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WO2023138612A1 - 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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WO2023138612A1
WO2023138612A1 PCT/CN2023/072854 CN2023072854W WO2023138612A1 WO 2023138612 A1 WO2023138612 A1 WO 2023138612A1 CN 2023072854 W CN2023072854 W CN 2023072854W WO 2023138612 A1 WO2023138612 A1 WO 2023138612A1
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amino
oxadiazol
hydroxy
phenylethyl
pyrimidin
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Haiquan Fang
Xiaolei Liu
Hui Yang
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Silexon Ai Technology Co Ltd
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Silexon Ai Technology 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 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
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring 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
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—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

  • 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 hematopoietic 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 (DC) 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.
  • the present disclosure is directed to a compound having Formula (I) :
  • X 1 and X 2 are each independently N or -CR 3 ;
  • X 4 is -NR 5 -or –O-;
  • R 1 is selected from the group consisting of -C (O) OR 1b , -C (O) NHR 1b , -C (O) NHNH 2 , -C (O) NHNHC (O) R 1c , cycloalkyl, heterocyclyl, aryl, and heteroaryl, each substituted with 0-4 R 1a ;
  • each R 1a is independently selected from the group consisting of halogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each substituted with 0-4 substituents independently selected from halo, hydroxyl, cyano, or amino;
  • R 1b and R 1c are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each substituted with 0-4 R 1a ;
  • 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 halogen, hydroxyl, deuterium or tritium;
  • R 2a-2 is aryl or heteroaryl, each substituted with 0-3 substituents independently selected from the group consisting of halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, haloalkoxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • R 3 is hydrogen, halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkoxy, and haloalkoxy;
  • R 3a is halogen or alkyl
  • R 4a and R 4b are each independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, or haloalkyl; or
  • R 4a and R 4b together with the same carbon atom to which they are both attached form a cycloalkyl, heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl;
  • R 4c is selected from hydrogen, halogen, hydroxyl, cyano, alkyl, alkenyl, alkynyl, or haloalkyl;
  • R 5 is selected from hydrogen, alkyl, alkenyl, alkynyl, or haloalkyl; or
  • R 5 and R 4b together with the atoms to which they are attached form a heterocyclyl optionally substituted with one or more R 5a ;
  • R 5 and R 4d together with the atoms to which they are attached form a heterocyclyl optionally substituted with one or more R 5a ;
  • each R 5a is independently selected from halogen, hydroxyl, cyano, amino, alkyl, alkenyl or alkynyl; or
  • n 0, 1, or 2;
  • n 1 or 2;
  • n is not 1.
  • 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
  • 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.
  • 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 (II-1) , Formula (II-2) , Formula (II-3) , Formula (II-4) , and Formula (II-5) 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-to 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, ethenyl (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.
  • alkynyl 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 6 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.
  • bridged refers to a ring fusion wherein non-adjacent atoms on a ring are joined by a divalent substituent, such as alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom.
  • a divalent substituent such as alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom.
  • Examples of bridged ring systems include quinuclidinyl and admantanyl.
  • fused refers to a ring which is bound to an adjacent ring.
  • spiro refers to a ring substituent which is joined by two bonds at the same carbon atom.
  • spiro groups include 1, 1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine, respectively, are the spiro substituents.
  • 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 and X 2 are each independently N or -CR 3 ;
  • X 4 is -NR 5 -or –O-;
  • R 1 is selected from the group consisting of -C (O) OR 1b , -C (O) NHR 1b , -C (O) NHNH 2 , -C (O) NHNHC (O) R 1c , cycloalkyl, heterocyclyl, aryl, and heteroaryl, each substituted with 0-4 R 1a ;
  • R 1 is selected from the group consisting of -C (O) OR 1b , 5-or 6-membered heteroaryl, each substituted with 0-4 R 1a ;
  • each R 1a is independently selected from the group consisting of halogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each substituted with 0-4 substituents independently selected from halo, hydroxyl, cyano, or amino;
  • R 1b and R 1c are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each substituted with 0-4 R 1a ;
  • 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 the group consisting of halogen, hydroxyl, deuterium or tritium;
  • R 2a-2 is aryl or heteroaryl, each substituted with 0-3 substituents independently selected from the group consisting of halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, haloalkoxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • R 3 is hydrogen, halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkoxy, and haloalkoxy;
  • R 3a is halogen or alkyl
  • R 4a and R 4b are each independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, or haloalkyl; or
  • R 4a and R 4b together with the same carbon atom to which they are both attached form a cycloalkyl, heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl;
  • R 4c is selected from hydrogen, halogen, hydroxyl, cyano, alkyl, alkenyl, alkynyl, or haloalkyl;
  • R 5 is selected from hydrogen, alkyl, alkenyl, alkynyl, or haloalkyl; or
  • R 5 and R 4b together with the atoms to which they are attached form a heterocyclyl optionally substituted with one or more R 5a ;
  • R 5 and R 4d together with the atoms to which they are attached form a heterocyclyl optionally substituted with one or more R 5a ;
  • each R 5a is independently selected from halogen, hydroxyl, cyano, amino, alkyl, alkenyl or alkynyl; or
  • n 0, 1 or 2;
  • n 1 or 2;
  • n is not 1.
  • each R 1a is independently selected from the group consisting of halogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each substituted with 0-4 substituents independently selected from the group consisting of halo, hydroxyl, cyano, and amino.
  • R 2a-1 is alkyl substituted with 0-3 substituents independently selected from the group consisting of halogen, hydroxyl, deuterium and tritium.
  • R 2a-2 is aryl or heteroaryl, each substituted with 0-3 substituents independently selected from the group consisting of halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, haloalkoxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • R 3 is hydrogen, halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkoxy, or haloalkoxy.
  • R 4a and R 4b are each independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, or haloalkyl.
  • R 4a and R 4b together with the same carbon atom to which they are both attached form a cycloalkyl, heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, amino and alkyl.
  • R 4c is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, alkyl, alkenyl, alkynyl, and haloalkyl.
  • R 5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and haloalkyl.
  • each R 5a is independently selected from the group consisting of halogen, hydroxyl, cyano, amino, alkyl, alkenyl and alkynyl.
  • two R 5a together with the different carbon atoms to which they are attached form a cycloalkyl or heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, amino and alkyl.
  • X 1 and X 2 are each independently N or -CR 3 ;
  • X 4 is -NR 5 -or –O-;
  • R 1 is selected from the group consisting of -C (O) OR 1b and 5-or 6-membered heteroaryl, each substituted with 0-4 R 1a ;
  • each R 1a is independently selected from the group consisting of halogen and heterocyclyl
  • R 1b is independently selected from -C 1-3 alkyl
  • R 2 is -NHR 2a , wherein R 2a is -CHR 2a-1 R 2a-2 ;
  • R 2a-1 is -C 1-3 alkyl substituted with 0-3 substituents independently selected from hydroxyl and deuterium;
  • R 2a-2 is 6-membered aryl, substituted with 0-3 substituents independently selected from halogen;
  • R 3 is hydrogen, or halogen
  • R 3a is hydrogen, halogen, or -C 1-3 alkyl
  • R 4a and R 4b are each independently hydrogen, halogen, hydroxyl, -C 1-3 alkyl, or -C 1-3 alkylene-OH; or
  • R 4a and R 4b together with the same carbon atom to which they are both attached form a
  • R 4c is selected from hydrogen, and -C 1-3 alkyl
  • R 5 is selected from hydrogen, -C 1-3 alkylene-aryl, or -C 1-3 alkyl; or
  • R 5 and R 4b together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl optionally substituted with one or more R 5a ;
  • R 5 and R 4d together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl optionally substituted with one or more R 5a ;
  • each R 5a is independently selected from -C 1-3 alkyl
  • n 0, 1, or 2;
  • n 1 or 2;
  • n is not 1.
  • X 1 is N.
  • X 1 is CR 3 .
  • X 2 is N.
  • X 2 is CR 3 .
  • X 3 is - (CR 4a R 4b ) n -.
  • X 3 is -NR 4d .
  • X 4 is -O-.
  • X 4 is -O-
  • X 3 is - (CR 4a R 4b ) n -.
  • R 4a and R 4b are each independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, or haloalkyl.
  • R 4a and R 4b are each independently hydrogen, halogen, hydroxyl, -C 1-3 alkyl, or -C 1-3 alkylene-OH.
  • R 4a and R 4b are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, -CH 2 CH 2 CH 2 OH, -CH (CH 3 ) CH 2 OH, -CH 2 CH 2 OH, or -CH 2 OH.
  • R 4a and R 4b are each independently hydrogen, fluorine, hydroxyl, methyl, or -CH 2 OH.
  • R 4a and R 4b are each independently hydrogen, fluorine, hydroxyl, or methyl.
  • R 4a and R 4b are each independently hydrogen, methyl, or -CH 2 OH.
  • R 4a and R 4b together with the same carbon atom to which they are both attached form a cycloalkyl, heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl.
  • R 4a and R 4b together with the same carbon atom to which they are both attached form a
  • X 4 is -O-, and X 3 is - (CR 4a R 4b ) n -, n is not 1.
  • X 4 is -O-
  • X 3 is - (CR 4a R 4b ) n -, n is 2.
  • X 4 is -O-
  • X 3 is - (CR 4a R 4b ) (CR 4a R 4b ) -.
  • X 4 is -N-
  • R 4c is selected from hydrogen, halogen, hydroxyl, cyano, alkyl, alkenyl, alkynyl, or haloalkyl.
  • R 4c is selected from the group consisting of hydrogen and -C 1-3 alkyl.
  • R 4c is selected from the group consisting of hydrogen, methyl, ethyl, propyl, and isopropyl.
  • R 4c is selected from the group consisting of hydrogen and methyl.
  • X 4 is -NR 5 .
  • X 4 is -NR 5
  • X 3 is - (CR 4a R 4b ) n -.
  • R 4a and R 4b together with the same carbon atom to which they are both attached form
  • R 5 is hydrogen or alkyl.
  • R 5 is hydrogen, or -C 1-3 alkyl.
  • R 5 is -C 1-3 alkylene-aryl.
  • R 5 is hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, or 2, 4-dimethoxybenzyl.
  • R 5 is 2, 4-dimethoxybenzyl.
  • R 4a is hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, or haloalkyl, and R 5 and R 4b together with the atoms to which they are attached form a heterocyclyl optionally substituted with one or more R 5a .
  • R 5 and R 4b together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl optionally substituted with one or more R 5a .
  • R 5 and R 4b together with the atoms to which they are attached form:
  • R 4a and R 4b are each independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, or haloalkyl.
  • R 5 is hydrogen or alkyl.
  • X 4 is -NR 5
  • X 3 is -NR 4d .
  • R 5 and R 4d together with the atoms to which they are attached form a heterocyclyl optionally substituted with one or more R 5a .
  • R 5 and R 4d together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl optionally substituted with one or more R 5a .
  • R 5 and R 4d together with the atoms to which they are attached form:
  • each R 5a is independently selected from halogen, hydroxyl, cyano, amino, alkyl, alkenyl or alkynyl.
  • each R 5a is independently selected from hydrogen.
  • each R 5a is independently selected from -C 1-3 alkyl.
  • each R 5a is independently selected from the group consisting of methyl, ethyl, propyl, and isopropyl.
  • two R 5a together with the different carbon atoms to which they are attached form a cycloalkyl or heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl.
  • R 1 is -C (O) OH, -C (O) NHNHC (O) R 1c , heterocyclyl or heteroaryl, wherein the heterocyclyl or heteroaryl substituted with 0-4 R 1a .
  • R 1 is selected from the group consisting of -C (O) OR 1b and 5-or 6-membered heteroaryl, each substituted with 0-4 R 1a .
  • the 5-or 6-membered heteroaryl is selected from the group consisting of oxadiazolyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • the 5-or 6-membered heteroaryl is selected from the group consisting of 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, and pyridazinyl.
  • each R 1a is independently selected from the group consisting of hydrogen, halogen and heterocyclyl.
  • each R 1a is independently selected from the group consisting of hydrogen and quinuclidinyl.
  • R 1b is independently selected from methyl, ethyl, propyl, and isopropyl, preferably ethyl.
  • R 1 is selected from the group consisting of: -COOCH 2 CH 3 ,
  • R 1 is -C (O) OH, -C (O) NHNHC (O) (hydroxylalkyl) , oxadiazolyl or 1, 8-dioxa-3-azaspiro [4.5] dec-2-enyl, each substituted with 0-4 R 1a .
  • R 1a is heterocyclyl.
  • R 2 is -NHR 2a , wherein R 2a is -CHR 2a-1 R 2a-2 , wherein R 2a-1 is alkyl substituted with 0-3 hydroxyl or deuterium, and R 2a-2 is aryl substituted with 0-3 halogen.
  • R 2a-1 is -C 1-3 alkyl substituted with 0-3 substituents independently selected from the group consisting of hydroxyl and deuterium.
  • R 2a-1 is methyl, ethyl, propyl, or isopropyl, substituted with 0-3 substituents independently selected from the group consisting of hydroxyl and deuterium.
  • R 2a-1 is methyl, substituted with 0-3 substituents independently selected from the group consisting of hydroxyl and deuterium.
  • R 2a-2 is 6-membered aryl, substituted with 0-3 substituents independently selected from the group consisting of halogen and -C 1-3 alkyl.
  • R 2a-2 is phenyl, substituted with 0-3 substituents independently selected from the group consisting of fluorine, chlorine, and bromine.
  • R 2a-2 is 4-fluorophenyl.
  • R 2a is selected from the groups consisting of:
  • 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 or deuterium, 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, each of which is substituted with 0-3 halogen.
  • 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 0-3 halogen.
  • R 3 is hydrogen or halogen. In certain embodiments, R 3 is hydrogen, fluorum or chlorine.
  • R 3 is hydrogen, fluorine, or chlorine.
  • R 3 is hydrogen or fluorine.
  • R 3a is halogen or -C 1-3 alkyl.
  • R 3a is fluorine, chlorine, bromine, methyl, ethyl, propyl, or isopropyl.
  • R 3a is fluorine
  • R 3a hydrogen
  • m is 0.
  • n 1
  • n 2
  • n 1
  • n is 2.
  • the moiety is selected from the group consisting of:
  • the moiety is selected from the group consisting of:
  • X 1 , X 2 , R 1 , R 2 , R 3a , R 4a , R 4b , R 4c , R 5 and m are defined as supra.
  • R 1 is selected from the group consisting of: -COOCH 2 CH 3 ,
  • R 2 is
  • X 1 is N.
  • X 2 is N or -CH-.
  • n 1
  • R 3a is H.
  • R 4a and R 4b are each independently hydrogen, halogen, hydroxyl, or alkyl. In certain embodiments, R 4a and R 4b are each independently hydrogen, halogen, or methyl.
  • R 4a and R 4b are each independently hydrogen, fluorine, hydroxyl, methyl, or -CH 2 OH; or R 4a and R 4b together with the same carbon atom to which they are both attached form a
  • R 4a and R 4b together with the same carbon atom to which they are both attached form or cycloalkyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl. In certain embodiments, R 4a and R 4b together with the same carbon atom to which they are both attached form or cyclopropyl.
  • R 4c is hydrogen or alkyl. In certain embodiments, R 4c is hydrogen or methyl.
  • R 4c is selected from the group consisting of hydrogen and methyl.
  • R 5 is hydrogen or alkyl. In certain embodiments, R 5 is hydrogen or methyl.
  • X 1 , X 2 , R 1 , R 2 , R 3a , R 4a , R 4b , R 4d , R 5 and m are defined as supra.
  • R 1 is selected from the group consisting of:
  • R 2 is
  • X 1 is N or -CH-.
  • X 1 is N, -CH-, or -CF-.
  • n 1
  • R 3a is H or F.
  • R 4a and R 4b together with the same carbon atom to which they are both attached form
  • R 4a is hydrogen, halogen, hydroxyl, or alkyl, and R 5 and R 4b together with the atoms to which they are attached form a heterocyclyl optionally substituted with one or more R 5a .
  • R 4a and R 4b are each independently hydrogen or methyl.
  • R 4a is hydrogen or methyl
  • R 5 and R 4b together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl optionally substituted with one or more R 5a .
  • R 4a is hydrogen or methyl
  • R 5 and R 4b together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl selected form the group consisting of:
  • R 4a is hydrogen, halogen, hydroxyl, or alkyl, and R 5 and R 4b together with the atoms to which they are attached form a heterocyclyl selected from the group consisting of:
  • each R 5a is independently halogen or alkyl. In certain embodiments, each R 5a is independently halogen or C 1-6 alkyl. In certain embodiments, each R 5a is independently halogen or methyl.
  • two R 5a together with the different carbon atoms to which they are attached form a cycloalkyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl.
  • two R 5a together with the different carbon atoms to which they are attached form a C 3-6 cycloalkyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl.
  • two R 5a together with the different carbon atoms to which they are attached form a cyclopropyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl.
  • each R 5a is independently selected from hydrogen and methyl.
  • R 5 and R 4d together with the atoms to which they are attached form a heterocyclyl optionally substituted with one or more R 5a .
  • R 5 and R 4d together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl optionally substituted with one or more R 5a .
  • R 5 and R 4d together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl selected from the group consisting of:
  • R 5 and R 4d together with the atoms to which they are attached form a heterocyclyl selected from the group consisting of:
  • each R 5a is independently halogen or alkyl. In certain embodiments, each R 5a is independently halogen or C 1-6 alkyl. In certain embodiments, each R 5a is independently halogen or methyl.
  • two R 5a together with the different carbon atoms to which they are attached form a cycloalkyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl.
  • two R 5a together with the different carbon atoms to which they are attached form a C 3-6 cycloalkyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl.
  • two R 5a together with the different carbon atoms to which they are attached form a cyclopropyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl.
  • each R 5a is independently selected from the group consisting of hydrogen and methyl.
  • Compounds provided herein or pharmaceutically acceptable salts thereof may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R) -or (S) -or, as (D) -or (L) -for amino acids.
  • the present disclosure includes all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-) , (R) -and (S) -, or (D) -and (L) -isomers may be prepared using chiral synthons or chiral reagents, or resolved by conventional techniques, such as, chromatography and fractional crystallization.
  • stereoisomer refers to a compound containing the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the current disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers” , which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.
  • enantiomers represent a pair of stereoisomers that are non-superimposable mirror images of each other.
  • a 1: 1 mixture of a pair of enantiomers is a "racemic” mixture.
  • a mixture of enantiomers at a ratio other than 1: 1 is a "scalemic" mixture.
  • diastereoisomers represent stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • Tautomer refers to a proton shift from one atom of a molecule to another atom of the same molecule.
  • the present disclosure includes tautomers of any compounds provided herein.
  • Tautomeric isomers are in equilibrium with one another.
  • amide containing compounds may exist in equilibrium with imidic acid tautomers. No matter which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. As the same, the imidic acid containing compounds are understood to include their amide tautomers.
  • any formula or structure provided herein also represents unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have the same structures as depicted by the formulas given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes include isotopes, such as, but not limited to, of hydrogen ( 2 H (deuterium, D) , 3 H (tritium) ) , carbon ( 11 C, 13 C, 14 C) , nitrogen ( 15 N) , oxygen ( 17 O, 18 O) , phosphorous ( 31 P, 32 P) , fluorine ( 18 F) , chlorine ( 36 Cl) , and iodine ( 125 I) .
  • isotopically labelled compounds may have usages in metabolic studies, reaction kinetic studies, detection, or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) in drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • the term “pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the subjects being treated therewith.
  • the term “subject” refers to an animal, preferably a mammal, more preferably a human, who has been the object of treatment, observation, or experiment.
  • the term “pharmaceutically acceptable salt” includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable.
  • Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and so on.
  • Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.
  • Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
  • acidic functional groups such as carboxylic acid or phenol are present.
  • salts can be prepared by standard techniques.
  • the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric acid
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • amino acids such as L-glycine, L-lysine, and L-arginine
  • ammonia primary, secondary, and tertiary amines
  • cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • the compounds of present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms) , and solid forms (e.g., amorphous, crystal, or polymorphic forms) , and the present disclosure is intended to encompass all such forms.
  • solvate or “solvated form” refers to solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H 2 O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • the compounds provided herein are intended for pharmaceutical use, they are preferably provided in substantially pure form, for example at least 60%pure, more suitably at least 75%pure, especially at least 98%pure (%are on a weight for weight basis) .
  • Synthesis of the compounds provided herein, including pharmaceutically acceptable salts thereof, are illustrated in the synthetic schemes in the examples.
  • the compounds provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, and thus these schemes are illustrative only and are not meant to limit other possible methods that can be used to prepare the compounds provided herein. Additionally, the steps in the Schemes are for better illustration and can be changed as appropriate.
  • the embodiments of the compounds in examples were synthesized for the purposes of research and potentially submission to regulatory agencies.
  • the reactions for preparing compounds of the present disclosure can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with the starting materials (reactants) , the intermediates, or products at the temperatures at which the reactions are carried out, e.g. temperatures that can range from the solvent’s freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by one skilled in the art.
  • Preparation of compounds of the present disclosure can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999) , in P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003, and in Peter G.M. Wuts, Greene's Protective Groups in Organic Synthesis, 5 th Edition, Wiley, 2014, all of which are incorporated herein by reference in its entirety.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C) , infrared spectroscopy, spectrophotometry (e.g. UV-visible) , mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) , liquid chromatography-mass spectroscopy (LCMS) , or thin layer chromatography (TLC) .
  • HPLC high performance liquid chromatography
  • LCMS liquid chromatography-mass spectroscopy
  • TLC thin layer chromatography
  • Compounds can be purified by one skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ( “Preparative LC-MS Purification: Improved Compound Specific Method Optimization” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6 (6) ,
  • the known starting materials of the present disclosure can be synthesized by using or according to the known methods in the art or can be purchased from commercial suppliers. Unless otherwise noted, analytical grade solvents and commercially available reagents were used without further purification.
  • the reactions of the present disclosure were all done under a positive pressure of nitrogen or argon or with a drying tube in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
  • the Examples section below shows synthetic route for preparing the compounds of the present disclosure as well as key intermediates. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
  • the compounds provided herein are administered as a raw chemical or are formulated as pharmaceutical compositions.
  • the present disclosure provides pharmaceutical compositions comprising one or more compounds provided herein or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions of the present disclosure comprise a compound selected from Formula (I) , Formula (II) , Formula (II-1) , Formula (II-2) , Formula (II-3) , Formula (II-4) , Formula (II-5) , or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions of the present disclosure comprise a first compound selected from Formula (I) , Formula (II) , Formula (II-1) , Formula (II-2) , Formula (II-3) , Formula (II-4) , Formula (II-5) or a pharmaceutically acceptable salt thereof and one or more additional compounds of the same formula but said first compound and additional compounds are not the same molecules.
  • the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject.
  • the pharmaceutical compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • compositions of the present disclosure comprise a therapeutically effective amount of one or more compounds of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the term “therapeutically effective amount” refers to an amount of a molecule, compound, or composition comprising the molecule or compound to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect.
  • the effect can be detected by any assay method known in the art.
  • the precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the discretion of the prescribing physician.
  • Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • the pharmaceutical composition comprises one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical acceptable carrier or excipient.
  • the term “pharmaceutically acceptable carrier” refers to a carrier or excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes carrier that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable carrier” as used herein includes both one and more than one such carrier.
  • pharmaceutically acceptable carrier also encompasses “pharmaceutically acceptable excipient” and “pharmaceutically acceptable diluent” .
  • the particular carrier used in the pharmaceutical compositions of the present disclosure will depend upon the means and purpose for which the compounds of the present disclosure are being applied.
  • the pharmaceutical acceptable carrier employed can be, for example, a solid, liquid or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • oral liquid preparations such as suspensions, elixirs, and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or non-aqueous techniques.
  • a tablet containing the pharmaceutical composition of the present disclosure may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
  • a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 0.05 to about 95 percent of the total composition.
  • compositions of the present disclosure suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropyl cellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
  • compositions of the present disclosure can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 0.05wt%to about 10wt%of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of the present disclosure can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
  • the pharmaceutical composition described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
  • the pharmaceutical compositions of the present disclosure can be formulated as a unit dosage form.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
  • the amount of the compounds provided herein in the unit dosage form will vary depending on the condition to be treated, the subject to be treated (e.g., the age, weight, and response of the individual subject) , the particular route of administration, the actual compound administered and its relative activity, and the severity of the subject's symptoms.
  • each dosage unit contains from about 0.01 mg to about 2000 mg of one or more compounds provided herein, for example, from about 0.01 mg to about 1000 mg, from about 0.02 mg to about 1000 mg, from about 1 mg to about 1000 mg, from about 2 mg to about 1000 mg, from about 3 mg to about 1000 mg, from about 4 mg to about 1000 mg, from about 5 mg to about 1000 mg, from about 10 mg to about 1000 mg, from about 25 mg to about 1000 mg, from about 50 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 200 mg to 1000 mg, from about 300 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 500 mg to about 1000 mg, from about 1 mg to 500 mg, from about 10 mg to about 500 mg, from about 50 mg to about 500 mg, from about 100 mg to about 500 mg, from about 200 mg to about 500 mg, from about 300 mg to about 500 mg, from about 400 mg to about 500 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about
  • each dosage unit contains from about 0.1 mg to about 100 mg of one or more compounds provided herein, for example from about 0.5 mg to about 100 mg, from about 1 mg to about 100 mg, from about 5 mg to about 100 mg, from about 10 mg to about 100 mg, from about 20 mg to about 100 mg, from about 30 mg to about 100 mg, from about 40 mg to about 100 mg, from about 50 mg to about 100 mg, from about 0.5 mg to about 90 mg, from about 0.5 mg to about 80 mg, from about 0.5 mg to about 70 mg, from about 0.5 mg to about 60 mg, from about 0.5 mg to about 50 mg, from about 0.5 mg to about 40 mg, from about 1 mg to about 90 mg, from about 5 mg to about 90 mg, from about 10 mg to about 80 mg, from about 20 mg to about 70 mg, from about 30 mg to about 60 mg, or from about 40 mg to about 50 mg.
  • dosage levels of the pharmaceutical compositions of the present disclosure can be between 0.001-1000 mg/kg body weight/day, for example, 0.01-900 mg/kg body weight/day, 0.01-800 mg/kg body weight/day, 0.01-700 mg/kg body weight/day, 0.01-600 mg/kg body weight/day, 0.01-500 mg/kg body weight/day, 0.01-400 mg/kg body weight/day, 0.01-300 mg/kg body weight/day, 0.05-900 mg/kg body weight/day, 0.05-800 mg/kg body weight/day, 0.05-700 mg/kg body weight/day, 0.05-600 mg/kg body weight/day, 0.05-500 mg/kg body weight/day, 0.1-200 mg/kg body weight/day, 0.1-150 mg/kg body weight/day, 0.1-100 mg/kg body weight/day, 0.5-100 mg/kg body weight/day, 0.5-80 mg/kg body weight/day, 0.5-60 mg/kg body weight/day, 0.5-50 mg/
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • routes of administration and dosage regimes see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board) , Pergamon Press 1990, which is specifically incorporated herein by reference.
  • the pharmaceutical composition of the present disclosure comprising one or more compounds provided herein or pharmaceutically acceptable salts thereof further comprises one or more additional therapeutically active agents.
  • additional therapeutically active agents include but not limited to an anti-viral agent, a chemotherapeutic agent, radiation, an anti-tumor vaccine, an antiviral vaccine, cytokine therapy, a tyrosine kinase inhibitor, or an immuno-oncology agent.
  • the immuno-oncology agents include but not limited to small molecule drug, antibody, or other biologic molecules.
  • biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines.
  • the immuno-oncology agents could antagonist of a protein that inhibits T cell and/or NK cell activation.
  • the antibody is a monoclonal antibody.
  • HPK1 can be used as a therapeutic in a variety of disorders wherein HPK1 is involved such as, but not limited to, disorders with dysregulated immune responses, autoimmune disease, inflammation, vaccination for infection and/or cancer, viral infections, obesity and diet-induced obesity, adiposity, metabolic disorders, hepatic steatosis, and uterine fibroids.
  • HPK1-associated diseases or disorders is a pathological condition in which HPK1 activity is necessary for the genesis or maintenance of the pathological condition.
  • treatment or “treating” describes the management and care of a patient for the purpose of reversing, inhibiting, or combating a disease, condition, or disorder.
  • prophylaxis refers to a measure taken to maintain health and prevent the spread of a disease, condition, or disorder.
  • the HPK1-associated disease or disorder is viral infection or cancer.
  • viral infections include, but are not limited to, diseases caused by hepatitis C virus (HCV) , human papilloma virus (HPV) , cytomegalovirus (CMV) , herpes simplex virus (HSV) , Epstein-Barr virus (EBV) , coronavirus, varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV) .
  • HCV hepatitis C virus
  • HPV human papilloma virus
  • CMV cytomegalovirus
  • HSV herpes simplex virus
  • EBV Epstein-Barr virus
  • coronavirus e.g., coronavirus
  • varicella zoster virus e.g., coxsackie virus
  • coxsackie virus e.g., human immunodeficiency virus
  • the viral infection is selected from the group consisting of human immunodeficiency virus (HIV) infection, hepatitis B virus (HBV) infection, and hepatitis C virus (HCV) infection.
  • HIV human immunodeficiency virus
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • cancer encompasses all forms of cancers, including, but not limited to, all forms of carcinomas, melanomas, blastomas, sarcomas, lymphomas and leukemias.
  • examples include but are not limited to breast cancer, bladder cancer, bladder carcinoma, uterine cancer, brain tumors, cervical cancer, colon cancer, colorectal cancer, cancer of the head and neck, esophageal cancer, endometrial cancer, liver cancer (including HCC) , laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal carcinoma, renal cancer, kidney cancer (including RCC) , thyroid cancer, lymphoma, leukemia, acute lymphocytic leukemia, acute myeloid leukemia, melanoma, ependymoma, Ewing’s sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma,
  • the cancer is characterized by amplification, mutation or overexpression of HPK1 kinase.
  • the cancer is selected from cancer of the breast cancer, cervical cancer, colon cancer, cancer of the head and neck, lymphoma, leukemia, and melanoma, lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, and renal cancer.
  • a method for the prophylaxis or treatment of viral infection or cancer in a subject in need thereof comprising administering a therapeutically effective amount of the compound (s) or a pharmaceutically acceptable salts thereof, or the pharmaceutical composition (s) provided herein, to the subject in need thereof.
  • the subject is at risk of HBV infection such as a subject who has one or more risk factors known to be associated with contracting the Hepatitis B virus.
  • the subject is at risk of HIV infection such as a subject who has one or more risk factors known to be associated with contracting the HIV virus.
  • the subject may have not previously received antiviral treatment (treatment naive) . In some embodiments, the subject may have previously received antiviral treatment (treatment experienced) . In some embodiments, the subject may have previously received antiviral treatment and developed resistance to the previously received antiviral treatment.
  • the compounds, or a pharmaceutically acceptable salts thereof or the pharmaceutical composition of the present disclosure can be administered as the sole active agent.
  • the compounds, or the pharmaceutically acceptable salts thereof or the pharmaceutical composition of the present disclosure can be administered in combination with one or more additional active ingredients.
  • additional active ingredient of the pharmaceutical combination formulation or dosing regimen has complementary activities to the compounds of disclosure such that they do not adversely affect each other. Such ingredients are suitably present in combination in amounts that are effective for the purpose intended.
  • the compounds or a pharmaceutically acceptable salts thereof provided herein, or the pharmaceutical composition (s) provided herein can be used in combination with an additional therapy.
  • the additional therapy may optionally include one or more therapeutic agents, radiation therapy, surgery (e.g., lumpectomy and a mastectomy) , chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, or a combination of the foregoing.
  • the compounds or a pharmaceutically acceptable salts thereof provided herein, or the pharmaceutical composition (s) provided herein may be administered simultaneously, sequentially, or separately with one or more additional therapeutic agents.
  • the compound (s) or a pharmaceutically acceptable salts thereof of the present disclosure, or the pharmaceutical composition (s) provided herein can be administered to the subject a therapeutically effective amount of an anti-viral agent, a chemotherapeutic agent, radiation, an anti-tumor vaccine, an antiviral vaccine, cytokine therapy and a tyrosine kinase inhibitor prior to, simultaneously with or after administration of the compound (s) .
  • a method of inhibiting activity of ⁇ K1 comprising contacting the HPK1 with the compound (s) or a pharmaceutically acceptable salts thereof provided herein, or the pharmaceutical composition (s) provided herein.
  • inhibitors refers to a decrease in the baseline activity of a biological activity or process.
  • “Inhibition of activity of HPK1” or “inhibiting activity of HPK1” and/or HPK1 variants thereof refers to a decrease in HPK1 activity as compared to the activity of that enzyme in the absence of the compounds of the present disclosure.
  • such decrease in HPK1 and/or HPK1 variants activity can be a direct or indirect response to the presence of a compound provided herein relative to the HPK1 activity in the absence of the compound provided herein.
  • the inhibition of HPK1 activity may be compared in the same subject prior to treatment, or other subjects not receiving the treatment.
  • the compound (s) or a pharmaceutically acceptable salts thereof provided herein, or the pharmaceutical composition (s) provided herein can be utilized to inhibit, block, reduce or decrease HPK1 activation for the reduction of tumor growth and the modulation of dysregulated immune responses e.g. to block immunosuppression and increase immune cell activation and infiltration in the context of cancer and cancer immunotherapy.
  • non-exemplified compounds according to the present disclosure may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks known in the art other than those described, and/or by making routine modifications of reaction conditions.
  • persons skilled in the art will also understand that individual steps described herein or in the separate batches of a compound may be combined.
  • other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure. The following description is, therefore, not intended to limit the scope of the present disclosure, but rather is specified by the claims appended hereto.
  • Step 1 Ethyl 2- (2-allyl-2- (tert-butoxycarbonyl) hydrazineyl) -6-chloronicotinate
  • Step 4 1, 2-Diallyl-6-chloro-1, 2-dihydro-3H-pyrazolo [3, 4-b] pyridin-3-one
  • Step 5 2-Chloro-7, 10-dihydro-5H-pyrido [2', 3': 3, 4] pyrazolo [1, 2-a] pyridazin-5-one
  • Step 3 1, 2-Diallyl-6-chloro-1, 2-dihydro-3H-indazol-3-one
  • Step 4 3-Chloro-6, 9-dihydro-11H-pyridazino [1, 2-a] indazol-11-one
  • Step 4 9-Bromo-1, 10b-dihydropyrido [2, 1-a] isoindol-6 (4H) -one
  • Step 1 2-Allyl-1- (but-3-en-1-yl) -6-chloro-1, 2-dihydro-3H-indazol-3-one
  • Step 2 3-Chloro-7, 10-dihydro-6H, 12H- [1, 2] diazepino [1, 2-a] indazol-12-one
  • Step 4 Methyl 6-chloro-2- (chloromethyl) nicotinate
  • Step 6 6, 7-Diallyl-2-chloro-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-5-one
  • Step 7 2-Chloro-10, 10a-dihydropyrido [2, 3-a] indolizin-5 (7H) -one
  • Step 2 9-Bromo-10b-methyl-1, 10b-dihydropyrido [2, 1-a] isoindol-6 (4H) -one
  • Step 2 6-Chloro-2- (3, 4-dimethoxybenzyl) -1, 2-dihydro-3H-indazol-3-one
  • Step 3 6-Chloro-2- (3, 4-dimethoxybenzyl) -1- (2-hydroxyethyl) -1, 2-dihydro-3H-indazol-3-one
  • Step 4 6-Chloro-1- (2-hydroxyethyl) -1, 2-dihydro-3H-indazol-3-one
  • Step 5 7-Chloro-3, 4-dihydro-1H, 10H- [1, 3, 4] oxadiazino [4, 3-a] indazol-10-one
  • Step 1 N- (2- ( (tert-Butyldimethylsilyl) oxy) ethyl) -4-chloro-2-nitrobenzamide
  • Step 2 2- (2- ( (tert-Butyldimethylsilyl) oxy) ethyl) -6-chloro-1, 2-dihydro-3H-indazol-3-one
  • Step 3 6-Chloro-2- (2-hydroxyethyl) -1, 2-dihydro-3H-indazol-3-one
  • Step 4 9-Chloro-3, 4-dihydro-1H, 6H- [1, 3, 4] oxadiazino [3, 4-a] indazol-6-one
  • Step 1 5-Bromo-2- (2- ( (tert-butyldimethylsilyl) oxy) ethyl) isoindolin-1-one
  • Step 3 9-Bromo-1, 3, 4, 10b-tetrahydro-6H- [1, 4] oxazino [3, 4-a] isoindol-6-one
  • Step 1 ethyl (S) -2-chloro-4- ( (2-hydroxy-1-phenylethyl) amino) pyrimidine-5-carboxylate
  • Step 2 ethyl (S) -4- ( (2-hydroxy-1-phenylethyl) amino) -2- ( (4-methoxybenzyl) amino) pyrimidine-5-carboxylate
  • Step 3 ethyl (S) -2-amino-4- ( (2-hydroxy-1-phenylethyl) amino) pyrimidine-5-carboxylate
  • Step 4 (S) -2-Amino-4- ( (2-hydroxy-1-phenylethyl) amino) pyrimidine-5-carbohydrazide
  • Step 5 (S) -2- ( (2-Amino-5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) -2-phenylethan-1-ol
  • Step 1 (S) -2-amino-2-phenylethan-1, 1-d2-1-ol
  • Step 2 ethyl (S) -2-chloro-4- ( (2-hydroxy-1-phenylethyl-2, 2-d2) amino) pyrimidine-5-carboxylate
  • Step 3 ethyl (S) -2- ( (3, 4-dimethylbenzyl) amino) -4- ( (2-hydroxy-1-phenylethyl-2, 2-d2) amino) pyrimidine-5-carboxylate
  • Step 4 ethyl (S) -2-amino-4- ( (2-hydroxy-1-phenylethyl-2, 2-d2) amino) pyrimidine-5-carboxylate
  • Step 5 (S) -2-Amino-4- ( (2-hydroxy-1-phenylethyl-2, 2-d2) amino) pyrimidine-5-carbohydrazide
  • Step 6 (S) -2- ( (2-Amino-5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) -2-phenylethan-1, 1-d 2 -1-ol
  • Step 1 (S) -2-amino-2- (4-fluorophenyl) ethan-1-ol (Intermediate (A) )
  • Step 2 Ethyl (S) -2-chloro-4- ( (1- (4-fluorophenyl) -2-hydroxyethyl) amino) pyrimidine-5-carboxylate
  • Step 3 Ethyl (S) -2- ( (2, 4-dimethoxybenzyl) amino) -4- ( (1- (4-fluorophenyl) -2-hydroxyethyl) amino) pyrimidine-5-carboxylate
  • Step 4 Ethyl (S) -2-amino-4- ( (1- (4-fluorophenyl) -2-hydroxyethyl) amino) pyrimidine-5-carboxylate
  • Step 5 (S) -2-Amino-4- ( (1- (4-fluorophenyl) -2-hydroxyethyl) amino) pyrimidine-5-carbohydrazide
  • Step 6 (S) -2- ( (2-Amino-5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) -2- (4-fluorophenyl) ethan-1-ol
  • Step 1 3- (4, 4, 5, 5-Tetramethyl-1, 3, 2-dioxaborolan-2-yl) but-3-en-2-ol
  • Step 3 6-Amino-3, 4-dimethylisochroman-1-one and 6-amino-3, 4-dimethyl-1H-isochromen-1-one
  • Step 3 Methyl 6-methoxy-2- (2-methylprop-1-en-1-yl) nicotinate
  • Step 2 N- (1- (3-Bromophenyl) -2-methylpropan-2-yl) -2-chloroacetamide
  • Step 4 2- ( (1- (3-Bromophenyl) -2-methylpropan-2-yl) amino) -2-oxoacetic acid
  • Step 5 6-Bromo-3, 3-dimethyl-3, 4-dihydroisoquinolin-1 (2H) -one
  • Step 1 Benzyl (3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) but-3-en-2-yl) carbamate
  • Step 2 Methyl 2- (3- ( ( (benzyloxy) carbonyl) amino) but-1-en-2-yl) -4-nitrobenzoate (A) and benzyl 3-methyl-4-methylene-6-nitro-1-oxo-3, 4-dihydroisoquinoline- 2 (1H) -carboxylate (B)
  • Step 3 6-Amino-3, 4-dimethyl-3, 4-dihydroisoquinolin-1 (2H) -one and 6-amino-3, 4-dimethylisoquinolin-1 (2H) -one
  • Step 4 Benzyl 6-amino-3-methyl-4-methylene-1-oxo-3, 4-dihydroisoquinoline-2 (1H) -carboxylate (Intermediate 29)
  • Step 1 (S) -2- ( (2- ( (4-methoxybenzyl) amino) -5- (3- (quinuclidin-4-yl) -1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) -2-phenylethan-1-ol
  • Step 2 (S) -2- ( (2-amino-5- (3- (quinuclidin-4-yl) -1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) -2-phenylethan-1-ol
  • Step 1 ethyl (S) -4- ( (1- (4-fluorophenyl) -2-hydroxyethyl) amino) -2- ( (4-methoxybenzyl) amino) pyrimidine-5-carboxylate
  • Step 2 (S) -2- (4-fluorophenyl) -2- ( (2- ( (4-methoxybenzyl) amino) -5- (3- (quinuclidin-4-yl) -1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethan-1-ol
  • Step 3 (S) -2- ( (2-amino-5- (3- (quinuclidin-4-yl) -1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) -2- (4-fluorophenyl) ethan-1-ol
  • Step 4 2- (but-3-en-2-yl) -6-chloro-1, 2-dihydro-3H-indazol-3-one
  • Step 5 1, 2-di (but-3-en-2-yl) -6-chloro-1, 2-dihydro-3H-indazol-3-one and (E) -1- (but-2-en-1-yl) -2- (but-3-en-2-yl) -6-chloro-1, 2-dihydro-3H-indazol-3-one
  • Step 6 3-chloro-6, 9-dimethyl-6, 9-dihydro-11H-pyridazino [1, 2-a] indazol-11-one and 3-chloro-9-methyl-6, 9-dihydro-11H-pyridazino [1, 2-a] indazol-11-one
  • the obtained residue was purified by prep-HPLC with the following conditions: mobile phase : ACN -H2O (0.1%FA) ; gradient : 50 –95; 9 min, to provide the title compound, 3-chloro-6, 9-dimethyl-6, 9-dihydro-11H-pyridazino [1, 2-a] indazol-11-one (100 mg, 30%yield) as a white solid and 3-chloro-9-methyl-6, 9-dihydro-11H-pyridazino [1, 2-a] indazol-11-one (100 mg, 30%yield) a white solid.
  • Step 3 8-chloro-9b-methyl-3-methylene-3, 9b-dihydro-5H-pyrrolo [2, 1-a] isoindol-5-one
  • Step 2 1-allyl-3- (allyloxy) -6-bromo-7-fluoro-1H-indazole
  • Step 3 1, 2-diallyl-6-bromo-7-fluoro-1, 2-dihydro-3H-indazol-3-one
  • Step 4 3-bromo-4-fluoro-6, 9-dihydro-11H-pyridazino [1, 2-a] indazol-11-one
  • Step 3 6-bromo-1- (2- ( (tert-butyldimethylsilyl) oxy) ethyl) -7-fluoro-1, 2-dihydro-3H-indazol-3-one
  • Step 4 6-bromo-7-fluoro-1- (2-hydroxyethyl) -1, 2-dihydro-3H-indazol-3-one
  • Step 5 7-bromo-6-fluoro-3, 4-dihydro-1H, 10H- [1, 3, 4] oxadiazino [4, 3-a] indazol-10-one
  • Step 1 3- (2, 4-dimethoxypyrimidin-5-yl) pyridazine
  • Step 2 5- (pyridazin-3-yl) pyrimidine-2, 4 (1H, 3H) -dione
  • Step 3 3- (2, 4-dichloropyrimidin-5-yl) pyridazine
  • Step 4 (S) -2- ( (2-chloro-5- (pyridazin-3-yl) pyrimidin-4-yl) amino) -2-phenylethan-1-ol
  • Step 1 4-bromo-2- (2-oxopropyl) benzo nitrile
  • Step 2 4-bromo-2- (1-fluoro-2-oxopropyl) benzonitrile
  • Step 3 4-bromo-2- (1-fluoro-2-hydroxypropyl) benzonitrile
  • Step 2 tert-butyl (3-methyl-1-oxo-1H-isochromen-6-yl) carbamate
  • Step 3 tert-butyl (3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) but-3-en-2-yl) carbamate
  • Tri-tert-butylphosphine (10%w/v in toluene) (1.43 mL, 0.709 mmol) was added to the above mixture at 0°C under N 2 atmosphere.
  • MeOH 378 mg, 11.81mmol was added to the resulting mixture.
  • the mixture was stirred at RT for 2h. TLC showed the reaction was completed.
  • the reaction mixture was diluted with MeOH (10.0 mL) and filtered; the filtrate was concentrated to dryness.
  • Step 4 tert-butyl 3-methyl-4-methylene-6-nitro-1-oxo-3, 4-dihydroisoquinoline-2 (1H) -carboxylate
  • Step 5 3-methyl-4-methylene-6-nitro-3, 4-dihydroisoquinolin-1 (2H) -one
  • Step 6 2, 3-dimethyl-4-methylene-6-nitro-3, 4-dihydroisoquinolin-1 (2H) -one

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  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La divulgation concerne des composés de formule (I) : ou des sels pharmaceutiquement acceptables de ceux-ci. La divulgation concerne également des procédés d'utilisation de tels composés pour moduler ou inhiber l'activité enzymatique de la kinase progénitrice hématopoïétique (HPK1), et des compositions pharmaceutiques comprenant de tels composés. Ces composés sont utiles dans le traitement de maladies ou de troubles associés à ΗΡK1, par exemple des infections virales et des cancers.
PCT/CN2023/072854 2022-01-19 2023-01-18 Composés hétérocycliques utiles en tant qu'inhibiteurs de hpk1 Ceased WO2023138612A1 (fr)

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Citations (6)

* 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
WO2019090198A1 (fr) * 2017-11-06 2019-05-09 Bristol-Myers Squibb Company Composés d'isofuranone utiles en tant qu'inhibiteurs de hpk1
CN114805330A (zh) * 2021-01-22 2022-07-29 苏州信诺维医药科技股份有限公司 Hpk1抑制剂、其制备方法、药物组合物及其应用
WO2022188735A1 (fr) * 2021-03-08 2022-09-15 Guangdong Newopp Biopharmaceuticals Co., Ltd. Composés hétérocycliques utilisés en tant qu'inhibiteurs de hpk1
WO2022253252A1 (fr) * 2021-06-03 2022-12-08 Silexon Biotech Co., Ltd. Composés hétérocycliques utiles en tant qu'inhibiteurs de hpk1
WO2023043630A1 (fr) * 2021-09-16 2023-03-23 Lomond Therapeutics, Inc. Composés comprenant des dérivés de n-arylpyrimidin-2-amine en tant qu'agents thérapeutiques

Patent Citations (6)

* 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
WO2019090198A1 (fr) * 2017-11-06 2019-05-09 Bristol-Myers Squibb Company Composés d'isofuranone utiles en tant qu'inhibiteurs de hpk1
CN114805330A (zh) * 2021-01-22 2022-07-29 苏州信诺维医药科技股份有限公司 Hpk1抑制剂、其制备方法、药物组合物及其应用
WO2022188735A1 (fr) * 2021-03-08 2022-09-15 Guangdong Newopp Biopharmaceuticals Co., Ltd. Composés hétérocycliques utilisés en tant qu'inhibiteurs de hpk1
WO2022253252A1 (fr) * 2021-06-03 2022-12-08 Silexon Biotech Co., Ltd. Composés hétérocycliques utiles en tant qu'inhibiteurs de hpk1
WO2023043630A1 (fr) * 2021-09-16 2023-03-23 Lomond Therapeutics, Inc. Composés comprenant des dérivés de n-arylpyrimidin-2-amine en tant qu'agents thérapeutiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DEGNAN, A.P. ET AL.: "Discovery of Orally Active Isofuranones as Potent, Selective Inhibitors of Hematopoetic Progenitor Kinase 1", ACS MEDICINAL CHEMISTRY LETTERS, vol. 12, 19 February 2021 (2021-02-19), pages 443 - 450, XP055964950, DOI: 10.1021/acsmedchemlett.0c00660 *

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