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WO2022253252A1 - Composés hétérocycliques utiles en tant qu'inhibiteurs de hpk1 - Google Patents

Composés hétérocycliques utiles en tant qu'inhibiteurs de hpk1 Download PDF

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Publication number
WO2022253252A1
WO2022253252A1 PCT/CN2022/096515 CN2022096515W WO2022253252A1 WO 2022253252 A1 WO2022253252 A1 WO 2022253252A1 CN 2022096515 W CN2022096515 W CN 2022096515W WO 2022253252 A1 WO2022253252 A1 WO 2022253252A1
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amino
pyridin
oxadiazol
phenylethyl
hydroxy
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Haiquan Fang
Hui Yang
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Silexon Biotech Co Ltd
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Silexon Biotech Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—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
    • C07D471/08—Bridged 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present disclosure generally relates to compounds useful as hematopoietic progenitor kinase 1 ( ⁇ K1) inhibitors, pharmaceutical compositions thereof, method of inhibiting HPK1 kinase activity and method for the treatment of diseases or disorders associated with HPK1, in particular viral infections and proliferative disorders, such as cancer.
  • ⁇ K1 hematopoietic progenitor kinase 1
  • T cells recognize tumor-associated neo-antigens that exist in cancer cells, and would then engage in cytolytic killing of these cancer cells.
  • cancer cells often develop strategies to evade or to suppress the immune system, which directly or indirectly dampen T cell activity. T cells eventually become exhausted and cannot continue to productively engage and kill cancer cells.
  • Immune checkpoint inhibitors CPIs
  • CTLs cytotoxic T cells
  • Hematopoietic progenitor kinase 1 also referred to as mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) , is a serine-threonine kinase that is expressed predominantly in cells of hematopoetic lineage (Kiefer F et al., EMBO J. 1996; 15 (24) : 7013–25) .
  • HPK1 kinase activity can be induced by activation signals generated by different cell surface receptors found in hematopoietic cells upon ligand engagement.
  • HPK1 is involved in modulating variety downstream signaling pathways, including c-Jun N-terminal kinase (JNK) , activator protein 1 (AP-1) , and nuclear factor- ⁇ B (NF- ⁇ B) .
  • JNK c-Jun N-terminal kinase
  • AP-1 activator protein 1
  • NF- ⁇ B nuclear factor- ⁇ B
  • HPK1 is a negative regulator of T-cell, B-cell, and dendritic cell (DCs) signaling pathways (Shui, J. W et al., Nat. Immunol. 2007, 8, 84–91) (Alzabin et al., J. Immunol. 2009, 182, 6187–6194) .
  • T-cell receptor (TCR) signaling or B-cell receptor (BCR) signaling activates HPK1 by inducing HPK1/lymphocyte cytosolic protein 2 (SLP-76) or HPK1/B cell linker protein (BLNK) interaction in T cells and B cells, respectively.
  • SLP-76 HPK1/lymphocyte cytosolic protein 2
  • BLNK HPK1/B cell linker protein
  • HPK1 Activated HPK1 then phosphorylates SLP-76 at Ser376 in T cells or BLNK at Thr-152 in B cells to mediate 14-3-3 binding, thus negatively regulating TCR and BCR signaling (Wang X et al., J Biol Chem. 2012; 287 (14) : 11037–11048) (Di Bartolo V et al., J Exp Med. 2007; 204 (3) : 681–91) .
  • High HPK1 expression have been reported to be positively associated with T cell exhaustion in human and murine cancer (Si J et al., Cancer Cell. 2020, 38 (4) : 551-566) .
  • HPK1 -/- T cells proliferate more rapidly than the haplotype-matched wild-type counterpart and are resistant to prostaglandin E2 (PGE2) -mediated suppression. Also, the loss of HPK1 from dendritic cells (DCs) endows them with superior antigen presentation ability (Alzabin et al., Cancer Immunology, Immunotherapy 59: 419–429) . Study results further demonstrated kinase activity of HPK1 is critical in conferring suppressive functions of HPK1. In vitro, T-cells derived from HPK1 kinase-dead mice showed enhanced proliferation in response to TCR stimulation with anti-CD3 relative to wild type mice (Sairy Hernandez et al., Cell report.
  • NK cells isolated from catalytically inactive K46M HPK1 mutant mice were shown to possess increased cytotoxic activity. Importantly, inactivation of kinase domain was sufficient to elicit robust anti-tumor immune responses in syngeneic tumor models. Co-blockade of PD-L1 further enhanced T effector cell function, resulting in superior anti-viral and anti-tumor immunity over single target blockade (Eric Johnson et al., J Biol Chem. 2019 Jun 7; 294 (23) : 9029-9036) . These results identified the important roles of HPK1 kinase activity in the anti-cancer immunity.
  • HPK1 kinase activity may be an attractive approach for the immunotherapy of cancer. Given that HPK1 is not expressed in any major organs, it is less likely that an inhibitor of HPK1 kinase activity would cause any serious side effects. Accordingly, HPK1 is taken as a valuable immuno-oncology target and a series of HPK1 small molecule kinase inhibitors have been disclosed.
  • the present disclosure relates to a new class of compounds that are effective inhibitors of HPK1 with improved potency and selectivity over other kinase targets such as IRAK4, which off-target would result in T cell suppression and diminish the beneficial effects of HPK1 inhibition.
  • the compounds of the present disclosure are useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity profiles that are important to their drugability.
  • X 1 , X 2 , and X 3 are each independently N or CR 7 ;
  • X 4 is C or B
  • X 5 is O or NR 5 ;
  • X 6 is NR 6 or CR 6a R 6b ;
  • R 1 is selected from the group consisting of -C (O) OH, -C (O) NHR 1a , -C (O) NHNH 2 , -C (O) NHNHC (O) R 1b , cycloalkyl, heterocyclyl, aryl, and heteroaryl, each substituted with 0-4 R 1c ;
  • R 1a and R 1b are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each substituted with 0-4 R 1c ;
  • each R 1c is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each substituted with 0-4 substituents independently selected from halo, hydroxyl, cyano, amino or alkyl;
  • R 2 is -NHR 2a , wherein R 2a is -CHR 2a-1 R 2a-2 ;
  • R 2a-1 is alkyl substituted with 0-3 substituents independently selected from D, halo or hydroxyl;
  • R 2a-2 is aryl or heteroaryl, each substituted with 0-3 substituents independently selected from the group consisting of halo, hydroxyl, cyano, amino, -P (O) (R 2b ) 2 , alkyl, haloalkyl, alkoxy, haloalkoxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • R 2b in each occurrence, is alkyl
  • R 3 and R 4 are each independently absent, hydrogen, halogen, hydroxyl, or -OR 3a ; or
  • R 3a is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl and haloalkyl;
  • R 5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, and heterocyclyl, each of which is substituted with 0-3 substituents independently selected from the group consisting of hydroxyl, halo, cyano, aryl and heteroaryl, wherein each of aryl and heteroaryl is optionally substituted with one or more substituents independently selected from hydroxyl, halo, cyano, alkyl or alkoxyl;
  • R 6 is –SO 2 (alkyl) , alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, or heterocyclyl, each of which is substituted with 0-3 substituents independently selected from the group consisting of hydroxyl, halo, cyano, cycloalkyl and heterocyclyl, wherein each of cycloalkyl and heterocyclyl is optionally substituted with one or more substituents independently selected from hydroxyl, halo, cyano, alkyl or alkoxyl;
  • R 6a and R 6b are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, or haloalkyl, or
  • R 6a and R 6b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl, each substituted with 0-3 substituents independently selected from halo, hydroxyl, or alkyl;
  • R 7 is selected from the group consisting of hydrogen, halo, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkoxy, and haloalkoxy;
  • the present disclosure is directed to pharmaceutical compositions comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • the present disclosure is directed to use of one or more compounds of the present disclosure for the prophylaxis or treatment of HPK1-associated diseases or disorders.
  • the present disclosure is directed to methods for the prophylaxis or treatment of viral infections or cancer, comprising administering a therapeutically effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to a subject in need thereof.
  • the present disclosure is directed to methods of inhibiting activity of hematopoietic progenitor kinase 1 ( ⁇ K1) comprising contacting said hematopoietic progenitor kinase 1 with the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure.
  • ⁇ K1 hematopoietic progenitor kinase 1
  • the present disclosure is directed to a process for preparing a compound of Formula (II) or a pharmaceutically acceptable salt thereof,
  • the present disclosure is directed to a process for preparing a compound of Formula (II) or a pharmaceutically acceptable salt thereof,
  • the present disclosure is directed to a process for preparing a compound of Formula (II) or a pharmaceutically acceptable salt thereof,
  • the present disclosure is directed to a compound having Formula (b) :
  • the present disclosure is directed to a compound having Formula (i) :
  • linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” , then it is understood that the “alkyl” represents a linking alkylene group.
  • any variable e.g., R i
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R i the definition at each occurrence is independent of its definition at every other occurrence.
  • the group may optionally be substituted with up to two R i moieties and R i at each occurrence is selected independently from the definition of R i .
  • combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.
  • a dash “-” at the front or end of a chemical group is used, a matter of convenience, to indicate a point of attachment for a substituent.
  • -OH is attached through the carbon atom; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • a wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.
  • a solid line coming out of the center of a ring indicates that the point of attachment for a substituent on the ring can be at any ring atom.
  • any variable e.g., R i
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R i the definition at each occurrence is independent of its definition at every other occurrence.
  • the group may optionally be substituted with up to two R i moieties and R i at each occurrence is selected independently from the definition of R i .
  • combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.
  • the term “about” directed to that value or parameter per se, includes the indicated amount ⁇ 10%, ⁇ 5%, or ⁇ 1%. Also, the term “about X” includes description of “X” .
  • the term “compounds provided herein” , or “compounds disclosed herein” or “compounds of the present disclosure” refers to the compounds of Formula (I) , Formula (II) , Formula (IIa) , Formula (IIb) , Formula (IIa-1) , Formula (IIa-2) , Formula (IIb-1) , Formula (IIb-2) as well as the specific compounds disclosed herein.
  • C i-j indicates a range of the carbon atoms numbers, wherein i and j are integers and the range of the carbon atoms numbers includes the endpoints (i.e. i and j) and each integer point in between, and wherein j is greater than i.
  • C 1-6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms.
  • the term “C 1-12 ” indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3 or particularly 1 to 2 carbon atoms.
  • the term “m-n membered” ring wherein m and n are integers and n is greater than m, refers to a ring containing m to n atoms.
  • alkyl refers to a saturated linear or branched-chain hydrocarbon radical, which may be optionally substituted independently with one or more substituents described below.
  • C i-j alkyl refers to a linear or branched-chain alkyl having i to j carbon atoms.
  • alkyl groups contain 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.
  • C 1-6 alkyl examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 2-ethyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3, 3-dimethyl-2-butyl, and the like.
  • alkenyl refers to linear or branched-chain hydrocarbon radical having at least one carbon-carbon double bond, which may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
  • alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms.
  • alkenyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkenyl groups contain 2 carbon atoms.
  • alkenyl group include, but are not limited to, ethylenyl (or vinyl) , propenyl (allyl) , butenyl, pentenyl, 1-methyl-2 buten-1-yl, 5-hexenyl, and the like.
  • alkynyl refers to a linear or branched hydrocarbon radical having at least one carbon-carbon triple bond, which may be optionally substituted independently with one or more substituents described herein.
  • alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms.
  • alkynyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkynyl groups contain 2 carbon atoms.
  • alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.
  • alkoxy refers to an alkyl group, as previously defined, attached to the parent molecule through an oxygen atom.
  • C i-j alkoxy means that the alkyl moiety of the alkoxy group has i to j carbon atoms.
  • alkoxy groups can contain 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.
  • Examples of “C 1-6 alkoxy” include, but are not limited to, methoxy, ethoxy, propoxy (e.g. n-propoxy and isopropoxy) , t-butoxy, neopentoxy, n-hexoxy, and the like.
  • amino refers to the group -NR a R b , wherein R a and R b are independently selected from groups consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl and each of which may be optionally substituted.
  • aryl refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 12 ring members.
  • aryl include, but are not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl” , as it is used herein, is a group in which an aromatic ring is fused to one or more additional rings.
  • polycyclic ring system In the case of polycyclic ring system, only one of the rings needs to be aromatic (e.g., 2, 3-dihydroindole) , although all of the rings may be aromatic (e.g., quinoline) .
  • the second ring can also be fused or bridged.
  • polycyclic aryl include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • cyano refers to -CN.
  • cycloalkyl refers to a monovalent non-aromatic, saturated or partially unsaturated monocyclic and polycyclic ring system, in which all the ring atoms are carbon and which contains at least three ring forming carbon atoms.
  • the cycloalkyl group may contain 3 to 12 ring forming carbon atoms, 3 to 10 ring forming carbon atoms, 3 to 9 ring forming carbon atoms, 3 to 8 ring forming carbon atoms, 3 to 7 ring forming carbon atoms, 3 to 6 ring forming carbon atoms, 3 to 5 ring forming carbon atoms, 4 to 12 ring forming carbon atoms, 4 to 10 ring forming carbon atoms, 4 to 9 ring forming carbon atoms, 4 to 8 ring forming carbon atoms, 4 to 7 ring forming carbon atoms, 4 to 6 ring forming carbon atoms, 4 to 5 ring forming carbon atoms.
  • the cycloalkyl group may be saturated or partially unsaturated. In some embodiments, the cycloalkyl group may be a saturated cyclic alkyl group. In some embodiments, the cycloalkyl group may be a partially unsaturated cyclic alkyl group that contains at least one double bond or triple bond in its ring system.
  • the cycloalkyl group may be saturated or partially unsaturated monocyclic carbocyclic ring system, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1- cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • the cycloalkyl group may be saturated or partially unsaturated polycyclic (e.g., bicyclic and tricyclic) carbocyclic ring system, which can be arranged as a fused, spiro or bridged ring system.
  • fused ring refers to a ring system having two rings sharing two adjacent atoms
  • spiro ring refers to a ring systems having two rings connected through one single common atom
  • bridged ring refers to a ring system with two rings sharing three or more atoms.
  • fused carbocyclyl examples include, but are not limited to, naphthyl, benzopyrenyl, anthracenyl, acenaphthenyl, fluorenyl and the like.
  • spiro carbocyclyl examples include, but are not limited to, spiro [5.5] undecanyl, spiro-pentadienyl, spiro [3.6] -decanyl, and the like.
  • bridged carbocyclyl examples include, but are not limited to bicyclo [1, 1, 1] pentenyl, bicyclo [2, 2, 1] heptenyl, bicyclo [2.2.1] heptanyl, bicyclo [2.2.2] octanyl, bicyclo [3.3.1] nonanyl, bicyclo [3.3.3] undecanyl, and the like.
  • halo refers to an atom selected from fluorine (or fluoro) , chlorine (or chloro) , bromine (or bromo) and iodine (or iodo) .
  • haloalkyl refers to an alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. If a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ( "di” ) or three ( “tri” ) halo groups, which may be, but are not necessarily, the same halogen. Some examples of haloalkyl include difluoromethyl (-CHF 2 ) and trifluoromethyl (-CF 3 ) .
  • haloalkenyl refers to an alkenyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
  • haloalkynyl refers to an alkynyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
  • haloalkoxyl refers to an alkoxyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
  • heteroatom refers to nitrogen, oxygen, sulfur or phosphorus, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • heteroalkyl refers to an alkyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, or S.
  • the heteroalkyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) , and may be optionally substituted independently with one or more substituents described herein.
  • heteroalkyl encompasses alkoxy and heteroalkoxy radicals.
  • heteroalkenyl refers to an alkenyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, or S.
  • the heteroalkenyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) , and may be optionally substituted independently with one or more substituents described herein.
  • heteroalkynyl refers to an alkynyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, or S.
  • the heteroalkynyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) , and may be optionally substituted independently with one or more substituents described herein.
  • heteroaryl refers to an aryl group having, in addition to carbon atoms, one or more heteroatoms.
  • the heteroaryl group can be monocyclic. Examples of monocyclic heteroaryl include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl and pteridinyl.
  • the heteroaryl group also includes polycyclic groups in which a heteroaromatic ring is fused to one or more aryl, heteroaryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • polycyclic heteroaryl examples include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo [1, 3] dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • heterocyclyl refers to a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, and the like, the remaining ring atoms being carbon, wherein one or more ring atoms may be optionally substituted independently with one or more substituents.
  • the heterocyclyl is a saturated heterocyclyl.
  • the heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system.
  • the heterocyclyl may contains any oxidized form of carbon, nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • the heterocyclyl radical may be carbon linked or nitrogen linked where such is possible.
  • the heterocycle is carbon linked.
  • the heterocycle is nitrogen linked.
  • a group derived from pyrrole may be pyrrol-1-yl (nitrogen linked) or pyrrol-3-yl (carbon linked) .
  • a group derived from imidazole may be imidazol-1-yl (nitrogen linked) or imidazol-3-yl (carbon linked) .
  • Heterocyclyl group may be monocyclic.
  • monocyclic heterocyclyl include, but are not limited to oxetanyl, 1, 1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, azetidinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like.
  • Heterocyclyl group may be polycyclic, including the fused, spiro and bridged ring systems.
  • the fused heterocyclyl group includes radicals wherein the heterocyclyl radicals are fused with a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring.
  • fused heterocyclyl examples include, but are not limited to, phenyl fused ring or pyridinyl fused ring, such as quinolinyl, isoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo [1, 2-a] pyridinyl, furo [3, 4-d] pyrimidinyl, pyrrolo [3, 4-d] pyrimidinyl, dihydrofuro [3, 4-b
  • spiro heterocyclyl examples include, but are not limited to, spiropyranyl, spirooxazinyl, 5-aza-spiro [2.4] heptanyl, 6-aza-spiro [2.5] octanyl, 6-aza-spiro [3.4] octanyl, 2-oxa-6-aza-spiro [3.3] heptanyl, 2-oxa-6-aza-spiro [3.4] octanyl, 6-aza-spiro [3.5] nonanyl, 7-aza-spiro [3.5] nonanyl, 1-oxa-7-aza-spiro [3.5] nonanyl, 3, 8-dioxa-1-azaspiro [4.5] dec-1-enyl and the like.
  • bridged heterocyclyl examples include, but are not limited to, 3-aza-bicyclo [3.1.0] hexanyl, 8-aza-bicyclo [3.2.1] octanyl, 1-aza-bicyclo [2.2.2] octanyl, 2-aza-bicyclo [2.2.1] heptanyl, 1, 4-diazabicyclo [2.2.2] octanyl, and the like.
  • hydroxyl refers to —OH.
  • partially unsaturated refers to a radical that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and that the substitution results in a stable or chemically feasible compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • the substituents may include, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.
  • X 1 , X 2 , and X 3 are each independently N or CR 7 ;
  • X 4 is C or B
  • X 5 is O or NR 5 ;
  • X 6 is NR 6 or CR 6a R 6b ;
  • R 1 is selected from the group consisting of -C (O) OH, -C (O) NHR 1a , -C (O) NHNH 2 , -C (O) NHNHC (O) R 1b , cycloalkyl, heterocyclyl, aryl, and heteroaryl, each substituted with 0-4 R 1c ;
  • R 1a and R 1b are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each substituted with 0-4 R 1c ;
  • each R 1c is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each substituted with 0-4 substituents independently selected from halo, hydroxyl, cyano, amino or alkyl;
  • R 2 is -NHR 2a , wherein R 2a is -CHR 2a-1 R 2a-2 ;
  • R 2a-1 is alkyl substituted with 0-3 substituents independently selected from D, halo or hydroxyl;
  • R 2a-2 is aryl or heteroaryl, each substituted with 0-3 substituents independently selected from the group consisting of halo, hydroxyl, cyano, amino, -P (O) (R 2b ) 2 , alkyl, haloalkyl, alkoxy, haloalkoxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • R 2b in each occurrence, is alkyl
  • R 3 and R 4 are each independently absent, hydrogen, halogen, hydroxyl, or -OR 3a ; or
  • R 3a is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl and haloalkyl;
  • R 5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, and heterocyclyl, each of which is substituted with 0-3 substituents independently selected from the group consisting of hydroxyl, halo, cyano, aryl and heteroaryl, wherein each of aryl and heteroaryl is optionally substituted with one or more substituents independently selected from hydroxyl, halo, cyano, alkyl or alkoxyl;
  • R 6 is –SO 2 (alkyl) , alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, or heterocyclyl, each of which is substituted with 0-3 substituents independently selected from the group consisting of hydroxyl, halo, cyano, cycloalkyl and heterocyclyl, wherein each of cycloalkyl and heterocyclyl is optionally substituted with one or more substituents independently selected from hydroxyl, halo, cyano, alkyl or alkoxyl;
  • R 6a and R 6b are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, or haloalkyl, or
  • R 6a and R 6b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl, each substituted with 0-3 substituents independently selected from halo, hydroxyl, or alkyl;
  • R 7 is selected from the group consisting of hydrogen, halo, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkoxy, and haloalkoxy;
  • X 1 is N.
  • X 1 is CR 7 .
  • X 2 is N.
  • X 2 is CR 7 .
  • X 3 is N.
  • X 3 is CR 7 .
  • both X 2 and X 3 are N.
  • X 2 is CR 7
  • X 3 is N
  • both X 2 and X 3 are CR 7 .
  • R 7 is hydrogen, halo, cyano, alkyl, or alkoxyl.
  • R 7 is hydrogen, chloro, cyano, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-6 alkoxyl, C 1-5 alkoxyl, C 1- 4 alkoxyl, or C 1-3 alkoxyl.
  • R 7 is hydrogen, chloro, cyano, methyl or methoxyl.
  • X 4 is C.
  • X 4 is B.
  • X 5 is O.
  • X 5 is NR 5 .
  • X 6 is NR 6 .
  • X 6 is CR 6a R 6b .
  • X 4 is C or B
  • X 5 is O
  • X 6 is CR 6a R 6b .
  • X 4 is C
  • X 5 is NR 5
  • X 6 is NR 6 or CR 6a R 6b .
  • R 1 is selected from -C (O) OH, -C (O) NHNHC (O) R 1b , heterocyclyl, or heteroaryl, each substituted with 0-4 R 1c .
  • R 1 is selected from -C (O) OH, -C (O) NHNHC (O) R 1b , 3-to 12-membered, 3-to 10-membered, 3-to 8-membered, 3-to 7-membered, 3-to 6-membered or 3-to 5-membered heterocyclyl, or 3-to 12-membered, 3-to 10-membered, 3-to 8-membered, 3-to 7-membered, 3-to 6-membered or 3-to 5-membered heteroaryl, each substituted with 0-4 R 1c .
  • R 1 is selected from -C (O) OH, -C (O) NHNHC (O) (hydroxylalkyl) , 1, 8-dioxa-3-azaspiro [4.5] dec-2-enyl, or oxadiazolyl, each substituted with 0-4 R 1c .
  • R 1c is selected from alkyl, heterocyclyl or heteroaryl, each .
  • R 1c is selected from C 1-6 alkyl, 3-to 12-membered, 3-to 10-membered, 3-to 8-membered, 3-to 7-membered, 3-to 6-membered or 3-to 5-membered heterocyclyl, or 3-to 12-membered, 3-to 10-membered, 3-to 8-membered, 3-to 7-membered, 3-to 6-membered or 3-to 5-membered heteroaryl.
  • R 1c is selected from methyl, ethyl, propyl, 1-methylpiperidinyl, quinuclidinyl, quinuclidinyl 1-oxide or pyridinyl.
  • R 2 is -NHR 2a , wherein R 2a is -CHR 2a-1 R 2a-2 , R 2a-1 is alkyl substituted with 0-3 hydroxyl, R 2a-2 is aryl or heteroaryl substituted with 0-3 substituents independently selected from halo, -P (O) (R 2b ) 2 , alkyl, haloalkyl or heteroaryl.
  • R 2 is -NHR 2a , wherein R 2a is -CHR 2a-1 R 2a-2 , R 2a-1 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, or C 1-2 alkyl, each of which is substituted with 0-3 hydroxyl, R 2a-2 is C 3-12 aryl, C 3-11 aryl, C 3-10 aryl, C 3-9 aryl, C 3-8 aryl, C 3-7 aryl, C 3-6 aryl, 3-to 12-membered heteroaryl, 3-to 11-membered heteroaryl, 3-to 10-membered heteroaryl, 3-to 9-membered heteroaryl, 3-to 8-membered heteroaryl, 3-to 7-membered heteroaryl, or 3-to 6-membered heteroaryl, each of which is substituted with 0-3 substituents independently selected from halo, -P (O) (R 2b ) 2 , C
  • R 2 is -NHR 2a , wherein R 2a is -CHR 2a-1 R 2a-2 , R 2a-1 is -CH 2 OH, and R 2a-2 is phenyl, furanyl, thiophenyl, oxazolyl, or pyridinyl, each of which is optionally substituted with one or more substituents independently selected from halo, -P (O) (R 2b ) 2 , alkyl, haloalkyl or heteroaryl.
  • R 3 is hydroxyl or -OR 3a
  • R 4 is absent or hydrogen
  • X 5 is O.
  • X 5 is NR 5 .
  • X 6 is NR 6 .
  • X 6 is CR 6a R 6b .
  • X 5 is O and X 6 is CR 6a R 6b .
  • X 5 is NR 5 and X 6 is NR 6 .
  • X 5 is NR 5 and X 6 is CR 6a R 6b .
  • X 1 , X 2 , X 3 , X 4 , X 6 , R 1 , R 2a-1 , R 2a-2 , R 3 , R 4 , R 5 , R 6a , R 6b and R 7 are defined as supra.
  • R 3a is alkyl or haloalkyl. In certain embodiments, R 3a is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, C 1-6 haloalkyl, C 1-5 haloalkyl, C 1- 4 haloalkyl, C 1-3 haloalkyl, or C 1-2 haloalkyl.
  • R 3a is methyl, ethyl, or trifluoroethyl.
  • X 1 , X 2 , X 3 , R 1 , R 2a-1 , R 2a-2 , R 5 , R 6a , R 6b and R 7 are defined as supra.
  • R 5 is selected from hydrogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, or heteroalkyl, each of which is substituted with 0-3 substituents independently selected from the group consisting of hydroxyl, halo, cyano, aryl and heteroaryl, wherein each of aryl and heteroaryl is optionally substituted with one or more substituents independently selected from hydroxyl, halo, cyano, alkyl or alkoxyl.
  • R 5 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, or C 1-2 alkyl, each optionally substituted with aryl or heteroaryl, wherein the C 3-8 aryl or 3-to 8-membered heteroaryl is optionally substituted with hydroxyl, halo, cyano, C 1-3 alkyl or C 1-3 alkoxyl.
  • R 5 is C 1-3 alkyl, -CH 2 -aryl or -CH 2 -heteroaryl, wherein each of aryl and heteroaryl is optionally substituted with one or more substituents independently selected from hydroxyl, halo, cyano, methyl, ethyl, propyl, methoxyl, ethoxyl or propoxyl.
  • R 5 is C 2-6 alkenyl, C 2-5 alkenyl, C 2-4 alkenyl, C 2-3 alkenyl, C 2-6 heteroalkyl, C 2-5 heteroalkyl, C 2-4 heteroalkyl, or C 2-3 heteroalkyl.
  • R 5 is selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, vinyl, 3-propenyl, or –CH 2 OCH 3 .
  • R 5 is C 3-12 cycloalkyl, C 3-11 cycloalkyl, C 3-10 cycloalkyl, C 3-9 cycloalkyl, C 3-8 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, 3-to 12-membered heterocyclyl, 3-to 11-membered heterocyclyl, 3-to 10-membered heterocyclyl, 3-to 9-membered heterocyclyl, 3-to 8-membered heterocyclyl, 3-to 7-membered heterocyclyl, or 3-to 6-membered heterocyclyl.
  • R 5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, or morpholinyl.
  • R 6a and R 6b are each independently selected from hydrogen, halogen, alkyl, or alkenyl. In certain embodiments, R 6a and R 6b are each independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, C 2-6 alkenyl, C 2-5 alkenyl, C 2-4 alkenyl, or C 2-3 alkenyl.
  • R 6a and R 6b are each independently selected from hydrogen, fluoro, methyl or vinyl.
  • R 6a and R 6b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl, each substituted with 0-3 substituents independently selected from halo, hydroxyl, or alkyl.
  • R 6a and R 6b together with the carbon atom to which they are attached form a C 3-12 cycloalkyl, C 3-11 cycloalkyl, C 3-10 cycloalkyl, C 3-9 cycloalkyl, C 3-8 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, 3-to 12-membered heterocyclyl, 3-to 11-membered heterocyclyl, 3-to 10-membered heterocyclyl, 3-to 9-membered heterocyclyl, 3-to 8-membered heterocyclyl, 3-to 7-membered heterocyclyl, or 3-to 6-membered heterocyclyl, each substituted with 0-3 substituents independently selected from halo, hydroxyl, or C 1-6 alkyl.
  • R 6 is —SO 2 (alkyl) . In certain embodiments, R 6 is –SO 2 CH 3 or –SO 2 CH 2 CH 3 .
  • R 6 is alkyl optionally substituted with cycloalkyl and heterocyclyl, wherein each of cycloalkyl and heterocyclyl is optionally substituted with one or more substituents independently selected from hydroxyl, halo, cyano, alkyl or alkoxyl.
  • R 6 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, or C 1-2 alkyl, each optionally substituted with cycloalkyl and heterocyclyl, wherein each of cycloalkyl and heterocyclyl is optionally substituted with one or more substituents independently selected from hydroxyl, halo, cyano, alkyl or alkoxyl.
  • R 6 is selected from methyl, ethyl, n-propyl or i-propyl.
  • R 6 is -CH 2 -cycloalkyl. In certain embodiments, R 6 is -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl or -CH 2 -cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from hydroxyl, halo, cyano, C 1-3 alkyl or C 1-3 alkoxyl.
  • R 6 is -CH 2 -hetercyclyl. In certain embodiments, R 6 is -CH 2 -oxetanyl, -CH 2 -tetrahydrofuranyl, -CH 2 -tetrahydropyranyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 -oxazetidinyl, -CH 2 -oxazolidinyl, or -CH 2 -morpholinyl, each of which is optionally substituted with one or more substituents independently selected from hydroxyl, halo, cyano, C 1-3 alkyl or C 1-3 alkoxyl.
  • R 6 is alkenyl. In certain embodiments, R 6 is C 2-6 alkenyl, C 2-5 alkenyl, C 2-4 alkenyl, or C 2-3 alkenyl. In certain embodiments, R 6 is vinyl, propenyl, butenyl or pentenyl.
  • R 2a-1 is -CH 2 OH.
  • R 2a-2 is phenyl optionally substituted with halo, -P (O) (R 2b ) 2 , alkyl (e.g., C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl) , haloalkyl (e.g., C 1-6 haloalkyl, C 1-5 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl, C 1-2 haloalkyl) , or heteroaryl (e.g., C 3-12 heteroaryl, C 3-11 heteroaryl, C 3-10 heteroaryl, C 3-9 heteroaryl, C 3-8 heteroaryl, C 3-7 heteroaryl, or C 3-6 heteroaryl) .
  • alkyl e.g., C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl
  • R 2a-2 is furanyl, thiophenyl, oxazolyl, or pyridinyl, each of which is optionally substituted with one or more substituents independently selected from halo, -P (O) (R 2b ) 2 , alkyl (e.g., C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl) , haloalkyl (e.g., C 1-6 haloalkyl, C 1-5 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl, C 1-2 haloalkyl) , or heteroaryl (e.g., C 3-12 heteroaryl, C 3-11 heteroaryl, C 3-10 heteroaryl, C 3-9 heteroaryl, C 3-8 heteroaryl, C 3-7 heteroaryl, or C 3-6 heteroaryl) .
  • alkyl e.g., C 1-6
  • R 7 is hydrogen, halo, cyano, alkyl (e.g., C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl) or alkoxyl (e.g., C 1-6 alkoxyl, C 1-5 alkoxyl, C 1-4 alkoxyl, C 1-3 alkoxyl, C 1-2 alkoxyl) .
  • R 7 is hydrogen, halo, cyano, methyl or methoxyl.
  • R 1 , R 2a-1 , R 2a-2 , R 3a , R 5 , R 6 , R 6a , R 6b and R 7 are defined as supra.
  • 6-ethyl-2- ( (5- (3- (4-fluoroquinuclidin-3-yl) -1, 2, 4-oxadiazol-5-yl) -4- ( ( (S) -2-hydroxy-1-phenylethyl) amino) pyridin-2-yl) amino) -7, 7-dimethyl-6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-5-one;(S) -2- ( (4- ( (2-hydroxy-1-phenylethyl) amino) -5- (3- (2-hydroxypropan-2-yl) -1, 2, 4-oxadiazol-5-yl) pyridin-2-yl) amino) -7, 7-dimethyl-6-propyl-6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-5-one;
  • (2S) -2- ( (5- (5- (2-fluoropropan-2-yl) -1, 3, 4-oxadiazol-2-yl) -2- ( (5-methoxy-7, 7-dimethyl-5, 7-dihydrofuro [3, 4-b] pyridin-2-yl) amino) pyridin-4-yl) amino) -2-phenylethan-1-ol;
  • (2S) -2- ( (5- (3- (4-fluorophenyl) -1, 2, 4-oxadiazol-5-yl) -2- ( (5-methoxy-7, 7-dimethyl-5, 7-dihydrofuro [3, 4-b] pyridin-2-yl) amino) pyridin-4-yl) amino) -2-phenylethan-1-ol;
  • (2S) -2- ( (5- (3- (3-fluorophenyl) -1, 2, 4-oxadiazol-5-yl) -2- ( (5-methoxy-7, 7-dimethyl-5, 7-dihydrofuro [3, 4-b] pyridin-2-yl) amino) pyridin-4-yl) amino) -2-phenylethan-1-ol;
  • (2S) -2- ( (5- (3- (2-fluorophenyl) -1, 2, 4-oxadiazol-5-yl) -2- ( (5-methoxy-7, 7-dimethyl-5, 7-dihydrofuro [3, 4-b] pyridin-2-yl) amino) pyridin-4-yl) amino) -2-phenylethan-1-ol;
  • (2S) -2- ( (5- (5-fluoro-1, 3, 4-oxadiazol-2-yl) -2- ( (5-methoxy-7, 7-dimethyl-5, 7-dihydrofuro [3, 4-b] pyridin-2-yl) amino) pyridin-4-yl) amino) -2-phenylethan-1-ol;
  • (2S) -2- ( (5- (3- (4-fluoroquinuclidin-3-yl) -1, 2, 4-oxadiazol-5-yl) -2- ( (5-methoxy-7, 7-dimethyl-5, 7-dihydrofuro [3, 4-b] pyridin-2-yl) amino) pyridin-4-yl) amino) -2-phenylethan-1-ol;
  • (2S) -2- ( (5- (3- (4-fluoroquinuclidin-3-yl) -1, 2, 4-oxadiazol-5-yl) -2- ( (1-methoxy-3, 3-dimethyl-1, 3-dihydro- [1, 2] oxaborolo [4, 3-b] pyridin-5-yl) amino) pyridin-4-yl) amino) -2-phenylethan-1-ol;
  • (2S) -2- ( (5- (3- (4-fluoroquinuclidin-3-yl) -1, 2, 4-oxadiazol-5-yl) -2- ( (1-methoxy-3, 3-dimethyl-1, 3-dihydrobenzo [c] [1, 2] oxaborol-5-yl) amino) pyridin-4-yl) amino) -2-phenylethan-1-ol;
  • (2S) -2- ( (5- (5- (2-fluoropropan-2-yl) -1, 3, 4-oxadiazol-2-yl) -2- ( (1-methoxy-3-methyl-1, 3-dihydrobenzo [c] [1, 2] oxaborol-5-yl) amino) pyridin-4-yl) amino) -2-phenylethan-1-ol;
  • (2S) -2- ( (5- (3- (4-fluorophenyl) -1, 2, 4-oxadiazol-5-yl) -2- ( (1-methoxy-3-methyl-1, 3-dihydrobenzo [c] [1, 2] oxaborol-5-yl) amino) pyridin-4-yl) amino) -2-phenylethan-1-ol;
  • (2S) -2- ( (5- (3- (4-fluoroquinuclidin-3-yl) -1, 2, 4-oxadiazol-5-yl) -2- ( (1-methoxy-3-methyl-1, 3-dihydrobenzo [c] [1, 2] oxaborol-5-yl) amino) pyridin-4-yl) amino) -2-phenylethan-1-ol;
  • 6-Ethyl-2- ( (5- (3- (4-fluoroquinuclidin-3-yl) -1, 2, 4-oxadiazol-5-yl) -4- ( ( (S) -2-hydroxy-1-phenylethyl) amino) pyridin-2-yl) amino) -7, 7-dimethyl-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-5-one;

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Abstract

L'invention concerne des composés de formule (I) : ou des sels pharmaceutiquement acceptables de ceux-ci. L'invention concerne également des procédés d'utilisation de tels composés pour moduler ou inhiber l'activité enzymatique de la kinase progénitrice hématopoïétique (HPK1), ainsi que des compositions pharmaceutiques comprenant de tels composés. Ces composés sont utiles dans le traitement de maladies ou de troubles associés à ΗΡ1, par exemple des infections virales et des cancers.
PCT/CN2022/096515 2021-06-03 2022-06-01 Composés hétérocycliques utiles en tant qu'inhibiteurs de hpk1 Ceased WO2022253252A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023138612A1 (fr) * 2022-01-19 2023-07-27 Silexon Ai Technology Co., Ltd. Composés hétérocycliques utiles en tant qu'inhibiteurs de hpk1
WO2024196841A1 (fr) * 2023-03-21 2024-09-26 Athos Therapeutics, Inc. Inhibiteurs de vanine-1
WO2025079989A1 (fr) * 2023-10-13 2025-04-17 주식회사유한양행 Dérivé de pyrazolo[3,4-b]pyridine ou sel de celui-ci, et composition pharmaceutique le comprenant

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016205942A1 (fr) * 2015-06-25 2016-12-29 University Health Network Inhibiteurs de hpk1 et leurs procédés d'utilisation
CN111527084A (zh) * 2017-11-06 2020-08-11 百时美施贵宝公司 可用作hpk1抑制剂的异呋喃酮化合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016205942A1 (fr) * 2015-06-25 2016-12-29 University Health Network Inhibiteurs de hpk1 et leurs procédés d'utilisation
CN111527084A (zh) * 2017-11-06 2020-08-11 百时美施贵宝公司 可用作hpk1抑制剂的异呋喃酮化合物

Non-Patent Citations (3)

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Title
BAKER, STEPHEN J. ET AL.: "Discovery of a New Boron-Containing Antifungal Agent, 5- Fluoro-1, 3-dihydro-1-hydroxy-2, 1-benzoxaborole (AN2690), for the Potential Treatment of Onychomycosis", JOURNAL OF MEDICINAL CHEMISTRY, vol. 49, no. 15, 27 June 2006 (2006-06-27), pages 4447 - 4750, XP002416532 *
DEGNAN, ANDREW P. ET AL.: "Discovery of Orally Active Isofuranones as Potent, Selective Inhibitors of Hematopoetic Progenitor Kinase 1", ACS MED. CHEM. LETT., vol. 12, 19 February 2021 (2021-02-19), pages 443 - 450, XP055964950, DOI: 10.1021/acsmedchemlett.0c00660 *
REN, JING ET AL.: "Design and synthesis of boron-containing diphenylpyrimidines as potent BTK and JAK3 dual inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 28, 30 November 2019 (2019-11-30), pages 1 - 12, XP086037339, DOI: 10.1016/j.bmc.2019.115236 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023138612A1 (fr) * 2022-01-19 2023-07-27 Silexon Ai Technology Co., Ltd. Composés hétérocycliques utiles en tant qu'inhibiteurs de hpk1
WO2024196841A1 (fr) * 2023-03-21 2024-09-26 Athos Therapeutics, Inc. Inhibiteurs de vanine-1
WO2025079989A1 (fr) * 2023-10-13 2025-04-17 주식회사유한양행 Dérivé de pyrazolo[3,4-b]pyridine ou sel de celui-ci, et composition pharmaceutique le comprenant

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