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WO2021246781A1 - Pyridine derivatives as immunomodulators - Google Patents

Pyridine derivatives as immunomodulators Download PDF

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Publication number
WO2021246781A1
WO2021246781A1 PCT/KR2021/006886 KR2021006886W WO2021246781A1 WO 2021246781 A1 WO2021246781 A1 WO 2021246781A1 KR 2021006886 W KR2021006886 W KR 2021006886W WO 2021246781 A1 WO2021246781 A1 WO 2021246781A1
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methyl
alkyl
alkynyl
alkenyl
aryl
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French (fr)
Inventor
Kwangwoo Chun
Hyangmi KIM
Young Il Choi
Soonnam KIM
Min Jung Seo
Hanyang CHO
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Kainos Medicine Inc
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Kainos Medicine Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D471/10—Spiro-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

Definitions

  • the present invention relates to pharmaceutically active compounds, or intermediates for making the compounds.
  • the present invention also relates to pharmaceutical compositions and methods of use.
  • PD-1 Programmed cell death protein 1
  • CD279 is expressed on CD4 + T cells, CD8 + T cells, natural killer T cells, B cells and activated monocytes.
  • PD-1 binds to the ligand PD-L1 or PD-L2 (Sharpe et al , Nature Immunology 2007, 8(3), 239-245).
  • PD-L1 is highly upregulated on many kinds of tumor cell, including melanoma, ovarian, and lung cancers.
  • APCs antigen presenting cells
  • T-cell dysfunction In viral diseases a similar mechanism is used by viruses to undermine the effective immune recognitions. Blocking the interactions between PD-1 and PD-L1 has emerged as a promising immunotherapy for treating cancer and infectious diseases.
  • nivolumab a monoclonal antibody (mAb), binding to PD-1, was approved in succession for the treatment of metastatic melanoma (Zhan et al , Drug Discovery Today 2016, 21(6), 1027-1036).
  • mAbs have shown impressive clinical activity, mAbs exhibit several disadvantages such as limited tissue and tumour penetration, very long half life time, lacking oral bioavailability, immunogenicity, difficult production, expensive production, and severe immune-related adverse effects (Adams et al , Nature Reviews Drug Discovery 2015, 14(9), 603-622).
  • the present invention provides a compound of formula (I):
  • the present invention further provides the compound of formula (I) as immunomodulators.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.
  • the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition comprising the same, is useful for inhibiting PD-1/PD-L1 signaling pathway.
  • the compound or the composition modulates PD-1/PD-L1 interaction and is useful in the treatment, prevention or alleviation of various diseases associated with inhibition of PD-1/PD-L1 interaction, including infectious diseases and cancer.
  • n-membered typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n.
  • piperidinyl is an example of a 6-membered heterocycloalkyl ring
  • pyrazolyl is an example of a 5-membered heteroaryl ring
  • pyridyl is an example of a 6-membered heteroaryl ring
  • 1,2,3,4-tetrahydroisoquinolyl is an example of a 10-membered cycloalkyl group.
  • each linking substituent include both the forward and backward forms of the linking substituent.
  • -C(R e R f )NR e - includes both -C(R e R f )NR e - and -NR e C(R e R f )- and is intended to disclose each of the forms individually.
  • the Markush variables listed for that group are understood to be linking groups.
  • substituted means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group.
  • substituted refers to any level of substitution, e.g., mono-, di-, tri-, tetra- or penta-substitution, where such substitution is permitted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. It is to be understood that substitution at a given atom results in a chemically stable molecule.
  • optionally substituted means unsubstituted or substituted.
  • substituted means that a hydrogen atom is removed and replaced by a substituent.
  • a single divalent substituent e.g., oxo, can replace two hydrogen atoms.
  • C n-m indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C 1-4 , C 2-6 and the like.
  • alkenyl employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds.
  • An alkenyl group formally corresponds to an alkene with one C-H bond replaced by the point of attachment of the alkenyl group to the remainder of the compound.
  • C n-m alkenyl refers to an alkenyl group having n to m carbons.
  • the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl and the like.
  • alkynyl employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more triple carbon-carbon bonds.
  • An alkynyl group formally corresponds to an alkyne with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound.
  • C n-m alkynyl refers to an alkynyl group having n to m carbons. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl and the like.
  • the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • alkylene employed alone or in combination with other terms, refers to a divalent alkyl linking group.
  • An alkylene group formally corresponds to an alkane with two C-H bond replaced by points of attachment of the alkylene group to the remainder of the compound.
  • C n-m alkylene refers to an alkylene group having n to m carbon atoms.
  • alkylene groups include, but are not limited to, ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl and the like.
  • alkoxy employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group is as defined above.
  • C n-m alkoxy refers to an alkoxy group, the alkyl group of which has n to m carbons. Examples of alkoxy groups include methoxy, ethoxy, propoxy ( e.g., n-propoxy and isopropoxy), tert -butoxy and the like.
  • the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • amino employed alone or in combination with other terms, refers to a group of formula -NH 2 .
  • carbamoyl employed alone or in combination with other terms, refers to a group of formula -C(O)NH 2 .
  • cyano or "nitrile” employed alone or in combination with other terms, refers to a group of formula -C ⁇ N, which also may be written as -CN.
  • halo refers to fluoro, chloro, bromo and iodo. In some embodiments, “halo” refers to a halogen atom selected from F, CI, or Br.
  • haloalkyl employed alone or in combination with other terms, as used herein refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen atom.
  • C n-m haloalkyl refers to a C n-m alkyl group having n to m carbon atoms and from at least one up to ⁇ 2(n to m) + 1 ⁇ halogen atoms, which may either be the same or different.
  • the halogen atoms are fluoro atoms.
  • the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Examples of haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 and the like.
  • haloalkoxy employed alone or in combination with other terms, refers to a group of formula -O-haloalkyl, wherein the haloalkyl group is as defined above.
  • C n-m haloalkoxy refers to a haloalkoxy group, the haloalkyl group of which has n to m carbons. Examples of haloalkoxy groups include trifluoromethoxy and the like. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • oxo refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to carbon, or attached to a heteroatom forming a sulfoxide or sulfone group, or an N-oxide group.
  • aromatic refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n + 2) delocalized ⁇ (pi) electrons where n is an integer).
  • aryl employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic ( e.g., having 2 fused rings).
  • C n-m aryl refers to an aryl group having from n to m ring carbon atoms.
  • Aryl groups include, e.g., phenyl, naphthyl, indenyl and the like. In some embodiments, aryl groups have from 6 to about 10 carbon atoms. In some embodiments, aryl groups have 6 carbon atoms. In some embodiments, aryl groups have 10 carbon atoms. In some embodiments, the aryl group is phenyl.
  • heteroaryl or “heteroaromatic” employed alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen.
  • the heteroaryl ring has 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.
  • any ring-forming ⁇ in a heteroaryl moiety can be an N-oxide.
  • the heteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heteroaryl has 5-14, or 5-10 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. In other embodiments, the heteroaryl is an eight-membered, nine-membered or ten-membered fused bicyclic heteroaryl ring.
  • heteroaryl groups include, but are not limited to, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridinyl), indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, and the like.
  • pyridinyl pyridyl
  • pyrimidinyl pyrazinyl
  • pyridazinyl pyr
  • a five-membered heteroaryl ring is a heteroaryl group having five ring atoms wherein one or more ( e.g., 1, 2 or 3) ring atoms are independently selected from N, O and S.
  • five-membered ring heteroaryls include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
  • a six-membered heteroaryl ring is a heteroaryl group having six ring atoms wherein one or more ( e.g., 1, 2 or 3) ring atoms are independently selected from N, O and S.
  • Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • cycloalkyl employed alone or in combination with other terms, refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.
  • C n-m cycloalkyl refers to a cycloalkyl that has n to m ring member carbon atoms.
  • Cycloalkyl groups can include mono- or polycyclic ( e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring-forming carbons (C 3-14 ).
  • the cycloalkyl group has 3 to 14 ring members, 3 to 10 ring members, 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members.
  • the cycloalkyl group is monocyclic.
  • the cycloalkyl group is monocyclic or bicyclic.
  • the cycloalkyl group is a C 3-6 monocyclic cycloalkyl group. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group.
  • Cycloalkyl groups also include cycloalkylidenes.
  • cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, e.g., benzo or thienyl derivatives of cyclopentane, cyclohexane and the like.
  • a cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • heterocycloalkyl employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur oxygen and phosphorus, and which has 4-14 ring members, 4-10 ring members, 4-7 ring members, or 4-6 ring members. Included within the term “heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyl groups.
  • Heterocycloalkyl groups can include mono- or bicyclic or poly cyclic ( e.g., having two or three fused or bridged rings) ring systems or spirocycles.
  • the heterocycloalkyl group is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally oxidized to form an oxo or sulfido group or other oxidized linkage ( e.g., C(O), S(O), C(S) or S(O) 2 , N-oxide etc. ) or a nitrogen atom can be quatemized.
  • the heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom.
  • the heterocycloalkyl group contains 0 to 3 double bonds.
  • the heterocycloalkyl group contains 0 to 2 double bonds.
  • moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the heterocycloalkyl ring e.g., benzo or thienyl derivatives of piperidine, morpholine, azepine, etc.
  • a heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • heterocycloalkyl groups include azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5,5]undecanyl, 1-oxa-8-azaspiro[4,5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, oxoimidazolidinyl ( e.g., 3-methyl-2-oxoimidazolidin-1-yl
  • the present invention provides a compound of formula (I):
  • R 1 is halogen, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl, C 3-14 cycloalkyl-C 1-6 alkyl-, (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-10 aryl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, C 3-14 cycloalkyl-C 2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-10 aryl-C 2-6 alkenyl-, (5-14 membered heteroaryl)-C 2-6 alkenyl-, C 3-14 cycloalkyl-C 2-6 alkenyl-, C 6-10 aryl-C 2-6 al
  • each R a is independently selected from H, halogen, OH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl, C 3-14 cycloalkyl-C 1-6 alkyl-, (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-10 aryl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, C 3-14 cycloalkyl-C 2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-10 aryl-C 2-6 alkenyl-, (5-14 membered heteroaryl)-C 2-6 alkenyl-, C 3-14 cycloalkyl-C 2-6 alkenyl-, C
  • each R b is independently selected from H, halogen, OH, CN, NO 2 , N 3 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl, C 3-14 cycloalkyl-C 1-6 alkyl-, (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-10 aryl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, C 3-14 cycloalkyl-C 2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-10 aryl-C 2-6 alkenyl-, (5-14 membered heteroaryl)-C 2-6 alkenyl-, C 3-14 cycloalkyl-C 2-6 alkyn
  • R 3 is -C(O)X, -C(O)OR d , -C(R e R f )OH, -C(R e R f )Y, -C(R e R f )NH 2 , -C(R e R f )N 3 or ;
  • Ar W is Ar E , -Ar E -L-Q E or -Ar E -L-Q E -R M ;
  • Y is halogen or OS(O) 2 R g ;
  • R e and R f are each independently selected from H, halogen, OH, CN, NO 2 , and C 1-6 alkyl;
  • R e and R f are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 4 groups independently selected from halogen, OH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl, C 3-14 cycloalkyl-C 1-6 alkyl-, (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-10 aryl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, C 3-14 cycloalkyl-C 2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-10 aryl-C 2-6 alkeny
  • A is -C(O)O-, -C(R e R f )O-, -C(R e R f )S-, -C(R e R f )S(O) 2 -, -C(O)NR e - or -C(R e R f )NR e -;
  • Each R 4 is independently selected from H, halogen, OH, CN, NH 2 , NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-14 cycloalkyl, and 4-14 membered heterocycloalkyl;
  • R 4 substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 4 groups independently selected from halogen, OH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl, C 3-14 cycloalkyl-C 1-6 alkyl-, (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-10 aryl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, C 3-14 cycloalkyl-C 2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-10 aryl-C 2-6 alkenyl-
  • n is an integer of 0, 1, 2 or 3;
  • Ar E is 4-14 membered heterocycloalkyl, C 6-10 aryl or 5-14 membered heteroaryl, wherein the 4-14 membered heterocycloalkyl, C 6-10 aryl and 5-14 membered heteroaryl of Ar E are each optionally substituted with 1 to 5 groups independently selected from R 4 substituents;
  • L is a bond, -O-, -S-, -C(O)-, -SO-, -SO 2 -, -(CR h R i ) m -, -(CR h R i ) m O(CR h R i ) m -, -(CR h R i ) m S(CR h R i ) m -, -(CR h R i ) m NR h (CR h R i ) m -, -(CR h R i ) m C(O)(CR h R i ) m -, -(CR h R i ) m C(O)NR h (CR h R i ) m -, -(CR h R i ) m C(O)NR h (CR h R i ) m -, -(CR h R i ) m NR
  • R h and R i are each independently selected from H, halogen, OH, CN, NO 2 , COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, (C 1-6 alkyl)NH-, (C 1-6 alkyl) 2 N-, C 3-14 cycloalkyl, and 4-14 membered heterocycloalkyl;
  • R h and R i are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 4 groups independently selected from halogen, OH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl, C 3-14 cycloalkyl-C 1-6 alkyl-, (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-10 aryl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, C 3-14 cycloalkyl-C 2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-10 aryl-C 2-6 alkeny
  • Q E is 4-14 membered heterocycloalkyl, C 6-10 aryl or 5-14 membered heteroaryl, wherein 4-14 membered heterocycloalkyl, C 6-10 aryl or 5-14 membered heteroaryl of Q E are each optionally substituted with 1 to 5 groups independently selected from R 1 substituents;
  • R M and R L are each independently selected from halogen, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl, C 3-14 cycloalkyl-C 1-6 alkyl-, (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-10 aryl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, C 3-14 cycloalkyl-C 2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-10 aryl-C 2-6 alkenyl-, (5-14 membered heteroaryl)-C 2-6 alkenyl-, C 3-14 cycloalkyl-C 2-6 alkenyl-, C 6-10
  • the present invention provides a compound of formula (I):
  • R 1 is halogen, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkenyl-, (5-10 membered heteroaryl)-C 2-6 alkenyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 al
  • R 2 is halogen, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkenyl-, (5-10 membered heteroaryl)-C 2-6 alkenyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 al
  • each R a is independently selected from H, halogen, OH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkenyl-, (5-10 membered heteroaryl)-C 2-6 alkenyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4
  • R a substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-10 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-10 aryl-C 2-6 alkenyl
  • each R b is independently selected from H, halogen, OH, CN, NO 2 , N 3 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkenyl-, (5-10 membered heteroaryl)-C 2-6 alkenyl-, C 3-8 cycloalkyl-C 2-6 alkyn
  • each R c is independently selected from H, halogen, OH, CF 3 , CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkenyl-, (5-10 membered heteroaryl)-C 2-6 alkenyl-, C 3-8 cycloalkyl-C 2-6 alky
  • R 3 is -C(O)X, -C(O)OR d , -C(R e R f )OH, -C(R e R f )Y, -C(R e R f )NH 2 , -C(R e R f )N 3 or ;
  • Ar W is Ar E , -Ar E -L-Q E or -Ar E -L-Q E -R M ;
  • Y is halogen or OS(O) 2 R g ;
  • R e and R f are each independently selected from H, halogen, OH, CN, NO 2 , and C 1-6 alkyl;
  • R e and R f are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkeny
  • R g is C 1-5 alkyl, C 1-5 alkoxy or phenyl, wherein the C 1-5 alkyl, C 1-5 alkoxy and phenyl of R g are each optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8
  • A is -C(R e R f )O-, -C(R e R f )S-, -C(R e R f )S(O) 2 -, -C(O)NR e - or -C(R e R f )NR e -;
  • Each R 4 is independently selected from H, halogen, OH, CN, NH 2 , NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, and 4-10 membered heterocycloalkyl;
  • R 4 substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkenyl-
  • Ar E is 4-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the 4-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl of Ar E are each optionally substituted with 1 to 3 groups independently selected from R 4 substituents;
  • L is a bond, -O-, -S-, -C(O)-, -SO-, -SO 2 -, -(CR h R i ) m -, -(CR h R i ) m O(CR h R i ) m -, -(CR h R i ) m S(CR h R i ) m -, -(CR h R i ) m NR h (CR h R i ) m -, -(CR h R i ) m C(O)(CR h R i ) m -, -(CR h R i ) m C(O)NR h (CR h R i ) m -, -(CR h R i ) m C(O)NR h (CR h R i ) m -, -(CR h R i ) m NR
  • R h and R i are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkeny
  • Q E is 4-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein 4-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl of Q E are each optionally substituted with 1 to 3 groups independently selected from R 1 substituents;
  • R M and R L are each independently selected from halogen, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkenyl-, (5-10 membered heteroaryl)-C 2-6 alkenyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, C 6-8
  • the present invention provides a compound of formula (I):
  • R 2 is halogen, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkenyl-, (5-10 membered heteroaryl)-C 2-6 alkenyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 al
  • each R a is independently selected from H, halogen, OH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkenyl-, (5-10 membered heteroaryl)-C 2-6 alkenyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4
  • R a substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen , OH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-10 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-10 aryl-C 2-6 alkeny
  • each R b is independently selected from H, halogen, OH, CN, NO 2 , N 3 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkenyl-, (5-10 membered heteroaryl)-C 2-6 alkenyl-, C 3-8 cycloalkyl-C 2-6 alkyn
  • each R c is independently selected from H, halogen, OH, CF 3 , CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkenyl-, (5-10 membered heteroaryl)-C 2-6 alkenyl-, C 3-8 cycloalkyl-C 2-6 alky
  • R 3 is -C(O)X, -C(O)OR d , -C(R e R f )OH, -C(R e R f )Y, -C(R e R f )NH 2 , -C(R e R f )N 3 or ;
  • Ar W is Ar E , -Ar E -L-Q E or -Ar E -L-Q E -R M ;
  • X is H or halogen
  • Y is halogen or OS(O) 2 R g ;
  • R d is H, C 1-6 alkyl or COR g ;
  • R e and R f are each independently selected from H, halogen, OH, CN, NO 2 , and C 1-6 alkyl;
  • R e and R f are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkeny
  • R g is C 1-5 alkyl, C 1-5 alkoxy or phenyl, wherein the C 1-5 alkyl, C 1-5 alkoxy and phenyl of R g are each optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8
  • A is -C(R e R f )O-, -C(R e R f )S-, -C(R e R f )S(O) 2 -, -C(O)NR e - or -C(R e R f )NR e -;
  • Each R 4 is independently selected from H, halogen, OH, CN, NH 2 , NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, and 4-10 membered heterocycloalkyl;
  • R 4 substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkenyl-
  • n is an integer of 0, 1, 2 or 3;
  • Ar E is 4-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the 4-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl of Ar E are each optionally substituted with 1 to 3 groups independently selected from R 4 substituents;
  • L is a bond, -O-, -S-, -C(O)-, -SO-, -SO 2 -, -(CR h R i ) m -, -(CR h R i ) m O(CR h R i ) m -, -(CR h R i ) m S(CR h R i ) m -, -(CR h R i ) m NR h (CR h R i ) m -, -(CR h R i ) m C(O)(CR h R i ) m -, -(CR h R i ) m C(O)NR h (CR h R i ) m -, -(CR h R i ) m C(O)NR h (CR h R i ) m -, -(CR h R i ) m NR
  • R h and R i are each independently selected from H, halogen, OH, CN, NO 2 , COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, (C 1-6 alkyl)NH-, (C 1-6 alkyl) 2 N-, C 3-8 cycloalkyl, and 4-10 membered heterocycloalkyl;
  • R h and R i are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkeny
  • Q E is 4-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein 4-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl of Q E are each optionally substituted with 1 to 3 groups independently selected from R 1 substituents;
  • R M and R L are each independently selected from halogen, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkenyl-, (5-10 membered heteroaryl)-C 2-6 alkenyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, C 6-8
  • the present invention provides a compound of formula (I):
  • R 1 is halogen, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkenyl-, (5-10 membered heteroaryl)-C 2-6 alkenyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 al
  • R 2 is halogen, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkenyl-, (5-10 membered heteroaryl)-C 2-6 alkenyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 al
  • R a substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH , CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-10 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-10 aryl-C 2-6 alkeny
  • each R c is independently selected from H, halogen, OH, CF 3 , CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkenyl-, (5-10 membered heteroaryl)-C 2-6 alkenyl-, C 3-8 cycloalkyl-C 2-6 alky
  • R 3 is -C(O)X, -C(O)OR d , -C(R e R f )OH, -C(R e R f )Y, -C(R e R f )NH 2 , -C(R e R f )N 3 or ;
  • Ar W is Ar E , -Ar E -L-Q E or -Ar E -L-Q E -R M ;
  • X is H or halogen
  • Y is halogen or OS(O) 2 R g ;
  • R e and R f are each independently selected from H, halogen, OH, CN, NO 2 , and C 1-6 alkyl;
  • R g is C 1-5 alkyl, C 1-5 alkoxy or phenyl, wherein the C 1-5 alkyl, C 1-5 alkoxy and phenyl of R g are each optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8
  • A is -C(R e R f )O-, -C(R e R f )S-, -C(R e R f )S(O) 2 -, -C(O)NR e - or -C(R e R f )NR e -;
  • Each R 4 is independently selected from H, halogen, OH, CN, NH 2 , NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, and 4-10 membered heterocycloalkyl;
  • R 4 substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkenyl-
  • n is an integer of 0, 1, 2 or 3;
  • Ar E is 4-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the 4-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl of Ar E are each optionally substituted with 1 to 3 groups independently selected from R 4 substituents;
  • R h and R i are each independently selected from H, halogen, OH, CN, NO 2 , COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, (C 1-6 alkyl)NH-, (C 1-6 alkyl) 2 N-, C 3-8 cycloalkyl, and 4-10 membered heterocycloalkyl;
  • R h and R i are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkeny
  • Q E is 4-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein 4-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl of Q E are each optionally substituted with 1 to 3 groups independently selected from R 1 substituents;
  • R M and R L are each independently selected from halogen, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C 2-6 alkenyl-, C 6-8 aryl-C 2-6 alkenyl-, (5-10 membered heteroaryl)-C 2-6 alkenyl-, C 3-8 cycloalkyl-C 2-6 alkenyl-, C 6-8
  • the present invention provides a compound of formula (Ia):
  • R 1 is halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, -OR a , -SR a , -C(O)R a , -C(O)NR a R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R a , -NR a R a , -NR a C(O)R a , -NR a C(O)OR a , -NR a C(O)NR a R a , -NR a S(O)R a , -NR a S(O) 2 R a , -NR a S(O) 2 NR a R a , -S(
  • R 2 is halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, -OR a , -SR a , -C(O)R a , -C(O)NR a R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R a , -NR a R a , -NR a C(O)R a , -NR a C(O)OR a , -NR a C(O)NR a R a , -NR a S(O)R a , -NR a S(O) 2 R a , -NR a S(O) 2 NR a R a , -S(
  • R 3 is -C(O)X, -C(O)OR d , -C(R e R f )OH, -C(R e R f )Y, -C(R e R f )NH 2 or -C(R e R f )N 3 ;
  • R a , R b , R d , R e , R f , X, Y and R L are as defined in the description.
  • the present invention provides a compound of formula (Ib):
  • R 1 is halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, -OR a , -SR a , -C(O)R a , -C(O)NR a R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R a , -NR a R a , -NR a C(O)R a , -NR a C(O)OR a , -NR a C(O)NR a R a , -NR a S(O)R a , -NR a S(O) 2 R a , -NR a S(O) 2 NR a R a , -S(
  • R 2 is halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, -OR a , -SR a , -C(O)R a , -C(O)NR a R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R a , -NR a R a , -NR a C(O)R a , -NR a C(O)OR a , -NR a C(O)NR a R a , -NR a S(O)R a , -NR a S(O) 2 R a , -NR a S(O) 2 NR a R a , -S(
  • R a , R b , R L , A, R 4 , n and Ar W are as defined in the description.
  • the present invention provides a compound of formula (II):
  • the present invention provides a compound of formula (IIa):
  • R 1 , R 2 , R 4 , R L , A and n are as defined in the description.
  • the present invention provides a compound of formula (IIb):
  • R 1 , R 2 , R 4 , R e , R f , n and R L are as defined in the description.
  • the present invention provides a compound of formula (IIc):
  • R 1 , R 2 , R 4 , R e , n and R L are as defined in the description.
  • the present invention provides a compound of formula (IId):
  • the present invention provides a compound of formula (IIe):
  • R 1 , R 2 , R 4 , R a , R e and n are as defined in the description
  • the present invention provides a compound of formula (III):
  • R 1 , R 2 , R 4 , A, n, Ar E , L, Q E , R L and R M are as defined in the description.
  • the present invention provides a compound of formula (IIIa):
  • the present invention provides a compound of formula (IIIb):
  • R 1 , R 2 , R 4 , R e , R f , n, L, Q E , R L and R M are as defined in the description.
  • the present invention provides a compound of formula (IIIc):
  • R 1 , R 2 , R 4 , R e , n, L, Q E , R L and R M are as defined in the description.
  • the present invention provides a compound of formula (IIId):
  • R 1 , R 2 , R 4 , R a , R e , R f , n, L, Q E and R M are as defined in the description.
  • the present invention provides a compound of formula (IIIe):
  • R 1 , R 2 , R 4 , R a , R e , n, L, Q E and R M are as defined in the description.
  • R 1 is halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, -OR a , -SR a , -C(O)R a , -C(O)NR a R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R a , -NR a R a , -NR a C(O)R a , -NR a C(O)OR a , -NR a C(O)NR a R a , -NR a S(O)R a , -NR a S(O) 2 R a , -NR a S(O) 2 NR a R a , -NR
  • R 1 is halogen, C 1-6 alkyl, or -OR a .
  • R 2 is halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, 5-10 membered heteroaryl, -OR a , -SR a , -C(O)R a , -C(O)NR a R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R a , -NR a R a , -NR a C(O)R a , -NR a C(O)OR a , -NR a C(O)NR a R a , -NR a S(O)R a , -NR a S(O) 2 R a , -NR a S(O) 2 NR a R a , -NR
  • R 2 is halogen, or C 1-6 alkyl.
  • each R a is independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C 6-8 aryl-C 1-6 alkyl-, and (5-10 membered heteroaryl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-8 aryl, and C 6-8 aryl-C 1-6 alkyl- of R a are each optionally substituted with 1 to 3 groups independently selected from R b substituents; or any two R a substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from OH, -(CR c R c )OR c , -C(
  • each R b is independently selected from OH, CN, C 1-6 alkyl, 4-10 membered heterocycloalkyl, -OR c , -(CR c R c )OR c , -C(O)R c , -C(O)NR c R c , -C(O)OR c , -NR c R c , -NR c C(O)R c , -S(O) 2 R c , and -S(O) 2 NR c R c .
  • each R c is independently selected from H, OH, CF 3 , C 1-6 alkyl and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-.
  • R 3 is -C(O)X, -C(O)OR d , -C(R e R f )OH, -C(R e R f )Y, -C(R e R f )NH 2 , or -C(R e R f )N 3.
  • R 3 is .
  • Ar W is Ar E .
  • Ar W is -Ar E -L-Q E -R M .
  • X is H or halogen.
  • Y is halogen or OS(O) 2 R g .
  • R d is H, C 1-6 alkyl or COR g .
  • R e and R f are each independently selected from H, halogen and CN.
  • R g is C 1-5 alkyl, C 1-5 alkoxy or phenyl.
  • A is -C(R e R f )O-, or -C(O)NR e -;
  • R 4 is independently selected from H, halogen, CN, C 1-6 alkyl or C 1-6 alkoxy; or any two R 4 substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from -OR c .
  • n is an integer of 0, 1 or 2.
  • Ar E is 4-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the 4-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl of Ar E are each optionally substituted with 1 to 3 groups independently selected from R 4 substituents.
  • L is -(CR h R i ) m -, -(CR h R i ) m O(CR h R i ) m - or -(CR h R i ) m NR h C(O)(CR h R i ) m -, wherein each m is independently 0 or 1.
  • Q E is 4-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein 4-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl of Q E are each optionally substituted with 1 to 3 groups independently selected from R 1 substituents.
  • R M and R L are each independently selected from C 1-6 alkyl, (4-10 membered heterocycloalkyl)-C 1-6 alkyl- and -C(R a R a )NR a R a , wherein the C 1-6 alkyl and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R M and R L are each optionally substituted with 1 to 3 groups independently selected from R b substituents.
  • C 1-6 alkyl is specifically intended to individually disclose (without limitation) methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl.
  • Exemplary compounds of the present invention are:
  • N N '-(2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-5-((( R )-3-hydroxypyrrolidin-1-yl)methyl)-6-methylpicolinamide);
  • the compounds described herein can be asymmetric ( e.g., having one or more stereo centers). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art.
  • One method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, e.g., optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ⁇ -camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane and the like.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
  • an optically active resolving agent e.g., dinitrobenzoylphenylglycine
  • Suitable elution solvent composition can be determined by one skilled in the art.
  • the compounds of the invention have the ( R )-configuration.
  • the compounds have the ( S )-configuration.
  • each of the chiral centers in the compound may be independently ( R ) or ( S ), unless otherwise indicated.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Examples prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, e.g., 1 H - and 3 H -imidazole, 1 H -, 2 H - and 4 H - 1,2,4-triazole, 1 H - and 2 H - isoindole and 1 H - and 2 H -pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance.
  • the compound includes at least one deuterium atom.
  • one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium.
  • the compound includes two or more deuterium atoms.
  • the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art.
  • compound as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted.
  • the term is also meant to refer to compounds of the inventions, regardless of how they are prepared, e.g. , synthetically, through biological process ( e.g. , metabolism or enzyme conversion), or a combination thereof.
  • All compounds, and pharmaceutically acceptable salts thereof can be found together with other substances such as water and solvents (e.g. , hydrates and solvates) or can be isolated.
  • the compounds described herein and salts thereof may occur in various forms and may, e.g. , take the form of solvates, including hydrates.
  • the compounds may be in any solid state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as encompassing any solid state form of the compound.
  • the compounds of the invention, or salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, e.g. , a composition enriched in the compounds of the invention.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof.
  • ambient temperature and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g. , a reaction temperature, that is about the temperature of the room in which the reaction is carried out, e.g. , a temperature from about 20°C to about 30°C.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the non-toxic salts of the parent compound formed, e.g. , from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols ( e.g. , methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred.
  • non-aqueous media like ether, ethyl acetate, alcohols ( e.g. , methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred.
  • suitable salts are found in Remington's Pharmaceutical Sciences, 17 th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al. , J. Pharm. Sci. , 1977, 66(1), 1-19 and in Stahl et
  • Examples of the pharmaceutically acceptable salts include, but are not limited to, a salt with an inorganic acid such as a hydrochloric acid, a bromic acid, a sulfuric acid, sodium hydrogen sulfate, a phosphoric acid, a nitric acid, or a carbonic acid, a salt with an organic acid such as a formic acid, an acetic acid, a trifluoroacetic acid, a propionic acid, an oxalic acid, a succinic acid, a benzoic acid, a citric acid, a maleic acid, a malonic acid, a mandelic acid, a cinnamic acid, a stearic acid, a palmitic acid, a glycolic acid, a glutamic acid, a tartaric acid, a gluconic acid, a lactic acid, a fumaric acid, a lactobionic acid, an ascorbic acid, a salicylic acid, or an acet
  • the compound of the present invention may be administered in the form of a prodrug which is decomposed in a human or animal body to provide the compound of the present invention.
  • the prodrug may be used for modifying or improving a physical and (or) pharmacokinetic profile of a parent compound, and may be formed when the parent compound contains an appropriate group or substituent which may be derived to form the prodrug.
  • the compound of formula (I) according to the present invention is a novel compound which has a high inhibitory activity against PD-1/PD-L1 interaction, and thus is useful as a therapeutic agent for treating, preventing or alleviating a disease or disorder associated with inhibition of PD-1/PD-L1 interaction, or as a therapeutic agent for enhancing, stimulating and/or increasing an immune response.
  • the disease or disorder associated with inhibition of PD-1/PD-L1 interaction is selected from infectious diseases and cancers.
  • the disease or disorder associated with inhibition of PD-1/PD-L1 interaction is selected from the group consisting of an infectious disease, a bacterial infectious disease, a viral infectious disease a fungal infectious disease, a solid tumor, a hematological malignancy, an immune disorder, an inflammatory disease, and cancer.
  • the disease or disorder is selected from the group consisting of melanoma, glioblastoma, esophagus tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary CNS (central nervous system) lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic myelocytic leukemia, Kaposi's sarcoma fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, sarcoma of soft tissue, sarcoma, sepsis, biliary tumor, basal
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in inhibiting PD-1/PD-L1 interaction.
  • the present invention further provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in treating, preventing or alleviating a disease or disorder associated with inhibition of PD-1/PD-L1 interaction.
  • the present invention further provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in enhancing, stimulating and/or increasing an immune response.
  • the present invention further provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as an intermediate for the synthesis of compounds for inhibiting PD-1/PD-L1 interaction.
  • the present invention further provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as an intermediate for the synthesis of compounds for treating, preventing or alleviating a disease or disorder associated with inhibition of PD-1/PD-L1 interaction.
  • the present invention further provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as an intermediate for the synthesis of compounds for use in enhancing, stimulating and/or increasing an immune response.
  • the present invention further provides a use of the compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, in the manufacture of a medicament for inhibiting PD-1/PD-L1 interaction.
  • the present invention further provides a use of the compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, in the manufacture of a medicament for treating, preventing or alleviating a disease or disorder associated with inhibition of PD-1/PD-L1 interaction.
  • the present invention further provides a use of the compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, in the manufacture of a medicament for enhancing, stimulating and/or increasing an immune response.
  • the present invention further provides a method of inhibiting PD-1/PD-L1 interaction, said method comprising administering to a patient a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • the present invention further provides a method of enhancing, stimulating and/or increasing an immune response in a patient, said method comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • the present invention further provides a pharmaceutical composition for inhibiting PD-1/PD-L1 interaction, comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, as an active ingredient.
  • the present invention further provides a pharmaceutical composition for treating, preventing or alleviating a disease or disorder associated with inhibition of PD-1/PD-L1 interaction, comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, as an active ingredient.
  • the present invention further provides a pharmaceutical composition for enhancing, stimulating and/or increasing an immune response, comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, as an active ingredient.
  • the pharmaceutical composition of the present invention may be formulated into a conventional preparation in the pharmaceutical field, for example, a preparation for oral administration such as a tablet, a pill, a hard/soft capsule, a liquid, a suspension, an emulsion, syrup, granules, and elixirs, or a preparation for parenteral administration of a sterile aqueous or oily solvent for intravenous, subcutaneous, sublingual, or intramuscular administration, by adding conventional non-toxic pharmaceutically acceptable carrier, excipient, and the like to the compound of formula (I), or a pharmaceutically acceptable salt, a prodrug, a solvate, or a stereoisomer thereof.
  • a preparation for oral administration such as a tablet, a pill, a hard/soft capsule, a liquid, a suspension, an emulsion, syrup, granules, and elixirs
  • the pharmaceutically acceptable carrier commonly used in formulations may be used in the pharmaceutical composition of the present invention, and includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, hydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and/or mineral oil, and the like, but not limited thereto.
  • the excipient which may be used in the pharmaceutical composition of the present invention may be a sweetener, a binder, a solubilizer, a solubilizing aid, a wetting agent, an emulsifier, an isotonic agent, an adsorbent, a disintegrant, an antioxidant, a preservative, a lubricant, a filler, a fragrance, or the like, and a ratio and properties of the excipient may be determined by solubility and chemical properties of a selected tablet, a selected administration route, and standard pharmaceutical practice.
  • excipient may include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, alginic acid, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, or the like.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition of the present invention may be formulated into a parenteral administration form, and in this case, intravenous administration, intraperitoneal administration, intramuscular administration, subcutaneous administration, topical administration, or the like may be used, but not limited thereto.
  • the pharmaceutical composition may be produced into a solution or suspension by mixing the active ingredient, i.e., the compound of formula (I), or a pharmaceutically acceptable salt, a prodrug, a solvate, or a stereoisomer thereof with a stabilizer or a buffer in water, and the solution or suspension may be prepared into a unit dosage form of an ampoule or vial.
  • the pharmaceutical composition of the present invention may be sterilized, or further include an adjuvant such as a preservative, a stabilizer, a hydrating agent or an emulsifying accelerator, a salt for regulating osmotic pressure, and/or a buffer, and other therapeutically useful materials, and may be formulated according to a conventional method of mixing, granulating or coating.
  • an adjuvant such as a preservative, a stabilizer, a hydrating agent or an emulsifying accelerator, a salt for regulating osmotic pressure, and/or a buffer, and other therapeutically useful materials
  • a dosage of the compound represented by formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof as the active ingredient in the pharmaceutical composition according to the present invention for mammals including a human may be varied depending on the age, weight, gender, dosage form, health status, and disease severity of a patient.
  • the compound of the present invention may be included in the pharmaceutical composition in an effective amount of 0.001 to 500 mg/kg (body weight), preferably 0.01 to 100 mg/kg (body weight) per day, and the pharmaceutical composition may be administered via an oral or parenteral route in divided portions once or twice a day.
  • the dosage may be increased or decreased according to the route of administration, the severity of the disease, sex, weight, age, etc., and thus the scope of the present invention is not limited thereto.
  • the reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill 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 which 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.
  • Preparation of compounds of the invention 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 is described, e.g. , in Kocienski, Protecting Groups , (Thieme, 2007); Robertson, Protecting Group Chemistry , (Oxford University Press, 2000); Smith et al. , March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure , 6th Ed. (Wiley, 2007); Peturssion et al. , Protecting Groups in Carbohydrate Chemistry , ( J. Chem. Educ. , 1997, 74(11), 1297); and Wuts et al., Protective Groups in Organic Synthesis , 4th Ed., (Wiley, 2006).
  • 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) or thin layer chromatography (TLC).
  • 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) or thin layer chromatography (TLC).
  • HPLC high performance liquid chromatography
  • TLC thin layer chromatography
  • Typical embodiments of compounds in accordance with the present disclosure may be synthesized using the general reaction schemes and/or examples described below. It will be apparent given the description herein that the general schemes may be altered by the substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Starting materials are typically obtained from commercial sources or synthesized using published methods for synthesizing compounds which are embodiments of the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein. Group labels (e.g.
  • R 1 , R 2 , R a , R b used in the reaction schemes herein are for illustrative purposes only and unless otherwise specified do not necessarily match by name or function the labels used elsewhere to describe compounds of formula (I) or aspects or fragments thereof.
  • Compound 1-4 is reacted with R a X (where X is, e.g. , halide) under base (e.g. , cesium carbonate, potassium carbonate, sodium hydride, sodium carbonate) in a suitable solvent (e.g. , 1,4-dioxane, N,N -dimethylformamide) to provide compound 1-5.
  • base e.g. , cesium carbonate, potassium carbonate, sodium hydride, sodium carbonate
  • a suitable solvent e.g. , 1,4-dioxane, N,N -dimethylformamide
  • Compound 1-6 is reacted with a reducing agent (e.g. , lithium aluminum hydride, sodium borohydride, lithium borohydride) to give compound 1-6.
  • a reducing agent e.g. , lithium aluminum hydride, sodium borohydride, lithium borohydride
  • Alcohol group of compound 1-6 is converted to a leaving group such as, but not limited to, mesylate, chloride, bromide, or iodide using a suitable reagent (e.g. , methanesulfonyl chloride, N -chlorosuccinimide, N -bromosuccinimide) to provide compound 1-7.
  • a suitable reagent e.g. , methanesulfonyl chloride, N -chlorosuccinimide, N -bromosuccinimide
  • Compound 1-5 can be oxidized using an oxidizing agent (e.g. , Oxone TM ) to provide compound 1-8 which is converted to compound 1-9 using a suitable reagent (e.g. , Pd/C at H 2 atmosphere).
  • Compound 1-3 is converted to compound 2-1 (where X is halide) using a suitable reagent (e.g. , N -chlorosuccinimide or N -bromosuccinimide). Methyl group of compound 2-1 is converted to a leaving group such as, but not limited to, chloride, bromide, or iodide to provide compound 2-2.
  • Compound 2-1 is reacted with N,N -dimethylformamide dimethyl acetal to give compound 2-3 which is converted to compound 2-4 using a oxidizing agent (e.g. , sodium periodate).
  • Compound 2-4 is reacted with a suitable coupling reagent (e.g.
  • compound 2-6 is reacted with a reducing agent (e.g. , lithium aluminum hydride, sodium borohydride, lithium borohydride) to give compound 2-6.
  • a reducing agent e.g. , lithium aluminum hydride, sodium borohydride, lithium borohydride
  • Alcohol group of Compound 2-6 is converted to a leaving group such as, but not limited to, mesylate, chloride, bromide, or iodide using a suitable reagent ( e.g. , Methanesulfonyl chloride, N -chlorosuccinimide, N -bromosuccinimide) to provide compound 2-7.
  • compound 2-5 can be oxidized using an oxidizing agent (e.g. , Oxone) to provide compound 2-8 which converted to compound 2-9 using a suitable reagent (e.g. , Pd/C at H 2 atmosphere).
  • Compound 3-1 is reacted with a suitable coupling reagent 3-2 (where M is, e.g. , -B(OH) 2 ) to produce compound 3-3 under a standard metal catalyzed cross-coupling condition such as Suzuki coupling reaction (e.g. , in the presence of a palladium catalyst ( e.g. , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 ) and a base (e.g. , sodium carbonate, potassium acetate)).
  • a palladium catalyst e.g. , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2
  • a base e.g. , sodium carbonate, potassium acetate
  • Compound 2-4 is converted to 3-5 using Pd-catalyzed coupling reaction such as Buchwald-Hartwig cross coupling reaction (e.g. , in the presence of a palladium catalyst (e.g. , Pd(OAc) 2 ), a ligand ( e.g. , tert -butyl XPhos), and a base ( e.g. , cesium carbonate)).
  • a palladium catalyst e.g. , Pd(OAc) 2
  • a ligand e.g. , tert -butyl XPhos
  • a base e.g. , cesium carbonate
  • Compound 3-5 is reacted with a reducing agent (e.g. , lithium aluminum hydride, sodium borohydride, lithium borohydride) to give compound 3-6 which is oxidized using an oxidizing agent ( e.g. , Dess-Martin periodinane) to provide compound 3-7.
  • Compound 4-1 is reacted with a suitable coupling reagent 4-2 (where M is, e.g. , -B(OH) 2 ) to produce compound 4-3 under a standard metal catalyzed cross-coupling condition such as Suzuki coupling reaction (e.g. , in the presence of a palladium catalyst (e.g. , Pd(dppf)Cl 2 , XPhos Pd G2) and a base (e.g. , sodium carbonate, potassium acetate)).
  • a palladium catalyst e.g. , Pd(dppf)Cl 2 , XPhos Pd G2
  • a base e.g. , sodium carbonate, potassium acetate
  • Compound 4-4 is synthesized by coupling compound 4-3 with compound 2-8 using coupling reagents (e.g. , HATU and N,N -diisopropylethylamine).
  • Compound 4-4 is reacted with a reducing agent (e.g. , lithium aluminum hydride, sodium borohydride, lithium borohydride) to give compound 4-5 which is oxidized using an oxidizing agent (e.g. , Dess-Martin periodinane) to provide compound 4-6.
  • a reducing agent e.g. , lithium aluminum hydride, sodium borohydride, lithium borohydride
  • an oxidizing agent e.g. , Dess-Martin periodinane
  • Compound 4-7 is obtained by a reductive amination between compound 4-6 and a suitable amine 3-8 using a reducing agent (e.g. , sodium cyanoborohydride).
  • Compound 4-1-1 is reacted with a suitable coupling reagent 4-2 (where M is, e.g. , -B(OH) 2 ) to produce compound 4-1-2 under a standard metal catalyzed cross-coupling condition such as Suzuki coupling reaction (e.g. , in the presence of a palladium catalyst (e.g. , Pd(dppf)Cl 2 , XPhos Pd G2) and a base (e.g. , sodium carbonate, potassium acetate)).
  • a palladium catalyst e.g. , Pd(dppf)Cl 2 , XPhos Pd G2
  • a base e.g. , sodium carbonate, potassium acetate
  • Compound 4-1-3 is synthesized by coupling compound 4-1-2 with compound 2-8 using coupling reagents (e.g. , HATU and N,N -diisopropylethylamine).
  • Compound 4-1-3 is reacted with a deprotecting reagent (e.g. , hydrogen chloride) to give compound 4-1-4.
  • Compound 4-1-5 is synthesized by coupling compound 4-1-4 with compound 9-4 using coupling reagents ( e.g. , HATU and N,N -diisopropylethylamine).
  • Compound 4-1-5 is reacted with a reducing agent (e.g. , lithium aluminum hydride, sodium borohydride, lithium borohydride) to give compound 4-1-6 which is oxidized using an oxidizing agent (e.g. , Dess-Martin periodinane) to provide compound 4-1-7.
  • Compound 4-1-8 is obtained by a reductive amination between compound 4-1-7 and a suitable amine 3-8 using a reducing agent (e.g. , sodium cyanoborohydride, sodium triacetoxyborohydride).
  • Compound 5-1 is reacted with a suitable coupling reagent 5-2 (where M is, e.g. , -B(OH) 2 ) to produce compound 4-3 under a standard metal catalyzed cross-coupling condition such as Suzuki coupling reaction (e.g. , in the presence of a palladium catalyst (e.g. , Pd(dppf)Cl 2 , XPhos Pd G2) and a base (e.g. , sodium carbonate, potassium acetate)).
  • a palladium catalyst e.g. , Pd(dppf)Cl 2 , XPhos Pd G2
  • a base e.g. , sodium carbonate, potassium acetate
  • Compound 5-4 is reacted with a reducing agent (e.g. , lithium aluminum hydride, sodium borohydride, lithium borohydride) to give compound 5-5 which is oxidized using an oxidizing agent (e.g. , Dess-Martin periodinane) to provide compound 5-6.
  • a reducing agent e.g. , lithium aluminum hydride, sodium borohydride, lithium borohydride
  • an oxidizing agent e.g. , Dess-Martin periodinane
  • Compound 5-7 is obtained by a reductive amination between compound 5-6 and a suitable amine 3-8 using a reducing agent (e.g. , sodium cyanoborohydride).
  • Compound 6-3 is synthesized by coupling compound 6-1 with compound 6-2 using a base (e.g. , cesium carbonate, potassium carbonate).
  • a base e.g. , cesium carbonate, potassium carbonate.
  • Compound 6-3 is reacted with a suitable coupling reagent 4-2 (where M is, e.g. , -B(OH) 2 ) to produce compound 6-4 under a standard metal catalyzed cross-coupling condition such as Suzuki coupling reaction (e.g. , in the presence of a palladium catalyst (e.g. , Pd(dppf)Cl 2 , XPhos Pd G2) and a base (e.g. , sodium carbonate, potassium acetate)).
  • a palladium catalyst e.g. , Pd(dppf)Cl 2 , XPhos Pd G2
  • a base e.g. , sodium carbonate, potassium acetate
  • Compound 6-5 is synthesized by coupling compound 6-4 with compound 2-8 using coupling reagents (e.g. , HATU and N,N -diisopropylethylamine).
  • Compound 6-5 is reacted with a reducing agent (e.g. , lithium aluminum hydride, sodium borohydride, lithium borohydride) to give compound 6-6 which is oxidized using an oxidizing agent (e.g. , Dess-Martin periodinane) to provide compound 6-7.
  • a reducing agent e.g. , lithium aluminum hydride, sodium borohydride, lithium borohydride
  • an oxidizing agent e.g. , Dess-Martin periodinane
  • Compound 6-8 is obtained by a reductive amination between compound 6-7 and a suitable amine 3-8 using a reducing agent (e.g. , sodium cyanoborohydride).
  • Compound 6-3 is synthesized by coupling compound 6-1 with compound 6-2 using a base (e.g. , cesium carbonate, potassium carbonate).
  • a base e.g. , cesium carbonate, potassium carbonate.
  • Compound 6-3 is reacted with a suitable coupling reagent 5-2 (where M is, e.g. , -B(OH) 2 ) to produce compound 6-1-4 under a standard metal catalyzed cross-coupling condition such as Suzuki coupling reaction (e.g. , in the presence of a palladium catalyst (e.g. , Pd(dppf)Cl 2 , XPhos Pd G2) and a base (e.g. , sodium carbonate, potassium acetate)).
  • a palladium catalyst e.g. , Pd(dppf)Cl 2 , XPhos Pd G2
  • a base e.g. , sodium carbonate, potassium acetate
  • Compound 6-1-5 is synthesized by coupling compound 6-1-4 with compound 2-7 using a base (e.g. , cesium carbonate, potassium carbonate).
  • a base e.g. , cesium carbonate, potassium carbonate.
  • Compound 6-1-5 is reacted with a reducing agent (e.g. , lithium aluminum hydride, sodium borohydride, lithium borohydride) to give compound 6-1-6 which is oxidized using an oxidizing agent (e.g. , Dess-Martin periodinane) to provide compound 6-1-7.
  • a reducing agent e.g. , lithium aluminum hydride, sodium borohydride, lithium borohydride
  • an oxidizing agent e.g. , Dess-Martin periodinane
  • Compound 6-1-8 is obtained by a reductive amination between compound 6-1-7 and a suitable amine 3-8 using a reducing agent (e.g. , sodium cyanoborohydride).
  • Compound 7-8 is synthesized in a manner similar to process of scheme 6 using the appropriate materials.
  • Compound 8-1 is synthesized by coupling compound 5-1 with compound 6-2 using a base (e.g. , cesium carbonate, potassium carbonate).
  • a base e.g. , cesium carbonate, potassium carbonate.
  • Compound 8-1 is reacted with a suitable coupling reagent 4-2 (where M is, e.g. , -B(OH) 2 ) to produce compound 8-2 under a standard metal catalyzed cross-coupling condition such as Suzuki coupling reaction (e.g. , in the presence of a palladium catalyst (e.g. , Pd(dppf)Cl 2 , XPhos Pd G2) and a base (e.g. , sodium carbonate, potassium acetate)).
  • a palladium catalyst e.g. , Pd(dppf)Cl 2 , XPhos Pd G2
  • a base e.g. , sodium carbonate, potassium acetate
  • Compound 8-3 is synthesized by coupling compound 8-2 with compound 2-8 using coupling reagents (e.g. , HATU and N,N -diisopropylethylamine).
  • Compound 8-3 is reacted with a reducing agent (e.g. , lithium aluminum hydride, sodium borohydride, lithium borohydride) to give compound 8-4 which is oxidized using an oxidizing agent (e.g. , Dess-Martin periodinane) to provide compound 8-5.
  • a reducing agent e.g. , lithium aluminum hydride, sodium borohydride, lithium borohydride
  • an oxidizing agent e.g. , Dess-Martin periodinane
  • Compound 8-6 is obtained by a reductive amination between compound 8-5 and a suitable amine 3-8 using a reducing agent (e.g. , sodium cyanoborohydride).
  • Compound 9-7 is synthesized in a manner similar to process of scheme 6 using the appropriate materials (where M is, e.g. , -B(OH) 2 ).
  • Compound 10-10 is synthesized in a manner similar to process of scheme 6 using the appropriate materials.
  • Electrospray ionization (ESI) mass spectrometry analysis was conducted on Agilent 6120 Quadrupole electrospray mass spectrometer using the Agilent 1290 infinity HPLC for sample delivery. All compounds could be analyzed in the positive or negative ESI mode, using acetonitrile / water with 0.1% formic acid as the delivery solvent.
  • ESI Electrospray ionization
  • the title compound was synthesized from methyl 2-hydroxy-6-methylnicotinate in a manner similar to the synthesis of methyl 5-chloro-2-hydroxy-6-methylnicotinate using N -bromosuccinimide in place of N -chlorosuccinimide.
  • the title compound was synthesized from methyl 5-bromo-2-hydroxy-6-methylnicotinate in a manner similar to the synthesis of methyl 5-chloro-6-formyl-2-methoxynicotinate.
  • the title compound was synthesized from methyl 5-fluoro-2-hydroxy-6-methylnicotinate in a manner similar to the synthesis of methyl 5-chloro-6-formyl-2-methoxynicotinate.
  • the title compound was synthesized from methyl 5-chloro-2-hydroxy-6-methylnicotinate in a manner similar to the synthesis of methyl 5-chloro-6-formyl-2-methoxynicotinate using iodoethane in place of iodomethane.
  • the title compound was synthesized from methyl 5-chloro-2-ethoxy-6-formylnicotinate in a manner similar to the synthesis of 3-chloro-6-methoxy-5-(methoxycarbonyl)picolinic acid using iodoethane in place of iodomethane.
  • the title compound was synthesized from 5-chloro-2-ethoxy-6-formylnicotinate in a manner similar to the synthesis of methyl 5-chloro-6-(hydroxymethyl)-2-methoxynicotinate.
  • the title compound was synthesized from methyl 6-formyl-2-methoxy-5-methylnicotinate in a manner similar to the synthesis of methyl 5-chloro-6-(hydroxymethyl)-2-methoxynicotinate.
  • the title compound was synthesized from methyl 5-chloro-2-ethoxy-6-(hydroxymethyl)nicotinate in a manner similar to the synthesis of methyl 5-chloro-2-methoxy-6-(((methylsulfonyl)oxy)methyl)nicotinate.
  • the title compound was synthesized from methyl 5-fluoro-6-(hydroxymethyl)-2-methoxynicotinate in a manner similar to the synthesis of methyl 6-(bromomethyl)-5-chloro-2-methoxynicotinate.
  • the title compound was synthesized from methyl 6-(hydroxymethyl)-2-methoxy-5-methylnicotinate in a manner similar to the synthesis of methyl 6-(bromomethyl)-5-chloro-2-methoxynicotinate.
  • Step 1 3-(2,3-dihydrobenzo[ b ][1,4]dioxin-6-yl)-2-methylphenol
  • Step 2 methyl 2,5-dichloro-6-((3-(2,3-dihydrobenzo[ b ][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)nicotinate
  • Step 4 5-chloro-6-((3-(2,3-dihydrobenzo[ b ][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)nicotinaldehyde
  • Step 5 ((5-chloro-6-((3-(2,3-dihydrobenzo[ b ][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)- L -serine
  • Step 3 N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3- chloro-6-ethoxy-5-formylpicolinamide)
  • Step 4 N,N' -(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((2-hydroxyethyl)amino)methyl)picolinamide)
  • Step 2 tert -butyl (3'-amino-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)carbamate
  • the reaction mixture was heated to 90°C for 15 hr, cooled to room temperature, quenched with water, and extracted with dichloromethane. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 , 20% ethyl acetate in hexanes) to give the desired product (388.8 mg, 79.1% yield).
  • Step 3 methyl 6-((3'-(( tert -butoxycarbonyl)amino)-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-5-chloro-2-methoxynicotinate
  • Step 4 methyl 6-((3'-amino-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-5-chloro-2-methoxynicotinate hydrochloride
  • Step 5 methyl 5-chloro-6-((2'-chloro-3'-(5-(methoxycarbonyl)picolinamido)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-2-methoxynicotinate
  • Step 6 3-chloro- N -(2'-chloro-3'-(5-formylpicolinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-5-formyl-6-methoxypicolinamide
  • Step 7 3-chloro- N -(2'-chloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypicolinamide
  • Step 3 dimethyl 6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-ethoxynicotinate)
  • Step 4 6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-ethoxynicotinaldehyde)
  • the title compound was synthesized from dimethyl 6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-ethoxynicotinate) in a manner similar to the synthesis of N,N' -(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-formylpicolinamide).
  • Step 5 2,2'-((((((((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-ethoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(ethan-1-ol)
  • the title compound was synthesized as the bis-TFA salt from 6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-ethoxynicotinaldehyde) in a manner similar to the synthesis of N,N' -(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((2-hydroxyethyl)amino)methyl)picolinamide).
  • Step 1 methyl 4-((4-bromo-1 H -indol-1-yl)methyl)benzoate
  • Step 3 methyl 4-((4-(3-amino-2-chlorophenyl)-1 H -indol-1-yl)methyl)benzoate
  • the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure.
  • the mixture was diluted with dichloromethane and washed with water and brine.
  • the organic layer was dried over MgSO 4 and concentrated under reduced pressure.
  • the crude product was purified by flash chromatography (SiO 2 , 20% ethyl acetate in hexanes) to give the desired product (328.0 mg, 66.6% yield).
  • Step 4 methyl 5-chloro-6-((2-chloro-3-(1-(4-(methoxycarbonyl)benzyl)-1 H -indol-4-yl)phenyl)carbamoyl)-2-methoxynicotinate
  • Step 5 3-chloro- N -(2-chloro-3-(1-(4-(hydroxymethyl)benzyl)-1 H -indol-4-yl)phenyl)-5-(hydroxymethyl)-6-methoxypicolinamide
  • Step 6 3-chloro- N -(2-chloro-3-(1-(4-formylbenzyl)-1 H -indol-4-yl)phenyl)-5-formyl-6-methoxypicolinamide
  • Step 7 3-chloro- N -(2-chloro-3-(1-(4-(((2-hydroxyethyl)amino)methyl)benzyl)-1 H -indol-4-yl)phenyl)-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypicolinamide
  • the title compound was synthesized as the bis-TFA salt from 3-chloro- N -(2-chloro-3-(1-(4-formylbenzyl)-1 H -indol-4-yl)phenyl)-5-formyl-6-methoxypicolinamide in a manner similar to the synthesis of N,N' -(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((2-hydroxyethyl)amino)methyl)picolinamide).
  • Step 2 methyl 4-((4-(3-hydroxy-2-methylphenyl)-1 H -indol-1-yl)methyl)benzoate
  • Step 3 methyl 5-chloro-2-methoxy-6-((3-(1-(4-(methoxycarbonyl)benzyl)-1 H -indol-4-yl)-2-methylphenoxy)methyl)nicotinate
  • Step 4 (4-((4-(3-((3-chloro-5-(hydroxymethyl)-6-methoxypyridin-2-yl)methoxy)-2-methylphenyl)-1 H -indol-1-yl)methyl)phenyl)methanol
  • Step 5 5-chloro-6-((3-(1-(4-formylbenzyl)-1 H -indol-4-yl)-2-methylphenoxy)methyl)-2-methoxynicotinaldehyde
  • Step 6 2-((4-((4-(3-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2-methylphenyl)-1 H -indol-1-yl)methyl)benzyl)amino)ethan-1-ol
  • the title compound was synthesized as the bis-TFA salt from 5-chloro-6-((3-(1-(4-formylbenzyl)-1 H -indol-4-yl)-2-methylphenoxy)methyl)-2-methoxynicotinaldehyde in a manner similar to the synthesis of N,N' -(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((2-hydroxyethyl)amino)methyl)picolinamide).
  • Step 2 2,2,2-trifluoro-1-(7-nitro-3,4-dihydroisoquinolin-2(1 H )-yl)ethan-1-one
  • Step 3 1-(7-amino-3,4-dihydroisoquinolin-2(1 H )-yl)-2,2,2-trifluoroethan-1-one
  • Step 4 1-(7-amino-8-chloro-3,4-dihydroisoquinolin-2(1 H )-yl)-2,2,2-trifluoroethan-1-one
  • Step 5 1-(7-bromo-8-chloro-3,4-dihydroisoquinolin-2(1 H )-yl)-2,2,2-trifluoroethan-1-one
  • the title compound was synthesized from methyl 5-chloro-6-((3-(8-chloro-2-(5-(methoxycarbonyl)pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylphenoxy)methyl)-2-methoxynicotinate in a manner similar to the synthesis of N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-formylpicolinamide).
  • Step 11 2-(((5-chloro-6-((3-(8-chloro-2-(5-(((2-hydroxyethyl)amino)methyl)pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylphenoxy)methyl)-2-methoxypyridin-3-yl)methyl)amino)ethan-1-ol
  • the title compound was synthesized as the bis-TFA salt from 5-chloro-6-((3-(8-chloro-2-(5-formylpyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylphenoxy)methyl)-2-methoxynicotinaldehyde in a manner similar to the synthesis of N,N' -(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((2-hydroxyethyl)amino)methyl)picolinamide).
  • the reaction mixture was heated to 100°C. After 16 hr, the mixture was cooled to room temperature, concentrated under reduced pressure, diluted with dichloromethane, and washed with water and saturated sodium bicarbonate solution. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure.
  • the crude product was purified by flash chromatography (SiO 2 , 33.0% ethyl acetate in hexanes) to give the desired product (3.6 g, 19.50 mmol, 56.1% yield).
  • Step 2 methyl 6-((3-bromo-2-methylphenoxy)methyl)nicotinate
  • Step 4 methyl 5-chloro-2-methoxy-6-((3'-((5-(methoxycarbonyl)pyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)nicotinate
  • Step 7 3-chloro-5-(((2-hydroxyethyl)amino)methyl)- N -(3'-((5-(((2-hydroxyethyl)amino)methyl)pyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-methoxypicolinamide
  • Step 2 methyl 6-(((3'-amino-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)-5-chloro-2-methoxynicotinate
  • the reaction mixture was heated to 100°C for 15 hr, cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 , 25% ethyl acetate in hexanes) to give the desired product (94.2 mg, 38.6% yield).
  • Step 4 N -(3'-((3-chloro-5-(hydroxymethyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)picolinamide
  • Step 5 N -(3'-((3-chloro-5-formyl-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-formylpicolinamide
  • Step 6 N -(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide
  • Step 1 methyl 6-((3-bromo-2-chlorophenoxy)methyl)-5-chloro-2-methoxynicotinate
  • Step 2 methyl 6-(((3'-amino-2,2'-dichloro-[1,1'-biphenyl]-3-yl)oxy)methyl)-5-chloro-2-methoxynicotinate
  • the title compound was synthesized from methyl 6-((3-bromo-2-chlorophenoxy)methyl)-5-chloro-2-methoxynicotinate in a manner similar to the synthesis of methyl 6-(((3'-amino-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)-5-chloro-2-methoxynicotinate (0.35 g, 65.3% yield).
  • Step 3 methyl 5-chloro-6-(((2,2'-dichloro-3'-(5-(methoxycarbonyl)picolinamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxynicotinate
  • the title compound was synthesized from methyl 6-(((3'-amino-2,2'-dichloro-[1,1'-biphenyl]-3-yl)oxy)methyl)-5-chloro-2-methoxynicotinate in a manner similar to the synthesis of methyl 5-chloro-2-methoxy-6-(((3'-(5-(methoxycarbonyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)nicotinate (0.42 g, 89.7% yield).
  • Step 4 N -(2,2'-dichloro-3'-((3-chloro-5-(hydroxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)picolinamide
  • the title compound was synthesized from methyl 5-chloro-6-(((2,2'-dichloro-3'-(5-(methoxycarbonyl)picolinamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxynicotinate in a manner similar to the synthesis of N -(3'-((3-chloro-5-(hydroxymethyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)picolinamide (0.15 g, 51.1% yield).
  • Step 6 N -(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)picolinamide
  • Step 2 6-((3-bromo-2-chlorophenoxy)methyl)-5-chloro-2-methoxynicotinaldehyde
  • Step 3 2-((3-bromo-2-chlorophenoxy)methyl)-3-chloro-5-(dimethoxymethyl)-6-methoxypyridine
  • Step 4 2,2'-dichloro-3'-((3-chloro-5-(dimethoxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-amine
  • the filtrate was diluted was ethyl acetate, washed with water, and dried over MgSO 4 .
  • the organic layer was concentrated under reduced pressure and purified by flash chromatography (SiO 2 , 20% ethyl acetate in hexanes) to give the desired product (518.0 mg, 67.8% yield).
  • Step 5 methyl 6-((2,2'-dichloro-3'-((3-chloro-5-(dimethoxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)carbamoyl)nicotinate
  • Step 6 N -(2,2'-dichloro-3'-((3-chloro-5-(dimethoxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)picolinamide
  • Step 7 N -(2,2'-dichloro-3'-((3-chloro-5-(dimethoxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-formylpicolinamide
  • Step 8 N -(2,2'-dichloro-3'-((3-chloro-5-(dimethoxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide
  • Step 9 N -(2,2'-dichloro-3'-((3-chloro-5-formyl-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide
  • Step 10 N -(3'-((5-(aminomethyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide
  • the title compound was synthesized as the bis-TFA salt from N -(2,2'-dichloro-3'-((3-chloro-5-formyl-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide in a manner similar to the synthesis of N -(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide.
  • Step 1 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
  • Step 2 methyl 6-(((3'-amino-2,2'-dichloro-[1,1'-biphenyl]-3-yl)oxy)methyl)-5-chloro-2-methoxynicotinate

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Abstract

Disclosed are pyridine derivatives of formula (I) and a pharmaceutical composition comprising the pyridine derivatives or their pharmaceutically acceptable salts or stereoisomers thereof, and at least one pharmaceutically acceptable carrier or excipient, which are useful as key intermediate for the synthesis of compounds to inhibit PD-1/PD-L1 signaling pathway or capable of inhibiting PD-1/PD-L1 signaling pathway.

Description

PYRIDINE DERIVATIVES AS IMMUNOMODULATORS
The present invention relates to pharmaceutically active compounds, or intermediates for making the compounds. The present invention also relates to pharmaceutical compositions and methods of use.
The immune system plays an important role in various diseases such as infectious diseases and cancer. Programmed cell death protein 1 (PD-1), also known as CD279, is expressed on CD4+ T cells, CD8+ T cells, natural killer T cells, B cells and activated monocytes. PD-1 binds to the ligand PD-L1 or PD-L2 (Sharpe et al, Nature Immunology 2007, 8(3), 239-245).
PD-L1 is highly upregulated on many kinds of tumor cell, including melanoma, ovarian, and lung cancers. PD-1 interaction with PD-L1 and PD-L2 expressed on antigen presenting cells (APCs) and tumors sends a negative signal to T cells, which can lead to T-cell dysfunction (Dyck et al, European Journal of Immunology 2017, 47(5), 765-779). In viral diseases a similar mechanism is used by viruses to undermine the effective immune recognitions. Blocking the interactions between PD-1 and PD-L1 has emerged as a promising immunotherapy for treating cancer and infectious diseases.
Current medication directed towards the PD-1/PD-L1 axis includes monoclonal antibodies. In 2014, nivolumab, a monoclonal antibody (mAb), binding to PD-1, was approved in succession for the treatment of metastatic melanoma (Zhan et al, Drug Discovery Today 2016, 21(6), 1027-1036). Although mAbs have shown impressive clinical activity, mAbs exhibit several disadvantages such as limited tissue and tumour penetration, very long half life time, lacking oral bioavailability, immunogenicity, difficult production, expensive production, and severe immune-related adverse effects (Adams et al, Nature Reviews Drug Discovery 2015, 14(9), 603-622). To overcome these limitations of mAbs, it is necessary to develop small molecules that block PD-1/PD-L1 protein/protein interaction.
[Prior art documents]
1. Sharpe et al, Nature Immunology 2007, 8 (3), 239-245
2. Dyck et al, European Journal of Immunology 2017, 47 (5), 765-779
3. Zhan et al, Drug Discovery Today 2016, 21(6), 1027-1036
4. Adams et al, Nature Reviews Drug Discovery 2015, 14(9), 603-622
Accordingly, It is an object of the present invention to provide pyridine derivatives of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, which are useful compounds capable of inhibiting PD-1/PD-L1 signaling pathway or key intermediates for the synthesis of such compounds.
It is another object of the present invention to provide pharmaceutical compositions and methods for use in modulating PD-1/PD-L1 interaction and in the treatment, prevention or alleviation of various diseases associated with inhibition of PD-1/PD-L1 interaction, including infectious diseases and cancer.
The present invention provides a compound of formula (I):
Figure PCTKR2021006886-appb-img-000001
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein constituent variables are defined herein.
The present invention further provides the compound of formula (I) as immunomodulators.
The present invention further provides a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.
The compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition comprising the same, is useful for inhibiting PD-1/PD-L1 signaling pathway. The compound or the composition modulates PD-1/PD-L1 interaction and is useful in the treatment, prevention or alleviation of various diseases associated with inhibition of PD-1/PD-L1 interaction, including infectious diseases and cancer.
The present invention will be further described in detail herein below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. The descriptions of known functions and configurations that may unnecessarily obscure the subject matter of the present invention will be omitted.
The term "n-membered" where n is an integer, typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring and 1,2,3,4-tetrahydroisoquinolyl is an example of a 10-membered cycloalkyl group.
At various places in the present specification, variables defining divalent linking groups may be described. It is specifically intended that each linking substituent include both the forward and backward forms of the linking substituent. For example, -C(ReRf)NRe- includes both -C(ReRf)NRe- and -NReC(ReRf)- and is intended to disclose each of the forms individually. Where the structure 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" or "aryl" then it is understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.
The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The term "substituted", unless otherwise indicated, refers to any level of substitution, e.g., mono-, di-, tri-, tetra- or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. It is to be understood that substitution at a given atom results in a chemically stable molecule. The phrase "optionally substituted" means unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms.
The term "Cn-m" indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-4, C2-6 and the like.
The term "alkyl" employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched. The term "Cn-m alkyl" refers to an alkyl group having n to m carbon atoms. An alkyl group formally corresponds to an alkane with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl and the like.
The term "alkenyl" employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds. An alkenyl group formally corresponds to an alkene with one C-H bond replaced by the point of attachment of the alkenyl group to the remainder of the compound. The term "Cn-m alkenyl" refers to an alkenyl group having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl and the like.
The term "alkynyl" employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more triple carbon-carbon bonds. An alkynyl group formally corresponds to an alkyne with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound. The term "Cn-m alkynyl" refers to an alkynyl group having n to m carbons. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
The term "alkylene" employed alone or in combination with other terms, refers to a divalent alkyl linking group. An alkylene group formally corresponds to an alkane with two C-H bond replaced by points of attachment of the alkylene group to the remainder of the compound. The term "Cn-m alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl and the like.
The term "alkoxy" employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group is as defined above. The term "Cn-m alkoxy" refers to an alkoxy group, the alkyl group of which has n to m carbons. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
The term "amino" employed alone or in combination with other terms, refers to a group of formula -NH2.
The term "carbamoyl" employed alone or in combination with other terms, refers to a group of formula -C(O)NH2.
The term "carbonyl" employed alone or in combination with other terms, refers to a -C(=O)- group, which also may be written as C(O).
The term "cyano" or "nitrile" employed alone or in combination with other terms, refers to a group of formula -C≡N, which also may be written as -CN.
The terms "halo" or "halogen" used alone or in combination with other terms, refers to fluoro, chloro, bromo and iodo. In some embodiments, "halo" refers to a halogen atom selected from F, CI, or Br.
The term "haloalkyl" employed alone or in combination with other terms, as used herein refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen atom. The term "Cn-m haloalkyl" refers to a Cn-m alkyl group having n to m carbon atoms and from at least one up to {2(n to m) + 1} halogen atoms, which may either be the same or different. In some embodiments, the halogen atoms are fluoro atoms. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Examples of haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5 and the like.
The term "haloalkoxy" employed alone or in combination with other terms, refers to a group of formula -O-haloalkyl, wherein the haloalkyl group is as defined above. The term "Cn-m haloalkoxy" refers to a haloalkoxy group, the haloalkyl group of which has n to m carbons. Examples of haloalkoxy groups include trifluoromethoxy and the like. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
The term "oxo" refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to carbon, or attached to a heteroatom forming a sulfoxide or sulfone group, or an N-oxide group. In some embodiments, heterocyclic groups may be optionally substituted by 1 or 2 oxo (=O) substituents.
The term "sulfido" refers to a sulfur atom as a divalent substituent, forming a thiocarbonyl group (C=S) when attached to carbon.
The term "aromatic" refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n + 2) delocalized π (pi) electrons where n is an integer).
The term "aryl" employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2 fused rings). The term "Cn-m aryl" refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, indenyl and the like. In some embodiments, aryl groups have from 6 to about 10 carbon atoms. In some embodiments, aryl groups have 6 carbon atoms. In some embodiments, aryl groups have 10 carbon atoms. In some embodiments, the aryl group is phenyl.
The term "heteroaryl" or "heteroaromatic" employed alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming Ν in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-14, or 5-10 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. In other embodiments, the heteroaryl is an eight-membered, nine-membered or ten-membered fused bicyclic heteroaryl ring. Examples of heteroaryl groups include, but are not limited to, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridinyl), indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, and the like.
A five-membered heteroaryl ring is a heteroaryl group having five ring atoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independently selected from N, O and S. Examples of five-membered ring heteroaryls include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
A six-membered heteroaryl ring is a heteroaryl group having six ring atoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independently selected from N, O and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
The term "cycloalkyl" employed alone or in combination with other terms, refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), including cyclized alkyl and alkenyl groups. The term "Cn-m cycloalkyl" refers to a cycloalkyl that has n to m ring member carbon atoms. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring-forming carbons (C3-14). In some embodiments, the cycloalkyl group has 3 to 14 ring members, 3 to 10 ring members, 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C3-6 monocyclic cycloalkyl group. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. Cycloalkyl groups also include cycloalkylidenes. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, e.g., benzo or thienyl derivatives of cyclopentane, cyclohexane and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcamyl, bicyclo[1,1,1]pentanyl, bicyclo[2,1,1]hexanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
The term "heterocycloalkyl" employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur oxygen and phosphorus, and which has 4-14 ring members, 4-10 ring members, 4-7 ring members, or 4-6 ring members. Included within the term "heterocycloalkyl" are monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include mono- or bicyclic or poly cyclic (e.g., having two or three fused or bridged rings) ring systems or spirocycles. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally oxidized to form an oxo or sulfido group or other oxidized linkage (e.g., C(O), S(O), C(S) or S(O)2, N-oxide etc.) or a nitrogen atom can be quatemized. The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the heterocycloalkyl ring, e.g., benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Examples of heterocycloalkyl groups include azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5,5]undecanyl, 1-oxa-8-azaspiro[4,5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, oxoimidazolidinyl (e.g., 3-methyl-2-oxoimidazolidin-1-yl), oxooxazolidinyl (e.g., 2-oxooxazolidin-3-yl), and thiomorpholino.
At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached at any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas an azetidin-3-yl ring is attached at the 3-position.
Compounds
The present invention provides a compound of formula (I):
Figure PCTKR2021006886-appb-img-000002
,
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
R1 is halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-14 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -NHORa, -N(OH)Ra, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NRa)NRaRa, -NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaRa, -OS(O)2Ra, -PRaRa, -P(O)RaRa or -BRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl- and (5-14 membered heteroaryl)-C2-6 alkynyl- of R1 are each optionally substituted with 1 to 5 groups independently selected from Rb substituents;
R2 is halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-14 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -NHORa, -N(OH)Ra, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NRa)NRaRa, -NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaRa, -OS(O)2Ra, -PRaRa, -P(O)RaRa or -BRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl- and (5-14 membered heteroaryl)-C2-6 alkynyl- of R2 are each optionally substituted with 1 to 5 groups independently selected from Rb substituents;
each Ra is independently selected from H, halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, and (5-14 membered heteroaryl)-C2-6 alkynyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl- and (5-14 membered heteroaryl)-C2-6 alkynyl- of Ra are each optionally substituted with 1 to 5 groups independently selected from Rb substituents;
or any two Ra substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 4 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-14 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
each Rb is independently selected from H, halogen, OH, CN, NO2, N3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-14 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -(CRcRc)ORc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
each Rc is independently selected from H, halogen, OH, CF3, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, and (5-14 membered heteroaryl)-C2-6 alkynyl-;
R3 is -C(O)X, -C(O)ORd, -C(ReRf)OH, -C(ReRf)Y, -C(ReRf)NH2, -C(ReRf)N3 or
Figure PCTKR2021006886-appb-img-000003
;
ArW is ArE, -ArE-L-QE or -ArE-L-QE-RM;
X is H or halogen;
Y is halogen or OS(O)2Rg;
Rd is H, C1-6 alkyl or CORg;
Re and Rf are each independently selected from H, halogen, OH, CN, NO2, and C1-6 alkyl;
or Re and Rf are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 4 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-14 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
Rg is C1-5 alkyl, C1-5 alkoxy or phenyl, wherein the C1-5 alkyl, C1-5 alkoxy and phenyl of Rg are each optionally substituted with 1 to 4 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, and (5-14 membered heteroaryl)-C2-6 alkynyl-;
A is -C(O)O-, -C(ReRf)O-, -C(ReRf)S-, -C(ReRf)S(O)2-, -C(O)NRe- or -C(ReRf)NRe-;
Each R4 is independently selected from H, halogen, OH, CN, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-14 cycloalkyl, and 4-14 membered heterocycloalkyl;
or any two R4 substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 4 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-14 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
The subscript n is an integer of 0, 1, 2 or 3;
ArE is 4-14 membered heterocycloalkyl, C6-10 aryl or 5-14 membered heteroaryl, wherein the 4-14 membered heterocycloalkyl, C6-10 aryl and 5-14 membered heteroaryl of ArE are each optionally substituted with 1 to 5 groups independently selected from R4 substituents;
L is a bond, -O-, -S-, -C(O)-, -SO-, -SO2-, -(CRhRi)m-, -(CRhRi)mO(CRhRi)m-, -(CRhRi)mS(CRhRi)m-, -(CRhRi)mNRh(CRhRi)m-, -(CRhRi)mC(O)(CRhRi)m-, -(CRhRi)mC(O)NRh(CRhRi)m-, -(CRhRi)mNRhC(O)(CRhRi)m-, -(CRhRi)mSO2NRh(CRhRi)m-, -(CRhRi)mNRhSO2(CRhRi)m-, -C2-6 alkenylene- or -C2-6 alkynylene-, wherein each m is independently 0, 1, 2 or 3;
Rh and Ri are each independently selected from H, halogen, OH, CN, NO2, COOH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, (C1-6 alkyl)NH-, (C1-6 alkyl)2N-, C3-14 cycloalkyl, and 4-14 membered heterocycloalkyl;
or Rh and Ri are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 4 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-14 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
QE is 4-14 membered heterocycloalkyl, C6-10 aryl or 5-14 membered heteroaryl, wherein 4-14 membered heterocycloalkyl, C6-10 aryl or 5-14 membered heteroaryl of QE are each optionally substituted with 1 to 5 groups independently selected from R1 substituents;
RM and RL are each independently selected from halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-14 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -NHORa, -N(OH)Ra, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -C(RaRa)NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NRa)NRaRa, -NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaRa, -OS(O)2Ra, -PRaRa, -P(O)RaRa, and -BRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl- and (5-14 membered heteroaryl)-C2-6 alkynyl- of RM and RL are each optionally substituted with 1 to 5 groups independently selected from Rb substituents.
In some embodiments, the present invention provides a compound of formula (I):
Figure PCTKR2021006886-appb-img-000004
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
R1 is halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -NHORa, -N(OH)Ra, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NRa)NRaRa, -NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaRa, -OS(O)2Ra, -PRaRa, -P(O)RaRa or -BRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl-of R1 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
R2 is halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -NHORa, -N(OH)Ra, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NRa)NRaRa, -NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaRa, -OS(O)2Ra, -PRaRa, -P(O)RaRa or -BRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl-of R2 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
each Ra is independently selected from H, halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, and (5-10 membered heteroaryl)-C2-6 alkynyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl- of Ra are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
or any two Ra substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
each Rb is independently selected from H, halogen, OH, CN, NO2, N3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -(CRcRc)ORc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
each Rc is independently selected from H, halogen, OH, CF3, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, and (5-10 membered heteroaryl)-C2-6 alkynyl-;
R3 is -C(O)X, -C(O)ORd, -C(ReRf)OH, -C(ReRf)Y, -C(ReRf)NH2, -C(ReRf)N3 or
Figure PCTKR2021006886-appb-img-000005
;
ArW is ArE, -ArE-L-QE or -ArE-L-QE-RM;
X is H or halogen;
Y is halogen or OS(O)2Rg;
Rd is H, C1-6 alkyl or CORg;
Re and Rf are each independently selected from H, halogen, OH, CN, NO2, and C1-6 alkyl;
or Re and Rf are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
Rg is C1-5 alkyl, C1-5 alkoxy or phenyl, wherein the C1-5 alkyl, C1-5 alkoxy and phenyl of Rg are each optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, and (5-10 membered heteroaryl)-C2-6 alkynyl-;
A is -C(ReRf)O-, -C(ReRf)S-, -C(ReRf)S(O)2-, -C(O)NRe- or -C(ReRf)NRe-;
Each R4 is independently selected from H, halogen, OH, CN, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, and 4-10 membered heterocycloalkyl;
or any two R4 substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
The subscript n is an integer of 0, 1, 2 or 3;
ArE is 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl of ArE are each optionally substituted with 1 to 3 groups independently selected from R4 substituents;
L is a bond, -O-, -S-, -C(O)-, -SO-, -SO2-, -(CRhRi)m-, -(CRhRi)mO(CRhRi)m-, -(CRhRi)mS(CRhRi)m-, -(CRhRi)mNRh(CRhRi)m-, -(CRhRi)mC(O)(CRhRi)m-, -(CRhRi)mC(O)NRh(CRhRi)m-, -(CRhRi)mNRhC(O)(CRhRi)m-, -(CRhRi)mSO2NRh(CRhRi)m-, -(CRhRi)mNRhSO2(CRhRi)m-, -C2-6 alkenylene- or -C2-6 alkynylene-, wherein each m is independently 0, 1, 2 or 3;
Rh and Ri are each independently selected from H, halogen, OH, CN, NO2, COOH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, (C1-6 alkyl)NH-, (C1-6 alkyl)2N-, C3-8 cycloalkyl, and 4-10 membered heterocycloalkyl;
or Rh and Ri are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
QE is 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, wherein 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl of QE are each optionally substituted with 1 to 3 groups independently selected from R1 substituents;
RM and RL are each independently selected from halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -NHORa, -N(OH)Ra, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -C(RaRa)NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NRa)NRaRa, -NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaRa, -OS(O)2Ra, -PRaRa, -P(O)RaRa, and -BRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl- of RM and RL are each optionally substituted with 1 to 3 groups independently selected from Rb substituents.
In some embodiments, the present invention provides a compound of formula (I):
Figure PCTKR2021006886-appb-img-000006
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
R1 is halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -NHORa, -N(OH)Ra, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra or -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl-of R1 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
R2 is halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -NHORa, -N(OH)Ra, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra or -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl-of R2 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
each Ra is independently selected from H, halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, and (5-10 membered heteroaryl)-C2-6 alkynyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl- of Ra are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
or any two Ra substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, and -OS(O)2Rc;
each Rb is independently selected from H, halogen, OH, CN, NO2, N3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -(CRcRc)ORc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, and -S(O)2NRcRc;
each Rc is independently selected from H, halogen, OH, CF3, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, and (5-10 membered heteroaryl)-C2-6 alkynyl-;
R3 is -C(O)X, -C(O)ORd, -C(ReRf)OH, -C(ReRf)Y, -C(ReRf)NH2, -C(ReRf)N3 or
Figure PCTKR2021006886-appb-img-000007
;
ArW is ArE, -ArE-L-QE or -ArE-L-QE-RM;
X is H or halogen;
Y is halogen or OS(O)2Rg;
Rd is H, C1-6 alkyl or CORg;
Re and Rf are each independently selected from H, halogen, OH, CN, NO2, and C1-6 alkyl;
or Re and Rf are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, and -S(O)2NRcRc;
Rg is C1-5 alkyl, C1-5 alkoxy or phenyl, wherein the C1-5 alkyl, C1-5 alkoxy and phenyl of Rg are each optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, and (5-10 membered heteroaryl)-C2-6 alkynyl-;
A is -C(ReRf)O-, -C(ReRf)S-, -C(ReRf)S(O)2-, -C(O)NRe- or -C(ReRf)NRe-;
Each R4 is independently selected from H, halogen, OH, CN, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, and 4-10 membered heterocycloalkyl;
or any two R4 substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, and -S(O)2NRcRc;
The subscript n is an integer of 0, 1, 2 or 3;
ArE is 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl of ArE are each optionally substituted with 1 to 3 groups independently selected from R4 substituents;
L is a bond, -O-, -S-, -C(O)-, -SO-, -SO2-, -(CRhRi)m-, -(CRhRi)mO(CRhRi)m-, -(CRhRi)mS(CRhRi)m-, -(CRhRi)mNRh(CRhRi)m-, -(CRhRi)mC(O)(CRhRi)m-, -(CRhRi)mC(O)NRh(CRhRi)m-, -(CRhRi)mNRhC(O)(CRhRi)m-, -(CRhRi)mSO2NRh(CRhRi)m-, -(CRhRi)mNRhSO2(CRhRi)m-, -C2-6 alkenylene- or -C2-6 alkynylene-, wherein each m is independently 0, 1, 2 or 3;
Rh and Ri are each independently selected from H, halogen, OH, CN, NO2, COOH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, (C1-6 alkyl)NH-, (C1-6 alkyl)2N-, C3-8 cycloalkyl, and 4-10 membered heterocycloalkyl;
or Rh and Ri are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, and -S(O)2NRcRc;
QE is 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, wherein 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl of QE are each optionally substituted with 1 to 3 groups independently selected from R1 substituents;
RM and RL are each independently selected from halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -NHORa, -N(OH)Ra, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -C(RaRa)NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NRa)NRaRa, -NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra, and -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl- of RM and RL are each optionally substituted with 1 to 3 groups independently selected from Rb substituents.
In some embodiments, the present invention provides a compound of formula (I):
Figure PCTKR2021006886-appb-img-000008
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
R1 is halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra or -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl- of R1 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
R2 is halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra or -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl- of R2 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
each Ra is independently selected from H, halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, and (5-10 membered heteroaryl)-C2-6 alkynyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl- of Ra are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
or any two Ra substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, and -OS(O)2Rc;
each Rb is independently selected from H, halogen, OH, CN, NO2, N3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -(CRcRc)ORc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, and -S(O)2NRcRc;
each Rc is independently selected from H, halogen, OH, CF3, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, and (5-10 membered heteroaryl)-C2-6 alkynyl-;
R3 is -C(O)X, -C(O)ORd, -C(ReRf)OH, -C(ReRf)Y, -C(ReRf)NH2, -C(ReRf)N3 or
Figure PCTKR2021006886-appb-img-000009
;
ArW is ArE, -ArE-L-QE or -ArE-L-QE-RM;
X is H or halogen;
Y is halogen or OS(O)2Rg;
Rd is H, C1-6 alkyl or CORg;
Re and Rf are each independently selected from H, halogen, OH, CN, NO2, and C1-6 alkyl;
or Re and Rf are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 4 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, and -S(O)2NRcRc;
Rg is C1-5 alkyl, C1-5 alkoxy or phenyl, wherein the C1-5 alkyl, C1-5 alkoxy and phenyl of Rg are each optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, and (5-10 membered heteroaryl)-C2-6 alkynyl-;
A is -C(ReRf)O-, -C(ReRf)S-, -C(ReRf)S(O)2-, -C(O)NRe- or -C(ReRf)NRe-;
Each R4 is independently selected from H, halogen, OH, CN, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, and 4-10 membered heterocycloalkyl;
or any two R4 substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, and -S(O)2NRcRc;
The subscript n is an integer of 0, 1, 2 or 3;
ArE is 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl of ArE are each optionally substituted with 1 to 3 groups independently selected from R4 substituents;
L is a bond, -O-, -S-, -C(O)-, -SO-, -SO2-, -(CRhRi)m-, -(CRhRi)mO(CRhRi)m-, -(CRhRi)mS(CRhRi)m-, -(CRhRi)mNRh(CRhRi)m-, -(CRhRi)mC(O)(CRhRi)m-, -(CRhRi)mC(O)NRh(CRhRi)m-, -(CRhRi)mNRhC(O)(CRhRi)m-, -(CRhRi)mSO2NRh(CRhRi)m-, -(CRhRi)mNRhSO2(CRhRi)m-, -C2-6 alkenylene- or -C2-6 alkynylene-, wherein each m is independently 0, 1, 2 or 3;
Rh and Ri are each independently selected from H, halogen, OH, CN, NO2, COOH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, (C1-6 alkyl)NH-, (C1-6 alkyl)2N-, C3-8 cycloalkyl, and 4-10 membered heterocycloalkyl;
or Rh and Ri are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, and -S(O)2NRcRc;
QE is 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, wherein 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl of QE are each optionally substituted with 1 to 3 groups independently selected from R1 substituents;
RM and RL are each independently selected from halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -C(RaRa)NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra, and -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl- of RM and RL are each optionally substituted with 1 to 3 groups independently selected from Rb substituents.
In some embodiments, the present invention provides a compound of formula (Ia):
Figure PCTKR2021006886-appb-img-000010
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
R1 is halogen, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, -ORa, -SRa, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra or -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, and 5-10 membered heteroaryl of R1 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
R2 is halogen, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, -ORa, -SRa, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra or -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, and 5-10 membered heteroaryl of R2 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
R3 is -C(O)X, -C(O)ORd, -C(ReRf)OH, -C(ReRf)Y, -C(ReRf)NH2 or -C(ReRf)N3;
Ra, Rb, Rd, Re, Rf, X, Y and RL are as defined in the description.
In some embodiments, the present invention provides a compound of formula (Ib):
Figure PCTKR2021006886-appb-img-000011
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
R1 is halogen, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, -ORa, -SRa, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra or -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, and 5-10 membered heteroaryl of R1 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
R2 is halogen, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, -ORa, -SRa, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra or -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, and 5-10 membered heteroaryl of R2 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
Ra, Rb, RL, A, R4, n and ArW are as defined in the description.
In some embodiments, the present invention provides a compound of formula (II):
Figure PCTKR2021006886-appb-img-000012
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1, R2, R4, A, n, ArE and RL are as defined in the description.
In some embodiments, the present invention provides a compound of formula (IIa):
Figure PCTKR2021006886-appb-img-000013
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1, R2, R4, RL, A and n are as defined in the description.
In some embodiments, the present invention provides a compound of formula (IIb):
Figure PCTKR2021006886-appb-img-000014
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1, R2, R4, Re, Rf, n and RL are as defined in the description.
In some embodiments, the present invention provides a compound of formula (IIc):
Figure PCTKR2021006886-appb-img-000015
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1, R2, R4, Re, n and RL are as defined in the description.
In some embodiments, the present invention provides a compound of formula (IId):
Figure PCTKR2021006886-appb-img-000016
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1, R2, R4, Ra, Re, Rf and n are as defined in the description.
In some embodiments, the present invention provides a compound of formula (IIe):
Figure PCTKR2021006886-appb-img-000017
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1, R2, R4, Ra, Re and n are as defined in the description
In some embodiments, the present invention provides a compound of formula (III):
Figure PCTKR2021006886-appb-img-000018
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1, R2, R4, A, n, ArE, L, QE, RL and RM are as defined in the description.
In some embodiments, the present invention provides a compound of formula (IIIa):
Figure PCTKR2021006886-appb-img-000019
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1, R2, R4, A, n, L, QE, RL and RM are as defined in the description.
In some embodiments, the present invention provides a compound of formula (IIIb):
Figure PCTKR2021006886-appb-img-000020
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1, R2, R4, Re, Rf, n, L, QE, RL and RM are as defined in the description.
In some embodiments, the present invention provides a compound of formula (IIIc):
Figure PCTKR2021006886-appb-img-000021
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1, R2, R4, Re, n, L, QE, RL and RM are as defined in the description.
In some embodiments, the present invention provides a compound of formula (IIId):
Figure PCTKR2021006886-appb-img-000022
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1, R2, R4, Ra, Re, Rf, n, L, QE and RM are as defined in the description.
In some embodiments, the present invention provides a compound of formula (IIIe):
Figure PCTKR2021006886-appb-img-000023
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1, R2, R4, Ra, Re, n, L, QE and RM are as defined in the description.
In some embodiments, R1 is halogen, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, -ORa, -SRa, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra or -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, and 5-10 membered heteroaryl of R1 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents.
In some embodiments, R1 is halogen, C1-6 alkyl, or -ORa.
In some embodiments, R2 is halogen, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, -ORa, -SRa, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra or -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, and 5-10 membered heteroaryl of R2 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents.
In some embodiments, R2 is halogen, or C1-6 alkyl.
In some embodiments, each Ra is independently selected from H, C1-6 alkyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, and (5-10 membered heteroaryl)-C1-6 alkyl-, wherein the C1-6 alkyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, and C6-8 aryl-C1-6 alkyl- of Ra are each optionally substituted with 1 to 3 groups independently selected from Rb substituents; or any two Ra substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from OH, -(CRcRc)ORc, -C(O)NRcRc, -C(O)ORc, -NRcRc, and -NRcC(O)Rc.
In some embodiments, each Rb is independently selected from OH, CN, C1-6 alkyl, 4-10 membered heterocycloalkyl, -ORc, -(CRcRc)ORc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -NRcRc, -NRcC(O)Rc, -S(O)2Rc, and -S(O)2NRcRc.
In some embodiments, each Rc is independently selected from H, OH, CF3, C1-6 alkyl and (4-10 membered heterocycloalkyl)-C1-6 alkyl-.
In some embodiments, R3 is -C(O)X, -C(O)ORd, -C(ReRf)OH, -C(ReRf)Y, -C(ReRf)NH2, or -C(ReRf)N3.
In some embodiments, R3 is
Figure PCTKR2021006886-appb-img-000024
.
In some embodiments, ArW is ArE.
In some embodiments, ArW is ArE-L-QE.
In some embodiments, ArW is -ArE-L-QE-RM.
In some embodiments, X is H or halogen.
In some embodiments, Y is halogen or OS(O)2Rg.
In some embodiments, Rd is H, C1-6 alkyl or CORg.
In some embodiments, Re and Rf are each independently selected from H, halogen and CN.
In some embodiments, Rg is C1-5 alkyl, C1-5 alkoxy or phenyl.
In some embodiments, A is -C(ReRf)O-, or -C(O)NRe-;
In some embodiments, R4 is independently selected from H, halogen, CN, C1-6 alkyl or C1-6 alkoxy; or any two R4 substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from -ORc.
In some embodiments, the subscript n is an integer of 0, 1 or 2.
In some embodiments, ArE is 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl of ArE are each optionally substituted with 1 to 3 groups independently selected from R4 substituents.
In some embodiments, L is -(CRhRi)m-, -(CRhRi)mO(CRhRi)m- or -(CRhRi)mNRhC(O)(CRhRi)m-, wherein each m is independently 0 or 1.
In some embodiments, Rh and Ri are H.
In some embodiments, QE is 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, wherein 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl of QE are each optionally substituted with 1 to 3 groups independently selected from R1 substituents.
In some embodiments, RM and RL are each independently selected from C1-6 alkyl, (4-10 membered heterocycloalkyl)-C1-6 alkyl- and -C(RaRa)NRaRa, wherein the C1-6 alkyl and (4-10 membered heterocycloalkyl)-C1-6 alkyl- of RM and RL are each optionally substituted with 1 to 3 groups independently selected from Rb substituents.
In some embodiments, the ring having 3-8 ring atoms that are C, N, O or S is each independently selected from C6-10 aryl, C3-8 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl.
It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment (while the embodiments are intended to be combined as if written in multiply dependent form). Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. Thus, it is contemplated that embodiments of the compounds of Formula (I) can be combined in any suitable combination.
At various places in the present specification, certain features of the compounds are disclosed in groups or in ranges. It is specifically intended that such a disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term "C1-6 alkyl" is specifically intended to individually disclose (without limitation) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.
Exemplary compounds of the present invention are:
1) ((5-chloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)-L-serine;
2) 2-(((5-chloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)amino)ethan-1-ol;
3) ((5-chloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)-L-proline;
4) N-(2-(((5-chloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)amino)ethyl)acetamide;
5) 3-(((5-chloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-3-(((2-hydroxyethyl)amino)methyl)pyridin-2-yl)oxy)methyl)benzonitrile;
6) ((5-chloro-6-(((2-methyl-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)-L-serine;
7) 2-(((5-chloro-6-(((2-methyl-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)amino)ethan-1-ol;
8) ((5-chloro-6-(((3'-methoxy-2-methyl-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)-L-serine;
9) ((5-chloro-2-((3'-methoxy-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-6-(((3'-methoxy-2-methyl-[1,1'-biphenyl]-3-yl)oxy)methyl)pyridin-3-yl)methyl)-L-serine;
10) ((5-chloro-6-(((2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)-L-serine;
11) ((5-chloro-6-(((2'-fluoro-3'-methoxy-2-methyl-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)-L-serine;
12) ((5-chloro-6-((3-(5-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)-L-serine;
13) ((5-chloro-2-((3-cyanobenzyl)oxy)-6-(((2-methyl-[1,1'-biphenyl]-3-yl)oxy)methyl)pyridin-3-yl)methyl)-L-serine;
14) 2-(((5-chloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)amino)-2-methylpropanoic acid;
15) (R)-1-((5-chloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)pyrrolidin-3-ol;
16) N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((2-hydroxyethyl)amino)methyl)picolinamide);
17) N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-((methylamino)methyl)picolinamide);
18) N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamide);
19) N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((2-sulfamoylethyl)amino)methyl)picolinamide);
20) N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(5-(((2-acetamidoethyl)amino)methyl)-3-chloro-6-ethoxypicolinamide);
21) N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methyl)picolinamide);
22) N,N'-(2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-6-methylpicolinamide);
23) 3-chloro-N-(2'-chloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypicolinamide;
24) 3-chloro-N-(2-chloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypicolinamide;
25) 3-chloro-5-(((2-hydroxyethyl)amino)methyl)-N-(3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-methoxypicolinamide;
26) 3-chloro-N-(2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-6-methylpicolinamide;
27) ((6-((3'-(5-((((S)-1-carboxy-2-hydroxyethyl)amino)methyl)-3-fluoro-6-methylpicolinamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-L-serine;
28) N-(2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-6-methoxy-3-methylpicolinamide;
29) 3-chloro-N-(2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypicolinamide;
30) ((6-((3'-(5-((((S)-1-carboxy-2-hydroxyethyl)amino)methyl)-3-chloro-6-methylpicolinamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-L-serine;
31) (S)-2-(((6-((3'-(5-((((S)-2-carboxy-1-hydroxypropan-2-yl)amino)methyl)-3-chloro-6-methylpicolinamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid;
32) methyl (S)-2-(((5-chloro-6-((2,2'-dichloro-3'-(5-((((S)-3-hydroxy-1-methoxy-2-methyl-1-oxopropan-2-yl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-2-methylpyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoate;
33) 3-chloro-N-(2,2'-dichloro-3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-6-methylpicolinamide;
34) 3-chloro-N-(2,2'-dichloro-3'-(5-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-6-methyl-5-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)picolinamide;
35) methyl (S)-2-(((5-chloro-6-((2,2'-dichloro-3'-(5-((((S)-3-hydroxy-1-methoxy-2-methyl-1-oxopropan-2-yl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-2-methylpyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoate;
36) (R)-1-((6-((3'-(5-(((R)-3-carboxypyrrolidin-1-yl)methyl)-3-chloro-6-methylpicolinamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid;
37) 2-(((6-((3'-(5-(((2-carboxypropan-2-yl)amino)methyl)-3-chloro-6-methylpicolinamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)-2-methylpropanoic acid;
38) ethyl (S)-2-(((5-chloro-6-((2,2'-dichloro-3'-(5-((((S)-1-ethoxy-3-hydroxy-2-methyl-1-oxopropan-2-yl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-2-methylpyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoate;
39) (S)-2-(((6-((3'-(5-((((S)-2-carboxy-1-hydroxypropan-2-yl)amino)methyl)-3-fluoro-6-methylpicolinamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid;
40) 2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-ethoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(ethan-1-ol);
41) 2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(ethan-1-ol);
42) (3R,3'R)-1,1'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(pyrrolidin-3-ol);
43) 1,1'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(N-methylmethanamine);
44) ((1R,1'R,3R,3'R)-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(cyclobutane-3,1-diyl))dimethanol;
45) 3-chloro-N-(2-chloro-3-(1-(4-(((2-hydroxyethyl)amino)methyl)benzyl)-1H-indol-4-yl)phenyl)-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypicolinamide;
46) 3-chloro-N-(2-chloro-3-(1-(4-((methylamino)methyl)benzyl)-1H-indol-4-yl)phenyl)-6-methoxy-5-((methylamino)methyl)picolinamide;
47) 2-((4-((4-(3-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2-methylphenyl)-1H-indol-1-yl)methyl)benzyl)amino)ethan-1-ol;
48) 2-(((5-chloro-6-((3-(8-chloro-2-(5-(((2-hydroxyethyl)amino)methyl)pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylphenoxy)methyl)-2-methoxypyridin-3-yl)methyl)amino)ethan-1-ol;
49) 3-chloro-5-(((2-hydroxyethyl)amino)methyl)-N-(3'-((5-(((2-hydroxyethyl)amino)methyl)pyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-methoxypicolinamide;
50) N-(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
51) N-(3'-((3-chloro-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamide;
52) 3-chloro-N-(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-6-methylpicolinamide;
53) N-(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypicolinamide;
54) N-(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2-cyano-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
55) N-(2-chloro-3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
56) N-(2'-chloro-3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
57) N-(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
58) N-(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2'-cyano-2-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
59) N-(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methylpyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
60) N-(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-6-methylpicolinamide;
61) N-(2,2'-dichloro-3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
62) N-(2,2'-dichloro-3'-((3-fluoro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
63) N-(2,2'-dichloro-3'-((5-(((2-hydroxyethyl)amino)methyl)-6-methoxy-3-methylpyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
64) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((2-morpholinoethyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-morpholinoethyl)amino)methyl)picolinamide;
65) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((3-morpholinopropyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((3-morpholinopropyl)amino)methyl)picolinamide;
66) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((3-(3-oxopiperazin-1-yl)propyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((3-(3-oxopiperazin-1-yl)propyl)amino)methyl)picolinamide;
67) N-(2,2'-dichloro-3'-(((3-chloro-6-methoxy-5-(((3-(4-methylpiperazin-1-yl)propyl)amino)methyl)pyridin-2-yl)oxy)methyl)-[1,1'-biphenyl]-3-yl)-5-(((3-(4-methylpiperazin-1-yl)propyl)amino)methyl)picolinamide;
68) N-(2,2'-dichloro-3'-(((3-chloro-6-methoxy-5-(((3-(piperazin-1-yl)propyl)amino)methyl)pyridin-2-yl)oxy)methyl)-[1,1'-biphenyl]-3-yl)-5-(((3-(piperazin-1-yl)propyl)amino)methyl)picolinamide;
69) (S)-2-(((6-((3'-((5-((((S)-2-carboxy-1-hydroxypropan-2-yl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid;
70) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((2-sulfamoylethyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-sulfamoylethyl)amino)methyl)picolinamide;
71) 4-(((6-((3'-((5-(((3-carboxypropyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)butanoic acid;
72) 3-(((6-((3'-((5-(((2-carboxyethyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)propanoic acid;
73) ((6-((3'-((5-(((carboxymethyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)glycine;
74) (1R,4R)-4-(((6-((3'-((5-((((1R,4R)-4-carboxycyclohexyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)cyclohexane-1-carboxylic acid;
75) N-(2,2'-dichloro-3'-((3-chloro-5-((((1R,3R)-3-hydroxycyclobutyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((((1R,3R)-3-hydroxycyclobutyl)amino)methyl)picolinamide;
76) ((6-((3'-((5-(((S)-2-carboxypyrrolidin-1-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-L-proline;
77) (2S,4R)-1-((6-((3'-((5-(((2S,4R)-2-carboxy-4-hydroxypyrrolidin-1-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid;
78) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((3-oxopiperazin-1-yl)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((3-oxopiperazin-1-yl)methyl)picolinamide;
79) N-(2,2'-dichloro-3'-((3-chloro-5-((1,1-dioxidothiomorpholino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((1,1-dioxidothiomorpholino)methyl)picolinamide;
80) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((S)-2-(methylcarbamoyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((S)-2-(methylcarbamoyl)pyrrolidin-1-yl)methyl)picolinamide;
81) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((1-oxo-2,7-diazaspiro[4.5]decan-7-yl)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((1-oxo-2,7-diazaspiro[4.5]decan-7-yl)methyl)picolinamide;
82) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((2-oxopiperidin-4-yl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-oxopiperidin-4-yl)amino)methyl)picolinamide;
83) N-(2,2'-dichloro-3'-((3-chloro-5-((((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)amino)methyl)picolinamide;
84) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((pyridin-4-ylmethyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((pyridin-4-ylmethyl)amino)methyl)picolinamide;
85) N-(2,2'-dichloro-3'-((3-chloro-5-(((3,4-dimethoxybenzyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((3,4-dimethoxybenzyl)amino)methyl)picolinamide;
86) 3-((6-((3'-((5-((6-carboxy-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid;
87) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((2-methoxyethyl)(methyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-methoxyethyl)(methyl)amino)methyl)picolinamide;
88) N-(2,2'-dichloro-3'-((3-chloro-5-((5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methyl)picolinamide;
89) N-(2,2'-dichloro-3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-4-(((2-hydroxyethyl)amino)methyl)picolinamide;
90) N-(2,2'-dichloro-3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)nicotinamide;
91) N-(2,2'-dichloro-3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-6-(((2-hydroxyethyl)amino)methyl)picolinamide;
92) 1-(((6-(((3'-((5-(((1-carboxycyclopropyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)pyridin-3-yl)methyl)amino)cyclopropane-1-carboxylic acid;
93) ((6-((3'-((5-((((S)-1-carboxy-2-hydroxyethyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-L-serine;
94) 2-(((6-((3'-((5-(((2-carboxypropan-2-yl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)-2-methylpropanoic acid;
95) ((6-((3'-((5-((((1R,2R)-1-carboxy-2-hydroxypropyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-D-allothreonine;
96) 1-((6-((3'-((5-((3-carboxyazetidin-1-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)azetidine-3-carboxylic acid;
97) 5-(((2-acetamidoethyl)amino)methyl)-N-(3'-((5-(((2-acetamidoethyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
98) (S)-1-((6-((3'-((5-(((S)-2-carboxypiperidin-1-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)piperidine-2-carboxylic acid;
99) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)picolinamide;
100) 5-(aminomethyl)-N-(3'-((5-(aminomethyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
101) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((methylamino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((methylamino)methyl)picolinamide;
102) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-methoxyethyl)amino)methyl)picolinamide;
103) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)picolinamide;
104) N-(2,2'-dichloro-3'-((3-chloro-5-(((3-hydroxypropyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((3-hydroxypropyl)amino)methyl)picolinamide;
105) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((3-(methylcarbamoyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((3-(methylcarbamoyl)pyrrolidin-1-yl)methyl)picolinamide;
106) N-(2,2'-dichloro-3'-((3-chloro-5-((5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)picolinamide;
107) 5-((((2H-tetrazol-5-yl)methyl)amino)methyl)-N-(3'-((5-((((2H-tetrazol-5-yl)methyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
108) 5-(((3-acetamidopropyl)amino)methyl)-N-(3'-((5-(((3-acetamidopropyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
109) 5-(((R)-3-aminopyrrolidin-1-yl)methyl)-N-(3'-((5-(((R)-3-aminopyrrolidin-1-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
110) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((piperidin-4-ylamino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((piperidin-4-ylamino)methyl)picolinamide;
111) 5-((4-aminopiperidin-1-yl)methyl)-N-(3'-((5-((4-aminopiperidin-1-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
112) 5-(((1-acetylpiperidin-4-yl)amino)methyl)-N-(3'-((5-(((1-acetylpiperidin-4-yl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
113) 5-(((R)-3-acetamidopyrrolidin-1-yl)methyl)-N-(3'-((5-(((R)-3-acetamidopyrrolidin-1-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
114) 5-((4-acetamidopiperidin-1-yl)methyl)-N-(3'-((5-((4-acetamidopiperidin-1-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
115) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((((1R,4R)-4-(methylcarbamoyl)cyclohexyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((((1R,4R)-4-(methylcarbamoyl)cyclohexyl)amino)methyl)picolinamide;
116) 5-((((1R,4R)-4-acetamidocyclohexyl)amino)methyl)-N-(3'-((5-((((1R,4R)-4-acetamidocyclohexyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
117) 5-(((1-acetylpiperidin-3-yl)amino)methyl)-N-(3'-((5-(((1-acetylpiperidin-3-yl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
118) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((2-(3-oxopiperazin-1-yl)ethyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-(3-oxopiperazin-1-yl)ethyl)amino)methyl)picolinamide;
119) N-(2,2'-dichloro-3'-((3-chloro-5-(((1-(2-hydroxyethyl)piperidin-4-yl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((1-(2-hydroxyethyl)piperidin-4-yl)amino)methyl)picolinamide;
120) 5-(((2-(4-acetylpiperazin-1-yl)ethyl)amino)methyl)-N-(3'-((5-(((2-(4-acetylpiperazin-1-yl)ethyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
121) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((2-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)ethyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)ethyl)amino)methyl)picolinamide;
122) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((2-(piperidin-4-yl)ethyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-(piperidin-4-yl)ethyl)amino)methyl)picolinamide;
123) (S)-4-(((6-((3'-((5-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)-3-hydroxybutanoic acid;
124) 5-(((2-acetamidoethyl)amino)methyl)-N-(3'-((5-(((2-acetamidoethyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
125) N-(2,2'-dichloro-3'-((3-chloro-5-(((S)-4-hydroxy-2-oxopyrrolidin-1-yl)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((S)-4-hydroxy-2-oxopyrrolidin-1-yl)methyl)picolinamide;
126) ((6-((3'-((5-((((R)-1-carboxy-2-hydroxyethyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-D-serine;
127) methyl ((5-chloro-6-(((2,2'-dichloro-3'-(5-((((S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methyl)-L-serinate;
128) 2-(((5-chloro-6-(((2,2'-dichloro-3'-(5-((methyl(2-sulfoethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methyl)(methyl)amino)ethane-1-sulfonic acid;
129) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)picolinamide;
130) N-(3'-((5-(aminomethyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
131) (S)-N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
132) ((5-chloro-6-(((2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methyl)-L-serine;
133) 2-(((5-chloro-6-(((2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methyl)amino)-2-methylpropanoic acid;
134) (S)-4-(((5-chloro-6-(((2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxybutanoic acid;
135) ((6-((2,2'-dichloro-3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-L-serine;
136) 2-(((6-((2,2'-dichloro-3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)-2-methylpropanoic acid;
137) (2S)-2-(((5-chloro-6-(((2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxohexahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid;
138) 2-(((6-(((3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)pyridin-3-yl)methyl)amino)ethan-1-ol;
139) (R)-1-((6-(((3'-((3-chloro-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)pyridin-3-yl)methyl)pyrrolidin-3-ol;
140) 1-(5-chloro-6-(((2,2'-dimethyl-3'-((5-((methylamino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)-N-methylmethanamine;
141) ((6-(((3'-((5-(((S)-2-carboxypyrrolidin-1-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)pyridin-3-yl)methyl)-L-proline;
142) 1-(((6-(((3'-((5-(((1-carboxycyclopropyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)pyridin-3-yl)methyl)amino)cyclopropane-1-carboxylic acid; and
143) 2-(((5-chloro-6-(((2,2'-dichloro-3'-(3-morpholinopropoxy)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methyl)amino)ethan-1-ol,
or a pharmaceutically acceptable salt or a stereoisomer thereof.
The compounds described herein can be asymmetric (e.g., having one or more stereo centers). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. One method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, e.g., optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane and the like.
Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art. In some embodiments, the compounds of the invention have the (R)-configuration. In other embodiments, the compounds have the (S)-configuration. In compounds with more than one chiral center, each of the chiral centers in the compound may be independently (R) or (S), unless otherwise indicated.
Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Examples prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art.
The term, "compound" as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted. The term is also meant to refer to compounds of the inventions, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof.
All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated. When in the solid state, the compounds described herein and salts thereof may occur in various forms and may, e.g., take the form of solvates, including hydrates. The compounds may be in any solid state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as encompassing any solid state form of the compound.
In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, e.g., a composition enriched in the compounds of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof.
The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, e.g., a temperature from about 20°C to about 30°C.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The present invention also includes pharmaceutically acceptable salts of the compounds described herein. The term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the non-toxic salts of the parent compound formed, e.g., from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002).
Examples of the pharmaceutically acceptable salts include, but are not limited to, a salt with an inorganic acid such as a hydrochloric acid, a bromic acid, a sulfuric acid, sodium hydrogen sulfate, a phosphoric acid, a nitric acid, or a carbonic acid, a salt with an organic acid such as a formic acid, an acetic acid, a trifluoroacetic acid, a propionic acid, an oxalic acid, a succinic acid, a benzoic acid, a citric acid, a maleic acid, a malonic acid, a mandelic acid, a cinnamic acid, a stearic acid, a palmitic acid, a glycolic acid, a glutamic acid, a tartaric acid, a gluconic acid, a lactic acid, a fumaric acid, a lactobionic acid, an ascorbic acid, a salicylic acid, or an acetylsalicylic acid (aspirin), a salt with an amino acid such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, an asparaginic acid, glutamine, lysine, arginine, tyrosine, or proline, a salt with a sulfonic acid such as a methanesulfonic acid, an ethanesulfonic acid, a benzenesulfonic acid, or a toluenesulfonic acid, a metal salt by a reaction with an alkali metal such as sodium or potassium, a salt with an ammonium ion, and the like.
The compound of the present invention may be administered in the form of a prodrug which is decomposed in a human or animal body to provide the compound of the present invention. The prodrug may be used for modifying or improving a physical and (or) pharmacokinetic profile of a parent compound, and may be formed when the parent compound contains an appropriate group or substituent which may be derived to form the prodrug.
Pharmaceutical Uses
The compound of formula (I) according to the present invention is a novel compound which has a high inhibitory activity against PD-1/PD-L1 interaction, and thus is useful as a therapeutic agent for treating, preventing or alleviating a disease or disorder associated with inhibition of PD-1/PD-L1 interaction, or as a therapeutic agent for enhancing, stimulating and/or increasing an immune response.
In some embodiments, the disease or disorder associated with inhibition of PD-1/PD-L1 interaction is selected from infectious diseases and cancers.
In some embodiments, the disease or disorder associated with inhibition of PD-1/PD-L1 interaction is selected from the group consisting of an infectious disease, a bacterial infectious disease, a viral infectious disease a fungal infectious disease, a solid tumor, a hematological malignancy, an immune disorder, an inflammatory disease, and cancer.
In some embodiments, the disease or disorder is selected from the group consisting of melanoma, glioblastoma, esophagus tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary CNS (central nervous system) lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic myelocytic leukemia, Kaposi's sarcoma fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, sarcoma of soft tissue, sarcoma, sepsis, biliary tumor, basal cell carcinoma, thymus neoplasm, cancer of the thyroid gland, cancer of the parathyroid gland, uterine cancer, cancer of the adrenal gland, liver infection, Merkel cell carcinoma, nerve tumor, follicle center lymphoma, colon cancer, Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, ovary tumor, myelodysplastic syndrome, cutaneous or intraocular malignant melanoma, renal cell carcinoma, SCLC (small-cell lung cancer), lung cancer, mesothelioma, breast cancer, squamous NSCLC (non-small cell lung cancer), non-squamous NSCLC, colorectal cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, squamous cell carcinoma of the head and neck, cancer of the head or neck, gastrointestinal tract, stomach cancer, HIV (human immunodeficiency virus), hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes viruses, papillomaviruses, influenza, bone cancer, skin cancer, rectal cancer, cancer of the anal region, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the urethra, cancer of the penis, cancer of the bladder, cancer of the kidney, cancer of the ureter, carcinoma of the renal pelvis, neoplasm of the CNS, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, epidermoid cancer, abestosis, carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, pleomorphic adenoma, liver cell papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma and fibroma.
Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in inhibiting PD-1/PD-L1 interaction.
The present invention further provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in treating, preventing or alleviating a disease or disorder associated with inhibition of PD-1/PD-L1 interaction.
The present invention further provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in enhancing, stimulating and/or increasing an immune response.
The present invention further provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as an intermediate for the synthesis of compounds for inhibiting PD-1/PD-L1 interaction.
The present invention further provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as an intermediate for the synthesis of compounds for treating, preventing or alleviating a disease or disorder associated with inhibition of PD-1/PD-L1 interaction.
The present invention further provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as an intermediate for the synthesis of compounds for use in enhancing, stimulating and/or increasing an immune response.
The present invention further provides a use of the compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, in the manufacture of a medicament for inhibiting PD-1/PD-L1 interaction.
The present invention further provides a use of the compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, in the manufacture of a medicament for treating, preventing or alleviating a disease or disorder associated with inhibition of PD-1/PD-L1 interaction.
The present invention further provides a use of the compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, in the manufacture of a medicament for enhancing, stimulating and/or increasing an immune response.
The present invention further provides a method of inhibiting PD-1/PD-L1 interaction, said method comprising administering to a patient a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof.
The present invention further provides a method of treating, preventing or alleviating a disease or disorder associated with inhibition of PD-1/PD-L1 interaction, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof.
The present invention further provides a method of enhancing, stimulating and/or increasing an immune response in a patient, said method comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof.
The present invention further provides a pharmaceutical composition for inhibiting PD-1/PD-L1 interaction, comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, as an active ingredient.
The present invention further provides a pharmaceutical composition for treating, preventing or alleviating a disease or disorder associated with inhibition of PD-1/PD-L1 interaction, comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, as an active ingredient.
The present invention further provides a pharmaceutical composition for enhancing, stimulating and/or increasing an immune response, comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, as an active ingredient.
In addition, the pharmaceutical composition of the present invention may be formulated into a conventional preparation in the pharmaceutical field, for example, a preparation for oral administration such as a tablet, a pill, a hard/soft capsule, a liquid, a suspension, an emulsion, syrup, granules, and elixirs, or a preparation for parenteral administration of a sterile aqueous or oily solvent for intravenous, subcutaneous, sublingual, or intramuscular administration, by adding conventional non-toxic pharmaceutically acceptable carrier, excipient, and the like to the compound of formula (I), or a pharmaceutically acceptable salt, a prodrug, a solvate, or a stereoisomer thereof.
The pharmaceutically acceptable carrier commonly used in formulations may be used in the pharmaceutical composition of the present invention, and includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, hydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and/or mineral oil, and the like, but not limited thereto.
The excipient which may be used in the pharmaceutical composition of the present invention may be a sweetener, a binder, a solubilizer, a solubilizing aid, a wetting agent, an emulsifier, an isotonic agent, an adsorbent, a disintegrant, an antioxidant, a preservative, a lubricant, a filler, a fragrance, or the like, and a ratio and properties of the excipient may be determined by solubility and chemical properties of a selected tablet, a selected administration route, and standard pharmaceutical practice. An example of the excipient may include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, alginic acid, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, or the like.
Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.
The pharmaceutical composition of the present invention may be formulated into a parenteral administration form, and in this case, intravenous administration, intraperitoneal administration, intramuscular administration, subcutaneous administration, topical administration, or the like may be used, but not limited thereto. In a formulation for parenteral administration, the pharmaceutical composition may be produced into a solution or suspension by mixing the active ingredient, i.e., the compound of formula (I), or a pharmaceutically acceptable salt, a prodrug, a solvate, or a stereoisomer thereof with a stabilizer or a buffer in water, and the solution or suspension may be prepared into a unit dosage form of an ampoule or vial.
In addition, the pharmaceutical composition of the present invention may be sterilized, or further include an adjuvant such as a preservative, a stabilizer, a hydrating agent or an emulsifying accelerator, a salt for regulating osmotic pressure, and/or a buffer, and other therapeutically useful materials, and may be formulated according to a conventional method of mixing, granulating or coating.
In addition, a dosage of the compound represented by formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof as the active ingredient in the pharmaceutical composition according to the present invention for mammals including a human, may be varied depending on the age, weight, gender, dosage form, health status, and disease severity of a patient. The compound of the present invention may be included in the pharmaceutical composition in an effective amount of 0.001 to 500 mg/kg (body weight), preferably 0.01 to 100 mg/kg (body weight) per day, and the pharmaceutical composition may be administered via an oral or parenteral route in divided portions once or twice a day. However, the dosage may be increased or decreased according to the route of administration, the severity of the disease, sex, weight, age, etc., and thus the scope of the present invention is not limited thereto.
General Methods of Synthesis
Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, such as those in the schemes below.
The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill 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 which 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.
Preparation of compounds of the invention 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 is described, e.g., in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Peturssion et al., Protecting Groups in Carbohydrate Chemistry, (J. Chem. Educ., 1997, 74(11), 1297); and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).
Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
The schemes below provide general guidance in connection with preparing the compounds of the invention. One skilled in the art would understand that the preparations shown in the schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the invention.
Typical embodiments of compounds in accordance with the present disclosure may be synthesized using the general reaction schemes and/or examples described below. It will be apparent given the description herein that the general schemes may be altered by the substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Starting materials are typically obtained from commercial sources or synthesized using published methods for synthesizing compounds which are embodiments of the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein. Group labels (e.g., R1, R2, Ra, Rb) used in the reaction schemes herein are for illustrative purposes only and unless otherwise specified do not necessarily match by name or function the labels used elsewhere to describe compounds of formula (I) or aspects or fragments thereof.
Compounds of Formula (I) can be prepared using a process as illustrated in schemes 1-10.
[Scheme 1]
Figure PCTKR2021006886-appb-img-000025
Compound 1-1 is converted to compound 1-2 using esterification condition (e.g., HCl, H2SO4, SOCl2) in a suitable solvent (e.g., methanol, ethanol). Compound 1-3 is synthesized using a suitable reagent such as, but not limited to, N-chlorosuccinimide, N-bromosuccinimide, or 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate. Methyl group of compound 1-3 can be oxidized using an oxidizing agent (e.g., MnO2, selenium oxide) to provide compound 1-4. Compound 1-4 is reacted with RaX (where X is, e.g., halide) under base (e.g., cesium carbonate, potassium carbonate, sodium hydride, sodium carbonate) in a suitable solvent (e.g., 1,4-dioxane, N,N-dimethylformamide) to provide compound 1-5. Compound 1-6 is reacted with a reducing agent (e.g., lithium aluminum hydride, sodium borohydride, lithium borohydride) to give compound 1-6. Alcohol group of compound 1-6 is converted to a leaving group such as, but not limited to, mesylate, chloride, bromide, or iodide using a suitable reagent (e.g., methanesulfonyl chloride, N-chlorosuccinimide, N-bromosuccinimide) to provide compound 1-7. Compound 1-5 can be oxidized using an oxidizing agent (e.g., OxoneTM) to provide compound 1-8 which is converted to compound 1-9 using a suitable reagent (e.g., Pd/C at H2 atmosphere).
[Scheme 2]
Figure PCTKR2021006886-appb-img-000026
Compound 1-3 is converted to compound 2-1 (where X is halide) using a suitable reagent (e.g., N-chlorosuccinimide or N-bromosuccinimide). Methyl group of compound 2-1 is converted to a leaving group such as, but not limited to, chloride, bromide, or iodide to provide compound 2-2. Compound 2-1 is reacted with N,N-dimethylformamide dimethyl acetal to give compound 2-3 which is converted to compound 2-4 using a oxidizing agent (e.g., sodium periodate). Compound 2-4 is reacted with a suitable coupling reagent (e.g., trimethylboroxine) using a palladium catalyst (e.g., Pd(PPh3)4) to afford compound 2-5. Compound 2-6 is reacted with a reducing agent (e.g., lithium aluminum hydride, sodium borohydride, lithium borohydride) to give compound 2-6. Alcohol group of Compound 2-6 is converted to a leaving group such as, but not limited to, mesylate, chloride, bromide, or iodide using a suitable reagent (e.g., Methanesulfonyl chloride, N-chlorosuccinimide, N-bromosuccinimide) to provide compound 2-7. compound 2-5 can be oxidized using an oxidizing agent (e.g., Oxone) to provide compound 2-8 which converted to compound 2-9 using a suitable reagent (e.g., Pd/C at H2 atmosphere).
[Scheme 3]
Figure PCTKR2021006886-appb-img-000027
Compound 3-1 is reacted with a suitable coupling reagent 3-2 (where M is, e.g., -B(OH)2) to produce compound 3-3 under a standard metal catalyzed cross-coupling condition such as Suzuki coupling reaction (e.g., in the presence of a palladium catalyst (e.g., Pd(PPh3)4, Pd(dppf)Cl2) and a base (e.g., sodium carbonate, potassium acetate)). Compound 3-4 is synthesized by coupling compound 3-3 with compound 2-2 using a base (e.g., cesium carbonate, potassium carbonate). Compound 2-4 is converted to 3-5 using Pd-catalyzed coupling reaction such as Buchwald-Hartwig cross coupling reaction (e.g., in the presence of a palladium catalyst (e.g., Pd(OAc)2), a ligand (e.g., tert-butyl XPhos), and a base (e.g., cesium carbonate)). Compound 3-5 is reacted with a reducing agent (e.g., lithium aluminum hydride, sodium borohydride, lithium borohydride) to give compound 3-6 which is oxidized using an oxidizing agent (e.g., Dess-Martin periodinane) to provide compound 3-7. Compound 3-9 is obtained by a reductive amination between compound 3-7 and a suitable amine 3-8 using a reducing agent (e.g., sodium cyanoborohydride).
[Scheme 4]
Figure PCTKR2021006886-appb-img-000028
Compound 4-1 is reacted with a suitable coupling reagent 4-2 (where M is, e.g., -B(OH)2) to produce compound 4-3 under a standard metal catalyzed cross-coupling condition such as Suzuki coupling reaction (e.g., in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2, XPhos Pd G2) and a base (e.g., sodium carbonate, potassium acetate)). Compound 4-4 is synthesized by coupling compound 4-3 with compound 2-8 using coupling reagents (e.g., HATU and N,N-diisopropylethylamine). Compound 4-4 is reacted with a reducing agent (e.g., lithium aluminum hydride, sodium borohydride, lithium borohydride) to give compound 4-5 which is oxidized using an oxidizing agent (e.g., Dess-Martin periodinane) to provide compound 4-6. Compound 4-7 is obtained by a reductive amination between compound 4-6 and a suitable amine 3-8 using a reducing agent (e.g., sodium cyanoborohydride).
[Scheme 4-1]
Figure PCTKR2021006886-appb-img-000029
Compound 4-1-1 is reacted with a suitable coupling reagent 4-2 (where M is, e.g., -B(OH)2) to produce compound 4-1-2 under a standard metal catalyzed cross-coupling condition such as Suzuki coupling reaction (e.g., in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2, XPhos Pd G2) and a base (e.g., sodium carbonate, potassium acetate)). Compound 4-1-3 is synthesized by coupling compound 4-1-2 with compound 2-8 using coupling reagents (e.g., HATU and N,N-diisopropylethylamine). Compound 4-1-3 is reacted with a deprotecting reagent (e.g., hydrogen chloride) to give compound 4-1-4. Compound 4-1-5 is synthesized by coupling compound 4-1-4 with compound 9-4 using coupling reagents (e.g., HATU and N,N-diisopropylethylamine). Compound 4-1-5 is reacted with a reducing agent (e.g., lithium aluminum hydride, sodium borohydride, lithium borohydride) to give compound 4-1-6 which is oxidized using an oxidizing agent (e.g., Dess-Martin periodinane) to provide compound 4-1-7. Compound 4-1-8 is obtained by a reductive amination between compound 4-1-7 and a suitable amine 3-8 using a reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride).
[Scheme 5]
Figure PCTKR2021006886-appb-img-000030
Compound 5-1 is reacted with a suitable coupling reagent 5-2 (where M is, e.g., -B(OH)2) to produce compound 4-3 under a standard metal catalyzed cross-coupling condition such as Suzuki coupling reaction (e.g., in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2, XPhos Pd G2) and a base (e.g., sodium carbonate, potassium acetate)). Compound 5-4 is synthesized by coupling compound 5-3 with compound 2-7 using a base (e.g., cesium carbonate, potassium carbonate). Compound 5-4 is reacted with a reducing agent (e.g., lithium aluminum hydride, sodium borohydride, lithium borohydride) to give compound 5-5 which is oxidized using an oxidizing agent (e.g., Dess-Martin periodinane) to provide compound 5-6. Compound 5-7 is obtained by a reductive amination between compound 5-6 and a suitable amine 3-8 using a reducing agent (e.g., sodium cyanoborohydride).
[Scheme 6]
Figure PCTKR2021006886-appb-img-000031
Compound 6-3 is synthesized by coupling compound 6-1 with compound 6-2 using a base (e.g., cesium carbonate, potassium carbonate). Compound 6-3 is reacted with a suitable coupling reagent 4-2 (where M is, e.g., -B(OH)2) to produce compound 6-4 under a standard metal catalyzed cross-coupling condition such as Suzuki coupling reaction (e.g., in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2, XPhos Pd G2) and a base (e.g., sodium carbonate, potassium acetate)). Compound 6-5 is synthesized by coupling compound 6-4 with compound 2-8 using coupling reagents (e.g., HATU and N,N-diisopropylethylamine). Compound 6-5 is reacted with a reducing agent (e.g., lithium aluminum hydride, sodium borohydride, lithium borohydride) to give compound 6-6 which is oxidized using an oxidizing agent (e.g., Dess-Martin periodinane) to provide compound 6-7. Compound 6-8 is obtained by a reductive amination between compound 6-7 and a suitable amine 3-8 using a reducing agent (e.g., sodium cyanoborohydride).
[Scheme 6-1]
Figure PCTKR2021006886-appb-img-000032
Compound 6-3 is synthesized by coupling compound 6-1 with compound 6-2 using a base (e.g., cesium carbonate, potassium carbonate). Compound 6-3 is reacted with a suitable coupling reagent 5-2 (where M is, e.g., -B(OH)2) to produce compound 6-1-4 under a standard metal catalyzed cross-coupling condition such as Suzuki coupling reaction (e.g., in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2, XPhos Pd G2) and a base (e.g., sodium carbonate, potassium acetate)). Compound 6-1-5 is synthesized by coupling compound 6-1-4 with compound 2-7 using a base (e.g., cesium carbonate, potassium carbonate). Compound 6-1-5 is reacted with a reducing agent (e.g., lithium aluminum hydride, sodium borohydride, lithium borohydride) to give compound 6-1-6 which is oxidized using an oxidizing agent (e.g., Dess-Martin periodinane) to provide compound 6-1-7. Compound 6-1-8 is obtained by a reductive amination between compound 6-1-7 and a suitable amine 3-8 using a reducing agent (e.g., sodium cyanoborohydride).
[Scheme 7]
Figure PCTKR2021006886-appb-img-000033
Compound 7-8 is synthesized in a manner similar to process of scheme 6 using the appropriate materials.
[Scheme 8]
Figure PCTKR2021006886-appb-img-000034
Compound 8-1 is synthesized by coupling compound 5-1 with compound 6-2 using a base (e.g., cesium carbonate, potassium carbonate). Compound 8-1 is reacted with a suitable coupling reagent 4-2 (where M is, e.g., -B(OH)2) to produce compound 8-2 under a standard metal catalyzed cross-coupling condition such as Suzuki coupling reaction (e.g., in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2, XPhos Pd G2) and a base (e.g., sodium carbonate, potassium acetate)). Compound 8-3 is synthesized by coupling compound 8-2 with compound 2-8 using coupling reagents (e.g., HATU and N,N-diisopropylethylamine). Compound 8-3 is reacted with a reducing agent (e.g., lithium aluminum hydride, sodium borohydride, lithium borohydride) to give compound 8-4 which is oxidized using an oxidizing agent (e.g., Dess-Martin periodinane) to provide compound 8-5. Compound 8-6 is obtained by a reductive amination between compound 8-5 and a suitable amine 3-8 using a reducing agent (e.g., sodium cyanoborohydride).
[Scheme 9]
Figure PCTKR2021006886-appb-img-000035
Compound 9-7 is synthesized in a manner similar to process of scheme 6 using the appropriate materials (where M is, e.g., -B(OH)2).
[Scheme 10]
Figure PCTKR2021006886-appb-img-000036
Compound 10-10 is synthesized in a manner similar to process of scheme 6 using the appropriate materials.
The compounds were named using the IUPAC naming convention or using ChemBioDraw Ultra Version 15.1. Structure are drawn ChemBioDraw Ultra Version 15.1.
Experiment procedures for compounds of the invention are provide below. When production of starting materials is not particularly described, the compounds are known or may be prepared analogously to methods known in the art or as described in the examples. One of skill in the art will appreciate that synthetic methodologics described herein are only representative of methods for preparation of the compounds described herein, and that other known methods and variants of methods described herein may be used. The methods or features described in various examples may be combined or adapted in various ways to provide additional ways of making the compounds described herein.
1H-NMR spectra were recorded on a Varian 400 MHz NMR spectrometer. Electrospray ionization (ESI) mass spectrometry analysis was conducted on Agilent 6120 Quadrupole electrospray mass spectrometer using the Agilent 1290 infinity HPLC for sample delivery. All compounds could be analyzed in the positive or negative ESI mode, using acetonitrile / water with 0.1% formic acid as the delivery solvent.
Intermediate 1: methyl 2-hydroxy-6-methylnicotinate
Figure PCTKR2021006886-appb-img-000037
To s solution of 2-hydroxy-6-methylnicotinic acid (3.0 g, 19.60 mmol) in methanol (20 ml) was slowly added SOCl2 (7.1 ml, 97.90) at 0°C and stirred at 70°C. After 2 hr, the solvent and excess SOCl2 was removed under reduced pressure. The mixture was diluted with chloroform and quenched with saturated sodium bicarbonate solution at 0°C. The crude product was extracted with chloroform many times. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The product was obtained without further purification (2.3 g, 71.0% yield). 1H NMR (400 MHz, DMSO-d 6) δ 13.28-12.09 (m, 1H), 8.27-7.98 (m, 1H), 6.55-6.09 (m, 1H), 3.70 (s, 3H), 2.37-2.23 (m, 3H). LC-MS m/z calculated for C8H9NO3 (M+H)+ 168.0, found 168.1.
Intermediate 2: methyl 5-chloro-2-hydroxy-6-methylnicotinate
Figure PCTKR2021006886-appb-img-000038
To a solution of methyl 2-hydroxy-6-methylnicotinate (2.3 g, 13.90 mmol) in acetonitrile (30 ml) was added N-chlorosuccinimide (1.9 g, 13.90 mmol) and stirred at 80°C. After 16 hr, the solvent was removed under reduced pressure. The crude product was diluted with chloroform, washed with water, and extracted with chloroform many times. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by recrystallization (dichloromethane/n-hexane) to give the desired product (2.2 g, 79.7% yield). 1H NMR (400 MHz, DMSO-d 6) δ 12.46 (s, 1H), 8.00 (s, 1H), 3.74 (s, 3H), 2.31 (s, 3H). LC-MS m/z calculated for C8H8ClNO3 (M+H)+ 202.0, found 202.0.
Intermediate 3: methyl 5-bromo-2-hydroxy-6-methylnicotinate
Figure PCTKR2021006886-appb-img-000039
The title compound was synthesized from methyl 2-hydroxy-6-methylnicotinate in a manner similar to the synthesis of methyl 5-chloro-2-hydroxy-6-methylnicotinate using N-bromosuccinimide in place of N-chlorosuccinimide.
Intermediate 4: methyl 5-fluoro-2-hydroxy-6-methylnicotinate
Figure PCTKR2021006886-appb-img-000040
To a solution of methyl 2-hydroxy-6-methylnicotinate (200.0 mg, 1.20 mmol) in acetonitrile (5 ml) was added SelectfluorTM (593.4 mg, 1.68 mmol) and stirred at 50°C. After 5 hr, the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (SiO2, 50% ethyl acetate in hexanes) to give the desired product (76.6 mg, 34.6% yield). 1H NMR (400 MHz, DMSO-d 6) δ 12.02 (s, 1H), 7.98 (d, J = 9.1 Hz, 1H), 3.75 (s, 3H), 2.26 (s, 3H). LC-MS m/z calculated for C8H8FNO3 (M+H)+ 186.1, found 186.1.
Intermediate 5: methyl 2,5-dichloro-6-methylnicotinate
Figure PCTKR2021006886-appb-img-000041
Methyl 5-chloro-2-hydroxy-a-methylnicotinate (0.60 g, 3.0 mmol) was dissolved in POCl3 (5 ml). The mixture was heated to 95°C. After 12 hr, the reaction mixture was cooled to room temperature, diluted with dichloromethane (10 ml), slowly poured into cold saturated sodium bicarbonate solution, and stirred for 30 min. the organic layer was separated, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to give the desired product (602.3 mg, 92.0% yield). 1H NMR (400 MHz, DMSO-d a) δ 8.31 (s, 1H), 3.87 (s, 3H), 2.57 (s, 3H). LC-MS m/z calculated for C8H7Cl2NO2 (M+H)+ 220.0, found 220.0.
Intermediate 6: methyl 6-(bromomethyl)-2,5-dichloronicotinate
Figure PCTKR2021006886-appb-img-000042
To a solution of methyl 2,5-dichloro-6-methylnicotinate (199.6 mg, 0.9 mmol) in acetonitrile (7 ml) was added N-bromosuccinimide (258.3 mg, 1.5 mmol) and benzoyl peroxide (2.2mg, 0.009 mmol). The mixture was heated to 95°C. After 15 hr, the reaction mixture was cooled to room temperature, diluted with dichloromethane (10 ml), and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to give the desired product (154.0 mg, 56.8% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.44 (s, 1H), 4.74 (s, 2H), 3.90 (s, 3H). LC-MS m/z calculated for C8H6Cl2NO2 (M+H)+ 297.9, found 297.9.
Intermediate 7: methyl 5-chloro-6-formyl-2-methoxynicotinate
Figure PCTKR2021006886-appb-img-000043
To a solution of methyl 5-chloro-2-hydroxy-6-methylnicotinate (500.0 mg, 2.48 mmol) in 1,4-dioxane (5 ml) was added selenium oxide (413.0 mg, 3.72 mmol) and stirred at 100°C. After 16 hr, the temperature was cooled to room temperature and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure. The crude was diluted with chloroform, washed with water, and extracted with chloroform many times. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 ml). Silver carbonate (1.0 g, 3.72 mmol) and iodomethane (0.8 ml, 12.40 mmol) were added. After 2 days, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to give the desired product (282.0 mg, 49.6% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.07 (s, 1H), 8.32 (s, 1H), 4.00 (s, 3H), 3.86 (s, 3H). LC-MS m/z calculated for C9H8ClNO4 (M+H)+ 230.0, found 230.0.
Intermediate 8: methyl 5-bromo-6-formyl-2-methoxynicotinate
Figure PCTKR2021006886-appb-img-000044
The title compound was synthesized from methyl 5-bromo-2-hydroxy-6-methylnicotinate in a manner similar to the synthesis of methyl 5-chloro-6-formyl-2-methoxynicotinate.
Intermediate 9: methyl 5-fluoro-6-formyl-2-methoxynicotinate
Figure PCTKR2021006886-appb-img-000045
The title compound was synthesized from methyl 5-fluoro-2-hydroxy-6-methylnicotinate in a manner similar to the synthesis of methyl 5-chloro-6-formyl-2-methoxynicotinate.
Intermediate 10: methyl 5-chloro-2-ethoxy-6-formylnicotinate
Figure PCTKR2021006886-appb-img-000046
The title compound was synthesized from methyl 5-chloro-2-hydroxy-6-methylnicotinate in a manner similar to the synthesis of methyl 5-chloro-6-formyl-2-methoxynicotinate using iodoethane in place of iodomethane.
Intermediate 11: methyl 6-formyl-2-methoxy-5-methylnicotinate
Figure PCTKR2021006886-appb-img-000047
To a solution of methyl methyl 5-bromo-6-formyl-2-methoxynicotinate (500.0 mg, 1.82 mmol) and trimethylboroxine (0.31 ml, 2.19 mmol) in 1,4-dioxane (9 ml) was added potassium carbonate (756.4 mg, 5.47 mmol) under N2 atmosphere. The mixture was purged with N2 and Pd(PPh3)4 (210.8 mg, 0.18 mmol) was added. The reaction mixture was heated to 100°C for 15 hr, cooled to room temperature, quenched with water, and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 17% ethyl acetate in hexanes) to give the desired product (244.8 mg, 64.1% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.02 (s, 1H), 8.14 (s, 1H), 3.99 (s, 3H), 3.85 (s, 1H), 2.52 (s, 3H). LC-MS m/z calculated for C10H11NO4 (M+H)+ 210.1, found 210.1.
Intermediate 12: 3-chloro-6-methoxy-5-(methoxycarbonyl)picolinic acid
Figure PCTKR2021006886-appb-img-000048
To a solution of methyl 5-chloro-6-formyl-2-methoxynicotinate (281.0 mg, 1.22 mmol) in N,N-dimethylformamide (2 ml) was added OxoneTM (414.0 mg, 1.35 mmol) and stirred at room temperature. After 1 day, the reaction mixture was admixed 1M HCl solution, extracted with dichloromethane, and washed with water. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The product was purified by recrystallization (ethyl acetate/n-hexane) to give the desired product (254.2 mg, 85.0% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.28 (s, 1H), 3.93 (s, 3H), 3.83 (s, 3H). LC-MS m/z calculated for C9H8ClNO5 (M+H)+ 246.0, found 246.0.
Intermediate 13: 3-chloro-6-ethoxy-5-(methoxycarbonyl)picolinic acid
Figure PCTKR2021006886-appb-img-000049
The title compound was synthesized from methyl 5-chloro-2-ethoxy-6-formylnicotinate in a manner similar to the synthesis of 3-chloro-6-methoxy-5-(methoxycarbonyl)picolinic acid using iodoethane in place of iodomethane.
Intermediate 14: methyl 5-chloro-6-(hydroxymethyl)-2-methoxynicotinate
Figure PCTKR2021006886-appb-img-000050
To a solution of methyl 5-chloro-6-formyl-2-methoxynicotinate (875.0 mg, 3.81 mmol) in tetrahydrofuran (10 ml) was added Sodium borohydride (144.0 mg, 3.81 mmol) at 0°C and stirred at room temperature. After 2 hr, the reaction mixture was quenched with 1M HCl solution, extracted with dichloromethane, and washed with water. The organic layer was dried over MgSO4 and concentrated under reduce pressure. The crude product was purified by recrystallization (dichloromethane/n-hexane) to give the desired product (748.0 mg, 84.8% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.13 (s, 1H), 5.28 (t, J = 6.0 Hz, 1H), 4.59 (d, J = 6.0 Hz, 1H), 3.97 (s, 3H), 3.81 (s, 3H). LC-MS m/z calculated for C9H10ClNO4 (M+H)+ 232.0, found 231.9.
Intermediate 15: methyl 5-fluoro-6-(hydroxymethyl)-2-methoxynicotinate
Figure PCTKR2021006886-appb-img-000051
The title compound was synthesized from methyl 5-fluoro-6-formyl-2-methoxynicotinate in a manner similar to the synthesis of methyl 5-chloro-6-(hydroxymethyl)-2-methoxynicotinate.
Intermediate 16: methyl 5-chloro-2-ethoxy-6-(hydroxymethyl)nicotinate
Figure PCTKR2021006886-appb-img-000052
The title compound was synthesized from 5-chloro-2-ethoxy-6-formylnicotinate in a manner similar to the synthesis of methyl 5-chloro-6-(hydroxymethyl)-2-methoxynicotinate.
Intermediate 17: methyl 6-(hydroxymethyl)-2-methoxy-5-methylnicotinate
Figure PCTKR2021006886-appb-img-000053
The title compound was synthesized from methyl 6-formyl-2-methoxy-5-methylnicotinate in a manner similar to the synthesis of methyl 5-chloro-6-(hydroxymethyl)-2-methoxynicotinate.
Intermediate 18: methyl 5-chloro-2-methoxy-6-(((methylsulfonyl)oxy)methyl)nicotinate
Figure PCTKR2021006886-appb-img-000054
To a solution of methyl 5-chloro-6-(hydroxymethyl)-2-methoxynicotinate (748.0 mg, 3.23 mmol) in dichloromethane was added methanesulfonyl chloride (0.3 ml, 3.87 mmol) and triethylamine (1.1 ml, 8.1 mmol) at 0°C and stirred at room temperature. After 4 hr, the reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 20% ethyl acetate in hexanes) to give the desired product (430.0 mg, 43.0% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.23 (s, 1H), 4.79 (s, 2H), 3.95 (s, 3H), 3.82 (s, 3H). LC-MS m/z calculated for C10H12ClNO6S (M+H)+ 310.0, found 310.1.
Intermediate 19: methyl 5-chloro-2-ethoxy-6-(((methylsulfonyl)oxy)methyl)nicotinate
Figure PCTKR2021006886-appb-img-000055
The title compound was synthesized from methyl 5-chloro-2-ethoxy-6-(hydroxymethyl)nicotinate in a manner similar to the synthesis of methyl 5-chloro-2-methoxy-6-(((methylsulfonyl)oxy)methyl)nicotinate.
Intermediate 20: methyl 6-(bromomethyl)-5-chloro-2-methoxynicotinate
Figure PCTKR2021006886-appb-img-000056
To a solution of methyl 5-chloro-6-(hydroxymethyl)-2-methoxynicotinate (2.4 g, 10.20 mmol) and triphenylphosphine (4.0 g, 15.30 mmol) in dichloromethane (20 ml) was stirred at 0°C and N-bromosuccinimide (2.7 g, 15.30 mmol) was slowly added. After 1 hr, the reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to give the desired product (2.0 g, 67.2% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.19 (s, 1H), 4.64 (s, 2H), 3.92 (s, 3H), 3.80 (s, 3H). LC-MS m/z calculated for C9H9BrClNO3 (M+H)+ 293.9, found 294.0.
Intermediate 21: methyl 6-(bromomethyl)-5-fluoro-2-methoxynicotinate
Figure PCTKR2021006886-appb-img-000057
The title compound was synthesized from methyl 5-fluoro-6-(hydroxymethyl)-2-methoxynicotinate in a manner similar to the synthesis of methyl 6-(bromomethyl)-5-chloro-2-methoxynicotinate.
Intermediate 22: methyl 6-(bromomethyl)-2-methoxy-5-methylnicotinate
Figure PCTKR2021006886-appb-img-000058
The title compound was synthesized from methyl 6-(hydroxymethyl)-2-methoxy-5-methylnicotinate in a manner similar to the synthesis of methyl 6-(bromomethyl)-5-chloro-2-methoxynicotinate.
Intermediate 23: 6-methoxy-5-(methoxycarbonyl)picolinic acid
Figure PCTKR2021006886-appb-img-000059
A solution of 3-chloro-6-methoxy-5-(methoxycarbonyl)picolinic acid (78.0 mg, 0.32 mmol) in methanol (1.7 ml) was added 10% Pd/C and the mixture was stirred at room temperature for 20 hr. The mixture was filtered through the celite pad and the filtrate was concentrated in vacuo. The residue was used in next step without purification. 1H NMR (400 MHz, methanol-d 4) δ 8.22 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H), 4.02 (s, 3H), 3.84 (s, 3H).
Intermediate 24: methyl ( E )-2,5-dichloro-6-(2-(dimethylamino)vinyl)nicotinate
Figure PCTKR2021006886-appb-img-000060
To a solution of methyl 2,5-dichloro-6-methylnicotinate (320.0 mg, 1.46 mmol) in N,N-dimethylformamide (1 ml) was added N,N-dimethylformamide dimethyl acetal (0.38 ml, 2.91 mmol) and stirred at 110°C. After 16 hr, the temperature was cooled to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 20% ethyl acetate in hexanes) to give the desired product (172.0 mg, 42.8% yield). 1H NMR (400 MHz, DMSO-d 6) δ δ 7.96 (s, 1H), 7.84 (d, J = 12.3 Hz, 1H), 5.29 (d, J = 12.3 Hz, 1H), 3.78 (s, 3H), 3.00 (br, 6H). LC-MS m/z calculated for C11H12Cl2N2O2 (M+H)+ 275.0, found 274.9.
Intermediate 25: methyl ( E )-2-chloro-6-(2-(dimethylamino)vinyl)-5-fluoronicotinate
Figure PCTKR2021006886-appb-img-000061
The title compound was synthesized from methyl 2-chloro-5-fluoro-6-methylnicotinate in a manner similar to the synthesis methyl (E)-2,5-dichloro-6-(2-(dimethylamino)vinyl)nicotinate (0.99 g, 66.2% yield). 1H NMR (400 MHz, chloroform-d) δ 7.81 (d, J = 12.8 Hz, 1H), 7.69 (d, J = 10.4 Hz, 1H), 5.20 (d, J = 12.8 Hz, 1H), 3.87 (s, 3H), 3.01 (br, 6H). LC-MS m/z calculated for C11H12ClFN2 (M+H)+ 259.0, found 258.9.
Intermediate 26: methyl 2,5-dichloro-6-formylnicotinate
Figure PCTKR2021006886-appb-img-000062
To a solution of methyl (E)-2,5-dichloro-6-[2-(dimethylamino)vinyl]nicotinate (5.47 g, 19.90 mmol) in tetrahydrofuran (40 ml) and water (10 ml) was added sodium periodate (8.51 g, 39.80 mmol). The mixture was stirred for 15 hr, quenched with saturated Na2S2O3 solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 20% ethyl acetate in hexanes) to give the desired product (3.22 g, 69.3% yield. 1H NMR (400 MHz, DMSO-d 6) δ 10.02 (s, 1H), 8.55 (s, 1H), 3.93 (s, 3H).
Intermediate 27: methyl 2-chloro-5-fluoro-6-formylnicotinate
Figure PCTKR2021006886-appb-img-000063
The title compound was synthesized from methyl (E)-2-chloro-6-(2-(dimethylamino)vinyl)-5-fluoronicotinate in a manner similar to the synthesis of methyl 2,5-dichloro-6-formylnicotinate (0.57 g, 44.2% yield). 1H NMR (400 MHz, chloroform-d) δ 10.10 (s 1H), 8.05(d, J = 8.0 Hz, 1H), 4.01(s, 3H).
Intermediate 28: methyl 5-chloro-6-formyl-2-methylnicotinate
Figure PCTKR2021006886-appb-img-000064
To a solution of methyl 2,5-dichloro-6-formylnicotinate (3.22 g, 13.78 mmol) and trimethylboroxine (2.32 ml, 16.53 mmol) in 1,4-dioxane (30 ml) was added potassium carbonate (5.71 g, 41.33 mmol) under N2 atmosphere. The mixture was purged with N2 and Pd(PPh3)4 (1.59 g, 1.38 mmol) was added. The reaction mixture was heated to 90°C for 15 hr, cooled to room temperature, quenched with water, and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 17% ethyl acetate in hexanes) to give the desired product (1.45 g, 49.3% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.08 (s, 1H), 8.36 (s, 1H), 3.90 (s, 3H), 2.76 (s, 3H). LC-MS m/z calculated for C9H8ClNO3 (M+H)+ 214.0, found 213.9.
Intermediate 29: methyl 5-fluoro-6-formyl-2-methylnicotinate
Figure PCTKR2021006886-appb-img-000065
The title compound was synthesized from methyl 2-chloro-5-fluoro-6-formylnicotinate in a manner similar to the synthesis of methyl 5-chloro-6-formyl-2-methylnicotinate (0.23 g, 44.9% yield). 1H NMR (400 MHz, chloroform-d) δ 10.18 (s 1H), 8.05 (d, J = 8.8 Hz, 1H), 4.37 (s, 3H). LC-MS m/z calculated for C9H8FNO3 (M+H)+ 198.0, found 197.9.
Intermediate 30: methyl 5-chloro-6-(hydroxymethyl)-2-methylnicotinate
Figure PCTKR2021006886-appb-img-000066
To a solution of methyl 5-chloro-6-formyl-2-methylnicotinate (211.0 mg, 0.99 mmol) in tetrahydrofuran (5 ml) was added sodium borohydride (75.1 mg, 1.98 mmol) at 0°C. After 1.5 hr, the mixture was quenched with 1M HCl, extracted with 5% methanol in dichloromethane, and washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purification by flash chromatography (SiO2, 50% ethyl acetate in hexanes) to give the desired product (74.7 mg, 35.0% yield). 1H NMR (400 MHz, chloroform-d) δ 8.19 (d, J = 6.0 Hz, 1H), 4.77 (d, J = 5.2 Hz, 2H), 3.94 (s, 3H), 2.83 (t, J = 5.6 Hz, 3 H).
Intermediate 31: methyl 6-(bromomethyl)-5-chloro-2-methylnicotinate
Figure PCTKR2021006886-appb-img-000067
To a solution of methyl 5-chloro-6-(hydroxymethyl)-2-methylnicotinate (146.0 mg, 0.68 mmol) in dichloromethane (10 ml) was added triphenylphosphine (898.0 mg, 3.42 mmol). The mixture was cooled to 0°C and N-bromosuccinimide (568.0 mg, 3.19 mmol) was added slowly. After 3 hr, the mixture was concentrated in vacuo and the residue was purification by flash chromatography (SiO2, 50% ethyl acetate in hexanes) to give the desired product (90.0 mg, 47.8% yield). 1H NMR (400 MHz, chloroform-d) δ 8.20 (s, 1H), 4.64 (s, 2H), 3.93 (s, 3H), 2.80 (s, 3H).
Intermediate 32: 3-chloro-5-(methoxycarbonyl)-6-methylpicolinic acid
Figure PCTKR2021006886-appb-img-000068
To a solution of methyl 5-chloro-6-formyl-2-methylnicotinate (37.6 mg, 0.18 mmol) in N,N-dimethylformamide (1 ml) was added OxoneTM (60.0 mg, 0.19 mmol) and stirred at room temperature. After 1 day, the reaction mixture was admixed 1M HCl solution, extracted with dichloromethane, and washed with water. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The product was purified by recrystallization (ethyl acetate/n-hexane) to give the desired product (39.6 mg, 95.8% yield). 1H NMR (400 MHz, methanol-d 4) δ 8.34 (s, 1H), 3.92 (s, 3H), 2.76 (s, 3H). LC-MS m/z calculated for C9H8ClNO4 (M+H)+ 230.0, found 229.9.
Intermediate 33: 3-fluoro-5-(methoxycarbonyl)-6-methylpicolinic acid
Figure PCTKR2021006886-appb-img-000069
The title compound was synthesized from methyl 5-fluoro-6-formyl-2-methylnicotinate in a manner similar to the synthesis of methyl 5-chloro-6-formyl-2-methylnicotinate (0.26 g, 99% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.49 (d, J = 10.4 Hz, 1H), 3.89 (s, 3H), 2.69 (H, 3H). LC-MS m/z calculated for C9H8FNO4 (M+H)+ 214.0, found 213.9.
Intermediate 34: 5-(methoxycarbonyl)-6-methylpicolinic acid
Figure PCTKR2021006886-appb-img-000070
To a solution of 3-chloro-5-(methoxycarbonyl)-6-methylpicolinic acid (141.2 mg, 0.62 mmol) in methanol (5 ml) was added 10% Pd/C (14.1mg, 10% w/w). The mixture was stirred under H2 atmosphere for 15 hr, filtered through a pad of celite, and concentrated under reduced pressure to give the desired product (120.0 mg, 100.0% yield). 1H NMR (400 MHz, methanol-d 4) δ 8.97 (d, J = 7.8 Hz, 1H), 8.41 (d, J = 7.8 Hz, 1H), 4.02 (s, 3H), 3.07 (s, 3H).
Example 1:
((5-chloro-6-((3-(2,3-dihydrobenzo[ b ][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)- L -serine
Figure PCTKR2021006886-appb-img-000071
Step 1: 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenol
Figure PCTKR2021006886-appb-img-000072
To a solution of 1,4-benzodioxane-6-boronic acid (1.0 g, 5.56 mmol) and 3-bromo-2-methylphenol (1.04 g, 5.56 mmol) in dichloromethane (20 ml) and ethanol (4 ml) was added sodium carbonate (2 M in H2O, 8.0 ml, 16.7 mmol) and Pd(PPh3)4 (321.0 mg, 0.28 mmol) under N2 atmosphere. The mixture was stirred at 95°C. After 5 hr, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 20% ethyl acetate in hexanes) to give the desired product (1.32 g, 98.0% yield). 1H NMR (400 MHz, DMSO-d 6) δ 9.34 (s, 1H), 7.01-6.59 (m, 6H), 4.26 (s, 4H), 2.01 (s, 3H). LC-MS m/z calculated for C15H14O3 (M+H)+ 243.1, found 243.1.
Step 2: methyl 2,5-dichloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)nicotinate
Figure PCTKR2021006886-appb-img-000073
To a solution of 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenol (137.3 mg, 0.6 mmol) and methyl 6-(bromomethyl)-2,5-dichloronicotinate (154.0 mg, 0.5 mmol) in N,N-dimethylformamide (7 ml) was added potassium carbonate (142.4 mg, 1.0 mmol). The mixture was stirred for 6 hr. the reaction mixture was diluted with ethyl acetate, washed with water, and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to give the desired product (129.9 mg, 49.8% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.45 (s, 1H), 7.72 (m, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 6.77-6.72 (m, 2H), 5.29 (s, 2H), 4.26 (s, 4H), 3.90 (s, 3H), 2.06 (s, 3H). LC-MS m/z calculated for C23H19Cl2NO5 (M+H)+ 460.1, found 460.1.
Step 3: methyl 5-chloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)nicotinate
Figure PCTKR2021006886-appb-img-000074
To a solution of methyl 2,5-dichloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)nicotinate (106.3 mg, 0.23 mmol), 3-pyridinemetanol (0.0289 ml, 0.30 mmol), and cesium carbonate (225.7 mg, 0.69 mmol) in toluene (4 ml) was added Pd(OAc)2 (5.2 mg, 0.023 mmol) and tert-butyl XPhos (19.6 mg, 0.46) under N2 atmosphere. The mixture was stirred at 90°C. After 15 hr, the reaction mixture was filtered through a pad of celite, washed with ethyl acetate, and concentrated. The crude product was purified by flash chromatography (SiO2, 75% ethyl acetate in hexanes) to give the desired product (32.0 mg, 26.0% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.27 (s, 1H), 7.80-7.77 (m, 1H), 7.39-7.35 (m, 1H), 7.16-6.70 (m, 6H), 5.42 (s, 2H), 5.32 (s, 2H), 4.26 (s, 4H), 3.83 (s, 3H), 2.08 (s, 3H). LC-MS m/z calculated for C29H25ClN2O6 (M+H)+ 533.1, found 533.2.
Step 4: 5-chloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)nicotinaldehyde
Figure PCTKR2021006886-appb-img-000075
To a solution of methyl 5-chloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)nicotinate (39.7 mg, 0.074 mmol) in tetrahydrofuran (4 ml) was added lithium aluminum hydride (5.7 mg, 0.149 mmol) at 0°C. The mixture was warmed at room temperature. After 30 min, the reaction mixture was quenched with water (0.14 ml), NaOH (15% in H2O. 0.14 ml), and water (0.28 ml). The mixture was filtered through a pad of celite, washed with ethyl acetate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (4 ml). Dess-Martin periodinane (54.3 mg, 0.13 mmol) was added at 0°C. The mixture was warmed at room temperature. After 30 min, the reaction mixture was quenched with 2M Na2S2O3 solution and saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 25% ethyl acetate in hexanes) to give the desired product (24.0 mg, 64.1% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.19 (s, 1H), 8.66-8.51 (m, 2H), 8.19 (s, 1H), 7.86-7.82 (m, 1H), 7.39-7.35 (m, 1H), 7.17-6.69 (m, 6H), 5.48 (s, 2H), 5.35 (s, 2H), 4.26 (s, 4H), 2.09 (s, 3H). LC-MS m/z calculated for C28H23ClN2O5 (M+H)+ 503.1, found 503.2.
Step 5: ((5-chloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)-L-serine
Figure PCTKR2021006886-appb-img-000076
To a solution of 5-chloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)nicotinaldehyde (28.2 mg, 0.056 mmol) and L-serine (11.8 mg, 0.11 mmol) in methanol (1.5 ml) and dichloromethane (1.5 ml) was glacial acetic acid (0.0065 ml, 0.11 mmol). The mixture was stirred for 1 hr, and then sodium cyanoborohydride (17.6 mg, 0.28 mmol) was added. The reaction mixture was stirred at 30°C for 15 hr and concentrated under reduced pressure. The crude product was purified by prep-HPLC (acetonitrile / 10 mM ammonium bicarbonate in H2O) to give the desired product (5.0 mg, 15.1% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.65 (s, 1H), 8.53-8.49 (m, 1H), 7.95-7.82 (m, 2H), 7.39-6.71 (m, 7H), 5.39 (s, 2H), 5.21 (s, 2H), 4.27 (s, 4H), 3.89-3.56 (m, 4H), 3.18-3.13 (m, 1H), 2.05 (s, 3H). LC-MS m/z calculated for C31H30ClN3O7 (M+H)+ 592.2, found 592.2.
The following compounds were prepared according to the methods provided herein using the appropriate materials and protecting group chemistry as needed.
[Table 1]
Figure PCTKR2021006886-appb-img-000077
Figure PCTKR2021006886-appb-img-000078
Figure PCTKR2021006886-appb-img-000079
Figure PCTKR2021006886-appb-img-000080
Figure PCTKR2021006886-appb-img-000081
Figure PCTKR2021006886-appb-img-000082
Example 16:
N,N' -(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((2-hydroxyethyl)amino)methyl)picolinamide)
Figure PCTKR2021006886-appb-img-000083
Step 1: 2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diamine
Figure PCTKR2021006886-appb-img-000084
To a solution of 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (559.0 mg, 2.39 mmol) and 3-bromo-2-chloroaniline (495 mg, 2.39 mmol), sodium carbonate (500.0 mg, 4.79 mmol) in 1,4-dioxane (8 ml) and water (2 ml) was added Pd(dppf)Cl2·DCM (137.0 mg, 0.16 mmol) at N2 atmosphere. Then, the reaction mixture was purged with N2 and heated to 90°C. After 3 hr, the mixture was diluted with 10% methanol in dichloromethane and extracted with water, washed with brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purification by flash chromatography (SiO2, 50% ethyl acetate in hexanes) to give the desired product (450.0 mg, 80.7% yield). 1H NMR (400 MHz, DMSO-d 6) δ 7.74 (t, J = 7.6 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.77 (dd, J = 8.0, 1.2 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 6.36 (dd, J = 7.6, 1.6 Hz, 1H), 6.28 (d, J = 6.8 Hz, 1H), 5.31 (s, 2H), 4.82 (s, 2H), 1.74 (s, 3H).
Step 2: dimethyl 6,6'-(((2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(5-chloro-2-ethoxynicotinate)
Figure PCTKR2021006886-appb-img-000085
To a solution of 2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diamine (50.0 mg, 0.22 mmol) and 3-chloro-6-ethoxy-5-(methoxycarbonyl)picolinic acid (122.7 mg, 0.47 mmol) in N,N-dimethylformamide (4 ml) was added HATU (245.1 mg, 0.65 mmol) and N,N-diisopropylethylamine (112.3 μl, 0.66 mmol). The mixture was heated to 60°C for 15 hr, quenched with water, and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by recrystallization (Ethyl acetate) to give the desired product (76.3 mg, 49.6% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.50 (s, 1H), 10.17 (s, 1H), 8.31-8.22 (m, 3H), 7.68 (d, J = 8.1 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H), 4.49 (q, J = 7.0 Hz, 4H), 3.85 (s, 6H), 2.04 (s, 3H), 1.34 (t, J = 7.0 Hz, 6H). LC-MS m/z calculated for C33H29Cl3N4O8 (M+H)+ 715.1, found 715.0.
Step 3: N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-formylpicolinamide)
Figure PCTKR2021006886-appb-img-000086
To a solution of dimethyl 6,6'-(((2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(5-chloro-2-ethoxynicotinate) (72.8 mg, 0.10 mmol) in tetrahydrofuran (2 ml), dichloromethane (2 ml), and methanol (3 drops) was added lithium borohydride (245.1 mg, 0.65 mmol). The mixture was stirred for 2 hr, quenched with 1M HCl, and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (4 ml). Dess-Martin periodinane (71.3 mg, 0.21 mmol) was added at 0°C. The mixture was warmed at room temperature. After 1 hr, the reaction mixture quenched with 2N Na2S2O3 solution, extracted with dichloromethane, and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (Ethyl acetate) to give the desired product (37.7 mg, 68.3% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.54 (s, 1H), 10.24 (s, 1H), 10.23 (s, 1H), 8.24 (s, 1H), 8.19 (d, J = 7.5 Hz, 1H), 8.20-7.09 (m, 6H), 4.57 (q, J = 7.0 Hz, 1H), 2.05 (s, 3H), 1.41 (t, J = 7.0 Hz, 6H). LC-MS m/z calculated for C31H25Cl3N4O6 (M+H)+ 655.1, found 655.0.
Step 4: N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((2-hydroxyethyl)amino)methyl)picolinamide)
Figure PCTKR2021006886-appb-img-000087
To a solution of N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-formylpicolinamide) (37.7 mg, 0.057 mmol) in dichloromethane (4 ml) was added ethanolamine (0.021 ml, 0.35 mmol) and acetic acid (0.021 ml, 0.35 mmol). After 30 min, sodium cyanoborohydride (14.4 mg, 0.23 mmol) was added. After 16 hr, the reaction mixture was concentrated under reduced pressure and purified by prep-HPLC (CH3CN:H2O with 0.1% TFA = 10:90 ~ 99:1) to give the desired product as the bis-TFA salt (20.6 mg, 36.9% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.54 (s, 1H), 10.14 (s, 1H), 8.85 (br, 4H), 8.29 (d, J = 7.7 Hz, 1H), 8.16 (s, 1H), 8.12 (s, 1H), 7.70-7.07 (m, 5H), 4.49 (q, J = 7.0 Hz, 4H), 4.23-3.05 (m, 12H), 2.05 (s, 3H), 1.38 (t, J = 7.0 Hz, 6H). LC-MS m/z calculated for C35H39Cl3N6O6 (M+H)+ 745.2, found 745.1.
The following compounds were prepared according to the methods provided herein using the appropriate materials and protecting group chemistry as needed.
[Table 2]
Figure PCTKR2021006886-appb-img-000088
Figure PCTKR2021006886-appb-img-000089
Figure PCTKR2021006886-appb-img-000090
Example 23:
3-chloro- N -(2'-chloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypicolinamide
Figure PCTKR2021006886-appb-img-000091
Step 1: tert-butyl (3-bromo-2-chlorophenyl)carbamate
Figure PCTKR2021006886-appb-img-000092
To a solution of 3-bromo-2-chloroaniline (1.14 g, 5.52 mmol) and di-tert-butyl dicarbonate (3.61 g, 16.55 mmol) in tetrahydrofuran (10 ml) was added 4-dimethylaminopyridine (67.4 mg, 0.55 mmol). The mixture refluxed for 5 hr, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with methanol (10 ml) and potassium carbonate (2.29 g, 16.55 mmol). The mixture was refluxed for 5 hr, quenched with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 3% ethyl acetate in hexanes) to give the desired product (1.36g, 80.7% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.85 (s, 1H), 7.59-7.53 (m, 2H), 7.24 (d, J = 8.1 Hz, 1H), 1.46 (s, 9H).
Step 2: tert-butyl (3'-amino-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)carbamate
Figure PCTKR2021006886-appb-img-000093
To a solution of tert-butyl (3-bromo-2-chlorophenyl)carbamate (498.1 mg, 1.63 mmol) and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (344.3 mg, 1.48 mmol) in tetrahydrofuran (6 ml) and water (3 ml) was added Potassium phosphate tribasic (627.1 mg, 2.95 mmol) under N2 atmosphere. The mixture was purged with N2 and XPhos Pd G2 (23.2 mg, 0.03 mmol) was added. The reaction mixture was heated to 90°C for 15 hr, cooled to room temperature, quenched with water, and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 20% ethyl acetate in hexanes) to give the desired product (388.8 mg, 79.1% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.56 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 6.99-6.91 (m, 2H), 6.55 (d, J = 8.0 Hz, 1H), 6.29 (d, J = 7.5 Hz, 1H), 4.91 (s, 2H), 1.74 (s, 3H), 1.46 (s, 9H). LC-MS m/z calculated for C18H21ClN2O2 (M+H)+ 333.1, found 332.9.
Step 3: methyl 6-((3'-((tert-butoxycarbonyl)amino)-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-5-chloro-2-methoxynicotinate
Figure PCTKR2021006886-appb-img-000094
To a solution of tert-butyl (3'-amino-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)carbamate (388.8 mg, 1.17 mmol) and 3-chloro-6-ethoxy-5-(methoxycarbonyl)picolinic acid (344.3 mg, 1.40 mmol) in N,N-dimethylformamide (5 ml) was added HATU (666.3 mg, 1.75 mmol) and N,N-diisopropylethylamine (192.7 μl, 1.75 mmol). The mixture was stirred for 7 hr, quenched with water, and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by recrystallization (ethanol/n-hexane) to give the desired product (610.9 mg, 93.3% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.19 (s, 1H), 8.66 (s, 1H), 8.32 (s, 1H), 7.67-7.61 (m, 2H), 7.40-7.31 (m, 2H), 7.07-7.02 (m, 2H), 4.02 (s, 3H), 3.86 (s, 3H), 2.02 (s, 3H), 1.46 (s, 9H).
Step 4: methyl 6-((3'-amino-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-5-chloro-2-methoxynicotinate hydrochloride
Figure PCTKR2021006886-appb-img-000095
To a solution of methyl 6-((3'-((tert-butoxycarbonyl)amino)-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-5-chloro-2-methoxynicotinate (610.9 mg, 1.09 mmol) in 1,4-dioxane (5 ml), methanol (2 ml), and dichloromethane (2 ml) was added 4N hydrogen chloride in 1,4-doixane (1.19 ml, 7.63 mmol). The mixture was stirred for 15 hr and concentrated under reduced pressure. 1,4-dioxane was added and the solid was filtered to give the desired product as the hydrochloride salt (425.6 mg, 78.6% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.16 (s, 1H), 8.31 (s, 1H), 7.64-6.99 (m, 4H), 6.83 (dd, J = 8.1, 1.5 Hz, 1H), 6.42 (dd, J = 7.4, 1.5 Hz, 1H), 4.02 (s, 3H), 3.86 (s, 3H), 2.03 (s, 3H).
Step 5: methyl 5-chloro-6-((2'-chloro-3'-(5-(methoxycarbonyl)picolinamido)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-2-methoxynicotinate
Figure PCTKR2021006886-appb-img-000096
To a solution of methyl 6-((3'-amino-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-5-chloro-2-methoxynicotinate hydrochloride (200.0 mg, 1.40 mmol) and 5-(methoxycarbonyl)picolinic acid (87.5 mg, 0.48 mmol) in N,N-dimethylformamide (5 ml) was added HATU (229.6 mg, 0.60 mmol) and N,N-diisopropylethylamine (110.7 μl, 1.01 mmol). The mixture was stirred for 15 hr, quenched with water, and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by recrystallization (ethyl acetate/n-hexane) to give the desired product (226.2 mg, 90.1% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.74 (s, 1H), 10.22 (s, 1H), 9.21 (d, J = 2.1 Hz, 1H), 8.60-8.32 (m, 4H), 7.70 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.18-7.09 (m, 2H), 4.02 (s, 3H), 3.94 (s, 3H), 3.86 (s, 3H), 2.06 (s, 3H).
Step 6: 3-chloro-N-(2'-chloro-3'-(5-formylpicolinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-5-formyl-6-methoxypicolinamide
Figure PCTKR2021006886-appb-img-000097
To a solution of methyl 5-chloro-6-((2'-chloro-3'-(5-(methoxycarbonyl)picolinamido)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-2-methoxynicotinate (226.2 mg, 0.36 mmol) in tetrahydrofuran (10 ml) was added lithium aluminum hydride (41.4 mg, 1.09 mmol) at 0°C and stirred at room temperature. After 3hr, the mixture was quenched with water (0.04 ml), NaOH (15% in H2O, 0.04 ml) and water (0.08 ml). The mixture was filtered through celite, washed with dichloromethane, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 ml). Dess-Martin periodinane (307.9 mg, 0.73 mmol) was added at 0°C. The mixture was warmed at room temperature. After 4 hr, the reaction mixture quenched with 2N Na2S2O3 solution, extracted with dichloromethane, and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 3% methanol in dichloromethanes) to give the desired product (61.1 mg, 30.1% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.77 (s, 1H), 10.29 (s, 1H), 10.23 (s, 1H), 10.22 (s, 1H), 9.23 (s, 1H), 8.55-8.40 (m, 3H), 8.26 (s, 1H), 7.70-7.10 (m, 5H), 4.11 (s, 3H), 2.07 (s, 3H).
Step 7: 3-chloro-N-(2'-chloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypicolinamide
Figure PCTKR2021006886-appb-img-000098
To a solution of 3-chloro-N-(2'-chloro-3'-(5-formylpicolinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-5-formyl-6-methoxypicolinamide (30.1 mg, 0.053 mmol) and ethanolamine (0.019 ml, 0.32 mmol) in dichloromethane (5 ml) was added acetic acid (0.019 ml, 0.32 mmol) and stirred at room temperature. After 30 min, sodium cyanoborohydride (13.4 mg, 0.21 mmol) was added. After 15 hr, the reaction mixture was concentrated under reduced pressure and purified by prep-HPLC (CH3CN:H2O with 0.1% TFA = 10:90 ~ 100:0) to give the desired product as the bis-TFA salt (16.5 mg, 35.0% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.71 (s, 1H), 10.20 (s, 1H), 9.04 (br, 2H), 8.88 (br, 2H), 8.83 (s, 1H), 8.42 (dd, J = 8.2, 1.4 Hz, 1H), 8.32-8.23 (m, 2H), 8.12 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.16-7.09 (m, 2H), 5.30 (br, 2H), 4.39-4.19 (m, 4H), 4.03 (s, 3H), 3.71-3.65 (m, 4H), 3.10-3.02 (m, 4H), 2.07 (s, 3H). LC-MS m/z calculated for C32H34Cl2N6O5 (M+H)+ 653.2, found 652.8.
The following compounds were prepared according to the methods provided herein using the appropriate materials and protecting group chemistry as needed.
[Table 3]
Figure PCTKR2021006886-appb-img-000099
Figure PCTKR2021006886-appb-img-000100
Figure PCTKR2021006886-appb-img-000101
Figure PCTKR2021006886-appb-img-000102
Figure PCTKR2021006886-appb-img-000103
Figure PCTKR2021006886-appb-img-000104
Example 40:
2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-ethoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(ethan-1-ol)
Figure PCTKR2021006886-appb-img-000105
Step 1: 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
Figure PCTKR2021006886-appb-img-000106
To a solution of 3-bromo-2-methylphenol (1.00 g, 4.63 mmol) and bis(pinacolato)diboron (1.41 g, 5.56 mmol) in 1,4-dioxane (10 ml) was added potassium acetate (0.68 g, 6.94 mmol) under N2 atmosphere. The mixture was purged with N2 and Pd(dppf)Cl2 (169.0 mg, 0.23 mmol) was added. The reaction mixture was heated to 90°C for 15 hr, cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 50~100% dichloromethane in hexanes) to give the desired product (825.6 mg, 76.2% yield). 1H NMR (400 MHz, DMSO-d 6) δ 9.20 (s, 1H), 7.06-6.85 (m, 3H), 2.27 (s, 3H), 1.28 (s, 12H). LC-MS m/z calculated for C13H19BO3 (M+H)+ 235.1, found 235.1.
Step 2: 2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diol
Figure PCTKR2021006886-appb-img-000107
To a solution of 3-bromo-2-methylphenol (369.1 mg, 1.71 mmol) and methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (400.0 mg, 1.71 mmol) in 1,4-dioxane (5 ml) and water (1.25 ml) was added Potassium acetate (335.4 mg, 3.42 mmol) under N2 atmosphere. The mixture was purged with N2 and Pd(dppf)Cl2 (62.5 mg, 0.09 mmol) was added. The reaction mixture was heated to 100°C for 15 hr, cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 25% ethyl acetate in hexanes) to give the desired product (181.0 mg, 49.4% yield). 1H NMR (400 MHz, DMSO-d 6) δ 9.32 (s, 2H), 7.01-6.47 (m, 6H), 1.78 (s, 6H). LC-MS m/z calculated for C14H14O2 (M+H)+ 215.1, found 215.1.
Step 3: dimethyl 6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-ethoxynicotinate)
Figure PCTKR2021006886-appb-img-000108
To a solution of 2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diol (47.1 mg, 0.22 mmol) and methyl 5-chloro-2-ethoxy-6-(((methylsulfonyl)oxy]methyl)nicotinate (177.9 mg, 0.55 mmol) in N,N-dimethylformamide (4 ml) was added cesium carbonate (250.7 mg, 0.77 mmol). The mixture was stirred at room temperature for 6 hr, quenched with water, and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 25% ethyl acetate in hexanes) to give the desired product (129.3 mg, 87.8% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.20 (s, 2H), 7.18-6.65 (m, 6H), 5.33 (s, 4H), 4.32-4.24 (m, 4H), 3.81 (s, 6H), 1.86 (s, 6H), 1.20 (t, J = 7.0 Hz, 6H).
Step 4: 6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-ethoxynicotinaldehyde)
Figure PCTKR2021006886-appb-img-000109
The title compound was synthesized from dimethyl 6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-ethoxynicotinate) in a manner similar to the synthesis of N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-formylpicolinamide). 1H NMR (400 MHz, DMSO-d 6) δ 10.15 (s, 2H), 8.12 (s, 2H), 7.19-6.66 (m, 6H), 5.37 (s, 4H), 4.39-4.33 (m, 4H), 1.88 (s, 6H), 1.26 (t, J = 7.0 Hz, 6H). LC-MS m/z calculated for C32H30Cl2N2O6 (M+H)+ 609.2, found 609.1.
Step 5: 2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-ethoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(ethan-1-ol)
Figure PCTKR2021006886-appb-img-000110
The title compound was synthesized as the bis-TFA salt from 6,6'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-ethoxynicotinaldehyde) in a manner similar to the synthesis of N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((2-hydroxyethyl)amino)methyl)picolinamide). 1H NMR (400 MHz, DMSO-d 6) δ 7.99 (s, 2H), 7.20-6.65 (m, 6H), 5.25 (s, 4H), 4.31 (q, J = 7.0 Hz, 4H), 4.08 (s, 4H), 3.66-3.63 (m, 4H), 3.02-2.98 (m, 4H), 1.84 (s, 6H), 1.27 (t, J = 7.0 Hz, 6H). LC-MS m/z calculated for C36H44Cl2N4O6 (M+H)+ 699.3 found 699.2
The following compounds were prepared according to the methods provided herein using the appropriate materials and protecting group chemistry as needed.
[Table 4]
Figure PCTKR2021006886-appb-img-000111
Figure PCTKR2021006886-appb-img-000112
Example 45:
3-chloro- N -(2-chloro-3-(1-(4-(((2-hydroxyethyl)amino)methyl)benzyl)-1 H -indol-4-yl)phenyl)-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypicolinamide
Figure PCTKR2021006886-appb-img-000113
Step 1: methyl 4-((4-bromo-1H-indol-1-yl)methyl)benzoate
Figure PCTKR2021006886-appb-img-000114
To a solution of 4-bromoindole (3.3 g, 16.60 mmol) in N,N-dimethylformamide (25 ml) was added methyl-4-(bromomethyl)benzoate (4.6 g, 19.90 mmol) and cesium carbonate (10.0 g, 33.10 mmol). The reaction mixture was stirred at room temperature for 18 hr, quenched with water, extracted with dichloromethane, and washed with brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purification by flash chromatography (SiO2, 50% dichloromethane in hexanes) to give the desired product (5.2 g, 91.3% yield). 1H NMR (400 MHz, DMSO-d 6) δ 7.90 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 3.1 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 7.6 Hz, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.48 (d, J = 3.1 Hz, 1H), 5.56 (s, 2H), 3.81 (s, 3H). LC-MS m/z calculated for C17H14BrNO2 (M+H)+ 344.0, found 344.0.
Step 2: 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
Figure PCTKR2021006886-appb-img-000115
To a solution of 3-bromo-2-chloroaniline (671.0 mg, 3.25 mmol), bis(pinacolato)diboron (990.0 mg, 3.90 mmol), potassium acetate (478.0 mg, 4.87 mmol), tricyclohexylphosphine (182 mg, 0.65 mmol), and Pd2(dba)3 (297.0 mg, 0.33 mmol) in 1,4-dioxane was stirred at 120°C under the N2 atmosphere. After 3 hr, the reaction mixture was filtered through celite. The filtrate was diluted with dichloromethane and washed with water and brine. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to give the desired product (471.4 mg, 57.2% yield). 1H NMR (400 MHz, DMSO-d 6) δ 6.99 (t, J = 7.5 Hz, 1H), 6.86 (dd, J = 7.9, 1.5 Hz, 1H), 6.77 (dd, J = 7.1, 1.5 Hz, 1H), 5.26 (s, 2H), 1.28 (s, 12H). LC-MS m/z calculated for C12H17BClNO2 (M+H)+ 254.1, found 254.1.
Step 3: methyl 4-((4-(3-amino-2-chlorophenyl)-1H-indol-1-yl)methyl)benzoate
Figure PCTKR2021006886-appb-img-000116
To a solution of methyl 4-((4-bromo-1H-indol-1-yl)methyl)benzoate (435.0 mg, 1.26 mmol) and 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (320.0 mg, 1.26 mmol) in 1,4-dioxane/water (5 ml, 4:1) was added Pd(dppf)Cl2·DCM (51.4 mg, 0.063 mmol) and potassium acetate (247.0 g, 2.52 mmol). The reaction mixture was stirred at 100°C under the N2 atmosphere. After 16 hr, the temperature was cooled to room temperature. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 20% ethyl acetate in hexanes) to give the desired product (328.0 mg, 66.6% yield). 1H NMR (400 MHz, DMSO-d 6) δ 7.92 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 3.2 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.14 (dd, J = 8.2, 7.3 Hz, 1H), 7.08 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 6.83 (dd, J = 8.1, 1.6 Hz, 1H), 6.57 (dd, J = 7.4, 1.6 Hz, 1H), 6.16 (d, J = 3.2 Hz, 1H), 5.54 (s, 2H), 5.40 (s, 2H), 3.82 (s, 3H). LC-MS m/z calculated for C23H19ClN2O2 (M+H)+ 391.1, found 391.0.
Step 4: methyl 5-chloro-6-((2-chloro-3-(1-(4-(methoxycarbonyl)benzyl)-1H-indol-4-yl)phenyl)carbamoyl)-2-methoxynicotinate
Figure PCTKR2021006886-appb-img-000117
To a solution of methyl 4-((4-(3-amino-2-chlorophenyl)-1H-indol-1-yl)methyl)benzoate (328.0 mg, 0.84 mmol), 3-chloro-6-methoxy-5-(methoxycarbonyl)picolinic acid (309.0 mg, 1.26 mmol), HATU (478.0 mg, 1.26 mmol) and N-methylmorphorine (0.14 ml, 1.26 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature. After 16 hr, the reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by recrystallization (dichloromethane/n-hexane) to give the desired product (517.6 mg, 99.6% yield). LC-MS m/z calculated for C32H25Cl2N3O6 (M+H)+ 618.1, found 618.0.
Step 5: 3-chloro-N-(2-chloro-3-(1-(4-(hydroxymethyl)benzyl)-1H-indol-4-yl)phenyl)-5-(hydroxymethyl)-6-methoxypicolinamide
Figure PCTKR2021006886-appb-img-000118
To a solution of methyl 5-chloro-6-((2-chloro-3-(1-(4-(methoxycarbonyl)benzyl)-1H-indol-4-yl)phenyl)carbamoyl)-2-methoxynicotinate (546.0 mg, 0.88 mmol) in tetrahydrofuran (5 ml), dichloromethane (5 ml), and methanol (3 drops) was added lithium borohydride (192.0 mg, 8.83 mmol). The reaction mixture was stirred at room temperature. After 6 hr, the reaction mixture was quenched with HCl (1M in H2O, 0.5 ml) at 0°C and stirred for 1h. The mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by recrystallization (dichloromethane/n-hexane) to give the desired product (141.0 mg, 0.25 mmol, 28.5% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.66 (s, 1H), 8.37 (d, J = 9.3 Hz, 1H), 7.86 (s, 1H), 7.54-7.47 (m, 3H), 7.28-7.23 (m, 5H), 7.19 (t, J = 7.7 Hz, 1H), 6.99 (d, J = 6.6 Hz, 1H), 6.15 (d, J = 3.0 Hz, 1H), 5.55 (t, J = 5.4 Hz, 1H), 5.43 (s, 2H), 5.12 (t, J = 5.7 Hz, 1H), 4.52 (d, J = 4.4 Hz, 2H), 4.44 (d, J = 5.6 Hz, 2H), 3.98 (s, 3H). LC-MS m/z calculated for C30H25Cl2N3O4 (M+H)+ 562.1, found 562.0.
Step 6: 3-chloro-N-(2-chloro-3-(1-(4-formylbenzyl)-1H-indol-4-yl)phenyl)-5-formyl-6-methoxypicolinamide
Figure PCTKR2021006886-appb-img-000119
To a solution of 3-chloro-N-(2-chloro-3-(1-(4-(hydroxymethyl)benzyl)-1H-indol-4-yl)phenyl)-5-(hydroxymethyl)-6-methoxypicolinamide (141.0 mg, 0.25 mmol) in dichloromethane (5 ml) was added Dess-Martin periodinane (319.0 mg, 0.75 mmol) and stirred at room temperature. After 16 hr, the reaction mixture was diluted with dichloromethane and washed with water and saturated sodium bicarbonate solution. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 25% ethyl acetate in hexanes) to give the desired product (89.2 mg, 63.9% yield). NMR (400 MHz, DMSO-d 6) δ 10.60 (s, 1H), 10.21 (s, 1H), 9.96 (S, 1H), 8.27 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.88(d, J = 8.1 Hz, 2H), 7.58 (d, J = 3.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 7.6 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.20 (d, J = 2.8 Hz, 1H), 5.60 (s, 2H), 4.10 (s, 3H).
Step 7: 3-chloro-N-(2-chloro-3-(1-(4-(((2-hydroxyethyl)amino)methyl)benzyl)-1H-indol-4-yl)phenyl)-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypicolinamide
Figure PCTKR2021006886-appb-img-000120
The title compound was synthesized as the bis-TFA salt from 3-chloro-N-(2-chloro-3-(1-(4-formylbenzyl)-1H-indol-4-yl)phenyl)-5-formyl-6-methoxypicolinamide in a manner similar to the synthesis of N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((2-hydroxyethyl)amino)methyl)picolinamide). 1H NMR (400 MHz, DMSO-d 6) δ 10.60 (s, 1H), 8.90 (s, 2H), 8.80 (s, 2H), 8.27 (d, J = 7.3 Hz, 1H), 8.17 (s, 1H), 7.57 (d, J = 3.2 Hz, 1H), 7.52 (ddd, J = 6.8, 5.0, 7.1 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.28 (dd, J = 7.7, 1.5 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 6.17 (d, J = 2.9 Hz, 1H), 5.49 (s, 2H), 5.25 (s, 2H), 4.22 (s, 2H), 4.12 (t, J = 5.1 Hz, 2H), 4.03 (s, 3H), 3.68 (t, J = 5.2 Hz, 2H), 3.62 (t, J = 5.3 Hz, 2H), 3.08 (s, 2H), 2.93 (s, 2H). LC-MS m/z calculated for C34H35Cl2N5O4 (M+H)+ 648.2, found 648.1.
The following compounds were prepared according to the methods provided herein using the appropriate materials and protecting group chemistry as needed.
[Table 5]
Figure PCTKR2021006886-appb-img-000121
Example 47:
2-((4-((4-(3-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2-methylphenyl)-1 H -indol-1-yl)methyl)benzyl)amino)ethan-1-ol
Figure PCTKR2021006886-appb-img-000122
Step 1: 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
Figure PCTKR2021006886-appb-img-000123
To a solution of 3-bromo-2-methylphenol (3.0 g, 13.9 mmol) and bis(pinacolato)diboron (4.2 g, 16.60 mmol), potassium acetate (2.1 g, 20.80 mmol) in 1,4-dioxane (30 ml) was added Pd(dppf)Cl2 (508.0 mg, 0.69 mmol) at N2 atmosphere. Then, the reaction mixture was purged with N2 and heated to 105°C. After 2 days, the mixture was diluted with ethyl acetate and extracted with water, washed with brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purification by flash chromatography (SiO2, 50% dichloromethane in hexanes) to give the desired product (2.5 g, 77.0% yield). 1H NMR (400 MHz, DMSO-d 6) δ 9.20 (s, 1H), 7.05-6.85 (m, 3H), 2.27 (s, 3H), 1.28 (s, 12H). LC-MS m/z calculated for C13H19BO3 (M+H)+ 235.1, found 235.1.
Step 2: methyl 4-((4-(3-hydroxy-2-methylphenyl)-1H-indol-1-yl)methyl)benzoate
Figure PCTKR2021006886-appb-img-000124
To a solution of methyl 4-((4-bromo-1H-indol-1-yl)methyl)benzoate (200.0 mg, 0.58 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (163.0 mg, 0.69 mmol), and potassium acetate (114.0 mg, 1.16 mmol) in 1,4-dioxane (8 ml) and water (2 ml) was added Pd(dppf)Cl2 (2.02 mg, 0.03mmol) at N2 atmosphere. The reaction mixture was purged with N2 and heated to 105°C for 20 hr and cooled to room temperature. The reaction mixture was filtered through the celite pad and the filtrate was diluted with dichloromethane and extracted with water, washed with brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purification by flash chromatography (SiO2, 50% dichloromethane in hexanes) to give the desired product (116.0 mg, 53.9% yield). 1H NMR (400 MHz, chloroform-d) δ 8.00 (d, J = 7.6 Hz, 2H), 7.22-7.11 (m, 2H), 7.02-6.97 (m, 2H), 6.86 (d, J = 7.6, 1H), 6.31 (dd, J = 2.8, 1.2 Hz, 1H), 5.40 (s, 2H), 3.91 (s, 3H), 2.10 (s, 3H).
Step 3: methyl 5-chloro-2-methoxy-6-((3-(1-(4-(methoxycarbonyl)benzyl)-1H-indol-4-yl)-2-methylphenoxy)methyl)nicotinate
Figure PCTKR2021006886-appb-img-000125
A solution of methyl 4-((4-(3-hydroxy-2-methylphenyl)-1H-indol-1-yl)methyl)benzoate (154.0 mg, 0.41 mmol), methyl 3-chloro-6-methoxy-5-(((methylsulfonyl)oxy)methyl)picolinate (154.0 mg, 0.49 mmol), and cesium carbonate (270.0 mg, 0.83 mmol) in N,N-dimethylformamide (4.2 ml) was stirred at room temperature. After 22.5 hr, methyl 3-chloro-6-methoxy-5-(((methylsulfonyl)oxy)methyl)picolinate (77.0 mg, 0.25 mmol) was more added and the reaction mixture was stirred at room temperature for 4 hr. The mixture was quenched with water, extracted with 5% methanol in dichloromethane, and washed with brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purification by flash chromatography (SiO2, 50% ethyl acetate in hexanes) to give the desired product (213.0 mg, 87.9% yield). 1H NMR (400 MHz, chloroform-d) δ 8.17 (s, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.21-7.17 (m, 5H), 7.11 (d, J = 3.2 Hz, 1H), 7.02-6.95 (m, 3H), 6.27 (d, J = 3.2 Hz, 1H), 5.39 (s, 2H), 5.32 (s, 2H), 3.97 (s, 3H), 3.91 (s, 3H), 2.12 (s, 3H).
Step 4: (4-((4-(3-((3-chloro-5-(hydroxymethyl)-6-methoxypyridin-2-yl)methoxy)-2-methylphenyl)-1H-indol-1-yl)methyl)phenyl)methanol
Figure PCTKR2021006886-appb-img-000126
To a solution of methyl 5-chloro-2-methoxy-6-((3-(1-(4-(methoxycarbonyl)benzyl)-1H-indol-4-yl)-2-methylphenoxy)methyl)nicotinate (188.0 mg, 0.32 mmol) in tetrahydrofuran (2 ml) was added lithium aluminum hydride (37 mg, 0.96 mmol) at 0°C and the mixture was warmed at room temperature. After 2 hr, the reaction mixture was quenched with excess tetrahydrofuran and Na2SO4.5H2O, and stirred at 0°C for 30 min. Then, the mixture was filtered through the celite pad and the filtrate was concentrated in vacuo. The residue was purification by flash chromatography (SiO2, 5% methanol in dichloromethane) to give the desired product (150.0 mg, 88.3% yield). 1H NMR (400 MHz, DMSO-d 6) δ 7.74 (s, 1H), 7.45-7.41 (m, 2H), 7.24-7.14 (m, 6H), 7.12 (d, J = 8.0 Hz, 2H), 6.85 (t, J = 8.0 Hz, 2H), 6.02 (d, J = 3.2 Hz, 1H), 5.38 (s, 2H), 5.20 (s, 2H), 4.43 (d, J = 6.8 Hz, 4H), 3.83 (s, 3H), 1.91 (s, 3H).
Step 5: 5-chloro-6-((3-(1-(4-formylbenzyl)-1H-indol-4-yl)-2-methylphenoxy)methyl)-2-methoxynicotinaldehyde
Figure PCTKR2021006886-appb-img-000127
To a solution of (4-((4-(3-((3-chloro-5-(hydroxymethyl)-6-methoxypyridin-2-yl)methoxy)-2-methylphenyl)-1H-indol-1-yl)methyl)phenyl)methanol (150.0 mg, 0.28 mmol) in dichloromethane (3 ml) was added Dess-Martin periodinane (300.6 mg, 0.71 mmol). The mixture was stirred at room temperature for 3 hr, quenched with water, extracted with dichloromethane, and washed with brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purification by flash chromatography (SiO2, 50% ethyl acetate in hexanes) to give the desired product (90.7 mg, 61.0% yield). 1H NMR (400 MHz, chloroform-d) δ 10.29 (s, 1H), 9.98 (s, 1H), 8.10 (s, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.29-7.18 (m, 5H), 7.13-7.11 (m, 1H), 7.03-6.95 (m, 3H), 6.30 (m, 1H), 5.43 (s, 2H), 5.34 (s, 2H), 4.00 (s, 3H), 2.14 (s, 3H).
Step 6: 2-((4-((4-(3-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2-methylphenyl)-1H-indol-1-yl)methyl)benzyl)amino)ethan-1-ol
Figure PCTKR2021006886-appb-img-000128
The title compound was synthesized as the bis-TFA salt from 5-chloro-6-((3-(1-(4-formylbenzyl)-1H-indol-4-yl)-2-methylphenoxy)methyl)-2-methoxynicotinaldehyde in a manner similar to the synthesis of N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((2-hydroxyethyl)amino)methyl)picolinamide). 1H NMR (400 MHz, methanol-d 4) δ 7.90 (s, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 5.8 Hz, 4H), 7.17-7.11 (m, 2H), 7.06 (d, J = 8.0 Hz, 2H), 6.89-6.84 (m, 2H), 6.13 (d, J = 2.8 Hz, 1H), 5.46 (s, 2H), 5.32 (s, 2H), 4.24 (s, 2H), 4.19 (s, 2H), 4.00 (s, 3H), 3.83 (t, J = 5.0 Hz, 2H), 3.78 (t, J = 5.4 Hz, 2H), 3.18 (t, J = 5.2 Hz, 2H), 3.10 (t, J = 5.2 Hz, 2H), 1.90 (s, 3H).
Example 48:
2-(((5-chloro-6-((3-(8-chloro-2-(5-(((2-hydroxyethyl)amino)methyl)pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylphenoxy)methyl)-2-methoxypyridin-3-yl)methyl)amino)ethan-1-ol
Figure PCTKR2021006886-appb-img-000129
Step 1: 2,2,2-trifluoro-N-(4-nitrophenethyl)acetamide
Figure PCTKR2021006886-appb-img-000130
To a solution of 2-(4-nitrophenyl)ethylamine hydrochloride (5.0 g, 24.67 mmol) and in tetrahydrofuran (20 ml) and dichloromethane (10 ml) was added pyridine (5.0 ml, 61.69 mmol) and trifluoroacetic anhydride (5.2 ml, 37.01 mmol) at 5°C. The mixture was warmed to room temperature, stirred for 2 hr, and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by recrystallization (ethyl acetate/n-hexane) to give the desired product (6.12 g, 94.6% yield). 1H NMR (400 MHz, DMSO-d 6) δ 9.51 (s, 1H), 8.17 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 3.49 (q, J = 7.0 Hz, 2H), 2.96 (t, J = 7.0 Hz, 2H). LC-MS m/z calculated for C10H9F3N2O3 (M+H)+ 263.1, found 263.2.
Step 2: 2,2,2-trifluoro-1-(7-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one
Figure PCTKR2021006886-appb-img-000131
To a solution of 2,2,2-trifluoro-N-(4-nitrophenethyl)acetamide (6.1 g, 23.3 mmol) and in H2SO4 (30 ml) and acetic acid (20 ml) was added paraformaldehyde (1.1 g, 37.30 mmol) at room temperature. The mixture was stirred for 2 days, poured to ice water, extracted with ethyl acetate, and washed with saturated sodium bicarbonate solution/water/brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude was purified by recrystallization (ethyl acetate/n-hexane) to give the desired product (5.7 g, 88.9% yield). 1H NMR (400 MHz, DMSO-d 6) δ (s, 1H), 8.32-7.48 (m, 3H), 4.93-4.88 (m, 2H), 3.86-3.83 (m, 2H), 3.07-3.02 (m, 2H). LC-MS m/z calculated for C11H9F3N2O3 (M+H)+ 275.1, found 275.2.
Step 3: 1-(7-amino-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one
Figure PCTKR2021006886-appb-img-000132
To a solution of 2,2,2-trifluoro-1-(7-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (5.7 g, 20.74 mmol) in ethanol (50 ml) was added 10% Pd/C (1.1 g, 20% w/w). The mixture was stirred under H2 atmosphere for 12 hr, filtered through a pad of celite, and concentrated under reduced pressure. The crude was purified by recrystallization (ethyl acetate/n-hexane) to give the desired product (4.5 g, 88.4% yield). 1H NMR (400 MHz, DMSO-d 6) δ 6.85-6.37 (m, 3H), 4.96 (s, 2H), 4.57(s, 2H), 3.76-3.72 (m, 2H), 2.74-2.69 (m, 2H). LC-MS m/z calculated for C11H11F3N2O (M+H)+ 245.1, found 245.2.
Step 4: 1-(7-amino-8-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one
Figure PCTKR2021006886-appb-img-000133
To a solution of 1-(7-amino-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (1.5 g, 6.14 mmol) in acetonitrile (20 ml) was added N-chlorosuccinimide (0.9 g, 6.76 mmol). The mixture was stirred at room temperature for 24 hr, quenched with water, extracted with ethyl acetate, and washed with water. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude was purified by recrystallization (ethyl acetate/n-hexane) to give the desired product (1.1 g, 62.1% yield). 1H NMR (400 MHz, DMSO-d 6) δ 6.90-6.70 (m, 2H), 5.30 (s, 2H), 4.65(s, 2H), 3.78-3.74 (m, 2H), 2.79-2.72 (m, 2H). LC-MS m/z calculated for C11H10ClF3N2O (M+H)+ 279.0, found 279.1.
Step 5: 1-(7-bromo-8-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one
Figure PCTKR2021006886-appb-img-000134
The solution of copper(I) bromide(I) (2.7 g, 18.84 mmol) in acetonitrile (50 ml) was heated to 60°C for 15 min. To this mixture was added isoamyl nitrite (2.6 ml, 19.73 mmol) followed by 1-(7-amino-8-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (5.0 g, 17.94 mmol). The reaction mixture was stirred at 60°C for 2 hr, cooled to room temperature, quenched with saturated sodium bicarbonate solution (100 ml), stirred vigorously for 1 hr, extracted with ethyl acetate, and washed with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by flash chromatography (SiO2, 9% ethyl acetate in hexanes) and recrystallization (n-hexane) to give the desired product (1.9 g, 30.8% yield). 1H NMR (400 MHz, DMSO-d 6) δ 7.66 (d, J = 8.3 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 4.76 (s, 2H), 3.81 (t, J = 5.7 Hz, 2H), 2.93 (t, J = 5.7 Hz, 2H). LC-MS m/z calculated for C11H8BrClF3NO (M+H)+ 341.9, found 341.9.
Step 6: 7-bromo-8-chloro-1,2,3,4-tetrahydroisoquinoline
Figure PCTKR2021006886-appb-img-000135
To a solution of 1-(7-bromo-8-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (876.0 mg, 2.56 mmol) in methanol (13 ml) was added NaOH (2M in H2O, 6.4 ml, 12.79 mmol). After 3 hr, the mixture was quenched with 1M HCl (6.4 ml), extracted with dichloromethane, and washed brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the desired product (625.0 mg, 98.8% yield). 1H NMR (400 MHz, DMSO-d 6) δ 7.52 (d, J = 8.2 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 3.82 (s, 2H), 2.88 (t, J = 5.7 Hz, 2H), 2.65 (t, J = 5.7 Hz, 2H). LC-MS m/z calculated for C9H9BrClN (M+H)+ 246.0, found 246.0.
Step 7: methyl 6-(7-bromo-8-chloro-3,4-dihydroisoquinolin-2(1H)-yl)nicotinate
Figure PCTKR2021006886-appb-img-000136
To a solution of 7-bromo-8-chloro-1,2,3,4-tetrahydroisoquinoline (625.0 mg, 2.54 mmol) and methyl 6-fluoronicotinate (432.6 mg, 2.79 mmol) in N,N-dimethylformamide (8 ml) was added potassium carbonate (525.6 mg, 3.80 mmol). The mixture was stirred at 110°C for 15 hr and cooled to room temperature. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 25% ethyl acetate in hexanes) to give the desired product (782.0 mg, 80.8% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.70 (d, J = 2.2 Hz, 1H), 8.01 (dd, J = 9.1, 2.2 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 9.1 Hz, 1H), 4.87 (s, 2H), 3.90 (t, J = 5.8 Hz, 2H), 3.80 (s, 3H), 2.90 (t, J = 5.8 Hz, 2H). LC-MS m/z calculated for C16H14BrClN2O2 (M+H)+ 381.0, found 381.0.
Step 8: methyl 6-(8-chloro-7-(3-hydroxy-2-methylphenyl)-3,4-dihydroisoquinolin-2(1H)-yl)nicotinate
Figure PCTKR2021006886-appb-img-000137
To a solution of methyl 6-(7-bromo-8-chloro-3,4-dihydroisoquinolin-2(1H)-yl)nicotinate (251.0 mg, 0.66 mmol) and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (184.8 mg, 0.79 mmol) in 1,4-dioxane (4 ml) and water (1 ml) was added potassium acetate (129.1 mg, 1.32 mmol) at N2 atmosphere. The mixture was purged with N2 and Pd(dppf)Cl2 (24.1 mg, 0.033 mmol) was added. The reaction mixture was heated to 100°C for 15 hr, cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 25% ethyl acetate in hexanes) to give the desired product (60.1 mg, 22.3% yield). 1H NMR (400 MHz, DMSO-d 6) δ 9.46(s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.02 (dd, J = 9.1, 2.4 Hz, 1H), 7.26-6.52 (m, 6H), 4.94-4.84 (m, 2H), 3.80 (s, 3H), 2.98 (t, J = 5.7 Hz, 2H), .1.83 (s, 3H). LC-MS m/z calculated for C23H21ClN2O3 (M+H)+ 409.1, found 409.0.
Step 9: methyl 5-chloro-6-((3-(8-chloro-2-(5-(methoxycarbonyl)pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylphenoxy)methyl)-2-methoxynicotinate
Figure PCTKR2021006886-appb-img-000138
To a solution of methyl 6-(8-chloro-7-(3-hydroxy-2-methylphenyl)-3,4-dihydroisoquinolin-2(1H)-yl)nicotinate (60.0 mg, 0.15 mmol) and methyl 5-chloro-2-methoxy-6-(((methylsulfonyl)oxy)methyl)nicotinate (54.5 mg, 0.18 mmol) in N,N-dimethylformamide (4 ml) was added cesium carbonate (95.6 mg, 0.29 mmol). The mixture was stirred at room temperature for 5 hr, quenched with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 25% ethyl acetate in hexanes) to give the desired product (52.6 mg, 57.6% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.71 (d, J = 2.3 Hz, 1H), 8.23 (s, 1H), 8.02 (dd, J = 9.1, 2.6 Hz, 1H), 7.28-6.71 (m, 6H), 5.33 (s, 2H), 4.89 (s, 2H), 3.97-3.93 (m, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 2.99 (t, J = 5.6 Hz, 2H), 1.91 (s, 3H).
Step 10: 5-chloro-6-((3-(8-chloro-2-(5-formylpyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylphenoxy)methyl)-2-methoxynicotinaldehyde
Figure PCTKR2021006886-appb-img-000139
The title compound was synthesized from methyl 5-chloro-6-((3-(8-chloro-2-(5-(methoxycarbonyl)pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylphenoxy)methyl)-2-methoxynicotinate in a manner similar to the synthesis of N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-formylpicolinamide). 1H NMR (400 MHz, DMSO-d 6) δ 10.12 (s, 1H), 9.74 (s, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.12 (s, 1H), 7.92 (dd, J = 9.1, 2.3 Hz, 1H), 7.26-7.03 (m, 5H), 6.69 (d, J = 7.5 Hz, 1H), 5.33 (s, 2H), 4.93 (s, 2H), 3.98-3.93 (m, 2H), 3.89 (s, 3H), 2.97 (t, J = 5.7 Hz, 2H), 1.89 (s, 3H).
Step 11: 2-(((5-chloro-6-((3-(8-chloro-2-(5-(((2-hydroxyethyl)amino)methyl)pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylphenoxy)methyl)-2-methoxypyridin-3-yl)methyl)amino)ethan-1-ol
Figure PCTKR2021006886-appb-img-000140
The title compound was synthesized as the bis-TFA salt from 5-chloro-6-((3-(8-chloro-2-(5-formylpyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylphenoxy)methyl)-2-methoxynicotinaldehyde in a manner similar to the synthesis of N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((2-hydroxyethyl)amino)methyl)picolinamide). 1H NMR (400 MHz, DMSO-d 6) δ 8.80 (br, 2H), 8.71 (br, 2H), 8.22 (s, 1H), 8.04 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.26-7.01 (m, 5H), 6.72 (d, J = 7.5 Hz, 1H), 5.27 (s, 2H), 4.79 (s, 2H), 4.17-4.02 (m, 4H), 3.91-3.83 (m, 2H), 3.89 (s, 3H), 3.65-3.53 (m, 4H), 3.08-2.91 (m, 6H), 1.89 (s, 3H). LC-MS m/z calculated for C34H39Cl2N5O4 (M+H)+ 652.2, found 652.1.
Example 49:
3-chloro-5-(((2-hydroxyethyl)amino)methyl)- N -(3'-((5-(((2-hydroxyethyl)amino)methyl)pyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-methoxypicolinamide
Figure PCTKR2021006886-appb-img-000141
Step 1: methyl 6-(chloromethyl)nicotinate
Figure PCTKR2021006886-appb-img-000142
To a solution of methyl 6-methylnicotinate (5.3 g, 34.80 mmol) in dichloromethane (100 ml) was added 3-chloroperbenzoic acid (9.0 g, 52.30 mmol). The reaction mixture was stirred at room temperature for 20 hr, quenched with saturated sodium bicarbonate solution (30 ml), and the mixture was stirred for 1 hr. The reaction mixture was extracted with dichloromethane and washed with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. To a solution of the crude in 1,4-dioxane (100 ml) was added p-toluenesulfonyl chloride (9.2 g, 48.00 mmol). The reaction mixture was heated to 100°C. After 16 hr, the mixture was cooled to room temperature, concentrated under reduced pressure, diluted with dichloromethane, and washed with water and saturated sodium bicarbonate solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 33.0% ethyl acetate in hexanes) to give the desired product (3.6 g, 19.50 mmol, 56.1% yield). 1H NMR (400 MHz, DMSO-d 6) δ 9.06 (s, 1H), 8.34 (dd, J = 8.1, 2.2 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 4.87 (s, 2H), 3.89 (s, 3H). LC-MS m/z calculated for C8H8ClNO2 (M+H)+ 186.0, found 186.1.
Step 2: methyl 6-((3-bromo-2-methylphenoxy)methyl)nicotinate
Figure PCTKR2021006886-appb-img-000143
To a solution of 3-bromo-2-methylphenol (390.0 mg, 1.81 mmol) and methyl 6-(chloromethyl)nicotinate (309.3 mg, 1.67 mmol) in N,N-dimethylformamide (4 ml) was added cesium carbonate (678.7 mg, 2.08 mmol). The mixture was heated to 60°C for 15 hr, quenched with water, and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 17% ethyl acetate in hexanes) to give the desired product (231.1 mg, 41.3% yield). 1H NMR (400 MHz, DMSO-d 6) δ 9.06 (d, J = 2.1 Hz, 1H), 8.36 (dd, J = 8.1, 2.1 Hz, 1H), 7.22-7.03 (m, 3H), 5.32 (s, 2H), 3.89 (s, 3H), 2.35 (s, 3H). LC-MS m/z calculated for C15H14BrNO3 (M+H)+ 336.0, found 335.9.
Step 3: methyl 6-(((3'-amino-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)nicotinate
Figure PCTKR2021006886-appb-img-000144
To a solution of methyl 6-((3-bromo-2-methylphenoxy)methyl)nicotinate (68.8 mg, 0.21 mmol) and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (52.5 mg, 0.23 mmol) in 1,4-dioxane (2.5 ml) and water (0.625 ml) was added Potassium acetate (40.2 mg, 3.42 mmol) under N2 atmosphere. The mixture was purged with N2 and Pd(dppf)Cl2 (7.5 mg, 0.01 mmol) was added. The reaction mixture was heated to 100°C for 15 hr, cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 25% ethyl acetate in hexanes) to give the desired product (33.7 mg, 45.4% yield). LC-MS m/z calculated for C22H22N2O3 (M+H)+ 363.2, found 363.1.
Step 4: methyl 5-chloro-2-methoxy-6-((3'-((5-(methoxycarbonyl)pyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)nicotinate
Figure PCTKR2021006886-appb-img-000145
The title compound was synthesized from methyl 6-(((3'-amino-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)nicotinate in a manner similar to the synthesis of methyl 5-chloro-6-((2-chloro-3-(1-(4-(methoxycarbonyl)benzyl)-1H-indol-4-yl)phenyl)carbamoyl)-2-methoxynicotinate. LC-MS m/z calculated for C31H28ClN3O7 (M+H)+ 590.2, found 590.1.
Step 5: 3-chloro-5-(hydroxymethyl)-N-(3'-((5-(hydroxymethyl)pyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-methoxypicolinamide
Figure PCTKR2021006886-appb-img-000146
The title compound was synthesized from methyl 5-chloro-2-methoxy-6-((3'-((5-(methoxycarbonyl)pyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)nicotinate in a manner similar to the synthesis of 3-chloro-N-(2-chloro-3-(1-(4-(hydroxymethyl)benzyl)-1H-indol-4-yl)phenyl)-5-(hydroxymethyl)-6-methoxypicolinamide. LC-MS m/z calculated for C29H28ClN3O5 (M+H)+ 534.2, found 534.1.
Step 6: 3-chloro-5-formyl-N-(3'-((5-formylpyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-methoxypicolinamide
Figure PCTKR2021006886-appb-img-000147
The title compound was synthesized from 3-chloro-5-(hydroxymethyl)-N-(3'-((5-(hydroxymethyl)pyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-methoxypicolinamide in a manner similar to the synthesis of 3-chloro-N-(2-chloro-3-(1-(4-formylbenzyl)-1H-indol-4-yl)phenyl)-5-formyl-6-methoxypicolinamide. LC-MS m/z calculated for C29H24ClN3O5 (M+H)+ 530.1, found 530.0.
Step 7: 3-chloro-5-(((2-hydroxyethyl)amino)methyl)-N-(3'-((5-(((2-hydroxyethyl)amino)methyl)pyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-methoxypicolinamide
Figure PCTKR2021006886-appb-img-000148
The title compound was synthesized as the bis-TFA salt from 3-chloro-5-formyl-N-(3'-((5-formylpyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-methoxypicolinamide in a manner similar to the synthesis of N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((2-hydroxyethyl)amino)methyl)picolinamide). LC-MS m/z calculated for C33H38ClN5O5 (M+H)+ 620.3, found 620.1.
Example 50:
N -(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide
Figure PCTKR2021006886-appb-img-000149
Step 1: methyl 6-((3-bromo-2-methylphenoxy)methyl)-5-chloro-2-methoxynicotinate
Figure PCTKR2021006886-appb-img-000150
To a solution of 3-bromo-2-methylphenol (168.4 mg, 0.78 mmol) and methyl 5-chloro-2-methoxy-6-(((methylsulfonyl)oxy)methyl)nicotinate (201.2 mg, 0.65 mmol) in N,N-dimethylformamide (5 ml) was added cesium carbonate (317.5 mg, 0.97 mmol). The mixture was stirred at room temperature for 15 hr, quenched with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to give the desired product (229.8 mg, 88.3% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.22 (s, 1H), 7.21-7.09 (m, 3H), 5.31 (s, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 2.27 (s, 3H). LC-MS m/z calculated for C16H15BrClNO4 (M+H)+ 400.0, found 399.9.
Step 2: methyl 6-(((3'-amino-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)-5-chloro-2-methoxynicotinate
Figure PCTKR2021006886-appb-img-000151
To a solution of methyl 6-((3-bromo-2-methylphenoxy)methyl)-5-chloro-2-methoxynicotinate (229.0 mg, 0.57 mmol) and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (159.9 mg, 0.69 mmol) in 1,4-dioxane (4 ml) and water (0.4 ml) was added potassium acetate (112.2 mg, 1.14 mmol) under N2 atmosphere. The mixture was purged with N2 and Pd(dppf)Cl2 (20.9 mg, 0.03 mmol) was added. The reaction mixture was heated to 100°C for 15 hr, cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 25% ethyl acetate in hexanes) to give the desired product (94.2 mg, 38.6% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.21 (s, 1H), 7.14 (t, J = 7.8, 1H), 6.99 (d, J = 8.5, 1H), 6.90 (t, J = 7.7, 1H), 6.65 (d, J = 7.0, 1H), 6.62 (d, J = 7.1, 1H), 6.25 (d, J = 6.4, 1H), 5.30 (s, 2H), 4.85 (s, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 1.86 (s, 3H), 1.69 (s, 3H). LC-MS m/z calculated for C23H23ClN2O4 (M+H)+ 427.1, found 427.0.
Step 3: methyl 5-chloro-2-methoxy-6-(((3'-(5-(methoxycarbonyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)nicotinate
Figure PCTKR2021006886-appb-img-000152
To a solution of methyl 6-(((3'-amino-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)-5-chloro-2-methoxynicotinate (94.2 mg, 0.22 mmol) and 5-(methoxycarbonyl)picolinic acid (48.0 mg, 0.27 mmol) in N,N-dimethylformamide (4 ml) was added HATU (125.9 mg, 0.33 mmol) and N-methylmorpholine (0.036 ml, 0.33 mmol). The mixture was stirred for 15 hr, quenched with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 25% ethyl acetate in hexanes) to give the desired product (118.8 mg, 91.2% yield). 1H NMR (400 MHz, chloroform-d) δ 10.12 (s, 1H), 9.22 (s, 1H), 8.51 (d, J = 8.1, 1H), 8.40 (d, J = 8.1, 1H), 8.26 (d, J = 8.1, 1H), 8.17 (s, 1H), 7.31 (t, J = 7.9, 1H), 7.16 (t, J = 7.9, 1H), 6.98 (d, J = 7.6, 1H), 6.93 (d, J = 8.2, 1H), 6.77 (d, J = 7.6, 1H), 5.30 (s, 2H), 3.99 (s, 3H), 3.96 (s, 3H), 3.06 (s, 3H), 2.11(s, 3H), 2.00 (s, 3H). LC-MS m/z calculated for C31H28ClN3O7 (M+H)+ 590.2, found 590.0.
Step 4: N-(3'-((3-chloro-5-(hydroxymethyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)picolinamide
Figure PCTKR2021006886-appb-img-000153
To a solution of methyl 5-chloro-2-methoxy-6-(((3'-(5-(methoxycarbonyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)nicotinate (118.0 mg, 0.20 mmol) in tetrahydrofuran (5 ml) was added lithium aluminum hydride (19.0 mg, 0.50 mmol) at 0°C and stirred at room temperature. After 3 hr, the reaction mixture was quenched with water (0.1 ml), NaOH (15% in H2O, 0.1 ml) and water (0.1 ml). The mixture was filtered through celite, washed with 10% methanol in dichloromethane, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 1% methanol in dichloromethanes) to give the desired product (83.0 mg, 0.16 mmol, 77.7% yield). NMR (400 MHz, DMSO-d 6) δ 10.29 (s, 1H), 8.64 (s, 1H), 8.16-8.09 (m, 1H), 8.01-7.94 (m, 1H), 7.86-7.80 (m, 1H), 7.74 (s, 1H), 7.30-7.16 (m, 1H), 7.15-7.10 (m, 1H), 6.95-6.90 (m, 1H), 6.75-6.67 (m, 1H), 5.74 (d, J = 4.0 Hz, 1H), 5.52-5.46 (m, 1H), 5.40-5.34 (m, 1H), 5.21 (S, 2H), 4.64 (s, 2H), 4.43 (s, 2H), 3.82 (s, 3H), 1.96 (s, 3H), 1.85 (s, 3H).
Step 5: N-(3'-((3-chloro-5-formyl-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-formylpicolinamide
Figure PCTKR2021006886-appb-img-000154
To a solution of N-(3'-((3-chloro-5-(hydroxymethyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)picolinamide (83.0 mg, 0.16 mmol) in dichloromethane (5 ml) was added Dess-Martin periodinane (198.0 mg, 0.47 mmol) and stirred at room temperature. After 16 hr, the reaction mixture was diluted with dichloromethane and washed with water and saturated sodium bicarbonate solution. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 25% ethyl acetate in hexanes) to give the desired product (60.0 mg, 70.7% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.46 (s, 1H), 10.21 (s, 1H), 10.13 (s, 1H), 9.19 (s, 1H), 8.48 (d, J = 8.7 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.14 (s, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 7.5 Hz, 1H), 5.35 (s, 2H), 3.91 (s, 3H), 1.97 (s, 3H), 1.90 (s, 3H).
Step 6: N-(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide
Figure PCTKR2021006886-appb-img-000155
To a solution of N-(3'-((3-chloro-5-formyl-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-formylpicolinamide (30.0 mg, 0.057 mmol) and ethanolamine (0.02 ml, 0.34 mmol) in dichloromethane (1 ml) was added acetic acid (0.0065 ml, 0.11 mmol) and stirred at room temperature. After 1 hr, sodium cyanoborohydride (21.4 mg, 0.34 mmol) was added. After 16 hr, the reaction mixture was concentrated under reduced pressure and purified by prep-HPLC (CH3CN:H2O with 0.1% TFA = 10:90 ~ 99:1) to give the desired product as the bis-TFA salt (9.8 mg, 20.3% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.35 (s, 1H), 8.78 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.01 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 5.25 (s, 3H), 5.22 (s, 1H), 4.31 (s, 2H), 4.11 (s, 2H), 3.87 (s, 3H), 3.64 (s, 4H), 3.01 (s, 4H), 1.95 (s, 3H), 1.86 (s, 3H). LC-MS m/z calculated for C33H38ClN5O5 (M+H)+ 620.2, found 620.1.
The following compounds were prepared according to the methods provided herein using the appropriate materials and protecting group chemistry as needed.
[Table 6]
Figure PCTKR2021006886-appb-img-000156
Figure PCTKR2021006886-appb-img-000157
Figure PCTKR2021006886-appb-img-000158
Figure PCTKR2021006886-appb-img-000159
Figure PCTKR2021006886-appb-img-000160
Figure PCTKR2021006886-appb-img-000161
Figure PCTKR2021006886-appb-img-000162
Figure PCTKR2021006886-appb-img-000163
Figure PCTKR2021006886-appb-img-000164
Figure PCTKR2021006886-appb-img-000165
Figure PCTKR2021006886-appb-img-000166
Figure PCTKR2021006886-appb-img-000167
Figure PCTKR2021006886-appb-img-000168
Figure PCTKR2021006886-appb-img-000169
Figure PCTKR2021006886-appb-img-000170
Figure PCTKR2021006886-appb-img-000171
Figure PCTKR2021006886-appb-img-000172
Figure PCTKR2021006886-appb-img-000173
Figure PCTKR2021006886-appb-img-000174
Figure PCTKR2021006886-appb-img-000175
Figure PCTKR2021006886-appb-img-000176
Figure PCTKR2021006886-appb-img-000177
Figure PCTKR2021006886-appb-img-000178
Figure PCTKR2021006886-appb-img-000179
Figure PCTKR2021006886-appb-img-000180
Figure PCTKR2021006886-appb-img-000181
Figure PCTKR2021006886-appb-img-000182
Figure PCTKR2021006886-appb-img-000183
Example 129:
N -(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)picolinamide
Figure PCTKR2021006886-appb-img-000184
Step 1: methyl 6-((3-bromo-2-chlorophenoxy)methyl)-5-chloro-2-methoxynicotinate
Figure PCTKR2021006886-appb-img-000185
To a solution of 3-bromo-2-chlorophenol (775.8 mg, 3.74 mmol), methyl 6-(bromomethyl)-5-chloro-2-methoxynicotinate (1.0 g, 3.40 mmol), and cesium carbonate (1.7 g, 5.10 mmol) in N,N-dimethylformamide (5 ml) was stirred at room temperature. After 4 hr, the reaction mixture was extracted with dichloromethane, washed with water and brine, and dried over MgSO4. The organic layer was concentrated under reduced pressure. The residue was purified by recrystallization (dichloromethane/n-hexane) to give the desired product (807.5 mg, 56.5% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.22 (s, 1H), 7.37-3.75 (m, 1H), 7.27-7.20 (m, 2H), 5.43 (s, 2H), 3.81 (s, 3H), 8.75 (s, 3H). LC-MS m/z calculated for C15H12BrCl2NO4 (M+H)+ 419.9.
Step 2: methyl 6-(((3'-amino-2,2'-dichloro-[1,1'-biphenyl]-3-yl)oxy)methyl)-5-chloro-2-methoxynicotinate
Figure PCTKR2021006886-appb-img-000186
The title compound was synthesized from methyl 6-((3-bromo-2-chlorophenoxy)methyl)-5-chloro-2-methoxynicotinate in a manner similar to the synthesis of methyl 6-(((3'-amino-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)-5-chloro-2-methoxynicotinate (0.35 g, 65.3% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.22 (s, 1H), 7.29 (dd, J = 8.3, 7.5 Hz, 1H), 7.22 (dd, J = 8.4, 1.4 Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H), 6.83 (ddd, J = 10.6, 7.8, 1.5 Hz, 2H), 6.4 (dd, J = 7.4, 1.5 Hz, 1H), 5.43 (s ,2H), 5.42 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H). LC-MS m/z calculated for C21H17Cl3N2O4 (M+H)+ 467.0.
Step 3: methyl 5-chloro-6-(((2,2'-dichloro-3'-(5-(methoxycarbonyl)picolinamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxynicotinate
Figure PCTKR2021006886-appb-img-000187
The title compound was synthesized from methyl 6-(((3'-amino-2,2'-dichloro-[1,1'-biphenyl]-3-yl)oxy)methyl)-5-chloro-2-methoxynicotinate in a manner similar to the synthesis of methyl 5-chloro-2-methoxy-6-(((3'-(5-(methoxycarbonyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)nicotinate (0.42 g, 89.7% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.72 (s, 1H), 9.21-9.20 (m, 1H), 8.58 (ddd, J = 8.2, 2.1, 0.67 Hz, 1H), 8.42-8.39 (m, 1H), 8.36-8.34 (m, 1H), 7.95 (s, 2H), 7.54-7.50 (m, 1H), 7.37 (dd, J = 8.2, 7.6 Hz, 1H), 7.31-7.29 (m, 1H), 7.17-7.14 (m, 1H), 6.97-6.95 (m, 1H), 5.47 (s, 2H), 3.94 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H). LC-MS m/z calculated for C29H22Cl3N3O7 (M+H)+ 630.0, found 630.0. 467.0.
Step 4: : N-(2,2'-dichloro-3'-((3-chloro-5-(hydroxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)picolinamide
Figure PCTKR2021006886-appb-img-000188
The title compound was synthesized from methyl 5-chloro-6-(((2,2'-dichloro-3'-(5-(methoxycarbonyl)picolinamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxynicotinate in a manner similar to the synthesis of N-(3'-((3-chloro-5-(hydroxymethyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)picolinamide (0.15 g, 51.1% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.69 (s, 1H), 8.67 (dd, J = 2.0, 0.8 Hz, 1H), 8.49 (dd, J = 8.2, 1.5 Hz, 1H), 8.19 (dd, J = 8.0, 0.7 Hz, 1H), 8.05-8.02 (m, 1H), 7.77 (t, J = 1.1 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.40-7.38 (m, 2H), 7.12 (dd, J = 7.6, 1.5 Hz, 1H), 6.95 (t, J = 6.3, 2.7 Hz, 1H), 5.53 (t, J = 5.6 Hz, 1H), 5.39 (t, J = 5.6 Hz, 1H), 5.33 (s, 2H), 4.66 (d, J = 5.5 Hz, 2H), 4.45 (d, J = 5.5 Hz, 2H), 3.82 (s, 3H). LC-MS m/z calculated for C27H22Cl3N3O5 (M+H)+ 574.0, found 574.1.
Step 5: 5-(bromomethyl)-N-(3'-((5-(bromomethyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide
Figure PCTKR2021006886-appb-img-000189
To a solution of N-(2,2'-dichloro-3'-((3-chloro-5-(hydroxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)picolinamide (70.2 mg, 0.12 mmol) in dichloromethane (5 ml) was added triphenylphosphine (70.8 mg, 0.27 mmol). The N-bromosuccinimide (47.8 mg, 0.27 mmol) was added at 0°C slowly. The reaction mixture was stirred at 0°C. After 1hr, the reaction mixture was extracted with dichloromethane, washed with water, and dried over MgSO4. The organic layer was concentrated under reduced pressure and purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to give the desired product (47.8 mg, 56.7% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.66 (s, 1H), 8.82 (s, 1H), 8.45 (dd, J = 8.2, 1.5 Hz, 1H), 8.23-8.12 (m, 2H), 8.07 (s, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.41-7.34 (m, 2H), 7.13 (dd, J = 7.6, 1.6 Hz, 1H), 6.96 (dd, J = 7.1, 1.8 Hz, 1H), 5.37 (s, 2H), 4.86 (s, 2H), 4.60 (s, 2H), 3.86 (s, 3H). LC-MS m/z calculated for C27H20Br2Cl3N3O3 (M+H)+ 697.9.
Step 6: N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)picolinamide
Figure PCTKR2021006886-appb-img-000190
To a solution of 1-methylimidazolidin-2-one (13.7 mg, 0.14 mmol) in tetrahydrofuran (3 ml) was added sodium hydride (60% dispersion in mineral oil, 4.2 mg, 0.10 mmol) and stirred at room temperature under the N2 atmosphere. After 1 hr, 5-(bromomethyl)-N-(3'-((5-(bromomethyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide (47.8 mg, 0.068 mmol) was added and the reaction mixture was stirred at room temperature. After 16 hr, the reaction mixture was concentrated under the reduced pressure and purified by prep-HPLC (CH3CN:H2O with 0.1% TFA = 10:90 ~ 99:1) to give the desired product (2.7 mg, 5.4% yield). 1H NMR (400 MHz, methanol-d 4) δ 8.63 (s, 1H), 8.57 (dd, J = 8.3, 1.5 Hz, 1H), 8.24 (d, J = 8.1 Hz, 1H), 7.96 (dd, J = 8.1, 2.1 Hz, 1H), 7.60 (s, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.32 (dd, J = 8.3, 7.5 Hz, 1H), 7.26-7.24 (m, 1H), 7.07 (dd, J = 7.6, 1.5 Hz, 1H), 6.90 (dd, J = 7.5, 1.5 Hz, 1H), 5.36 (s, 2H), 4.50 (s, 2H), 4.30 (s, 3H), 3.41-3.33 (m, 8H), 2.82 (s, 3H), 2.79 (s, 3H). LC-MS m/z calculated for C35H34Cl3N7O5 (M+H)+ 738.1, found 738.2.
Example 130:
N -(3'-((5-(aminomethyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide
Figure PCTKR2021006886-appb-img-000191
Step 1: (6-((3-bromo-2-chlorophenoxy)methyl)-5-chloro-2-methoxypyridin-3-yl)methanol
Figure PCTKR2021006886-appb-img-000192
To a solution of methyl 6-((3-bromo-2-chlorophenoxy)methyl)-5-chloro-2-methoxynicotinate (step 1 in Example 129, 807.5 mg, 1.92 mmol) in tetrahydrofuran (10 ml) and methanol (3 drop) was added lithium borohydride (208.8 mg, 9.59 mmol) at 0°C. The reaction mixture was stirred at room temperature. After 2 hr, the reaction mixture was quenched with 1N HCl solution, extracted with dichloromethane, and dried over MgSO4. The organic layer was concentrated under reduced pressure and purified by flash chromatography (SiO2, 20% ethyl acetate in hexanes) to give the desired product (376.0 mg, 97.6% yield). 1H NMR (400 MHz, DMSO-d 6) δ 7.75 (s, 1H), 7.36-7.31 (m, 2H), 7.24 (t, J = 8.1 Hz, 1H), 5.39 (t, J = 5.6 Hz, 1H), 5.30 (s, 2H), 4.44 (d, J = 5.3 Hz, 2H), 3.78 (s, 3H). LC-MS m/z calculated for C14H12BrCl2NO3 (M+H)+ 391.9.
Step 2: 6-((3-bromo-2-chlorophenoxy)methyl)-5-chloro-2-methoxynicotinaldehyde
Figure PCTKR2021006886-appb-img-000193
To a solution of (6-((3-bromo-2-chlorophenoxy)methyl)-5-chloro-2-methoxypyridin-3-yl)methanol (745.4 mg, 1.90 mmol) in dichloromethane (10 ml) was added Dess-Martin periodinane (1.2 g, 2.84 mmol) and stirred at room temperature. After 16h, the reaction mixture was extracted with dichloromethane, washed with water, and dried over MgSO4. The organic layer was concentrated under reduced pressure and purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to give the desired product (603.5 mg, 81.0% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.13 (s, 1H), 8.14 (s, 1H), 7.36 (dd, J = 7.7, 1.7 Hz, 1H), 7.28-7.20 (m, 2H), 5.47 (s, 2H), 3.83 (s, 3H). LC-MS m/z calculated for C14H10BrCl2NO3 (M+H)+ 489.9.
Step 3: 2-((3-bromo-2-chlorophenoxy)methyl)-3-chloro-5-(dimethoxymethyl)-6-methoxypyridine
Figure PCTKR2021006886-appb-img-000194
To a solution of 6-((3-bromo-2-chlorophenoxy)methyl)-5-chloro-2-methoxynicotinaldehyde (603.5 mg, 1.54 mmol) and trimethyl orthoformate (0.85 ml, 7.72 mmol) in methanol (10 ml) was added p-toluene sulfonic acid (29.3 mg, 0.15 mmol) and stirred at room temperature. After 2 hr, the reaction mixture was quenched with saturated sodium bicarbonate solution, extracted with 10% methanol in dichloromethane, and dried over MgSO4. The organic was concentrated under reduced pressure and purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to give the desired product (666.4 mg, 99.9% yield). 1H NMR (400 MHz, DMSO-d 6) δ 7.77 (s, 1H), 7.36-7.29 (m, 2H), 7.23 (t, J = 8.1 Hz, 1H), 5.75 (s, 1H), 5.44 (s, 1H), 5.34 (s, 2H), 3.77 (s, 3H), 3.28 (s, 6H). LC-MS m/z calculated for C16H16BrCl2NO4 (M+H)+ 435.9, found 435.6.
Step 4: 2,2'-dichloro-3'-((3-chloro-5-(dimethoxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-amine
Figure PCTKR2021006886-appb-img-000195
To a solution of 2-((3-bromo-2-chlorophenoxy)methyl)-3-chloro-5-(dimethoxymethyl)-6-methoxypyridine (689.6 mg, 1.58 mmol), 3-bromo-2-chloroaniline (440.0 mg, 1.74 mmol), potassium phosphate tribasic (672.1 mg, 3.16 mmol), and XPhos Pd G2 (24.8 mg, 0.032 mmol) in tetrahydrofuran (3 ml) and water (1.5 ml) was stirred at 90°C under the N2 atmosphere. After 16 hr, the reaction mixture was filtered through celite pad. The filtrate was diluted was ethyl acetate, washed with water, and dried over MgSO4. The organic layer was concentrated under reduced pressure and purified by flash chromatography (SiO2, 20% ethyl acetate in hexanes) to give the desired product (518.0 mg, 67.8% yield). 1H NMR (400 MHz, DMSO-d 6) δ 7.77 (s, 1H), 7.33-7.26 (m, 2H), 7.06 (t, J = 7.7 Hz, 1H), 6.86-6.81 (m, 2H), 6.40 (dd, J = 7.4, 1.5 Hz, 1H), 5.45 (s, 1H), 5.41 (s, 2H), 5.34 (s, 2H), 3.80 (s, 3H), 3.28 (s, 6H). LC-MS m/z calculated for C22H21Cl3N2O4 (M+H)+ 483.0, found 482.8.
Step 5: methyl 6-((2,2'-dichloro-3'-((3-chloro-5-(dimethoxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)carbamoyl)nicotinate
Figure PCTKR2021006886-appb-img-000196
To a solution of 2,2'-dichloro-3'-((3-chloro-5-(dimethoxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-amine (518.0 mg, 1.07 mmol), 5-(methoxycarbonyl)picolinic acid (213.4 mg, 1.18 mmol), HATU (610.3 mg, 1.61 mmol), and 4-methyl morpholine (0.18 ml, 1.61 mmol) in N,N-dimethylformamide (3 ml) was stirred at room temperature. After 16 hr, the reaction mixture was diluted with dichloromethane, washed with water and brine, and dried over MgSO4. The organic was concentrated under reduced pressure and purified by flash chromatography (SiO2, 20% ethyl acetate in hexanes) to give the desired product (585.7 mg, 91.1% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.71 (s, 1H), 9.21 (s, 1H), 8.58 (dd, J = 8.1, 2.1 Hz, 1H), 8.40 (dd, J = 8.2, 1.4 Hz, 1H), 8.34 (d, J = 8.1 Hz, 1H), 7.78 (s, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.41-7.34 (m, 2H), 7.15 (dd, J = 7.6, 1.5 Hz, 1H), 6.95 (s, 1H), 5.38 (s, 2H), 3.94 (s, 3H), 3.81 (s, 3H), 3.29 (s, 6H). LC-MS m/z calculated for C30H26Cl3N3O7 (M+H)+ 646.1, found 645.7.
Step 6: N-(2,2'-dichloro-3'-((3-chloro-5-(dimethoxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)picolinamide
Figure PCTKR2021006886-appb-img-000197
To a solution of methyl 6-((2,2'-dichloro-3'-((3-chloro-5-(dimethoxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)carbamoyl)nicotinate (495.1 mg, 0.76 mmol) in tetrahydrofuran (5 ml) was added lithium aluminum hydride (34.9 mg, 0.92 mmol) at 0°C under N2 atmosphere and stirred at room temperature. After 1 hr, the reaction mixture was quenched with water (0.1 ml), 15% NaOH solution (0.1 ml), and water (0.1 ml) sequentially. The mixture was dried over Na2SO4 and filtered through celite. The filtrate was concentrated under reduced pressure and purified by flash chromatography (SiO2, 50% ethyl acetate in hexanes) to give the desired product (325.4 mg, 69.2% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.69 (s, 1H), 8.67 (s, 1H), 8.49 (dd, J = 8.2, 1.5 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.03 (dd, J = 8.0, 2.1 Hz, 1H), 7.78 (s, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.41-7.34 (m, 2H), 7.11 (dd, J = 7.6, 1.5 Hz, 1H), 6.96 (dd, J = 7.2, 1.7 Hz, 1H), 5.53 (t, J = 5.6 Hz, 1H), 5.45 (s, 1H), 5.38 (s, 2H), 4.66 (d, J = 5.2 Hz, 2H), 3.81 (s, 3H), 3.29 (s, 6H). LC-MS m/z calculated for C29H26Cl3N3O6 (M+H)+618.1.
Step 7: N-(2,2'-dichloro-3'-((3-chloro-5-(dimethoxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-formylpicolinamide
Figure PCTKR2021006886-appb-img-000198
To a solution of N-(2,2'-dichloro-3'-((3-chloro-5-(dimethoxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)picolinamide (325.4 mg, 0.53 mmol) in dichloromethane (5 ml) was added Dess-Martin periodinane (269.8 mg, 0.64 mmol) and sodium bicarbonate (89.1 mg, 1.06 mmol) and stirred at room temperature. After 1hr, the reaction mixture was extracted with dichloromethane, washed with water and dried over MgSO4. The organic layer was concentrated under reduced pressure and purified by flash chromatography (SiO2, 20% ethyl acetate in hexanes) to give the desired product (275.1 mg, 84.1% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.74 (s, 1H), 10.23 (s, 1H), 9.23 (s, 1H), 8.55-8.53 (m, 1H), 8.41 (t, J = 7.6 Hz, 2H), 7.79 (s, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.42-7.35 (m, 2H), 7.17 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 5.46 (s, 1H), 5.38 (s, 2H), 3.81 (s, 3H), 3.29 (s, 6H). LC-MS m/z calculated for C29H24Cl3N3O6 (M+H)+ 616.1, found 615.7.
Step 8: N-(2,2'-dichloro-3'-((3-chloro-5-(dimethoxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide
Figure PCTKR2021006886-appb-img-000199
To a solution of N-(2,2'-dichloro-3'-((3-chloro-5-(dimethoxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-formylpicolinamide (275.1 mg, 0.46 mmol) and ethanolamine (0.083 ml, 1.38 mmol) in dichloromethane (3 ml) was added acetic acid (0.026 ml, 0.46 mmol) and stirred at room temperature. After 1 hr, sodium cyanoborohydride (86.7 mg, 1.38 mmol) was added. After 16 hr, the reaction mixture was concentrated under reduced pressure. The reaction mixture was concentrated under reduced pressure and purified by prep-HPLC (CH3CN:H2O with 0.1% TFA = 10:90 ~ 99:1) to give the desired product (158.8 mg, 52.2% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.70 (s, 1H), 8.68 (d, J = 1.5 Hz, 1H), 8.49 (dd, J = 8.2, 1.5 Hz, 1H), 8.19-8.16 (m, 1H), 8.05 (dd, J = 8.0, 2.1 Hz, 1H), 7.78 (s, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.41-7.34 (m, 2H), 7.11 (dd, J = 7.6, 1.5 Hz, 1H), 6.96 (dd, J = 7.2, 1.8 Hz, 1H), 5.45 (s, 1H), 5.38 (s, 2H), 4.49 (t, J = 5.4 Hz, 1H), 3.85 (s, 2H), 3.80 (s, 3H), 3.30 (s, 2H), 3.29 (s, 6H). LC-MS m/z calculated for C31H31Cl3N4O6 (M+H)+ 661.1, found 660.8
Step 9: N-(2,2'-dichloro-3'-((3-chloro-5-formyl-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide
Figure PCTKR2021006886-appb-img-000200
To a solution of N-(2,2'-dichloro-3'-((3-chloro-5-(dimethoxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide (158.8 mg, 0.24 mmol) in dioxane (1 ml) was added 4N HCl in dioxane (0.5 ml) and stirred at room temperature. After 1 day, the reaction mixture was concentrated under reduced pressure. The desired product was obtained without further purification (147.7 mg, 99.9% yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.70 (s, 1H), 10.15 (s, 1H), 9.28 (s, 2H), 8.88 (s, 1H), 8.44 (dd, J = 8.2, 1.5 Hz, 1H), 8.29 (d, J = 1.4 Hz, 2H), 8.16 (s, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.38 (dd, J = 8.3, 7.5 Hz, 1H), 7.32 (dd, J = 8.4, 1.5 Hz, 1H), 7.15 (dd, J = 7.6, 1.5 Hz, 1H), 6.96 (dd, J = 7.5, 1.5 Hz, 1H), 5.50 (s, 2H), 4.35 (t, J = 5.7 Hz, 2H), 3.88 (s, 3H), 3.70 (s, 2H), 3.04 (s, 2H). LC-MS m/z calculated for C29H25Cl3N4O5 (M+H)+ 615.1, found 614.7.
Step 10: N-(3'-((5-(aminomethyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide
Figure PCTKR2021006886-appb-img-000201
The title compound was synthesized as the bis-TFA salt from N-(2,2'-dichloro-3'-((3-chloro-5-formyl-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide in a manner similar to the synthesis of N-(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide. 1H NMR (400 MHz, methanol-d 4) δ 8.82 (s, 1H), 8.58 (dd, J = 8.3, 1.3 Hz, 1H), 8.36 (d, J = 8.7 Hz, 1H), 8.20 (dd, J = 8.1, 2.2 Hz, 1H), 7.86 (s, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.25 (dd, J = 8.4, 1.5 Hz, 1H), 7.09 (dd, J = 7.6, 1.5 Hz, 1H), 6.92 (dd, J = 7.5, 1.5 Hz, 1H), 5.41 (s, 2H), 4.43 (s, 2H), 4.11 (s, 2H), 3.98 (s, 3H), 3.87-3.84 (m, 2H), 3.26-3.22 (m, 3H). LC-MS m/z calculated for C29H28Cl3N5O4 (M+H)+ 616.1, found 616.7
The following compounds were prepared according to the methods provided herein using the appropriate materials and protecting group chemistry as needed.
[Table 7]
Figure PCTKR2021006886-appb-img-000202
Figure PCTKR2021006886-appb-img-000203
Figure PCTKR2021006886-appb-img-000204
Example 137:
(2S)-2-(((5-chloro-6-(((2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxohexahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid
Figure PCTKR2021006886-appb-img-000205
Step 1: 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
Figure PCTKR2021006886-appb-img-000206
To a solution of 2,4-dihydroxypyrimidine-5-carboxylic acid (500.0 mg, 3.20 mmol) and potassium hydroxide (1.08 g, 19.22 mmol) in water (10 ml) was added dimethyl sulfate (1.62 g, 12.82 mmol). The reaction mixture was stirred at room temperature for 2 hr. The mixture was acidified with conc. HCl. The Acidic solution was extracted with ethyl acetate. The Organic layer was dried over Na2SO4 and concentrated under reduced pressure. To give the desired product (300 mg, 50.9 %, white solid). 1H NMR (400 MHz, DMSO-d 6) δ 8.71 (s, 1H), 3.45 (s, 3H), 3.21 (s, 3H). LC-MS m/z calculated for C7H8N2O4 (M+H)+ 184.0, not found
Step 2: methyl 6-(((3'-amino-2,2'-dichloro-[1,1'-biphenyl]-3-yl)oxy)methyl)-5-chloro-2-methoxynicotinate
Figure PCTKR2021006886-appb-img-000207
To a solution of methyl 6-((3-bromo-2-chlorophenoxy)methyl)-5-chloro-2-methoxynicotinate (step 1 in Example 129, 455.7 mg, 0.1.08 mmol), 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (250.0 mg, 0.98 mmol), potassium phosphate tribasic (418.6 mg, 1,97 mmol), and XPhos Pd G2 (15.5 mg, 0.02 mmol) in tetrahydrofuran (12 ml) and water (6 ml) was stirred at 90°C under the N2 atmosphere. After 16 hr, the reaction mixture was filtered through celite pad. The filtrate was diluted was ethyl acetate, washed with water, and dried over MgSO4. The organic layer was concentrated under reduced pressure and purified by flash chromatography (SiO2, 15% ethyl acetate in hexanes) to give the desired product (274.3 mg, 59.5% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.22 (s, 1H), 7.32-7.27 (m, 1H), 7.24-7.20 (m, 1H), 7.09-7.03 (m, 1H), 6.87-6.80 (m, 2H), 6.42-6.38 (m, 1H), 5.43 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H). LC-MS m/z calculated for C21H17Cl3N2O4 (M+H)+ 466.03, found 466.6.
Step 3: methyl 5-chloro-6-(((2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxynicotinate
Figure PCTKR2021006886-appb-img-000208
To a solution of 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (73.6 mg, 0.40 mmol) and oxalyl chloride (0.09 ml, 1.09 mmol) in dichloromethane was added cat. N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 1.5 hr. Concentrated under reduced pressure, dried in vacuo. The residue was purged in N2 and dissolved in dichloromethane. A solution of methyl 6-(((3'-amino-2,2'-dichloro-[1,1'-biphenyl]-3-yl)oxy)methyl)-5-chloro-2-methoxynicotinate (138.7 mg, 0.36 mmol) in dichloromethane and triethylamine were added. The reaction mixture was stirred at room temperature 16 hr. The mixture was quenched by water, extracted with 10% methanol/dichloromethane. The organic layer was dried over NaSO4. The organic layer was concentrated under reduced pressure and purified by flash chromatography (SiO2, 4% methanol in dichloromethane) to give the desired product (196.0 mg, 85.1% yield). 1H NMR (400 MHz, DMSO-d 6) δ 11.59 (s, 1H), 8.79 (s, 1H), 8.54 (dd, J = 8.4, 1.6 Hz, 1H), 8.23 (s, 1H), 7.48-7.42 (m, 1H), 7.39-7.33 (m, 1H), 7.29 (dd, J = 8.4, 1.2 Hz, 1H), 7.06-7.02 (m, 1H), 6.94 (dd, J = 7.6, 1.2 Hz, 1H), 5.46 (s, 2H), 3.81 (s, 3H), 3.78 (s, 3H), 3.50 (s, 3H), 3.26 (s, 3H). LC-MS m/z calculated for C28H23Cl3N4O7 (M+H)+ 632.0, found 632.0.
Step 4: N-(2,2'-dichloro-3'-((3-chloro-5-(hydroxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxohexahydropyrimidine-5-carboxamide
Figure PCTKR2021006886-appb-img-000209
To a solution of methyl 5-chloro-6-(((2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxynicotinate (190.0 mg, 0.30 mmol) in tetrahydrofuran (5 ml) was added lithium aluminum hydride (13.7 mg, 0.36 mmol) at 0°C and stirred at room temperature. After 2 hr, the reaction mixture was quenched with water (0.1 ml), NaOH (15% in H2O, 0.1 ml) and water (0.2 ml). The mixture was filtered through celite, extracted with dichloromethane and water, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 4% methanol in dichloromethanes) to give the desired product (157.0 mg, 71.8 % yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.06 (d, J = 24.8 Hz, 1H), 7.92-7.86 (m, 1H), 7.76 (s, 1H), 7.50-7.30 (m, 3H), 7.20-7.10 (m, 1H), 6.93-6.80 (m, 1H), 5.41 (t, J = 7.2 Hz, 1H), 5.32 (S, 2H), 4.45 (d, J = 7.2 Hz, 2 H), 4.20-4.10 (m, 1H), 3.81 (s, 3H), 3.73-3.71 (m, 2H), 3.03 (s, 3H), 2.95 (d, J = 4.0 Hz, 3H). LC-MS m/z calculated for C27H25Cl3N4O6 (M+H)+ 606.1, found 606.6.
Step 5: N-(2,2'-dichloro-3'-((3-chloro-5-formyl-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxohexahydropyrimidine-5-carboxamide
Figure PCTKR2021006886-appb-img-000210
To a solution of N-(2,2'-dichloro-3'-((3-chloro-5-(hydroxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxohexahydropyrimidine-5-carboxamide (140.0 mg, 0.23 mmol) in dichloromethane (5 ml) was added Dess-Martin periodinane (117.2 mg, 0.27 mmol) and stirred at room temperature. After 15 hr, the reaction mixture was diluted with dichloromethane and washed with water and saturated sodium bicarbonate solution. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 4% methanol in dichloromethane) to give the desired product (138.0 mg, 98.9 % yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.14 (s, 1H), 10.07 (d, J = 24.0 Hz, 1H), 8.16 (s, 1H), 7.93-7.80 (m, 1H), 7.45-7.20 (m, 3H), 7.15-7.05 (m, 1H), 6.95-6.89 (m, 1H), 5.49 (s, 2H), 4.15-4.05 (m, 1H), 3.86 (s, 3H), 3.70-3.60 (m, 1H), 3.03 (s, 3H), 2.95 (d, J = 4.0 Hz, 3H). LC-MS m/z calculated for C27H23Cl3N4O6 (M+H)+ 604.1, found 604.5.
Step 6: (2S)-2-(((5-chloro-6-(((2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxohexahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid trifluoroacetic acid salt
Figure PCTKR2021006886-appb-img-000211
To a solution of N-(2,2'-dichloro-3'-((3-chloro-5-formyl-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxohexahydropyrimidine-5-carboxamide (50.0 mg, 0.083 mmol) and (s)-2-amino-3-hydroxy-2-methylpropanoic acid (19.7 ml, 0.17 mmol) in methanol (2 ml) was added acetic acid (0.2 ml) and stirred at room temperature. After 10 min, picoline borane (17.6 mg, 0.17 mmol) was added. The reaction mixture was stirred at 40 °C for 16 hr. The reaction mixture was concentrated under reduced pressure and purified by prep-HPLC (CH3CN:H2O with 0.1% TFA = 10:90 ~ 99:1) to give the desired product as the TFA salt (12.0 mg, 17.6 % yield). 1H NMR (400 MHz, DMSO-d 6) δ 10.06 (d, J = 14.8 Hz, 1H), 9.12 (s, 2H), 8.01 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.45-7.35 (m, 3H), 7.13-7.05 (m, 1H), 7.00-6.91 (m, 1H), 5.86 (s, 1H), 5.37 (s, 2H), 4.19-4.10 (m, 3H), 3. 84 (s, 3H), 3.70-3.60 (m, 2H), 3.03 (s, 3H), 2.95 (d, J = 1.6 Hz, 3H), 1.47 (s, 3H). LC-MS m/z calculated for C31H32Cl3N5O8 (M+H)+ 707.1, found 707.5.
Example 138:
2-(((6-(((3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)pyridin-3-yl)methyl)amino)ethan-1-ol
Figure PCTKR2021006886-appb-img-000212
Step 1: methyl 6-(((3'-hydroxy-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)nicotinate
Figure PCTKR2021006886-appb-img-000213
The title compound was synthesized from methyl 6-((3-bromo-2-methylphenoxy)methyl)nicotinate in a manner similar to the synthesis of methyl 6-(((3'-amino-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)nicotinate using 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol in place of 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. LC-MS m/z calculated for C22H21NO4 (M+H)+ 364.2, found 364.0.
Step 2: methyl 5-chloro-2-methoxy-6-(((3'-((5-(methoxycarbonyl)pyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)nicotinate
Figure PCTKR2021006886-appb-img-000214
To a solution of methyl 6-(((3'-hydroxy-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)nicotinate (68.8 mg, 0.19 mmol) and methyl 5-chloro-2-methoxy-6-(((methylsulfonyl)oxy)methyl)nicotinate (70.4 mg, 0.23 mmol) in N,N-dimethylformamide (4 ml) was added cesium carbonate (123.4 mg, 0.38 mmol). The mixture was stirred at room temperature for 15 hr, quenched with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 40% ethyl acetate in hexanes) to give the desired product (109.2 mg, 100.0% yield). LC-MS m/z calculated for C31H29ClN2O7 (M+H)+ 577.2, found 577.0.
Step 3: (6-(((3'-((3-chloro-5-(hydroxymethyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)pyridin-3-yl)methanol
Figure PCTKR2021006886-appb-img-000215
The title compound was synthesized from methyl 5-chloro-2-methoxy-6-(((3'-((5-(methoxycarbonyl)pyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)nicotinate in a manner similar to the synthesis of 3-chloro-N-(2-chloro-3-(1-(4-(hydroxymethyl)benzyl)-1H-indol-4-yl)phenyl)-5-(hydroxymethyl)-6-methoxypicolinamide. LC-MS m/z calculated for C29H29ClN2O5 (M+H)+ 521.2, found 521.0.
Step 4: 5-chloro-6-(((3'-((5-formylpyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxynicotinaldehyde
Figure PCTKR2021006886-appb-img-000216
The title compound was synthesized from (6-(((3'-((3-chloro-5-(hydroxymethyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)pyridin-3-yl)methanol in a manner similar to the synthesis of 3-chloro-N-(2-chloro-3-(1-(4-formylbenzyl)-1H-indol-4-yl)phenyl)-5-formyl-6-methoxypicolinamide. LC-MS m/z calculated for C29H25ClN2O5 (M+H)+ 517.2, found 517.0.
Step 5: 2-(((6-(((3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)pyridin-3-yl)methyl)amino)ethan-1-ol
Figure PCTKR2021006886-appb-img-000217
The title compound was synthesized as the bis-TFA salt from 5-chloro-6-(((3'-((5-formylpyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxynicotinaldehyde in a manner similar to the synthesis of N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((2-hydroxyethyl)amino)methyl)picolinamide). LC-MS m/z calculated for C33H30ClN4O5 (M+H)+ 607.3, found 607.1.
The following compounds were prepared according to the methods provided herein using the appropriate materials and protecting group chemistry as needed.
[Table 8]
Figure PCTKR2021006886-appb-img-000218
Figure PCTKR2021006886-appb-img-000219
Figure PCTKR2021006886-appb-img-000220
Example 143:
2-(((5-chloro-6-(((2,2'-dichloro-3'-(3-morpholinopropoxy)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methyl)amino)ethan-1-ol
Figure PCTKR2021006886-appb-img-000221
Step 1: 4-(3-(3-bromo-2-chlorophenoxy)propyl)morpholine
Figure PCTKR2021006886-appb-img-000222
To a solution of 3-bromo-2-chlorophenol (500.0 mg, 2.41 mmol) and 4-(3-chloropropyl)morpholine (0.55 ml, 3.61 mmol) in acetonitrile (10 ml) was added potassium carbonate (999.1 mg, 7.23 mmol). The mixture was heated to 60 °C for 15 hr, quenched with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 5% methanol in dichloromethane) to give the desired product (754.5 mg, 93.6% yield). 1H NMR (400 MHz, DMSO-d 6) δ 7.32 (dd, J = 8.0, 7.6 Hz, 1H), 7.24 (dd, J = 8.4, 8.0 Hz, 1H), 7.17 (dd, J = 8.4, 7.0 Hz, 1H), 4.12 (t, J = 6.2 Hz, 2H), 3.56 (t, J = 4.6 Hz, 2H), 2.43 (t, J = 7.2 Hz, 2H), 2.31-2.39 (m, 4H), 1.84-1.91 (m, 2H).
Step 2: 4-(3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)morpholine
Figure PCTKR2021006886-appb-img-000223
To a solution of 4-(3-(3-bromo-2-chlorophenoxy)propyl)morpholine (754.0 mg, 2.25 mmol) and bis(pinacolato)diboron (1.1 g, 4.51 mmol) and potassium acetate (773.9 mg, 7.89 mmol) in 1,4-dioxane (10 ml) was added Pd(dppf)Cl2·DCM (91.9 mg, 0.11 mmol) at N2 atmosphere. The reaction mixture was purged with N2 and heated to 105°C for 20 hr and cooled to room temperature. The reaction mixture was filtered through the celite pad and the filtrate was diluted with dichloromethane and extracted with water, washed with brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purification by flash chromatography (SiO2, 5% methanol in dichloromethane) to give the desired product (723.3 mg, 84.1% yield). 1H NMR (400 MHz, chloroform-d) δ 1H NMR (400 MHz, DMSO-d 6) δ 7.20-7.29 (m, 2H), 7.13 (dd, J = 7.2, 7.2 Hz, 1H), 4.08 (t, J = 6.2 Hz, 2H), 3.56 (t, J = 4.4 Hz, 2H), 2.43 (t, J = 7.2 Hz, 2H), 2.30-2.39 (m, 4H), 1.85-1.91 (m, 2H), 1.30 (s, 12H). LC-MS m/z calculated for C19H29BClNO4 (M+H)+ 382.2, found 382.1.
Step 3: methyl 5-chloro-6-(((2,2'-dichloro-3'-(3-morpholinopropoxy)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxynicotinate
Figure PCTKR2021006886-appb-img-000224
To a solution of methyl 6-((3-bromo-2-chlorophenoxy)methyl)-5-chloro-2-methoxynicotinate (step 1 in Example 129, 150.0 mg, 0.36 mmol) and 4-(3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)morpholine (163.2 mg, 0.43 mmol) in tetrahydrofuran (4.5 ml) and water (1.5 ml) was added potassium phosphate tribasic (151.2 mg, 0.71 mmol) under N2 atmosphere. The mixture was purged with N2 and XPhos Pd G2 (0.01 mg, 0.02 mmol) was added. The reaction mixture was heated to 95 °C for 15 hr, cooled to room temperature, quenched with water, and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 3% methanol in ethyl acetate) to give the desired product (388.8 mg, 79.1% yield). 1H NMR (400 MHz, DMSO-d 6) δ 8.56 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.30-7.33 (m, 1H), 7.25 (dd, J = 8.4, 8.4 Hz, 1H), 7.18 (dd, J = 8.4, 8.4 Hz, 1H), 6.87 (dd, J = 7.6, 7.2 Hz, 1H), 6.83 (dd, J = 7.6, 7.6 Hz, 1H), 5.45 (s, 2H), 4.10-4.14 (m, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 3.55-3.58 (m, 4H), 2.46 (t, J = 6.8 Hz, 2H), 2.32-2.36 (m, 4H), 1.88-1.94 (m, 2H). LC-MS m/z calculated for C28H29Cl3N2O6 (M+H)+ 595.1, found 595.0.
Step 4: (5-chloro-6-(((2,2'-dichloro-3'-(3-morpholinopropoxy)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methanol
Figure PCTKR2021006886-appb-img-000225
The title compound was synthesized from methyl 5-chloro-6-(((2,2'-dichloro-3'-(3-morpholinopropoxy)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxynicotinate in a manner similar to the synthesis of N-(2,2'-dichloro-3'-((3-chloro-5-(dimethoxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)picolinamide. The crude product was used for the next step without further purification.
Step 5: 5-chloro-6-(((2,2'-dichloro-3'-(3-morpholinopropoxy)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxynicotinaldehyde
Figure PCTKR2021006886-appb-img-000226
The title compound was synthesized from (5-chloro-6-(((2,2'-dichloro-3'-(3-morpholinopropoxy)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methanol in a manner similar to the synthesis of N-(2,2'-dichloro-3'-((3-chloro-5-(dimethoxymethyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-formylpicolinamide. LC-MS m/z calculated for C27H27Cl3N2O5 (M+H)+ 565.1, found 564.9.
Step 6: 2-(((5-chloro-6-(((2,2'-dichloro-3'-(3-morpholinopropoxy)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methyl)amino)ethan-1-ol
Figure PCTKR2021006886-appb-img-000227
The title compound was synthesized as the bis-TFA salt from 5-chloro-6-(((2,2'-dichloro-3'-(3-morpholinopropoxy)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxynicotinaldehyde in a manner similar to the synthesis of : (2S)-2-(((5-chloro-6-(((2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxohexahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid. 1H NMR (400 MHz, DMSO-d 6) δ 9.87 (br, 1H), 8.84 (br, 2H), 8.05 (s, 1H), 7.40-7.33 (m, 3H), 7.21 (d, J = 8.4 Hz, 1H), 6.89-6.85 (m, 2H), 5.36 (s, 2H), 4.21-3.96 (m, 6H), 3.85 (s, 3H), 3.68-3.66 (m, 4H), 3.35-3.03 (m, 8H), 2.24-2.17 (m, 2H). LC-MS m/z calculated for C29H34ClN4O5 (M+H)+ 610.2, found 610.0.
Example A
PD-1/PD-L1 Homogenous Time-Resolved Fluorescence (HTRF) binding assay
The assay was conducted in a standard white small volumeTM Hibase polystyrene microplate (Greiner, Cat. No.: 784075) with a final volume of 20 μl. Inhibitors were first serially diluted in DMSO and then added (2 μl) to the plate wells before the addition of other reaction components. The final concentration of DMSO in the assay was 0.1%. The assays were carried out at room temperature in PBS buffer (pH 7.4) with 0.05% Tween-20 and 0.1% BSA. Recombinant human PD-L1 protein (19-238) with a His-tag at the C-terminus was purchased from ACROBiosystems (PD1-H5229). Recombinant human PD-1 protein (25-167) with Fc tag at the C-terminus was also purchased from ACROBiosystems (PD1-H5257). PD-L1 and PD-1 proteins were diluted in the assay buffer and 8 μl was added to the plate well. Proteins were pre-incubated with inhibitors for 40 min. The incubation was followed by the addition of 10 μl of HTRF detection buffer supplemented with Europium cryptate-labeled anti-human IgG (PerkinElmer-AD0212) specific for Fc and anti-His antibody conjugated to SureLightTM-Allophycocyanin (APC, PerkinElmer-AD0059H). The plate was incubated at room temperature for 2 hr, before reading on a PerkinElmer Victor3V Microplate Reader (665nm/620nm ratio). It was tested in the assay with final assay concentrations of each component: 10 nM PD-L1, 3 nM PD-1, 1 nM Europium anti-human IgG, and 20 nM anti-His-Allophycocyanin. Data analysis is performed using the HTRF ratio.
[HTRF Ratio = (665 nm emission/620 nm emission) x 104]
IC50 determination was performed by fitting the curve of percent control activity versus the log of the inhibitor concentration using the Sigma Plot program. The results are shown in Table 9.
Compounds in Table 9 were prepared by methods as described in the Examples and evaluated according to the assay below. The IC50 of the compounds are presented in Table 9.
Example B
Thermal Shift Assay (TSA)
Protein thermal shift assay was performed following the instructions indicated in Protein Thermal ShiftTM dye Kit (Applied Biosystems, Cat. No. 4461146). PD-L1 (0.4 mg/ml, Acrobiosystems, Cat. No. PD1-H5229) was used in a final concentration of 3 μM, and the tested compounds dissolved in DMSO were added to the protein sample to the final concentration of 10 μM. The protein incubated with DMSO alone was included as a control. Protein Thermal ShiftTM Dye was mixed with the protein. Prior to use, the dye stock was diluted 1:125 (1000X) and used immediately while protecting from light to reduce photobleaching. The thermal denaturation assay was performed in a total volume of 20 μl. All samples were run in duplicates. The thermal scan was conducted from 25 to 99 °C, at 1 °C/min (ViiATM 7 Real-Time PCR System, Applied Biosystems). The melting point (Tm) was calculated by fitting the raw fluorescence data over the temperature using the Boltzmann equation in GraphPad Prism program (GraphPad Prism 5 for Windows). The results are shown in Table 9.
ΔT = Tm (Tested compound)-Tm (Control)
Example C
Cell-based assay: Nuclear Factor of Activated T-cell (NFAT) assay
Compounds were tested in a functional co-culture reporter assay in which TCR-mediated NFAT activity is inhibited by the engagement of PD-1 with PD-L1. Blocking the PD-1/PD-L1 interaction impairs PD-1 mediated blunting of TCR signaling and significantly increases NFAT-mediated transcription of luciferase. PD-L1/TCR Activator CHO cells were seeded at a density of 35,000 cells per well into a white clear-bottom 96-well microplate in 100 μl of growth media (Ham's F-12 with 10% FBS) without added GeneticinTM or hygromycin. The next day compounds and the control antibody (Anti-PD-L1 neutralizing antibody, BPS Bioscience Cat. No. 71213) were diluted in assay media (RPMI1640 with 10% FBS and 1% Pen/Strep). The media was removed from the PD-L1/TCR Activator CHO cells, and 50 μl/well of diluted compounds or control antibody was added. The plates were incubated for 30 min at 37°C and 5% CO2. The PD-1/NFAT-reporter Jurkat cells were harvested by centrifugation and resuspended in assay media to a concentration of 4x105 cells/ml. Following the 30 min incubation, 50 μl/well of the PD-1/NFAT reporter-Jurkat cells were added to the PD-L1/TCR Activator CHO cells to achieve a final concentration of 20,000 cells/well and the dose of compound indicated. After 5-6 hr, cells were lysed and a luciferase assay was performed using One-Step luciferase assay system (BPS Bioscience, Cat. No. 60690): add 100 μl of One-Step Luciferase reagent per well and rock at room temperature for 20-30 min. Luminescence was measured using a luminometer (BioTek SynergyTM 2 microplate reader). The assay was performed in triplicate at 1 μM compound. The fold induction of luminescence in the presence of control antibody was calculated according to the following equation:
Fold induction = RLU (induced-background) / RLU (no antibody control-background)
RLU means Relative Light Units. The results are shown in Table 9.
[Table 9]
Figure PCTKR2021006886-appb-img-000228
Figure PCTKR2021006886-appb-img-000229
Figure PCTKR2021006886-appb-img-000230
Figure PCTKR2021006886-appb-img-000231
It can be seen from Table 9 that the compounds of Examples 1 to 143 are effective in inhibiting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling pathway. Accordingly, the pyridine derivatives of the present invention are useful in the treatment, prevention or alleviation of various diseases associated with inhibition of PD-1/PD-L1 interaction.

Claims (29)

  1. A compound of formula (I):
    Figure PCTKR2021006886-appb-img-000232
    or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
    R1 is halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-14 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -NHORa, -N(OH)Ra, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NRa)NRaRa, -NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaRa, -OS(O)2Ra, -PRaRa, -P(O)RaRa or -BRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl- and (5-14 membered heteroaryl)-C2-6 alkynyl- of R1 are each optionally substituted with 1 to 5 groups independently selected from Rb substituents;
    R2 is halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-14 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -NHORa, -N(OH)Ra, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NRa)NRaRa, -NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaRa, -OS(O)2Ra, -PRaRa, -P(O)RaRa or -BRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl- and (5-14 membered heteroaryl)-C2-6 alkynyl- of R2 are each optionally substituted with 1 to 5 groups independently selected from Rb substituents;
    each Ra is independently selected from H, halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, and (5-14 membered heteroaryl)-C2-6 alkynyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl- and (5-14 membered heteroaryl)-C2-6 alkynyl- of Ra are each optionally substituted with 1 to 5 groups independently selected from Rb substituents;
    or any two Ra substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 4 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-14 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
    each Rb is independently selected from H, halogen, OH, CN, NO2, N3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-14 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -(CRcRc)ORc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
    each Rc is independently selected from H, halogen, OH, CF3, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, and (5-14 membered heteroaryl)-C2-6 alkynyl-;
    R3 is -C(O)X, -C(O)ORd, -C(ReRf)OH, -C(ReRf)Y, -C(ReRf)NH2, -C(ReRf)N3 or
    Figure PCTKR2021006886-appb-img-000233
    ;
    ArW is ArE, -ArE-L-QE or -ArE-L-QE-RM;
    X is H or halogen;
    Y is halogen or OS(O)2Rg;
    Rd is H, C1-6 alkyl or CORg;
    Re and Rf are each independently selected from H, halogen, OH, CN, NO2, and C1-6 alkyl;
    or Re and Rf are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 4 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-14 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
    Rg is C1-5 alkyl, C1-5 alkoxy or phenyl, wherein the C1-5 alkyl, C1-5 alkoxy and phenyl of Rg are each optionally substituted with 1 to 4 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, and (5-14 membered heteroaryl)-C2-6 alkynyl-;
    A is -C(O)O-, -C(ReRf)O-, -C(ReRf)S-, -C(ReRf)S(O)2-, -C(O)NRe- or -C(ReRf)NRe-;
    Each R4 is independently selected from H, halogen, OH, CN, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-14 cycloalkyl, and 4-14 membered heterocycloalkyl;
    or any two R4 substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 4 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-14 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
    The subscript n is an integer of 0, 1, 2 or 3;
    ArE is 4-14 membered heterocycloalkyl, C6-10 aryl or 5-14 membered heteroaryl, wherein the 4-14 membered heterocycloalkyl, C6-10 aryl and 5-14 membered heteroaryl of ArE are each optionally substituted with 1 to 5 groups independently selected from R4 substituents;
    L is a bond, -O-, -S-, -C(O)-, -SO-, -SO2-, -(CRhRi)m-, -(CRhRi)mO(CRhRi)m-, -(CRhRi)mS(CRhRi)m-, -(CRhRi)mNRh(CRhRi)m-, -(CRhRi)mC(O)(CRhRi)m-, -(CRhRi)mC(O)NRh(CRhRi)m-, -(CRhRi)mNRhC(O)(CRhRi)m-, -(CRhRi)mSO2NRh(CRhRi)m-, -(CRhRi)mNRhSO2(CRhRi)m-, -C2-6 alkenylene- or -C2-6 alkynylene-, wherein each m is independently 0, 1, 2 or 3;
    Rh and Ri are each independently selected from H, halogen, OH, CN, NO2, COOH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, (C1-6 alkyl)NH-, (C1-6 alkyl)2N-, C3-14 cycloalkyl, and 4-14 membered heterocycloalkyl;
    or Rh and Ri are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 4 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-14 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
    QE is 4-14 membered heterocycloalkyl, C6-10 aryl or 5-14 membered heteroaryl, wherein 4-14 membered heterocycloalkyl, C6-10 aryl or 5-14 membered heteroaryl of QE are each optionally substituted with 1 to 5 groups independently selected from R1 substituents;
    RM and RL are each independently selected from halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-14 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -NHORa, -N(OH)Ra, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -C(RaRa)NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NRa)NRaRa, -NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaRa, -OS(O)2Ra, -PRaRa, -P(O)RaRa, and -BRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl-C1-6 alkyl-, (4-14 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-14 membered heteroaryl)-C1-6 alkyl-, C3-14 cycloalkyl-C2-6 alkenyl-, (4-14 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-14 membered heteroaryl)-C2-6 alkenyl-, C3-14 cycloalkyl-C2-6 alkynyl-, (4-14 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl- and (5-14 membered heteroaryl)-C2-6 alkynyl- of RM and RL are each optionally substituted with 1 to 5 groups independently selected from Rb substituents.
  2. A compound of formula (I):
    Figure PCTKR2021006886-appb-img-000234
    or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
    R1 is halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -NHORa, -N(OH)Ra, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NRa)NRaRa, -NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaRa, -OS(O)2Ra, -PRaRa, -P(O)RaRa or -BRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl-of R1 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
    R2 is halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -NHORa, -N(OH)Ra, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NRa)NRaRa, -NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaRa, -OS(O)2Ra, -PRaRa, -P(O)RaRa or -BRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl-of R2 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
    each Ra is independently selected from H, halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, and (5-10 membered heteroaryl)-C2-6 alkynyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl- of Ra are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
    or any two Ra substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
    each Rb is independently selected from H, halogen, OH, CN, NO2, N3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -(CRcRc)ORc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
    each Rc is independently selected from H, halogen, OH, CF3, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, and (5-10 membered heteroaryl)-C2-6 alkynyl-;
    R3 is -C(O)X, -C(O)ORd, -C(ReRf)OH, -C(ReRf)Y, -C(ReRf)NH2, -C(ReRf)N3 or
    Figure PCTKR2021006886-appb-img-000235
    ;
    ArW is ArE, -ArE-L-QE or -ArE-L-QE-RM;
    X is H or halogen;
    Y is halogen or OS(O)2Rg;
    Rd is H, C1-6 alkyl or CORg;
    Re and Rf are each independently selected from H, halogen, OH, CN, NO2, and C1-6 alkyl;
    or Re and Rf are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
    Rg is C1-5 alkyl, C1-5 alkoxy or phenyl, wherein the C1-5 alkyl, C1-5 alkoxy and phenyl of Rg are each optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, and (5-10 membered heteroaryl)-C2-6 alkynyl-;
    A is -C(ReRf)O-, -C(ReRf)S-, -C(ReRf)S(O)2-, -C(O)NRe- or -C(ReRf)NRe-;
    Each R4 is independently selected from H, halogen, OH, CN, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, and 4-10 membered heterocycloalkyl;
    or any two R4 substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
    The subscript n is an integer of 0, 1, 2 or 3;
    ArE is 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl of ArE are each optionally substituted with 1 to 3 groups independently selected from R4 substituents;
    L is a bond, -O-, -S-, -C(O)-, -SO-, -SO2-, -(CRhRi)m-, -(CRhRi)mO(CRhRi)m-, -(CRhRi)mS(CRhRi)m-, -(CRhRi)mNRh(CRhRi)m-, -(CRhRi)mC(O)(CRhRi)m-, -(CRhRi)mC(O)NRh(CRhRi)m-, -(CRhRi)mNRhC(O)(CRhRi)m-, -(CRhRi)mSO2NRh(CRhRi)m-, -(CRhRi)mNRhSO2(CRhRi)m-, -C2-6 alkenylene- or -C2-6 alkynylene-, wherein each m is independently 0, 1, 2 or 3;
    Rh and Ri are each independently selected from H, halogen, OH, CN, NO2, COOH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, (C1-6 alkyl)NH-, (C1-6 alkyl)2N-, C3-8 cycloalkyl, and 4-10 membered heterocycloalkyl;
    or Rh and Ri are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, -OS(O)2Rc, -PRcRc, -P(O)RcRc, and -BRcRc;
    QE is 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, wherein 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl of QE are each optionally substituted with 1 to 3 groups independently selected from R1 substituents;
    RM and RL are each independently selected from halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -NHORa, -N(OH)Ra, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -C(RaRa)NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NRa)NRaRa, -NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaRa, -OS(O)2Ra, -PRaRa, -P(O)RaRa, and -BRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl- of RM and RL are each optionally substituted with 1 to 3 groups independently selected from Rb substituents.
  3. A compound of formula (I):
    Figure PCTKR2021006886-appb-img-000236
    or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
    R1 is halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -NHORa, -N(OH)Ra, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra or -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl-of R1 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
    R2 is halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -NHORa, -N(OH)Ra, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra or -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl-of R2 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
    each Ra is independently selected from H, halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, and (5-10 membered heteroaryl)-C2-6 alkynyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl- of Ra are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
    or any two Ra substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, and -OS(O)2Rc;
    each Rb is independently selected from H, halogen, OH, CN, NO2, N3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -(CRcRc)ORc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, and -S(O)2NRcRc;
    each Rc is independently selected from H, halogen, OH, CF3, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, and (5-10 membered heteroaryl)-C2-6 alkynyl-;
    R3 is -C(O)X, -C(O)ORd, -C(ReRf)OH, -C(ReRf)Y, -C(ReRf)NH2, -C(ReRf)N3 or
    Figure PCTKR2021006886-appb-img-000237
    ;
    ArW is ArE, -ArE-L-QE or -ArE-L-QE-RM;
    X is H or halogen;
    Y is halogen or OS(O)2Rg;
    Rd is H, C1-6 alkyl or CORg;
    Re and Rf are each independently selected from H, halogen, OH, CN, NO2, and C1-6 alkyl;
    or Re and Rf are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, and -S(O)2NRcRc;
    Rg is C1-5 alkyl, C1-5 alkoxy or phenyl, wherein the C1-5 alkyl, C1-5 alkoxy and phenyl of Rg are each optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, and (5-10 membered heteroaryl)-C2-6 alkynyl-;
    A is -C(ReRf)O-, -C(ReRf)S-, -C(ReRf)S(O)2-, -C(O)NRe- or -C(ReRf)NRe-;
    Each R4 is independently selected from H, halogen, OH, CN, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, and 4-10 membered heterocycloalkyl;
    or any two R4 substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, and -S(O)2NRcRc;
    The subscript n is an integer of 0, 1, 2 or 3;
    ArE is 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl of ArE are each optionally substituted with 1 to 3 groups independently selected from R4 substituents;
    L is a bond, -O-, -S-, -C(O)-, -SO-, -SO2-, -(CRhRi)m-, -(CRhRi)mO(CRhRi)m-, -(CRhRi)mS(CRhRi)m-, -(CRhRi)mNRh(CRhRi)m-, -(CRhRi)mC(O)(CRhRi)m-, -(CRhRi)mC(O)NRh(CRhRi)m-, -(CRhRi)mNRhC(O)(CRhRi)m-, -(CRhRi)mSO2NRh(CRhRi)m-, -(CRhRi)mNRhSO2(CRhRi)m-, -C2-6 alkenylene- or -C2-6 alkynylene-, wherein each m is independently 0, 1, 2 or 3;
    Rh and Ri are each independently selected from H, halogen, OH, CN, NO2, COOH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, (C1-6 alkyl)NH-, (C1-6 alkyl)2N-, C3-8 cycloalkyl, and 4-10 membered heterocycloalkyl;
    or Rh and Ri are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -C(=NRc)Rc, -C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, and -S(O)2NRcRc;
    QE is 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, wherein 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl of QE are each optionally substituted with 1 to 3 groups independently selected from R1 substituents;
    RM and RL are each independently selected from halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -NHORa, -N(OH)Ra, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -C(RaRa)NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NRa)NRaRa, -NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra, and -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl- of RM and RL are each optionally substituted with 1 to 3 groups independently selected from Rb substituents.
  4. A compound of formula (I):
    Figure PCTKR2021006886-appb-img-000238
    or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
    R1 is halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra or -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl- of R1 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
    R2 is halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra or -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl- of R2 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
    each Ra is independently selected from H, halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, and (5-10 membered heteroaryl)-C2-6 alkynyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl- of Ra are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
    or any two Ra substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-10 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-10 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-10 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, and -OS(O)2Rc;
    each Rb is independently selected from H, halogen, OH, CN, NO2, N3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -(CRcRc)ORc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, and -S(O)2NRcRc;
    each Rc is independently selected from H, halogen, OH, CF3, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, and (5-10 membered heteroaryl)-C2-6 alkynyl-;
    R3 is -C(O)X, -C(O)ORd, -C(ReRf)OH, -C(ReRf)Y, -C(ReRf)NH2, -C(ReRf)N3 or
    Figure PCTKR2021006886-appb-img-000239
    ;
    ArW is ArE, -ArE-L-QE or -ArE-L-QE-RM;
    X is H or halogen;
    Y is halogen or OS(O)2Rg;
    Rd is H, C1-6 alkyl or CORg;
    Re and Rf are each independently selected from H, halogen, OH, CN, NO2, and C1-6 alkyl;
    or Re and Rf are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 4 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, and -S(O)2NRcRc;
    Rg is C1-5 alkyl, C1-5 alkoxy or phenyl, wherein the C1-5 alkyl, C1-5 alkoxy and phenyl of Rg are each optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, and (5-10 membered heteroaryl)-C2-6 alkynyl-;
    A is -C(ReRf)O-, -C(ReRf)S-, -C(ReRf)S(O)2-, -C(O)NRe- or -C(ReRf)NRe-;
    Each R4 is independently selected from H, halogen, OH, CN, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, and 4-10 membered heterocycloalkyl;
    or any two R4 substituents are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -NHORc, -N(OH)Rc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, and -S(O)2NRcRc;
    The subscript n is an integer of 0, 1, 2 or 3;
    ArE is 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl of ArE are each optionally substituted with 1 to 3 groups independently selected from R4 substituents;
    L is a bond, -O-, -S-, -C(O)-, -SO-, -SO2-, -(CRhRi)m-, -(CRhRi)mO(CRhRi)m-, -(CRhRi)mS(CRhRi)m-, -(CRhRi)mNRh(CRhRi)m-, -(CRhRi)mC(O)(CRhRi)m-, -(CRhRi)mC(O)NRh(CRhRi)m-, -(CRhRi)mNRhC(O)(CRhRi)m-, -(CRhRi)mSO2NRh(CRhRi)m-, -(CRhRi)mNRhSO2(CRhRi)m-, -C2-6 alkenylene- or -C2-6 alkynylene-, wherein each m is independently 0, 1, 2 or 3;
    Rh and Ri are each independently selected from H, halogen, OH, CN, NO2, COOH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, (C1-6 alkyl)NH-, (C1-6 alkyl)2N-, C3-8 cycloalkyl, and 4-10 membered heterocycloalkyl;
    or Rh and Ri are combined to form a ring having 3-8 ring atoms that are C, N, O, or S, wherein the ring is optionally substituted with 1 to 3 groups independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORc, -SRc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -OC(O)Rc, -OC(O)NRcRc, -NRcRc, -NRcC(O)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -NRcS(O)Rc, -NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc, and -S(O)2NRcRc;
    QE is 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, wherein 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl of QE are each optionally substituted with 1 to 3 groups independently selected from R1 substituents;
    RM and RL are each independently selected from halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl-, (5-10 membered heteroaryl)-C2-6 alkynyl-, -ORa, -SRa, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -C(RaRa)NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra, and -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl-C1-6 alkyl-, (4-10 membered heterocycloalkyl)-C1-6 alkyl-, C6-8 aryl-C1-6 alkyl-, (5-10 membered heteroaryl)-C1-6 alkyl-, C3-8 cycloalkyl-C2-6 alkenyl-, (4-10 membered heterocycloalkyl)-C2-6 alkenyl-, C6-8 aryl-C2-6 alkenyl-, (5-10 membered heteroaryl)-C2-6 alkenyl-, C3-8 cycloalkyl-C2-6 alkynyl-, (4-10 membered heterocycloalkyl)-C2-6 alkynyl-, C6-8 aryl-C2-6 alkynyl- and (5-10 membered heteroaryl)-C2-6 alkynyl- of RM and RL are each optionally substituted with 1 to 3 groups independently selected from Rb substituents.
  5. The compound of any one of claims 1-4, having Formula (Ia):
    Figure PCTKR2021006886-appb-img-000240
    or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
    R1 is halogen, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, -ORa, -SRa, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra or -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, and 5-10 membered heteroaryl of R1 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
    R2 is halogen, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, -ORa, -SRa, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra or -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, and 5-10 membered heteroaryl of R2 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
    R3 is -C(O)X, -C(O)ORd, -C(ReRf)OH, -C(ReRf)Y, -C(ReRf)NH2 or -C(ReRf)N3;
    Ra, Rb, Rd, Re, Rf, X, Y and RL are as defined in each cited claim.
  6. The compound of any one of claims 1-4, having Formula (Ib):
    Figure PCTKR2021006886-appb-img-000241
    or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
    R1 is halogen, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, -ORa, -SRa, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra or -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, and 5-10 membered heteroaryl of R1 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
    R2 is halogen, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, 5-10 membered heteroaryl, -ORa, -SRa, -C(O)Ra, -C(O)NRaRa, -C(O)ORa, -OC(O)Ra, -OC(O)NRaRa, -NRaRa, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra or -S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-8 aryl, and 5-10 membered heteroaryl of R2 are each optionally substituted with 1 to 3 groups independently selected from Rb substituents;
    Ra, Rb, RL, A, R4, n and ArW are as defined in each cited claim.
  7. The compound of any one of claims 1-4 and 6, having Formula (II):
    Figure PCTKR2021006886-appb-img-000242
    or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein
    R1, R2, R4, A, n, ArE and RL are as defined in each cited claim.
  8. The compound of any one of claims 1-4 and 6-7, having Formula (IIa):
    Figure PCTKR2021006886-appb-img-000243
    or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein
    R1, R2, R4, RL, A and n are as defined in each cited claim.
  9. The compound of any one of claims 1-4 and 6-8, having Formula (IIb):
    Figure PCTKR2021006886-appb-img-000244
    or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein
    R1, R2, R4, Re, Rf, n and RL are as defined in each cited claim.
  10. The compound of any one of claims 1-4 and 6-8, having Formula (IIc):
    Figure PCTKR2021006886-appb-img-000245
    or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein
    R1, R2, R4, Re, n and RL are as defined in each cited claim.
  11. The compound of any one of claims 1-4 and 6-9, having Formula (IId):
    Figure PCTKR2021006886-appb-img-000246
    or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein
    R1, R2, R4, Ra, Re, Rf and n are as defined in each cited claim.
  12. The compound of any one of claims 1-4, 6-8 and 10, having Formula (IIe):
    Figure PCTKR2021006886-appb-img-000247
    or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein
    R1, R2, R4, Ra, Re and n are as defined in each cited claim.
  13. The compound of any one of claims 1-4 and 6, having Formula (III):
    Figure PCTKR2021006886-appb-img-000248
    or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein
    R1, R2, R4, A, n, ArE, L, QE, RL and RM are as defined in each cited claim.
  14. The compound of any one of claims 1-4, 6 and 13, having Formula (IIIa):
    Figure PCTKR2021006886-appb-img-000249
    or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein
    R1, R2, R4, A, n, L, QE, RL and RM are as defined in each cited claim.
  15. The compound of any one of claims 1-4, 6 and 13-14, having Formula (IIIb):
    Figure PCTKR2021006886-appb-img-000250
    or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein
    R1, R2, R4, Re, Rf, n, L, QE, RL and RM are as defined in each cited claim.
  16. The compound of any one of claims 1-4, 6 and 13-14, having Formula (IIIc):
    Figure PCTKR2021006886-appb-img-000251
    or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein
    R1, R2, R4, Re, n, L, QE, RL and RM are as defined in each cited claim.
  17. The compound of any one of claims 1-4, 6 and 13-15, having Formula (IIId):
    Figure PCTKR2021006886-appb-img-000252
    or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein
    R1, R2, R4, Ra, Re, Rf, n, L, QE and RM are as defined in each cited claim.
  18. The compound of any one of claims 1-4, 6, 13-14 and 16, having Formula (IIIe):
    Figure PCTKR2021006886-appb-img-000253
    or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein
    R1, R2, R4, Ra, Re, n, L, QE and RM are as defined in each cited claim.
  19. The compound of claim 1 selected from:
    1) ((5-chloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)-L-serine;
    2) 2-(((5-chloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)amino)ethan-1-ol;
    3) ((5-chloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)-L-proline;
    4) N-(2-(((5-chloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)amino)ethyl)acetamide;
    5) 3-(((5-chloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-3-(((2-hydroxyethyl)amino)methyl)pyridin-2-yl)oxy)methyl)benzonitrile;
    6) ((5-chloro-6-(((2-methyl-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)-L-serine;
    7) 2-(((5-chloro-6-(((2-methyl-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)amino)ethan-1-ol;
    8) ((5-chloro-6-(((3'-methoxy-2-methyl-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)-L-serine;
    9) ((5-chloro-2-((3'-methoxy-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-6-(((3'-methoxy-2-methyl-[1,1'-biphenyl]-3-yl)oxy)methyl)pyridin-3-yl)methyl)-L-serine;
    10) ((5-chloro-6-(((2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)-L-serine;
    11) ((5-chloro-6-(((2'-fluoro-3'-methoxy-2-methyl-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)-L-serine;
    12) ((5-chloro-6-((3-(5-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)-L-serine;
    13) ((5-chloro-2-((3-cyanobenzyl)oxy)-6-(((2-methyl-[1,1'-biphenyl]-3-yl)oxy)methyl)pyridin-3-yl)methyl)-L-serine;
    14) 2-(((5-chloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)amino)-2-methylpropanoic acid;
    15) (R)-1-((5-chloro-6-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenoxy)methyl)-2-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)pyrrolidin-3-ol;
    16) N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((2-hydroxyethyl)amino)methyl)picolinamide);
    17) N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-((methylamino)methyl)picolinamide);
    18) N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamide);
    19) N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((2-sulfamoylethyl)amino)methyl)picolinamide);
    20) N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(5-(((2-acetamidoethyl)amino)methyl)-3-chloro-6-ethoxypicolinamide);
    21) N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-6-ethoxy-5-(((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methyl)picolinamide);
    22) N,N'-(2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(3-chloro-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-6-methylpicolinamide);
    23) 3-chloro-N-(2'-chloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypicolinamide;
    24) 3-chloro-N-(2-chloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypicolinamide;
    25) 3-chloro-5-(((2-hydroxyethyl)amino)methyl)-N-(3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-methoxypicolinamide;
    26) 3-chloro-N-(2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-6-methylpicolinamide;
    27) ((6-((3'-(5-((((S)-1-carboxy-2-hydroxyethyl)amino)methyl)-3-fluoro-6-methylpicolinamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-L-serine;
    28) N-(2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-6-methoxy-3-methylpicolinamide;
    29) 3-chloro-N-(2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypicolinamide;
    30) ((6-((3'-(5-((((S)-1-carboxy-2-hydroxyethyl)amino)methyl)-3-chloro-6-methylpicolinamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-L-serine;
    31) (S)-2-(((6-((3'-(5-((((S)-2-carboxy-1-hydroxypropan-2-yl)amino)methyl)-3-chloro-6-methylpicolinamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid;
    32) methyl (S)-2-(((5-chloro-6-((2,2'-dichloro-3'-(5-((((S)-3-hydroxy-1-methoxy-2-methyl-1-oxopropan-2-yl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-2-methylpyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoate;
    33) 3-chloro-N-(2,2'-dichloro-3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-6-methylpicolinamide;
    34) 3-chloro-N-(2,2'-dichloro-3'-(5-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-6-methyl-5-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)picolinamide;
    35) methyl (S)-2-(((5-chloro-6-((2,2'-dichloro-3'-(5-((((S)-3-hydroxy-1-methoxy-2-methyl-1-oxopropan-2-yl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-2-methylpyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoate;
    36) (R)-1-((6-((3'-(5-(((R)-3-carboxypyrrolidin-1-yl)methyl)-3-chloro-6-methylpicolinamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid;
    37) 2-(((6-((3'-(5-(((2-carboxypropan-2-yl)amino)methyl)-3-chloro-6-methylpicolinamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)-2-methylpropanoic acid;
    38) ethyl (S)-2-(((5-chloro-6-((2,2'-dichloro-3'-(5-((((S)-1-ethoxy-3-hydroxy-2-methyl-1-oxopropan-2-yl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-2-methylpyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoate;
    39) (S)-2-(((6-((3'-(5-((((S)-2-carboxy-1-hydroxypropan-2-yl)amino)methyl)-3-fluoro-6-methylpicolinamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid;
    40) 2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-ethoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(ethan-1-ol);
    41) 2,2'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(ethan-1-ol);
    42) (3R,3'R)-1,1'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(pyrrolidin-3-ol);
    43) 1,1'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(N-methylmethanamine);
    44) ((1R,1'R,3R,3'R)-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(methylene))bis(5-chloro-2-methoxypyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(cyclobutane-3,1-diyl))dimethanol;
    45) 3-chloro-N-(2-chloro-3-(1-(4-(((2-hydroxyethyl)amino)methyl)benzyl)-1H-indol-4-yl)phenyl)-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypicolinamide;
    46) 3-chloro-N-(2-chloro-3-(1-(4-((methylamino)methyl)benzyl)-1H-indol-4-yl)phenyl)-6-methoxy-5-((methylamino)methyl)picolinamide;
    47) 2-((4-((4-(3-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2-methylphenyl)-1H-indol-1-yl)methyl)benzyl)amino)ethan-1-ol;
    48) 2-(((5-chloro-6-((3-(8-chloro-2-(5-(((2-hydroxyethyl)amino)methyl)pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylphenoxy)methyl)-2-methoxypyridin-3-yl)methyl)amino)ethan-1-ol;
    49) 3-chloro-5-(((2-hydroxyethyl)amino)methyl)-N-(3'-((5-(((2-hydroxyethyl)amino)methyl)pyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-methoxypicolinamide;
    50) N-(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
    51) N-(3'-((3-chloro-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamide;
    52) 3-chloro-N-(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-6-methylpicolinamide;
    53) N-(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypicolinamide;
    54) N-(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2-cyano-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
    55) N-(2-chloro-3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
    56) N-(2'-chloro-3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
    57) N-(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
    58) N-(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2'-cyano-2-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
    59) N-(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methylpyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
    60) N-(3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-6-methylpicolinamide;
    61) N-(2,2'-dichloro-3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
    62) N-(2,2'-dichloro-3'-((3-fluoro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
    63) N-(2,2'-dichloro-3'-((5-(((2-hydroxyethyl)amino)methyl)-6-methoxy-3-methylpyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
    64) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((2-morpholinoethyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-morpholinoethyl)amino)methyl)picolinamide;
    65) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((3-morpholinopropyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((3-morpholinopropyl)amino)methyl)picolinamide;
    66) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((3-(3-oxopiperazin-1-yl)propyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((3-(3-oxopiperazin-1-yl)propyl)amino)methyl)picolinamide;
    67) N-(2,2'-dichloro-3'-(((3-chloro-6-methoxy-5-(((3-(4-methylpiperazin-1-yl)propyl)amino)methyl)pyridin-2-yl)oxy)methyl)-[1,1'-biphenyl]-3-yl)-5-(((3-(4-methylpiperazin-1-yl)propyl)amino)methyl)picolinamide;
    68) N-(2,2'-dichloro-3'-(((3-chloro-6-methoxy-5-(((3-(piperazin-1-yl)propyl)amino)methyl)pyridin-2-yl)oxy)methyl)-[1,1'-biphenyl]-3-yl)-5-(((3-(piperazin-1-yl)propyl)amino)methyl)picolinamide;
    69) (S)-2-(((6-((3'-((5-((((S)-2-carboxy-1-hydroxypropan-2-yl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid;
    70) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((2-sulfamoylethyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-sulfamoylethyl)amino)methyl)picolinamide;
    71) 4-(((6-((3'-((5-(((3-carboxypropyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)butanoic acid;
    72) 3-(((6-((3'-((5-(((2-carboxyethyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)propanoic acid;
    73) ((6-((3'-((5-(((carboxymethyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)glycine;
    74) (1R,4R)-4-(((6-((3'-((5-((((1R,4R)-4-carboxycyclohexyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)cyclohexane-1-carboxylic acid;
    75) N-(2,2'-dichloro-3'-((3-chloro-5-((((1R,3R)-3-hydroxycyclobutyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((((1R,3R)-3-hydroxycyclobutyl)amino)methyl)picolinamide;
    76) ((6-((3'-((5-(((S)-2-carboxypyrrolidin-1-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-L-proline;
    77) (2S,4R)-1-((6-((3'-((5-(((2S,4R)-2-carboxy-4-hydroxypyrrolidin-1-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid;
    78) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((3-oxopiperazin-1-yl)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((3-oxopiperazin-1-yl)methyl)picolinamide;
    79) N-(2,2'-dichloro-3'-((3-chloro-5-((1,1-dioxidothiomorpholino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((1,1-dioxidothiomorpholino)methyl)picolinamide;
    80) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((S)-2-(methylcarbamoyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((S)-2-(methylcarbamoyl)pyrrolidin-1-yl)methyl)picolinamide;
    81) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((1-oxo-2,7-diazaspiro[4.5]decan-7-yl)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((1-oxo-2,7-diazaspiro[4.5]decan-7-yl)methyl)picolinamide;
    82) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((2-oxopiperidin-4-yl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-oxopiperidin-4-yl)amino)methyl)picolinamide;
    83) N-(2,2'-dichloro-3'-((3-chloro-5-((((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)amino)methyl)picolinamide;
    84) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((pyridin-4-ylmethyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((pyridin-4-ylmethyl)amino)methyl)picolinamide;
    85) N-(2,2'-dichloro-3'-((3-chloro-5-(((3,4-dimethoxybenzyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((3,4-dimethoxybenzyl)amino)methyl)picolinamide;
    86) 3-((6-((3'-((5-((6-carboxy-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid;
    87) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((2-methoxyethyl)(methyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-methoxyethyl)(methyl)amino)methyl)picolinamide;
    88) N-(2,2'-dichloro-3'-((3-chloro-5-((5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methyl)picolinamide;
    89) N-(2,2'-dichloro-3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-4-(((2-hydroxyethyl)amino)methyl)picolinamide;
    90) N-(2,2'-dichloro-3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)nicotinamide;
    91) N-(2,2'-dichloro-3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-6-(((2-hydroxyethyl)amino)methyl)picolinamide;
    92) 1-(((6-(((3'-((5-(((1-carboxycyclopropyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)pyridin-3-yl)methyl)amino)cyclopropane-1-carboxylic acid;
    93) ((6-((3'-((5-((((S)-1-carboxy-2-hydroxyethyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-L-serine;
    94) 2-(((6-((3'-((5-(((2-carboxypropan-2-yl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)-2-methylpropanoic acid;
    95) ((6-((3'-((5-((((1R,2R)-1-carboxy-2-hydroxypropyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-D-allothreonine;
    96) 1-((6-((3'-((5-((3-carboxyazetidin-1-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)azetidine-3-carboxylic acid;
    97) 5-(((2-acetamidoethyl)amino)methyl)-N-(3'-((5-(((2-acetamidoethyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
    98) (S)-1-((6-((3'-((5-(((S)-2-carboxypiperidin-1-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)piperidine-2-carboxylic acid;
    99) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)picolinamide;
    100) 5-(aminomethyl)-N-(3'-((5-(aminomethyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
    101) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((methylamino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((methylamino)methyl)picolinamide;
    102) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-methoxyethyl)amino)methyl)picolinamide;
    103) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)picolinamide;
    104) N-(2,2'-dichloro-3'-((3-chloro-5-(((3-hydroxypropyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((3-hydroxypropyl)amino)methyl)picolinamide;
    105) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((3-(methylcarbamoyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((3-(methylcarbamoyl)pyrrolidin-1-yl)methyl)picolinamide;
    106) N-(2,2'-dichloro-3'-((3-chloro-5-((5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)picolinamide;
    107) 5-((((2H-tetrazol-5-yl)methyl)amino)methyl)-N-(3'-((5-((((2H-tetrazol-5-yl)methyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
    108) 5-(((3-acetamidopropyl)amino)methyl)-N-(3'-((5-(((3-acetamidopropyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
    109) 5-(((R)-3-aminopyrrolidin-1-yl)methyl)-N-(3'-((5-(((R)-3-aminopyrrolidin-1-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
    110) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((piperidin-4-ylamino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((piperidin-4-ylamino)methyl)picolinamide;
    111) 5-((4-aminopiperidin-1-yl)methyl)-N-(3'-((5-((4-aminopiperidin-1-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
    112) 5-(((1-acetylpiperidin-4-yl)amino)methyl)-N-(3'-((5-(((1-acetylpiperidin-4-yl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
    113) 5-(((R)-3-acetamidopyrrolidin-1-yl)methyl)-N-(3'-((5-(((R)-3-acetamidopyrrolidin-1-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
    114) 5-((4-acetamidopiperidin-1-yl)methyl)-N-(3'-((5-((4-acetamidopiperidin-1-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
    115) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((((1R,4R)-4-(methylcarbamoyl)cyclohexyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((((1R,4R)-4-(methylcarbamoyl)cyclohexyl)amino)methyl)picolinamide;
    116) 5-((((1R,4R)-4-acetamidocyclohexyl)amino)methyl)-N-(3'-((5-((((1R,4R)-4-acetamidocyclohexyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
    117) 5-(((1-acetylpiperidin-3-yl)amino)methyl)-N-(3'-((5-(((1-acetylpiperidin-3-yl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
    118) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((2-(3-oxopiperazin-1-yl)ethyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-(3-oxopiperazin-1-yl)ethyl)amino)methyl)picolinamide;
    119) N-(2,2'-dichloro-3'-((3-chloro-5-(((1-(2-hydroxyethyl)piperidin-4-yl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((1-(2-hydroxyethyl)piperidin-4-yl)amino)methyl)picolinamide;
    120) 5-(((2-(4-acetylpiperazin-1-yl)ethyl)amino)methyl)-N-(3'-((5-(((2-(4-acetylpiperazin-1-yl)ethyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
    121) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((2-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)ethyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)ethyl)amino)methyl)picolinamide;
    122) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-(((2-(piperidin-4-yl)ethyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-(piperidin-4-yl)ethyl)amino)methyl)picolinamide;
    123) (S)-4-(((6-((3'-((5-((((S)-3-carboxy-2-hydroxypropyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)-3-hydroxybutanoic acid;
    124) 5-(((2-acetamidoethyl)amino)methyl)-N-(3'-((5-(((2-acetamidoethyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)picolinamide;
    125) N-(2,2'-dichloro-3'-((3-chloro-5-(((S)-4-hydroxy-2-oxopyrrolidin-1-yl)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((S)-4-hydroxy-2-oxopyrrolidin-1-yl)methyl)picolinamide;
    126) ((6-((3'-((5-((((R)-1-carboxy-2-hydroxyethyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-D-serine;
    127) methyl ((5-chloro-6-(((2,2'-dichloro-3'-(5-((((S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methyl)-L-serinate;
    128) 2-(((5-chloro-6-(((2,2'-dichloro-3'-(5-((methyl(2-sulfoethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methyl)(methyl)amino)ethane-1-sulfonic acid;
    129) N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)picolinamide;
    130) N-(3'-((5-(aminomethyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
    131) (S)-N-(2,2'-dichloro-3'-((3-chloro-6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide;
    132) ((5-chloro-6-(((2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methyl)-L-serine;
    133) 2-(((5-chloro-6-(((2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methyl)amino)-2-methylpropanoic acid;
    134) (S)-4-(((5-chloro-6-(((2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxybutanoic acid;
    135) ((6-((2,2'-dichloro-3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-L-serine;
    136) 2-(((6-((2,2'-dichloro-3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)-2-methylpropanoic acid;
    137) (2S)-2-(((5-chloro-6-(((2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxohexahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid;
    138) 2-(((6-(((3'-((3-chloro-5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)pyridin-3-yl)methyl)amino)ethan-1-ol;
    139) (R)-1-((6-(((3'-((3-chloro-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)pyridin-3-yl)methyl)pyrrolidin-3-ol;
    140) 1-(5-chloro-6-(((2,2'-dimethyl-3'-((5-((methylamino)methyl)pyridin-2-yl)methoxy)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)-N-methylmethanamine;
    141) ((6-(((3'-((5-(((S)-2-carboxypyrrolidin-1-yl)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)pyridin-3-yl)methyl)-L-proline;
    142) 1-(((6-(((3'-((5-(((1-carboxycyclopropyl)amino)methyl)-3-chloro-6-methoxypyridin-2-yl)methoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)methyl)pyridin-3-yl)methyl)amino)cyclopropane-1-carboxylic acid; and
    143) 2-(((5-chloro-6-(((2,2'-dichloro-3'-(3-morpholinopropoxy)-[1,1'-biphenyl]-3-yl)oxy)methyl)-2-methoxypyridin-3-yl)methyl)amino)ethan-1-ol,
    or a pharmaceutically acceptable salt or a stereoisomer thereof.
  20. A pharmaceutical composition comprising a compound of any one of claim 1-19, or a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.
  21. A pharmaceutical composition for inhibiting PD-1/PD-L1 interaction, comprising a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt or a stereoisomer thereof, as an active ingredient.
  22. A pharmaceutical composition for treating, preventing or alleviating a disease or disorder associated with inhibition of PD-1/PD-L1 interaction, comprising a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt or a stereoisomer thereof, as an active ingredient.
  23. A pharmaceutical composition for enhancing, stimulating and/or increasing an immune response, comprising a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt or a stereoisomer thereof, as an active ingredient.
  24. A compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in inhibiting PD-1/PD-L1 interaction.
  25. A compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in treating, preventing or alleviating a disease or disorder associated with inhibition of PD-1/PD-L1 interaction.
  26. A compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in enhancing, stimulating and/or increasing an immune response.
  27. A method of inhibiting PD-1/PD-L1 interaction, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  28. A method of treating, preventing or alleviating a disease or disorder associated with inhibition of PD-1/PD-L1 interaction, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  29. A method of enhancing, stimulating and/or increasing an immune response in a patient in need thereof, said method comprising administering to the patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt or a stereoisomer thereof.
PCT/KR2021/006886 2020-06-03 2021-06-02 Pyridine derivatives as immunomodulators Ceased WO2021246781A1 (en)

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CN116903595A (en) * 2023-06-01 2023-10-20 遵义医科大学珠海校区 Pyrimidine diketone compound and preparation method and application thereof
WO2024214088A1 (en) * 2023-04-14 2024-10-17 Aurigene Oncology Limited Heterocyclic compounds as dual inhibitors of pd-l1 and adenosine receptors
KR20250003360A (en) 2023-06-30 2025-01-07 주식회사 종근당 New preparation method of Compound and New Crystalline Form

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US20110166123A1 (en) * 2008-01-07 2011-07-07 Aardea Biosciences, Inc. Novel compositions and methods of use
US20110281884A1 (en) * 2010-04-14 2011-11-17 Combs Andrew P Fused derivatives as pi3kdelta inhibitors
WO2019191624A1 (en) * 2018-03-29 2019-10-03 Arbutus Biopharma, Inc. Substituted 1,1'-biphenyl compounds, analogues thereof, and methods using same

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WO2024214088A1 (en) * 2023-04-14 2024-10-17 Aurigene Oncology Limited Heterocyclic compounds as dual inhibitors of pd-l1 and adenosine receptors
CN116903595A (en) * 2023-06-01 2023-10-20 遵义医科大学珠海校区 Pyrimidine diketone compound and preparation method and application thereof
CN116903595B (en) * 2023-06-01 2024-02-13 遵义医科大学珠海校区 Pyrimidine diketone compound and preparation method and application thereof
KR20250003360A (en) 2023-06-30 2025-01-07 주식회사 종근당 New preparation method of Compound and New Crystalline Form

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