen, cyano, , -C (O) NH 2 , unsubstituted C 1-6 alkyl (such as unsubstituted C 1-5 alkyl, unsubstituted C 1-4 alkyl, unsubstituted C 1-3 alkyl, or unsubstituted C 1-2 alkyl, etc) , C 2-6 alkynyl (such as C 2-5 alkynyl, C 2-4 alkynyl or C 2-3 alkynyl, etc) , C 1-6 haloalkyl (such as C 1-5 haloalkyl, C 1-4 haloalkyl, C 1- 3 haloalkyl or C 1-2 haloalkyl, etc) , C 1-6 hydroxylalkyl (such as C 1-5 hydroxylalkyl, C 1-4 hydroxylalkyl, C 1-3 hydroxylalkyl or C 1-2 hydroxylalkyl, etc
  • each R 600 is independently selected from halogen, cyano, C 1-3 alkyl, C 1-3 hydroxylalkyl, -C 2-3 alkynyl-N (C 1-3 alkyl) 2 , C 2-3 haloalkynyl, and -C 2-3 alkynyl- (5-to 6-membered heterocyclyl) .
  • each R 600 is a C 3-6 cycloalkyl (such as C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 3-5 cycloalkyl, or C 5-6 cycloalkyl, etc) , which is optionally substituted with one or more (e.g., two or three, etc) R’ .
  • each R 600 is a 3-to 6-membered heterocyclyl (such as 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-to 5-membered heterocyclyl, or 5-to 6-membered heterocyclyl, etc) , which is optionally substituted with one or more (e.g., two or three, etc) R’ .
  • each R 600 is piperazinyl, piperidinyl, or azetidinyl, which are optionally substituted with one or more (e.g., two or three, etc) R’ .
  • each R 600 is a spirocyclic bicyclic heterocyclyl (such as 6-to 15-membered spirocyclic bicyclic heterocyclyl, 6-membered spirocyclic bicyclic heterocyclyl, 7-membered spirocyclic bicyclic heterocyclyl, 8-membered spirocyclic bicyclic heterocyclyl, or 9-membered spirocyclic bicyclic heterocyclyl) , each is optionally substituted with one or more (e.g., two or three, etc) R’ .
  • each R 600 is a bridged bicyclic heterocyclyl (such as 6-to 15-membered bridged bicyclic heterocyclyl, 6-membered bridged bicyclic heterocyclyl, 7-membered bridged bicyclic heterocyclyl, 8-membered bridged bicyclic heterocyclyl, or 9-membered bridged bicyclic heterocyclyl) , which is optionally substituted with one or more (e.g., two or three, etc) R’ .
  • a bridged bicyclic heterocyclyl such as 6-to 15-membered bridged bicyclic heterocyclyl, 6-membered bridged bicyclic heterocyclyl, 7-membered bridged bicyclic heterocyclyl, 8-membered bridged bicyclic heterocyclyl, or 9-membered bridged bicyclic heterocyclyl
  • each R 600 is a fused bicyclic heterocyclyl (such as 6-to 15-membered fused bicyclic heterocyclyl, 6-membered fused bicyclic heterocyclyl, 7-membered fused bicyclic heterocyclyl, 8-membered fused bicyclic heterocyclyl, or 9-membered fused bicyclic heterocyclyl) , each is optionally substituted with one or more (e.g., two or three, etc) R’ . In some embodiments, each R 600 is each is optionally substituted with one or more (e.g., two or three, etc) R’ .
  • each R’ is independently halogen, cyano, oxo, -OH, -NH 2 , alkyl, alkoxyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, or heterocyclyl.
  • each R’ is independently halogen, -OH, -NH 2 , C 1-6 alkyl (such as C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, or C 1 alkyl, etc) , C 1-6 haloalkyl (such as C 1-5 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl or C 1-2 haloalkyl, etc) , or C 1-6 hydroxylalkyl (such as C 1-5 hydroxylalkyl, C 1-4 hydroxylalkyl, C 1-3 hydroxylalkyl or C 1-2 hydroxylalkyl, etc) .
  • R’ is independently halogen, -OH, -NH 2 , -CH 3 , or -CH 2 CH 3 .
  • -CH 3 is -CD 3 .
  • each R 600 is independently selected from -Cl, -F, -CN, -CH 3 , -CH (CH 3 ) 2 , -CH 2 OH, -CF 3 , -CHF 2 , -CF 2 CF 3 , -CH (CH 3 ) CF 2 , -CH 2 CHF 2 , -OCH 2 F, -OCHF 2 , -OCClF 2 , -C (O) NH 2 , In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is, is In some embodiments, is, is
  • two R 600 taken together with the atom to which they are attached form a cycloalkyl, heterocyclyl or heteroaryl, each optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a cycloalkyl optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a C 3-6 cycloalkyl (such as C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 3-5 cycloalkyl, or C 5-6 cycloalkyl, etc) optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a heterocyclyl optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a 5-to 10-membered heterocyclyl, 5-to 9-membered heterocyclyl, 5-to 8-membered heterocyclyl, 5-to 7-membered heterocyclyl, or 5-to 6-membered heterocyclyl, each optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a 10-membered heterocyclyl, 9-membered heterocyclyl, 8-membered heterocyclyl, 7-membered heterocyclyl, 6-membered heterocyclyl, or 5-membered heterocyclyl, each optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a monocyclic heterocyclyl optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a 5-to 7-membered monocyclic heterocyclyl optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a 5-to 6-membered monocyclic heterocyclyl optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a 5-membered monocyclic heterocyclyl optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a 6-membered monocyclic heterocyclyl optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a heteroaryl optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a is 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, 5-to 8-membered heteroaryl, 5-to 7-membered heteroaryl, or 5-to 6-membered heteroaryl, each optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a 10-membered heteroaryl, 9-membered heteroaryl, 8-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl, or 5-membered heteroaryl, each optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a monocyclic heteroaryl optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a polycyclic heteroaryl optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a bicyclic heteroaryl optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a 5-to 7-membered monocyclic heteroaryl optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a 5-to 6-membered monocyclic heteroaryl optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a 5-membered monocyclic heteroaryl optionally substituted with one or more R.
  • two R 600 taken together with the atom to which they are attached form a 6-membered monocyclic heteroaryl optionally substituted with one or more R.
  • each R 600a is independently R 600 ; g1 is 0, 1, or 2; and g2 is 0, 1, 2, 3, or 4.
  • R 1 to R 10 , R 6A to R 6D , R 600 , R 600a , V, Ring G, m, n, p, q, k and g1 are as defined herein.
  • R 1 to R 10 , V, R 5A to R 5C , R 6A to R 6D , R 600 , R 600a , Ring G, n, k and g1 are as defined herein.
  • each R 600a1 , R 600a2 , R 600a3 , and R 600a4 is independently selected from hydrogen or R 600 ; n, R 1A , R 2 , R 3 , R 4 and R 5A are as defined herein.
  • the compound disclosed herein, or a pharmaceutically acceptable salt thereof is one of the compounds in Table 1, Table 2 or Table 3.
  • the blood samples were taken via cephalic vein at timepoints 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after intravenous (iv) administration or at timepoints 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6h, 8 h, and 24 h after oral gavage administration, with 30 ⁇ L collected per time point.
  • Blood samples were placed in tubes containing K2-EDTA and stored on ice until centrifuged. The blood samples were centrifuged at 6800 g for 6 minutes at 2-8°C within 1 h after collected and stored frozen at approximately -80 °C.

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Abstract

L'invention concerne des inhibiteurs Cbl (Casitas B-lineage lymphoma) et des compositions pharmaceutiques comprenant lesdits inhibiteurs. Les composés et compositions de l'invention sont utiles pour le traitement d'une maladie ou d'un état pathologique associé à l'activité de Cbl-b, tels que des cancers.
PCT/CN2024/121873 2023-09-28 2024-09-27 Inhibiteurs de cbl-b et leurs méthodes d'utilisation Pending WO2025067468A1 (fr)

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CNPCT/CN2023/122735 2023-09-28
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CNPCT/CN2024/071520 2024-01-10
CN2024071520 2024-01-10
CNPCT/CN2024/075999 2024-02-05
CN2024075999 2024-02-05
CN2024096583 2024-05-31
CNPCT/CN2024/096583 2024-05-31
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WO2024062363A1 (fr) * 2022-09-21 2024-03-28 Glenmark Pharmaceuticals Ltd Composés hétérocycliques bicycliques en tant qu'inhibiteurs de cbl-b
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