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WO2024140679A1 - Antagonistes de hpk1 spirocycliques et utilisations associées - Google Patents

Antagonistes de hpk1 spirocycliques et utilisations associées Download PDF

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Publication number
WO2024140679A1
WO2024140679A1 PCT/CN2023/141942 CN2023141942W WO2024140679A1 WO 2024140679 A1 WO2024140679 A1 WO 2024140679A1 CN 2023141942 W CN2023141942 W CN 2023141942W WO 2024140679 A1 WO2024140679 A1 WO 2024140679A1
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Prior art keywords
compound
alkyl
heterocycloalkyl
cycloalkyl
pharmaceutically acceptable
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Application number
PCT/CN2023/141942
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English (en)
Inventor
Xiao DING
Xiaoyu Ding
Hongfu LU
Jingjing PENG
Feng Ren
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Insilico Medicine Ip Limited
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Publication of WO2024140679A1 publication Critical patent/WO2024140679A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-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
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

Definitions

  • a new cancer treatment paradigm has emerged that harnesses the patient's own immune system to overcome immunoevasive strategies utilized by many cancers and to enhance anti-tumor immunity.
  • One such strategy is to inhibit negative regulators of immune responses that normally function to maintain peripheral tolerance, allowing tumor antigens to be recognized as non-self entities.
  • HPK1 The hematopoietic progenitor kinase 1 (HPK1) is an example of a negative regulator of dendritic cell activation, and T and B cell responses that can be targeted to enhance anti-tumor immunity.
  • HPK1 is expressed predominantly by hematopoietic cells, including early progenitors.
  • T cells it is believed that HPK1 negatively regulates T cell activation by reducing the persistence of signaling microclusters by phosphorylating SLP76 at Ser376 and Gads at Thr254, which leads to the recruitment of 14-3-3 proteins that bind to the phosphorylated SLP76 and Gads, releasing the SLP76-Gads-14-3-3 complex from LAT-containing microclusters.
  • HPK1 can also become activated in response to prostaglandin E2, which is often secreted by tumors, contributing to the escape of tumor cells from the immune system.
  • the compound is of Formula (II) :
  • the compound is of Formula (IIIa) , (IIIb) , (IIIc) , or (IIId) :
  • the compound is of Formula (IV) :
  • HPK1-mediated disorder is a proliferative disorder.
  • the proliferative disorder is cancer.
  • the proliferative disorder is associated with one or more activating mutations in HPK1.
  • the HPK1-mediated disorder is a chronic viral infection.
  • Cyano refers to -CN.
  • the alkyl is a C 1 - 3 alkyl.
  • an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkyl is optionally substituted with halogen.
  • an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkenyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
  • heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH (CH 3 ) OCH 3 , -CH 2 NHCH 3 , -CH 2 N (CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N (CH 3 ) 2 .
  • the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl.
  • each R 6 is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; and
  • R X3 is imidazopyrazinyl optionally substituted with one or more R X3a .
  • R X3 is imidazo [1, 2-a] pyrazinyl optionally substituted with one or more R X3a .
  • each R X3a is independently halogen, -CN, -OH, -OR a , -SH, -SR a , -SF 3 , -SF 5 , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R X3a is independently halogen or C 1 -C 6 alkyl.
  • each R 8 is independently halogen, -CN, -OH, -OR a , -SH, -SR a , -SF 3 , -SF 5 , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) , (II) , (IIa) - (IId) , (III) , or (IIIa) - (IIId) , R 3 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R X3 is imidazopyridinyl substituted with one or more R X3a . In some embodiments of a compound of Formula (I) or (IV) , R X3 is imidazo [1, 2-a] pyridinyl substituted with one or more R X3a .
  • R X3 is each optionally substituted with one or more R X3a .
  • R X3 is optionally substituted with one or more R X3a . In some embodiments of a compound of Formula (I) or (IV) , R X3 is optionally substituted with one or more R X3a .
  • each R X3a is independently halogen, -CN, -OH, -OR a , -SH, -SR a , -SF 3 , -SF 5 , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R X3a is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R X3a is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (IV) , each R X3a is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (IV) , each R X3a is independently halogen. In some embodiments of a compound of Formula (I) or (IV) , each R X3a is independently C 1 -C 6 alkyl.
  • the compound is of Formula (IVa) :
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • n 0, 1, 2, 3, or 4.
  • a compound of Formula (IVa) is In some embodiments of a compound of Formula (IVa) , is
  • Ring B is 5-or 6-membered cycloalkyl, 5-to 9-membered heterocycloalkyl, phenyl, or 5-to 9-membered heteroaryl.
  • Ring B is cycloalkyl. In some embodiments of a compound of Formula (IV) or (IVa) , Ring B is 5-or 6-membered cycloalkyl. In some embodiments of a compound of Formula (IV) or (IVa) , Ring B is cyclohexenyl. In some embodiments of a compound of Formula (IV) or (IVa) , Ring B is heterocycloalkyl. In some embodiments of a compound of Formula (IV) or (IVa) , Ring B is 5-to 9-membered heterocycloalkyl. In some embodiments of a compound of Formula (IV) or (IVa) , Ring B is aryl.
  • Ring B is 6-to 10-membered aryl. In some embodiments of a compound of Formula (IV) or (IVa) , Ring B is phenyl. In some embodiments of a compound of Formula (IV) or (IVa) , Ring B is heteroaryl. In some embodiments of a compound of Formula (IV) or (IVa) , Ring B is 5-to 10-membered heteroaryl. In some embodiments of a compound of Formula (IV) or (IVa) , Ring B is 5-to 9-membered heteroaryl. In some embodiments of a compound of Formula (IV) or (IVa) , Ring B is 5-to 10-membered heteroaryl.
  • Ring B is 5-or 6-membered heteroaryl. In some embodiments of a compound of Formula (IV) or (IVa) , Ring B is 9-or 10-membered heteroaryl. In some embodiments of a compound of Formula (IV) or (IVa) , Ring B is 9-membered heteroaryl.
  • Ring B is a monocyclic heteroaryl. In some embodiments of a compound of Formula (IV) or (IVa) , Ring B is a bicyclic heteroaryl.
  • Ring B is imidazopyridinyl. In some embodiments of a compound of Formula (IV) or (IVa) , Ring B is imidazo [1, 2-a] pyridinyl.
  • Ring B is imidazopyridinyl. In some embodiments of a compound of Formula (IV) or (IVa) , Ring B is imidazo [1, 2-a] pyridinyl.
  • Ring B is imidazopyrazinyl. In some embodiments of a compound of Formula (IV) or (IVa) , Ring B is imidazo [1, 2-a] pyrazinyl.
  • Ring B is In some embodiments of a compound of Formula (IV) or (IVa) , Ring B is
  • each R 8 is independently halogen, -CN, -OH, -OR a , -SH, -SR a , -SF 3 , -SF 5 , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 8 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 8 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IV) or (IVa) , each R 8 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IV) or (IVa) , each R 8 is independently halogen. In some embodiments of a compound of Formula (IV) or (IVa) , each R 8 is independently C 1 -C 6 alkyl.
  • X 4 is N. In some embodiments of a compound of Formula (I) , (IV) , or (IVa) , X 4 is CR X4 .
  • R X4 is hydrogen
  • Ring A is heterocycloalkyl.
  • Ring A is 5-or 6-membered heterocycloalkyl comprising 1 or 2 heteroatoms selected from the group consisting of O and N.
  • Ring A is tetrahydrofuranyl or tetrahydropyranyl.
  • Ring A is piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl.
  • Ring A is tetrahydropyranyl.
  • Ring A is piperidinyl.
  • each R 1 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • n is 0, 1, or 2. In some embodiments of a compound of Formula (I) , (II) , (IIa) -(IId) , (III) , (IIIa) - (IIId) , (IV) , or (IVa) , n is 0.
  • n is 3.
  • W is -NR W1 -. In some embodiments of a compound of Formula (I) , (II) , (IIa) - (IId) , (III) , (IIIa) - (IIId) , (IV) , or (IVa) , W is -C (R W2 ) 2 -.
  • R W1 is C 1 -C 6 alkyl optionally substituted with one or more R W1a .
  • each R W2 are independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R W2 are independently hydrogen, halogen, or C 1 -C 6 alkyl.
  • each R W2 are independently hydrogen or halogen. In some embodiments of a compound of Formula (I) , (II) , (IIa) - (IId) , (III) , (IIIa) - (IIId) , (IV) , or (IVa) , each R W2 are independently hydrogen or C 1 -C 6 alkyl.
  • R Y1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R Y1a .
  • R 1’ is C 1 -C 6 alkyl.
  • Z 2 is CR Z2 .
  • X 2 is CR X2 .
  • X 2 is N.
  • R X2 is hydrogen, halogen, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R X2a .
  • R X2 is hydrogen, halogen, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • R X2 is hydrogen, C 1 -C 6 alkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) , (II) , (IIa) - (IId) , (III) , (IIIa) - (IIId) , (IV) , or (IVa) , R X2 is C 1 -C 6 alkyl or cycloalkyl.
  • R X2 is hydrogen.
  • R X2 is aryl optionally substituted with one or more R X2a .
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , or C 1 -C 6 alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl or cycloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R a is independently cycloalkyl.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , or C 1 -C 6 alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen, C 1 -C 6 alkyl, or cycloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R b is hydrogen. In some embodiments of a compound disclosed herein, each R b is independently C 1 -C 6 alkyl.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , or C 1 -C 6 alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
  • each R is independently halogen, -CN, -OH, -OCF 3 , -OCClF 2 , -NH 2 , -NHC 1 -C 3 alkyl, -N (C 1 -C 3 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl.
  • each R is independently halogen, -CN, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl.
  • two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, two R on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl. In some embodiments of a compound disclosed herein, two R on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • one or more 1 H are replaced with one or more deuteriums in one or more of the following groups R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R W1 , R W2 , R W1a , R Y1 , R Y2 , R Y1a , R Z1 , R Z2 , R Z3 , R X1 , R X2 , R X2a , R X3 , R X3a , R X4 , R a , R b , R c , and R d .
  • the abundance of deuterium in each of R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R W1 , R W2 , R W1a , R Y1 , R Y2 , R Y1a , R Z1 , R Z2 , R Z3 , R X1 , R X2 , R X2a , R X3 , R X3a , R X4 , R a , R b , R c , and R d is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%of by molar.
  • one or more 1 H of Ring A and Ring B are replaced with one or more deuteriums.
  • the compound disclosed herein, or a pharmaceutically acceptable salt thereof is one of the compounds in Table 2.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate,
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedis
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • Step 1 8- ( (diphenylmethylene) amino) -5- (7-fluoroimidazo [1, 2-a] pyridin-3-yl) -2- ( (2- (trimethylsilyl) ethoxy) methyl) isoquinolin-1 (2H) -one
  • Step 2 8-amino-5- (7-fluoroimidazo [1, 2-a] pyridin-3-yl) -2- ( (2- (trimethylsilyl) ethoxy) methyl) isoquinolin-1 (2H) -one
  • Step 1 5-bis (2- ( (tert-butyldimethylsilyl) oxy) ethyl) -2-chloro-6- (4-methoxybenzyl) -5, 6-dihydro-7H-pyrrolo [3, 4-b] pyridin-7-one
  • Step 3 (2-chloro-6- (4-methoxybenzyl) -7-oxo-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridine-5, 5-diyl) bis (ethane-2, 1-diyl) dimethanesulfonate
  • Step 1 5- (7-fluoroimidazo [1, 2-a] pyridin-3-yl) -8- ( (6'-methyl-2, 3, 5, 6, 6', 7'-hexahydrospiro [pyran-4, 5'-pyrrolo [3, 4-b] pyridin] -2'-yl) amino) -2- ( (2- (trimethylsilyl) ethoxy) methyl) isoquinolin-1 (2H) -one
  • Step 2 tert-butyl 7- ( (1'- (2- (dimethylamino) ethyl) -2'-oxo-1', 2, 2', 3, 5, 6-hexahydrospiro [pyran-4, 3'-pyrrolo [2, 3-b] pyridin] -6'-yl) amino) -4- (7-fluoroimidazo [1, 2-a] pyridin-3-yl) -1-oxoisoindoline-2-carboxylate
  • Step 3 1'- (2- (dimethylamino) ethyl) -6'- ( (7- (7-fluoroimidazo [1, 2-a] pyridin-3-yl) -3-oxoisoindolin-4-yl) amino) -2, 3, 5, 6-tetrahydrospiro [pyran-4, 3'-pyrrolo [2, 3-b] pyridin] -2' (1'H) -one
  • Step 2 N- (3- (6-cyano-5- ( (1'- (2- (dimethylamino) ethyl) -1', 2, 2', 3, 5, 6-hexahydrospiro [pyran-4, 3'-pyrrolo [2, 3-b] pyridin] -6'-yl) amino) pyridin-2-yl) cyclohexan-1-yl) benzamide
  • Step 3 6- (5-benzamidocyclohex-1-en-1-yl) -3- ( (1'- (2- (dimethylamino) ethyl) -1', 2, 2', 3, 5, 6-hexahydrospiro [pyran-4, 3'-pyrrolo [2, 3-b] pyridin] -6'-yl) amino) picolinamide
  • Step 1 N- (3- (6-cyano-5- ( (6'-methyl-2, 3, 5, 6, 6', 7'-hexahydrospiro [pyran-4, 5'-pyrrolo [3, 4-b] pyridin] -2'-yl) amino) pyridin-2-yl) cyclohexan-1-yl) benzamide
  • Step 2 6- (5-benzamidocyclohex-1-en-1-yl) -3- ( (6'-methyl-2, 3, 5, 6, 6', 7'-hexahydrospiro [pyran-4, 5'-pyrrolo [3, 4-b] pyridin] -2'-yl) amino) picolinamide
  • Step 5 tert-butyl 7- ( (1'- (2- (dimethylamino) ethyl) -1', 2, 2', 3, 5, 6-hexahydrospiro [pyran-4, 3'-pyrrolo [2, 3-b] pyridin] -6'-yl) amino) -4- (7-fluoroimidazo [1, 2-a] pyridin-3-yl) -1-oxoisoindoline-2-carboxylate
  • reaction mixture was purged with N 2 for 3 mins and stirred at 130 °C under N 2 for 3 hrs. After cooling to room temperature, the reaction mixture was poured into 10 mL of water and extracted with EtOAc (5 mL*3) . The combined organic layers were washed with brine (10 mL) , dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by column chromatography on silica gel eluting with methanol (from 0%to 9%) in dichloromethane to afford 8-5 (42 mg, 62.6%yield) .
  • LC-MS (ESI+) m/z 642.4 (M+H) + .
  • Step 6 7- ( (1'- (2- (dimethylamino) ethyl) -1', 2, 2', 3, 5, 6-hexahydrospiro [pyran-4, 3'-pyrrolo [2, 3-b] pyridin] -6'-yl) amino) -4- (7-fluoroimidazo [1, 2-a] pyridin-3-yl) isoindolin-1-one
  • Step 3 4- (7-fluoroimidazo [1, 2-a] pyridin-3-yl) -7- ( (1'- (2- (methylamino) ethyl) -1', 2, 2', 3, 5, 6-hexahydrospiro [pyran-4, 3'-pyrrolo [2, 3-b] pyridin] -6'-yl) amino) isoindolin-1-one
  • Step 7 4- (7-fluoroimidazo [1, 2-a] pyridin-3-yl) -7- ( (6'- (1-methylpyrrolidin-3-yl) -2, 3, 5, 6, 6', 7'-hexahydrospiro [pyran-4, 5'-pyrrolo [3, 4-b] pyridin] -2'-yl) amino) isoindolin-1-one
  • Step 4 4- (imidazo [1, 2-a] pyrazin-3-yl) -7- ( (6'-methyl-2, 3, 5, 6, 6', 7'-hexahydrospiro [pyran-4, 5'-pyrrolo [3, 4-b] pyridin] -2'-yl) amino) isoindolin-1-one

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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Abstract

L'invention concerne des inhibiteurs de HPK1 spirocycliques et des compositions pharmaceutiques comprenant lesdits inhibiteurs. Les composés et compositions de l'invention sont utiles dans le traitement d'une maladie ou d'un trouble associés à HPK1.
PCT/CN2023/141942 2022-12-26 2023-12-26 Antagonistes de hpk1 spirocycliques et utilisations associées WO2024140679A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015170266A1 (fr) * 2014-05-07 2015-11-12 Lupin Limited Composés pyrimidine substitués en tant qu'inhibiteurs de la tyrosine kinase de bruton (btk)
WO2021050964A1 (fr) * 2019-09-13 2021-03-18 Nimbus Saturn, Inc. Antagonistes de hpk1 et leurs utilisations
WO2022174253A1 (fr) * 2021-02-12 2022-08-18 Nimbus Saturn, Inc. Antagonistes de hpk1 et leurs utilisations
CN116023378A (zh) * 2021-10-26 2023-04-28 江苏先声药业有限公司 作为hpk1抑制剂的内酰胺类化合物及其应用
CN117050095A (zh) * 2022-05-13 2023-11-14 南京再明医药有限公司 作为hpk1抑制剂的三环类化合物及其应用
CN117164571A (zh) * 2022-06-02 2023-12-05 贝达药业股份有限公司 Hpk1抑制剂及其在医药上的应用
WO2023237085A1 (fr) * 2022-06-10 2023-12-14 贝达药业股份有限公司 Inhibiteur de hpk1 et son utilisation médicale

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015170266A1 (fr) * 2014-05-07 2015-11-12 Lupin Limited Composés pyrimidine substitués en tant qu'inhibiteurs de la tyrosine kinase de bruton (btk)
WO2021050964A1 (fr) * 2019-09-13 2021-03-18 Nimbus Saturn, Inc. Antagonistes de hpk1 et leurs utilisations
WO2022174253A1 (fr) * 2021-02-12 2022-08-18 Nimbus Saturn, Inc. Antagonistes de hpk1 et leurs utilisations
CN116023378A (zh) * 2021-10-26 2023-04-28 江苏先声药业有限公司 作为hpk1抑制剂的内酰胺类化合物及其应用
CN117050095A (zh) * 2022-05-13 2023-11-14 南京再明医药有限公司 作为hpk1抑制剂的三环类化合物及其应用
CN117164571A (zh) * 2022-06-02 2023-12-05 贝达药业股份有限公司 Hpk1抑制剂及其在医药上的应用
WO2023237085A1 (fr) * 2022-06-10 2023-12-14 贝达药业股份有限公司 Inhibiteur de hpk1 et son utilisation médicale

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