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WO2023193759A1 - Antagonistes de hpk1 et leurs utilisations - Google Patents

Antagonistes de hpk1 et leurs utilisations Download PDF

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Publication number
WO2023193759A1
WO2023193759A1 PCT/CN2023/086571 CN2023086571W WO2023193759A1 WO 2023193759 A1 WO2023193759 A1 WO 2023193759A1 CN 2023086571 W CN2023086571 W CN 2023086571W WO 2023193759 A1 WO2023193759 A1 WO 2023193759A1
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alkyl
compound
heterocycloalkyl
cycloalkyl
stereoisomer
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Xiao DING
Xiaoyu Ding
Yingtao LIU
Hongfu LU
Jingjing PENG
Feng Ren
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InSilico Medicine IP Ltd
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InSilico Medicine IP Ltd
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    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • 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.
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 1a ;
  • R 1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 1a ;
  • R 1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
  • n 0-6;
  • L is -O-, -S-, or -NR 2 -;
  • R 2 is hydrogen, -CN, 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;
  • W is N or CR W ;
  • Z is N or CR Z ;
  • X is C (R X ) 2 , O, S, or NR X1
  • Y is C (R Y ) 2 , O, S, or NR Y1 ;
  • X is CR X or N
  • Y is CR Y or N
  • R X1 is hydrogen, -CN, 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;
  • R Y1 is hydrogen, -CN, 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;
  • R 3 is 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;
  • Ring B is a bicyclic ring
  • R 4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 4a ;
  • R 4a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R;
  • R 4a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each independently optionally substituted with one or more R;
  • n 0-6;
  • 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, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl 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, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl 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, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl 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;
  • the compound is of Formula (Ia) :
  • the compound is of Formula (Ib) :
  • the compound is of Formula (Ic) :
  • the compound is of Formula (Id) :
  • the compound is of Formula (Ie) :
  • Ring C is heterocycloalkyl or heteroaryl
  • R 1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 1a ;
  • R 1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 1a ;
  • R 1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
  • n 0-6;
  • L is -O-, -S-, or -NR 2 -;
  • R 2 is hydrogen, -CN, 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;
  • W is N or CR W ;
  • Z is N or CR Z ;
  • X is C (R X ) 2 , O, S, or NR X1
  • Y is C (R Y ) 2 , O, S, or NR Y1 ;
  • X is CR X or N
  • Y is CR Y or N
  • R X1 is hydrogen, -CN, 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;
  • R Y1 is hydrogen, -CN, 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;
  • R 3 is 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;
  • Ring D is a 3-to 5-membered ring
  • R 4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 4a ;
  • R 4a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R;
  • R 4a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each independently optionally substituted with one or more R;
  • n 0-6;
  • 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, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl 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, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl 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, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl 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;
  • the compound is of Formula (IIa) :
  • the compound is of Formula (IIb) :
  • the compound is of Formula (IIc) :
  • the compound is of Formula (IId) :
  • the compound is of Formula (IIe) :
  • composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
  • 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.
  • Also disclosed herein is a method of increasing the efficacy of vaccination in a patient comprising administering to said patient a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.
  • Carboxyl refers to -COOH.
  • Cyano refers to -CN.
  • Alkyl refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopent
  • a numerical range such as “C 1 -C 6 alkyl” or “C 1-6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1- 10 alkyl.
  • the alkyl is a C 1-6 alkyl.
  • the alkyl is a C 1-5 alkyl.
  • the alkyl is a C 1-4 alkyl.
  • 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.
  • Alkenyl refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • a numerical range such as “C 2 -C 6 alkenyl” or “C 2 - 6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • 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.
  • Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl and the like.
  • a numerical range such as “C 2 -C 6 alkynyl” or “C 2-6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl 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 alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkynyl 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.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy 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 alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6-to 10-membered aryl.
  • the aryl is a 6-membered aryl (phenyl) .
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • 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 .
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 -C 15 cycloalkyl or C 3 -C 15 cycloalkenyl) , from three to ten carbon atoms (C 3 -C 10 cycloalkyl or C 3 -C 10 cycloalkenyl) , from three to eight carbon atoms (C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkenyl) , from three to six carbon atoms (C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkenyl) , from three to five carbon atoms (C 3 -C 5 cycloalkyl or C 3 -C 5 cycloalkenyl) , or three to four carbon atoms (C 3 -C 4 cycloalkyl or C 3 -C 4 cycloalkenyl) .
  • the cycloalkyl is a 3-to 10-membered cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered cycloalkyl or a 5-to 6-membered cycloalkenyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, fluorochloromethyl, difluorochloromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • 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 .
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heterocycloalkyl refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
  • the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C 2 -C 15 heterocycloalkyl or C 2 -C 15 heterocycloalkenyl) , from two to ten carbon atoms (C 2 -C 10 heterocycloalkyl or C 2 -C 10 heterocycloalkenyl) , from two to eight carbon atoms (C 2 -C 8 heterocycloalkyl or C 2 -C 8 heterocycloalkenyl) , from two to seven carbon atoms (C 2 -C 7 heterocycloalkyl or C 2 -C 7 heterocycloalkenyl) , from two to six carbon atoms (C 2 -C 6 heterocycloalkyl or C 2 -C 6 heterocycloalkenyl) , from two to five carbon atoms (C 2 -C 5 heterocycloalkyl or C 2 -C 5 heterocycloalkenyl) , or two
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
  • heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) .
  • the heterocycloalkyl is a 3-to 8-membered heterocycloalkyl.
  • the heterocycloalkyl is a 3-to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl.
  • 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.
  • a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5-to 10-membered heteroaryl.
  • the heteroaryl is a 5-to 6-membered heteroaryl.
  • the heteroaryl is a 6-membered heteroaryl.
  • the heteroaryl is a 5-membered heteroaryl.
  • examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, di
  • a heteroaryl 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 heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • an optionally substituted group may be un-substituted (e.g., -CH 2 CH 3 ) , fully substituted (e.g., -CF 2 CF 3 ) , mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc. ) .
  • any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
  • one or more when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.
  • an “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • treat, ” “treating” or “treatment, ” as used herein, include alleviating, abating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • a “disease or disorder associated with HPK1” or, alternatively, “a HPK1-mediated disease or disorder” means any disease or other deleterious condition in which HPK1, or a mutant thereof, is known or suspected to play a role.
  • HPK1 antagonist or a “HPK1 inhibitor” is a molecule that reduces, inhibits, or otherwise diminishes one or more of the biological activities of HPK1 (e.g., serine/threonine kinase activity, recruitment to the TCR complex upon TCR activation, interaction with a protein binding partner, such as SLP76) .
  • Antagonism using the HPK1 antagonist does not necessarily indicate a total elimination of the HPK1 activity.
  • the activity could decrease by a statistically significant amount including, for example, a decrease of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%or 100%of the activity of HPK1 compared to an appropriate control.
  • the HPK1 antagonist reduces, inhibits, or otherwise diminishes the serine/threonine kinase activity of HPK1.
  • the HPK1 antagonist reduces, inhibits, or otherwise diminishes the HPK1-mediated phosphorylation of SLP76 and/or Gads.
  • the presently disclosed compounds bind directly to HPK1 and inhibit its kinase activity.
  • Described herein are compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof useful in the treatment of a disease or disorder associated with HPK1.
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 1a ;
  • R 1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 1a ;
  • R 1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
  • n 0-6;
  • L is -O-, -S-, or -NR 2 -;
  • R 2 is hydrogen, -CN, 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;
  • W is N or CR W ;
  • Z is N or CR Z ;
  • X is C (R X ) 2 , O, S, or NR X1
  • Y is C (R Y ) 2 , O, S, or NR Y1 ;
  • X is CR X or N
  • Y is CR Y or N
  • R X1 is hydrogen, -CN, 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;
  • R Y1 is hydrogen, -CN, 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;
  • R 3 is 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;
  • Ring B is a bicyclic ring
  • R 4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 4a ;
  • R 4a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R;
  • R 4a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each independently optionally substituted with one or more R;
  • n 0-6;
  • 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, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl 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, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl 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, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl 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;
  • the compound is of Formula (Ia) :
  • X is C (R X ) 2 or NR X1 ; and Y is C (R Y ) 2 or NR Y1 .
  • X is C (R X ) 2 ; and Y is C (R Y ) 2 .
  • X is C (R X ) 2 ; and Y is C (R Y ) 2 , O, S, or NR Y1 .
  • X is C (R X ) 2 ; and Y is C (R Y ) 2 , O, or NR Y1 .
  • X is C (R X ) 2 ; and Y is C (R Y ) 2 or O.
  • the compound is of Formula (Ib) :
  • the compound is of Formula (Ic) :
  • the compound is of Formula (Id) :
  • the compound is of Formula (Ie) :
  • each R X is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R X is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R X is independently hydrogen or C 1 -C 6 alkyl.
  • each R X is hydrogen.
  • each R Y is independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R Y is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R Y is independently hydrogen or halogen.
  • each R Y is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) , (Ia) - (Ic) , or (Ie) , each R Y is hydrogen.
  • R X1 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) , R X1 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia) , R X1 is hydrogen.
  • R Y1 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) , R Y1 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia) , R Y1 is hydrogen.
  • Ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is phenyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is 5-or 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is 6-membered heteroaryl.
  • Ring A is pyridinyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is 5-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is bicyclic or tricyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is bicyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is tricyclic heteroaryl.
  • each R 1 is independently 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 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 1a .
  • each R 1 is independently halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, heterocycloalkyl, or heteroaryl; wherein each alkyl, heterocycloalkyl, and heteroaryl is independently optionally substituted with one or more R 1a .
  • each R 1 is independently C 1 -C 6 alkyl or heterocycloalkyl; wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more R 1a .
  • each R 1 is independently heterocycloalkyl optionally substituted with one or more R 1a .
  • two R 1 on the same atom are taken together to form an oxo.
  • two R 1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 1a .
  • two R 1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 1a .
  • each R 1a is independently cycloalkyl or heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R 1a is independently heterocycloalkyl; optionally substituted with one or more R.
  • the heterocycloalkyl is a bicyclic heterocycloalkyl (e.g., a spiro cyclic ring) .
  • each R 1a is independently -NR c R d .
  • two R 1a on the same atom are taken together to form an oxo.
  • two R 1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R.
  • two R 1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.
  • n is 1-4. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , n is 2-4. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , n is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , n is 0. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , n is 1. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , n is 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , n is 3.
  • At least two R 1 independently comprises a cyclic group. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , two R 1 each independently comprises a cyclic group. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , at least two R 1 are independently selected from a cyclic group. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , at least an R 1 comprises a substituted cyclic group.
  • At least one R 1 comprises a halogen substituted cyclic group. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , at least one R 1 comprises a halogen (e.g., fluoro) substituted heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , at least one R 1 comprises a halogen (e.g., fluoro) substituted cycloalkyl.
  • Ring E is cycloalkyl or heterocycloalkyl
  • p 0, 1, 2, 3, or 4.
  • Ring E is cycloalkyl
  • Ring E is heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring E is a monocyclic heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring E is a bicyclic heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring E is a pyrrolidinyl.
  • each R 5 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, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl.
  • each R 5 is independently halogen, -CN, -OH, -NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R 5 is independently halogen, -OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • each R 5 is independently halogen, -OH, or C 1 -C 6 alkoxy. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R 5 is independently halogen.
  • p is 0, 1, or 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 0. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 1. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 2.
  • a compound of Formula (I) or (Ia) - (Ie) is In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is In some embodiments of a compound of Formula (Id) or (Ie) , is In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is not In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is In some embodiments of a compound of Formula (I) or (Ia) - (I
  • Ring B is a bicyclic heteroaryl or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring B is a bicyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring B is a bicyclic partially saturated ring. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring B is a bicyclic fully saturated ring. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring B is a bicyclic unsaturated ring.
  • each R 4 is independently halogen, -CN, -OH, -OR a , -SF 3 , - SF 5 , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is independently optionally substituted with one or more R 4a .
  • one or more R 4 is -OCF 3 , OCClF 2, -SCF 3 , or -SCClF 2 .
  • each R 4 is independently halogen, -SF 3 , -SF 5 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R 4 is independently halogen or C 1 -C 6 alkyl.
  • two R 4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 4a .
  • two R 4 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 1a .
  • each R 4a 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; wherein each alkyl is independently optionally substituted with one or more R.
  • each R 4a is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is independently optionally substituted with one or more R.
  • each R 4a 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 4a is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • m is 0-4. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 0-2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 0. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 1. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 3.
  • a compound of Formula (I) or (Ia) - (Ie) is In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is
  • R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R 3 is hydrogen.
  • W is N. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , W is CR W .
  • R W is hydrogen, halogen, -CN, -OH, -OR a (e.g., -OCF 3 or OCClF 2 ) , SH, -SR a (e.g., -SCF 3 or -SCClF 2 ) , -SF 3 , -SF 5 , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • -OR a e.g., -OCF 3 or OCClF 2
  • SH e.g., -SR a (e.g., -SCF 3 or -SCClF 2 )
  • -SF 3 e.g., -SF 3 , -SF 5 , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R W is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R W is hydrogen.
  • Z is N. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Z is CR Z .
  • R Z is hydrogen, halogen, -CN, -OH, -OR a (e.g., -OCF 3 or OCClF 2 ) , SH, -SR a (e.g., -SCF 3 or -SCClF 2 ) , -SF 3, -SF 5, -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • -OR a e.g., -OCF 3 or OCClF 2
  • SH e.g., -SR a (e.g., -SCF 3 or -SCClF 2 )
  • -SF 3 e.g., -SF 3 or -SCClF 2
  • R Z is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R Z is hydrogen.
  • L is -O-. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , L is -S-. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , L is -NR 2 -.
  • R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R 2 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R 2 is hydrogen.
  • Ring C is heterocycloalkyl or heteroaryl
  • R 1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 1a ;
  • R 1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 1a ;
  • R 1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
  • n 0-6;
  • L is -O-, -S-, or -NR 2 -;
  • R 2 is hydrogen, -CN, 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;
  • W is N or CR W ;
  • Z is N or CR Z ;
  • X is C (R X ) 2 , O, S, or NR X1
  • Y is C (R Y ) 2 , O, S, or NR Y1 ;
  • X is CR X or N
  • Y is CR Y or N
  • R X1 is hydrogen, -CN, 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;
  • R Y1 is hydrogen, -CN, 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;
  • R 3 is 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;
  • Ring D is a 3-to 5-membered ring
  • R 4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 4a ;
  • R 4a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R;
  • R 4a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each independently optionally substituted with one or more R;
  • n 0-6;
  • 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, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl 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, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl 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, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl 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;
  • the compound is not
  • the compound is of Formula (IIa) :
  • X is C (R X ) 2 or NR X1 ; and Y is C (R Y ) 2 or NR Y1 .
  • X is C (R X ) 2 ; and Y is C (R Y ) 2 .
  • X is C (R X ) 2 ; and Y is C (R Y ) 2 , O, S, or NR Y1 .
  • X is C (R X ) 2 ; and Y is C (R Y ) 2 , O, or NR Y1 .
  • X is C (R X ) 2 ; and Y is C (R Y ) 2 or O.
  • the compound is of Formula (IIb) :
  • the compound is of Formula (IIc) :
  • the compound is of Formula (IId) :
  • the compound is of Formula (IIe) :
  • each R X is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R X is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R X is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IId) , each R X is hydrogen.
  • each R Y is independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R Y is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R Y is independently hydrogen or halogen.
  • each R Y is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) , (IIa) - (IIc) , or (IIe) , each R Y is hydrogen.
  • R X1 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (IIa) , R X1 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa) , R X1 is hydrogen.
  • R Y1 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (IIa) , R Y1 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa) , R Y1 is hydrogen.
  • Ring C is heteroaryl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring C is 5-or 6-membered heteroaryl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring C is 6-membered heteroaryl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring C is pyridinyl.
  • Ring C is bicyclic or tricyclic heteroaryl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring C is bicyclic heteroaryl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring C is tricyclic heteroaryl.
  • each R 1 is independently 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 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 1a .
  • each R 1 is independently halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, heterocycloalkyl, or heteroaryl; wherein each alkyl, heterocycloalkyl, and heteroaryl is independently optionally substituted with one or more R 1a .
  • each R 1 is independently C 1 -C 6 alkyl or heterocycloalkyl; wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more R 1a .
  • two R 1 on the same atom are taken together to form an oxo.
  • two R 1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 1a .
  • two R 1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 1a .
  • each R 1a is independently cycloalkyl or heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R 1a is independently heterocycloalkyl optionally substituted with one or more R.
  • two R 1a on the same atom are taken together to form an oxo.
  • two R 1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R.
  • two R 1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.
  • n is 1-4. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 1-3. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 2-4. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 0.
  • n is 1. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 2. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 3.
  • At least two R 1 independently comprises a cyclic group. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , at least two R 1 each independently comprises a cyclic group. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , at least two R 1 are independently selected from a cyclic group. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , at least an R 1 comprises a substituted cyclic group.
  • At least one R 1 comprises a halogen substituted cyclic group. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , at least one R 1 comprises a halogen (e.g., fluoro) substituted heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , at least one R 1 comprises a halogen (e.g., fluoro) substituted cycloalkyl.
  • Ring E is cycloalkyl or heterocycloalkyl
  • p 0, 1, 2, 3, or 4.
  • Ring E is cycloalkyl.
  • Ring E is heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring E is a monocyclic heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring E is a bicyclic heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring E is a pyrrolidinyl.
  • each R 5 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, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl.
  • each R 5 is independently halogen, -CN, -OH, -NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl.
  • each R 5 is independently halogen, -OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • each R 5 is independently halogen, -OH, or C 1 -C 6 alkoxy. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R 5 is independently halogen.
  • p is 0, 1, or 2. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , p is 0 or 1. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , p is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , p is 0. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , p is 1. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , p is 2.
  • a compound of Formula (II) or (IIa) - (IIe) is In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , is not In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , is
  • Ring D is a 5-membered ring.
  • Ring D is cyclopropyl.
  • Ring D is a 5-membered ring comprising 1 to 4 heteroatoms selected from the group consisting of O, S, or N.
  • Ring D is a 5-membered ring comprising 1 to 3 heteroatoms selected from the group consisting of O or N.
  • Ring D is a 5-membered ring comprising 1 to 3 heteroatoms that are N.
  • Ring D is imidazolyl, pyrazolyl. or oxadiazolyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring D is imidazolyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring D is pyrazolyl.
  • Ring D is not imidazolyl.
  • one or more R 4 is -OCF 3 , OCClF 2, -SCF 3 , or -SCCl
  • each R 4 is independently aryl or heteroaryl; wherein each aryl and heteroaryl is independently optionally substituted with one or more R 4a .
  • two R 4 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 4a .
  • two R 4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 4a .
  • each R 4a 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; wherein each alkyl is independently optionally substituted with one or more R.
  • each R 4a is independently halogen, -CN, - OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is independently optionally substituted with one or more R.
  • each R 4a is independently aryl.
  • m is 0-4. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , m is 0-2. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , m is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , m is 0. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , m is 1. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , m is 2.
  • R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , R 3 is hydrogen.
  • W is N. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , W is CR W .
  • R W is hydrogen, halogen, -CN, -OH, -OR a (e.g., -OCF 3 or OCClF 2 ) , SH, -SR a (e.g., -SCF 3 or -SCClF 2 ) , -SF 3, -SF 5, -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R W is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , R W is hydrogen.
  • Z is N. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Z is CR Z .
  • R z is hydrogen, halogen, -CN, -OH, -OR a (e.g., -OCF 3 or OCClF 2 ) , SH, -SR a (e.g., -SCF 3 or -SCClF 2 ) , -SF 3, -SF 5, -NR c R d , C 1 - C 6 alkyl, or C 1 -C 6 haloalkyl.
  • -OR a e.g., -OCF 3 or OCClF 2
  • SH e.g., -SR a (e.g., -SCF 3 or -SCClF 2 )
  • -SF 3 e.g., -SF 3 or -SCClF 2
  • R Z is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R Z is hydrogen.
  • L is -O-. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , L is -S-. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , L is -NR 2 -.
  • R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , R 2 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , R 2 is hydrogen.
  • 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, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl 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, heterocycloalkyl; wherein each alkyl, 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, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) .
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl.
  • 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, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl 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, or cycloalkyl, 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, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) .
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. 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.
  • each R c and R d are 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, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R c and R d are 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, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) .
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R c and R d are hydrogen. In some embodiments of a compound disclosed herein, each R c and R d are independently C 1 -C 6 alkyl.
  • 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, -SH, -SF 3 , -SF 5 , -SCF 3 , -SCClF 2, -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl; or two R on the same atom form an oxo.
  • each R is independently halogen, -CN, -OH, -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl; or two R on the same atom form an oxo.
  • each R is independently halogen, -CN, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, or C 1 -C 6 alkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -OH, or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R is independently halogen.
  • one or more of R, R 1 , R 1a , R 2 , R 3 , R 4 , R 4a , R 5 , R X , R X1 , R Y , R Y1 , R W , R Z , R a , R b , R c , and R d groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more 1 H are replaced with one or more deuteriums in one or more of the following groups R, R 1 , R 1a , R 2 , R 3 , R 4 , R 4a , R 5 , R X , R X1 , R Y , R Y1 , R W , R Z , R a , R b , R c , and R d .
  • the abundance of deuterium in each of R, R 1 , R 1a , R 2 , R 3 , R 4 , R 4a , R 5 , R X , R X1 , R Y , R Y1 , R W , R Z , 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%by molar.
  • one or more 1 H of Ring A, Ring B, Ring C, Ring D, or Ring E are replaced with one or more deuteriums.
  • the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is one of the compounds in Table 1 or Table 2.
  • the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is one of the compounds in Table 3.
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • the compounds described herein exist in their isotopically-labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H (D) , 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • the abundance of deuterium in each of the substituents disclosed herein 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%by molar.
  • one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more 1 H are replaced with one or more deuteriums in one or more of the substituents disclosed herein.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • 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, or a solvate, or stereoisomer 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
  • other acids such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
  • 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.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
  • the compounds described herein exist as solvates.
  • the invention provides for methods of treating diseases by administering such solvates.
  • the invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • 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.
  • HPK1 also referred to as mitogen activated protein kinase 1 or MAP4K1
  • MAP4K1 mitogen activated protein kinase 1
  • HPK1 functions as a MAP4K by phosphorylating and activating MAP3K proteins, including MEKK1, MLK3 and TAK1, leading to the activation of the MAPK Jnk.
  • the presently disclosed compounds bind directly to HPK1 and inhibit its kinase activity. In some embodiments, the presently disclosed compounds reduce, inhibit, or otherwise diminish the HPK1-mediated phosphorylation of SLP76 and/or Gads.
  • the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are used in a method for inhibiting HPK1.
  • Such methods comprise contacting HPK1 with an effective amount of a presently disclosed compound.
  • contact is intended bringing the compound within close enough proximity to an isolated HPK1 enzyme or a cell expressing HPK1 (e.g., T cell, B cell, dendritic cell) such that the compound is able to bind to and inhibit the activity of HPK1.
  • the compound can be contacted with HPK1 in vitro or in vivo via administration of the compound to a subject.
  • any method known in the art to measure the kinase activity of HPK1 may be used to determine if HPK1 has been inhibited, including in vitro kinase assays, immunoblots with antibodies specific for phosphorylated targets of HPK1, such as SLP76 and Gads, or the measurement of a downstream biological effect of HPK1 kinase activity, such as the recruitment of 14-3-3 proteins to phosphorylated SLP7 and Gads, release of the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, or T or B cell activation.
  • in vitro kinase assays immunoblots with antibodies specific for phosphorylated targets of HPK1, such as SLP76 and Gads
  • a downstream biological effect of HPK1 kinase activity such as the recruitment of 14-3-3 proteins to phosphorylated SLP7 and Gads, release of the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, or
  • the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are used to treat a HPK1-dependent disorder.
  • a “HPK1-dependent disorder” is a pathological condition in which HPK1 activity is necessary for the genesis or maintenance of the pathological condition.
  • the HPK1-dependent disorder is cancer.
  • the compounds disclosed herein are used in enhancing an immune response in a subject in need thereof.
  • enhancing an immune response refers to an improvement in any immunogenic response to an antigen.
  • improvements in an immunogenic response to an antigen include enhanced maturation or migration of dendritic cells, enhanced activation of T cells (e.g., CD4 T cells, CD8 T cells) , enhanced T cell (e.g., CD4 T cell, CD8 T cell) proliferation, enhanced B cell proliferation, increased survival of T cells and/or B cells, improved antigen presentation by antigen presenting cells (e.g., dendritic cells) , improved antigen clearance, increase in production of cytokines by T cells (e.g., interleukin-2) , increased resistance to prostaglandin E2-induced immune suppression, and enhanced priming and/or cytolytic activity of CD8 T cells.
  • the CD8 T cells in the subject have enhanced priming, activation, proliferation and/or cytolytic activity relative to prior to the administration of the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the CD8 T cell priming is characterized by elevated CD44 expression and/or enhanced cytolytic activity in CD8 T cells.
  • the CD8 T cell activation is characterized by an elevated frequency of ⁇ -IFN+ CD8 T cells.
  • the CD8 T cell is an antigen-specific T-cell.
  • the antigen presenting cells in the subject have enhanced maturation and activation relative to prior to the administration of a compound disclosed herein.
  • the antigen presenting cells are dendritic cells.
  • the maturation of the antigen presenting cells is characterized by an increased frequency of CD83+ dendritic cells.
  • the activation of the antigen presenting cells is characterized by elevated expression of CD80 and CD86 on dendritic cells.
  • the serum levels of cytokine IL-10 and/or chemokine IL-8, a human homolog of murine KC, in the subject are reduced relative to prior to the administration of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • HPK1 activation which functions as a negative regulator of TCR-induced AP-1 response pathway. 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, which leads to T cell dysfunction, including anergy and exhaustion.
  • disfunction in the context of immune dysfunction, refers to a state of reduced immune responsiveness to antigenic stimulation.
  • the term includes the common elements of both exhaustion and/or anergy in which antigen recognition may occur, but the ensuing immune response is ineffective to control infection or tumor growth.
  • disfunctional also includes refractory or unresponsive to antigen recognition, specifically, impaired capacity to translate antigen recognition into downstream T-cell effector functions, such as proliferation, cytokine production (e.g., IL-2, ⁇ -IFN) and/or target cell killing.
  • cytokine production e.g., IL-2, ⁇ -IFN
  • T cell anergy refers to the state of unresponsiveness to antigen stimulation resulting from incomplete or insufficient signals delivered through the T-cell receptor (e.g. increase in intracellular Ca+2 in the absence of ras-activation) .
  • T cell anergy can also result upon stimulation with antigen in the absence of co-stimulation, resulting in the cell becoming refractory to subsequent activation by the antigen even in the context of costimulation.
  • the unresponsive state can often be overridden by the presence of Interleukin-2. Anergic T-cells do not undergo clonal expansion and/or acquire effector functions.
  • exhaustion refers to T cell exhaustion as a state of T cell dysfunction that arises from sustained TCR signaling that occurs during many chronic infections and cancer. It is distinguished from anergy in that it arises not through incomplete or deficient signaling, but from sustained signaling. It is defined by poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. Exhaustion prevents optimal control of infection and tumors. Exhaustion can result from both extrinsic negative regulatory pathways (e.g., immunoregulatory cytokines) as well as cell intrinsic negative regulatory (costimulatory) pathways (PD-1, B7-H3, B7-H4, etc. ) .
  • extrinsic negative regulatory pathways e.g., immunoregulatory cytokines
  • costimulatory costimulatory
  • administration of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, results in an enhancement of T cell function.
  • Enhancing T cell function means to induce, cause, or stimulate a T cell to have a sustained or amplified biological function, or renew or reactivate exhausted or inactive T cells.
  • enhancing T cell function include: increased secretion of cytokines (e.g., ⁇ -interferon, IL-2, IL-12, and TNF ⁇ ) , increased proliferation, increased antigen responsiveness (e.g., viral, pathogen, or tumor clearance) relative to such levels before the intervention, and increased effector granule production by CD8 T cells, such as granzyme B.
  • the level of enhancement is as least 50%, alternatively 60%, 70%, 80%, 90%, 100%, 120%, 150%, 200%. The manner of measuring this enhancement is known to one of ordinary skill in the art.
  • T cell dysfunctional disorder is a disorder or condition of T cells characterized by decreased responsiveness to antigenic stimulation.
  • a T cell dysfunctional disorder is a disorder that is specifically associated with increased kinase activity of HPK1.
  • a T cell dysfunctional disorder is one in which T cells are anergic or have decreased ability to secrete cytokines, proliferate, or execute cytolytic activity.
  • the decreased responsiveness results in ineffective control of a pathogen or tumor expressing an immunogen. Examples of T cell dysfunctional disorders characterized by T-cell dysfunction include unresolved acute infection, chronic infection, and tumor immunity.
  • the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are used in treating conditions where enhanced immunogenicity is desired, such as increasing tumor immunogenicity for the treatment of cancer.
  • Immunogenicity refers to the ability of a particular substance to provoke an immune response. Tumors are immunogenic and enhancing tumor immunogenicity aids in the clearance of the tumor cells by the immune response.
  • Tumor immunity refers to the process in which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is “treated” when such evasion is attenuated, and the tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage and tumor clearance.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the subject has melanoma.
  • the melanoma may be at early stage or at late stage.
  • the subject has colorectal cancer.
  • the colorectal cancer may be at early stage or at late stage.
  • the subject has non-small cell lung cancer.
  • the non-small cell lung cancer may be at early stage or at late stage.
  • the subject has pancreatic cancer.
  • the pancreatic cancer may be at early stage or late state.
  • the subject has a hematological malignancy.
  • the hematological malignancy may be at early stage or late stage.
  • the subject has ovarian cancer.
  • the ovarian cancer may be at early stage or at late stage.
  • the subject has breast cancer.
  • the breast cancer may be at early stage or at late stage.
  • the subject has renal cell carcinoma.
  • the renal cell carcinoma may be at early stage or at late stage.
  • the cancer has elevated levels of T-cell infiltration.
  • provided herein is a method of treating a viral infection in a subject in need thereof comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the viral infection is a chronic viral infection.
  • provided herein is a method of increasing the efficacy of vaccination in a patient comprising administering to the patient a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.
  • compositions containing the compound (s) described herein are administered for therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms.
  • the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day.
  • the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg per body weight.
  • the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.
  • long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody.
  • the liposomes are targeted to and taken up selectively by the organ.
  • the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • the compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
  • the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.
  • the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
  • Disclosed herein are methods of treating a disease or disorder associated with HPK1 using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.
  • the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein.
  • the additional therapeutic agent is an anti-cancer agent.
  • Step 1 Procedure for preparation of 1-2
  • Step 2 Procedure for preparation of 1-3
  • Step 3 Procedure for preparation of 1-4
  • Step 5 Procedure for preparation of 1-6
  • Step 1 Procedure for preparation of 2-2
  • Step 3 Procedure for preparation of 2-4
  • Step 4 Procedure for preparation of 3-5
  • Step 5 Procedure for preparation of 3-6
  • Step 4 Procedure for preparation of 4-6
  • Step 1 Procedure for preparation of 5-2
  • Step 3 Procedure for preparation of 6-3
  • Step 12 Procedure for preparation of Example 15-P1 an d 15-P2
  • the 15-11 (16 mg, 0.033 mmol) was further purified by pre-SFC (column: DAICEL CHIRALCEL OD (250mm*30mm, 10um) ; mobile phase: [0.1%NH 3 H 2 O ETOH] ; B%: 60%-60%, min) to afford two fractions.
  • Step 1 Procedure for preparation of 20-1
  • Step 5 Procedure for preparation of 24-5
  • INT 24-4 (0.38 g, 1.21 mmol) in DCM (0.5 mL) being cooled to 0 °C was added TEA (0.34 mL, 2.42 mmol) , followed by MsCl (0.11 mL, 1.45 mmol) dropwise. After additional, the resulting mixture was stirred at 20 °C for 30 mins under N 2 . The reaction mixture was concentrated to afford the INT 24-5 (0.42 g, 1.06 mmol, 87.5%) as a yellow solid, which was used in next step without further purification.
  • Example A The data for Example A is shown in Table 4.
  • HPK1 IC 50 (nM) 0 ⁇ A ⁇ 100; 100 ⁇ B ⁇ 500; 500 ⁇ C ⁇ 5000
  • Example B Cellar p-SLP76 assay
  • Example B Seed cells into the culture plate, then add compounds into the cells, incubate at 37 °C &5%CO 2 ; Add CD3 antibody into cells, incubate at 37 °C &5%CO 2 . After that lyse cell with lysis buffer on ice, transfer the cell lysis into a 96-well plate and store at -80 °C. p-SLP76 was detected by ELISA Kit. The data for Example B is shown in Table 5.
  • p-SLP76 IC 50 (nM) 0 ⁇ A ⁇ 100; 100 ⁇ B ⁇ 500; 500 ⁇ C ⁇ 5000; D>5000
  • Example C Cellar IL-2 assay
  • Human Pan T cells were isolated from PBMC, then coat the plate with anti-human CD3, seed cells into the culture plate, add compounds into the cells, incubate at 37°C &5%CO 2 . Collect supernatant after 24 hours and store it in -80 °C, after that, IL-2 was detected by ELISA Kit.
  • the data for Example C is shown in Table 6.
  • IL-2 IC 50 (nM) 0 ⁇ A ⁇ 300; 300 ⁇ B ⁇ 1000; C>1000

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Abstract

L'invention concerne des inhibiteurs de hpk1et des compositions pharmaceutiques comprenant lesdits inhibiteurs. Les composés et compositions de l'invention sont utiles pour le traitement d'une maladie ou d'un trouble associé à HPK1.
PCT/CN2023/086571 2022-04-07 2023-04-06 Antagonistes de hpk1 et leurs utilisations Ceased WO2023193759A1 (fr)

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Citations (8)

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Publication number Priority date Publication date Assignee Title
CN101990539A (zh) * 2008-02-01 2011-03-23 Irm责任有限公司 作为激酶抑制剂的化合物和组合物
CN102977125A (zh) * 2011-09-06 2013-03-20 江苏先声药物研究有限公司 一类2,7-萘啶衍生物及其制备方法和应用
CN103384669A (zh) * 2011-01-21 2013-11-06 Abbvie公司 Alk的二环抑制剂
US20190256520A1 (en) * 2018-02-20 2019-08-22 Incyte Corporation Indazole compounds and uses thereof
CN110678466A (zh) * 2017-03-30 2020-01-10 豪夫迈·罗氏有限公司 作为hpk1抑制剂的二氮杂萘类
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

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101990539A (zh) * 2008-02-01 2011-03-23 Irm责任有限公司 作为激酶抑制剂的化合物和组合物
CN103384669A (zh) * 2011-01-21 2013-11-06 Abbvie公司 Alk的二环抑制剂
CN102977125A (zh) * 2011-09-06 2013-03-20 江苏先声药物研究有限公司 一类2,7-萘啶衍生物及其制备方法和应用
CN110678466A (zh) * 2017-03-30 2020-01-10 豪夫迈·罗氏有限公司 作为hpk1抑制剂的二氮杂萘类
US20190256520A1 (en) * 2018-02-20 2019-08-22 Incyte Corporation Indazole compounds and uses thereof
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

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