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WO2024153175A1 - Heteroaromatic compounds and their use as usp1 inhibitors - Google Patents

Heteroaromatic compounds and their use as usp1 inhibitors Download PDF

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Publication number
WO2024153175A1
WO2024153175A1 PCT/CN2024/072984 CN2024072984W WO2024153175A1 WO 2024153175 A1 WO2024153175 A1 WO 2024153175A1 CN 2024072984 W CN2024072984 W CN 2024072984W WO 2024153175 A1 WO2024153175 A1 WO 2024153175A1
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Prior art keywords
alkyl
compound
cancer
cycloalkyl
heterocyclyl
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PCT/CN2024/072984
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French (fr)
Inventor
Ming Li
Yan Chen
Chun-Yen Chen
Jintao Wang
Xiang-Ju Justin Gu
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Laekna Therapeutics Shanghai Co., Ltd.
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Publication of WO2024153175A1 publication Critical patent/WO2024153175A1/en

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    • 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
    • C07D401/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • heteroaromatic compounds such as a compound of Formula (I) , as ubiquitin-specific-processing protease 1 (USP1) inhibitors, pharmaceutical compositions comprising the compounds, and method of use of the compounds or pharmaceutical compositions in the treatment of diseases or disorders.
  • a compound of Formula (I) as ubiquitin-specific-processing protease 1 (USP1) inhibitors
  • USP1 ubiquitin-specific-processing protease 1
  • Ubiquitin is a highly conserved 76–amino acid peptide that is post-transcriptionally attached to target proteins.
  • the ubiquitin–proteasome system (UPS) is the major proteolytic system that controls protein degradation, and it also regulates many cellular processes in eukaryotic cells. Poly-ubiquitination via surface Lysine-48 (K48) or Lysine-11 (K11) residues of ubiquitin often leads to protein proteolysis through the 26S proteasome.
  • mono-ubiquitination or poly-ubiquitin chains linked through other lysines are always involved in DNA damage and repair, cell cycle progression, apoptosis, receptor-mediated endocytosis, and signal transduction.
  • ubiquitination is a reversible process, and there is a family of enzymes, termed deubiquitinases (DUBs) , that act on ubiquitinated substrates to catalyze the removal of ubiquitin moieties.
  • DRBs deubiquitinases
  • USP1 ubiquitin-specific protease 1
  • USP1 ubiquitin-specific protease 1
  • UAF1 cofactor UAF1
  • UAF1-associated factor 1 acts during DNA repair processes to specifically to remove mono-ubiquitin signals.
  • the mono-ubiquitinated FANCI-FANCD2 heterodimer is one such substrate and is involved in the repair of DNA interstrand crosslinks via the Fanconi Anemia pathway.
  • a second DNA repair-related process, translesion synthesis (TLS) is also regulated by USP1, further supporting the crucial role of this DUB in the DNA damage response.
  • the critical USP1 substrate in TLS is mono- ubiquitinated PCNA (Proliferating Cell Nuclear Antigen) .
  • PCNA Proliferating Cell Nuclear Antigen
  • USP1 contributes to prevent unscheduled recruitment of TLS polymerases, and may thus help maintaining genome stability.
  • Knockdown of USP1 results in elevated levels of FANCD2-Ub and PCNA-Ub and in increased cellular sensitivity to interstrand cross-linking agents, such as mitomycin C (MMC) . Mutations and altered expression of deubiquitinases have been found associated with many human diseases including cancers. There is a need for development of safe and effective treatments targeting deubiquitinases.
  • heteroaromatic compounds as ubiquitin-specific-processing protease 1 (USP1) inhibitors.
  • the compounds have a pyrimidine core structure.
  • compositions comprising a compound provided herein and a pharmaceutically acceptable excipient.
  • the terms “comprising” and “including” can be used interchangeably.
  • the terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of” . Consequently, the term “consisting of” can be used in place of the terms “comprising” and “including” to provide for more specific embodiments.
  • the term “or” is to be interpreted as an inclusive “or” meaning any one or any combination. Therefore, “A, B or C” means any of the following: “A; B; C; A and B; A and C; B and C; A, B and C” . An exception to this definition will occur only when a combination of elements, functions, steps or acts are in some way inherently mutually exclusive.
  • phrase “and/or” as used in a phrase such as “A and/or B” herein is intended to include both A and B; A or B; A (alone) ; and B (alone) .
  • phrase “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone) ; B (alone) ; and C (alone) .
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which is saturated.
  • the alkyl group has, for example, from one to twenty-four carbon atoms (C 1 -C 24 alkyl) , four to twenty carbon atoms (C 4 -C 20 alkyl) , six to sixteen carbon atoms (C 6 -C 16 alkyl) , six to nine carbon atoms (C 6 -C 9 alkyl) , one to fifteen carbon atoms (C 1 -C 15 alkyl) , one to twelve carbon atoms (C 1 -C 12 alkyl) , one to eight carbon atoms (C 1 -C 8 alkyl) or one to six carbon atoms (C 1 -C 6 alkyl) and which is attached to the rest of the molecule by a single bond.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl) , n-butyl, n-pentyl, 1, 1-dimethylethyl (t-butyl) , 3-methylhexyl, 2-methylhexyl, and the like. Unless otherwise specified, an alkyl group is optionally substituted.
  • alkenyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbon double bonds.
  • alkenyl also embraces radicals having “cis” and “trans” configurations, or alternatively, “E” and “Z” configurations, as appreciated by those of ordinary skill in the art.
  • the alkenyl group has, for example, from two to twenty-four carbon atoms (C 2 -C 24 alkenyl) , four to twenty carbon atoms (C 4 -C 20 alkenyl) , six to sixteen carbon atoms (C 6 -C 16 alkenyl) , six to nine carbon atoms (C 6 -C 9 alkenyl) , two to fifteen carbon atoms (C 2 -C 15 alkenyl) , two to twelve carbon atoms (C 2 -C 12 alkenyl) , two to eight carbon atoms (C 2 -C 8 alkenyl) or two to six carbon atoms (C 2 -C 6 alkenyl) and which is attached to the rest of the molecule by a single bond.
  • alkenyl groups include, but are not limited to, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1, 4-dienyl, and the like. Unless otherwise specified, an alkenyl group is optionally substituted.
  • alkynyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbon triple bonds.
  • the alkynyl group has, for example, from two to twenty-four carbon atoms (C 2 -C 24 alkynyl) , four to twenty carbon atoms (C 4 -C 20 alkynyl) , six to sixteen carbon atoms (C 6 -C 16 alkynyl) , six to nine carbon atoms (C 6 -C 9 alkynyl) , two to fifteen carbon atoms (C 2 -C 15 alkynyl) , two to twelve carbon atoms (C 2 -C 12 alkynyl) , two to eight carbon atoms (C 2 -C 8 alkynyl) or two to six carbon atoms (C 2 -C 6 alkynyl) and which is attached to the
  • alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like. Unless otherwise specified, an alkynyl group is optionally substituted.
  • cycloalkyl refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, and which is saturated. Cycloalkyl group may include fused, bridged, or spiro ring systems. In one embodiment, the cycloalkyl has, for example, from 3 to 15 ring carbon atoms (C 3 -C 15 cycloalkyl) , from 3 to 10 ring carbon atoms (C 3 -C 10 cycloalkyl) , or from 3 to 8 ring carbon atoms (C 3 -C 8 cycloalkyl) .
  • the cycloalkyl is attached to the rest of the molecule by a single bond.
  • monocyclic cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • polycyclic cycloalkyl radicals include, but are not limited to, adamantyl, norbornyl, decalinyl, 7, 7-dimethyl-bicyclo [2.2.1] heptanyl, and the like. Unless otherwise specified, a cycloalkyl group is optionally substituted.
  • cycloalkenyl refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, and which includes one or more carbon-carbon double bonds. Cycloalkenyl may include fused, bridged, or spiro ring systems. In one embodiment, the cycloalkenyl has, for example, from 3 to 15 ring carbon atoms (C 3 -C 15 cycloalkenyl) , from 3 to 10 ring carbon atoms (C 3 -C 10 cycloalkenyl) , or from 3 to 8 ring carbon atoms (C 3 -C 8 cycloalkenyl) .
  • cycloalkenyl is attached to the rest of the molecule by a single bond.
  • monocyclic cycloalkenyl radicals include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.
  • a cycloalkenyl group is optionally substituted.
  • cycloalkynyl refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, and which includes one or more carbon-carbon triple bonds.
  • heteroalkyl refers to an alkyl radical that has one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, and phosphorus, or combinations thereof.
  • a numerical range can be given to refer to the chain length in total.
  • a -CH 2 OCH 2 CH 3 radical is referred to as a “C4” heteroalkyl.
  • Connection to the parent molecular structure can be through either a heteroatom or a carbon in the heteroalkyl chain.
  • One or more heteroatom (s) in the heteroalkyl radical can be optionally oxidized.
  • One or more nitrogen atoms, if present, can also be optionally quaternized.
  • a heteroalkyl group is optionally substituted.
  • aryl refers to a monocyclic aromatic group and/or multicyclic aromatic group that contain at least one aromatic hydrocarbon ring.
  • the aryl has from 6 to 18 ring carbon atoms (C 6 -C 18 aryl) , from 6 to 14 ring carbon atoms (C 6 -C 14 aryl) , or from 6 to 10 ring carbon atoms (C 6 -C 10 aryl) .
  • aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
  • aryl also refers to bicyclic, tricyclic, or other multicyclic hydrocarbon rings, where at least one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl) . Unless otherwise specified, an aryl group is optionally substituted.
  • heteroaryl refers to a monocyclic aromatic group and/or multicyclic aromatic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more (e.g., one, one or two, one to three, or one to four) heteroatoms independently selected from O, S, and N.
  • the heteroaryl may be attached to the main structure at any heteroatom or carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • heteroaryl also refers to bicyclic, tricyclic, or other multicyclic rings, where at least one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N.
  • Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.
  • bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl.
  • tricyclic heteroaryl groups include, but are not limited to, carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, and xanthenyl. Unless otherwise specified, a heteroaryl group is optionally substituted.
  • heterocyclyl refers to a monocyclic and/or multicyclic non-aromatic group that contains one or more (e.g., one, one or two, one to three, or one to four) heteroatoms independently selected from nitrogen, oxygen, phosphorous, and sulfur.
  • the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom.
  • a heterocyclyl group can be a monocyclic, bicyclic, tricyclic, tetracyclic, or other multicyclic ring system, wherein the multicyclic ring systems can be a fused, bridged or spiro ring system.
  • Heterocyclyl multicyclic ring systems can include one or more heteroatoms in one or more rings.
  • a heterocyclyl group can be saturated or partially unsaturated.
  • Saturated heterocycloalkyl groups can be termed “heterocycloalkyl” .
  • Partially unsaturated heterocycloalkyl groups can be termed “heterocycloalkenyl” if the heterocyclyl contains at least one double bond, or “heterocycloalkynyl” if the heterocyclyl contains at least one triple bond.
  • the heterocyclyl has, for example, 3 to 18 ring atoms (3-to 18-membered heterocyclyl) , 4 to 18 ring atoms (4-to 18-membered heterocyclyl) , 5 to 18 ring atoms (5-to 18-membered heterocyclyl) , 4 to 8 ring atoms (4-to 8-membered heterocyclyl) , or 5 to 8 ring atoms (5-to 8-membered heterocyclyl) .
  • heterocyclyl groups include, but are not limited to, imidazolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, isoxazolidinyl, isothiazolidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuryl, and piperidinyl. Unless otherwise specified, a heterocyclyl group is optionally substituted.
  • a numerical range such as “3 to 18” refers to each integer in the given range; e.g., a heterocyclyl with “3 to 18 ring atoms” means that the heterocyclyl group can consist of 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, etc., up to and including 18 ring atoms.
  • a C 1 -C 6 alkyl means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms.
  • a “cycloalkylalkyl” group is a radical of the formula: -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined above. Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl, or both the alkyl and the cycloalkyl portions of the group.
  • Representative cycloalkylalkyl groups include but are not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl and the like.
  • an “aralkyl” group is a radical of the formula: -alkyl-aryl, wherein alkyl and aryl are defined above. Substituted aralkyl groups may be substituted at the alkyl, the aryl, or both the alkyl and the aryl portions of the group.
  • Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and aralkyl groups wherein the aryl group is fused to a cycloalkyl group such as indan-4-yl ethyl.
  • cycloalkylalkyl As used herein and unless otherwise specified, other similar composite terms mirror the above description for “cycloalkylalkyl” and “aralkyl” .
  • a “heterocyclylalkyl” group is a radical of the formula: -alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above.
  • a “heteroarylalkyl” group is a radical of the formula: -alkyl-heteroaryl, wherein alkyl and heteroaryl are defined above.
  • a “heterocycloalkylalkyl” group is a radical of the formula: -alkyl-heterocycloalkyl, wherein alkyl and heterocycloalkyl are defined above.
  • halogen refers to fluorine, chlorine, bromine, and/or iodine.
  • haloalkyl, ” “haloalkenyl, ” “haloalkynyl, ” and “haloalkoxy” refer to alkyl, alkenyl, alkynyl, and alkoxy structures that are substituted with one or more halo groups or with combinations thereof.
  • alkoxy refers to -O- (alkyl) , wherein alkyl is defined above.
  • aryloxy refers to -O- (aryl) , wherein aryl is defined above.
  • alkyl sulfonyl refers to —SO 2 -alkyl, wherein alkyl is defined above.
  • arylalkyloxy refers to -O- (alkyl) - (aryl) , wherein alkyl and aryl are defined above.
  • cycloalkyloxy refers to -O- (cycloalkyl) , wherein cycloalkyl is defined above.
  • cycloalkylalkyloxy refers to -O- (alkyl) - (cycloalkyl) , wherein cycloalkyl and alkyl are defined above.
  • acyl refers to –C (O) -R a , wherein R a can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. In certain embodiments, R a may be unsubstituted or substituted with one or more substituents.
  • acyloxy refers to –O-C (O) -R a , wherein R a can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. In certain embodiments, R a may be unsubstituted or substituted with one or more substituents.
  • amino refers to –N (R # ) (R # ) , wherein each R # independently can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above.
  • R # independently can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above.
  • R # When a -N (R # ) (R # ) group has two R # other than hydrogen, they can be combined with the nitrogen atom to form a ring.
  • the ring is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring.
  • one or more ring atoms are heteroatoms independently selected from O, S, or N.
  • amino also includes N-oxide (–N + (R # ) (R # ) O - ) .
  • each R # or the ring formed by -N (R # ) (R # ) independently may be unsubstituted or substituted with one or more substituents.
  • amide or “amido” refers to –C (O) N (R # ) 2 or –NR # C (O) R # , wherein each R # independently can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above.
  • R # independently can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above.
  • R # independently can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above.
  • R # independently can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alken
  • one or more ring atoms are heteroatoms independently selected from O, S, or N.
  • each R # or the ring formed by -N (R # ) (R # ) independently may be unsubstituted or substituted with one or more substituents.
  • aminoalkyl refers to - (alkyl) - (amino) , wherein alkyl and amino are defined above.
  • aminoalkoxy refers to -O- (alkyl) - (amino) , wherein alkyl and amino are defined above.
  • alkylamino refers to -NH (alkyl) or -N (alkyl) (alkyl) , wherein alkyl is defined above.
  • alkylamino groups include, but are not limited to, -NHCH 3 , -NHCH 2 CH 3 , -NH (CH 2 ) 2 CH 3 , - NH (CH 2 ) 3 CH 3 , -NH (CH 2 ) 4 CH 3 , -NH (CH 2 ) 5 CH 3 , -N (CH 3 ) 2 , -N (CH 2 CH 3 ) 2 , -N ( (CH 2 ) 2 CH 3 ) 2 , -N (CH 3 ) (CH 2 CH 3 ) , and the like.
  • arylamino refers to -NH (aryl) or -N (aryl) (aryl) , wherein aryl is defined above.
  • similar composite terms such as “arylalkylamino” and “cycloalkylamino” mirrors the descriptions above for “alkylamino” and “arylamino” .
  • sulfanyl As used herein, and unless otherwise specified, the term “sulfanyl” , “sulfide” , or “thio” refers to -S-R a , wherein R a can be, but is not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. In certain embodiments, R a may be unsubstituted or substituted with one or more substituents.
  • sulfoxide refers to –S (O) -R a , wherein R a can be, but is not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. In certain embodiments, R a may be unsubstituted or substituted with one or more substituents.
  • sulfonyl or “sulfone” refers to –S (O) 2 -R a , wherein R a can be, but is not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. In certain embodiments, R a may be unsubstituted or substituted with one or more substituents.
  • R # independently can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above.
  • R # independently can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above.
  • the ring is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring.
  • one or more ring atoms are heteroatoms independently selected from O, S, or N.
  • each R # or the ring formed by -N (R # ) (R # ) independently may be unsubstituted or substituted with one or more substituents.
  • Azide refers to a –N 3 radical.
  • Niro refers to the —NO 2 radical.
  • Oxa refers to the –O–radical.
  • optionally substituted means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted alkyl means that the alkyl radical may or may not be substituted and that the description includes both substituted alkyl radicals and alkyl radicals having no substitution.
  • substituents include, but are not limited to, those found in the exemplary compounds and embodiments provided herein, as well as halogen (chloro, iodo, bromo, or fluoro) ; alkyl; alkenyl; alkynyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine
  • the term “isomer” refers to different compounds that have the same molecular formula.
  • “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space.
  • “Atropisomers” are stereoisomers from hindered rotation about single bonds.
  • “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any proportion can be known as a “racemic” mixture.
  • “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • the absolute stereochemistry can be specified according to the Cahn-Ingold-Prelog R-S system.
  • the stereochemistry at each chiral carbon can be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro-or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • the sign of optical rotation, (+) and (-) is not related to the absolute configuration of the molecule, R and S.
  • Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry at each asymmetric atom, as (R) -or (S) -.
  • the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically substantially pure forms and intermediate mixtures.
  • Optically active (R) -and (S) -isomers can be prepared, for example, using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • enantiomeric purity or “enantiomer purity” refers to a qualitative or quantitative measure of a purified enantiomer.
  • the enantiomeric purity of compounds described herein may be described in terms of enantiomeric excess (ee) , which indicates the degree to which a sample contains one enantiomer in greater amounts than the other.
  • ee enantiomeric excess
  • a racemic mixture has an ee of 0%, while a single completely pure enantiomer has an ee of 100%.
  • Examples of the enantiomeric purity include an ee of at least about 10%, at least about 12%, at least about 14%, at least about 16%, at least about 18%, at least about 20%, at least about 22%, at least about 24%, at least about 26%, at least about 28%, at least about 30%, at least about 32%, at least about 34%, at least about 36%, at least about 38%, at least about 40%, at least about 42%, at least about 44%, at least about 46%, at least about 48%, at least about 50%, at least about 52%, at least about 54%, at least about 56%, at least about 58%, at least about 60%, at least about 62%, at least about 64%, at least about 66%, at least about 68%, at least about 70%, at least about 72%, at least about 74%, at least about 76%, at least about 78%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%,
  • substantially purified enantiomer refers to a compound wherein one enantiomer has been enriched over the other.
  • the other enantiomer represents less than about 20%, less than about 10%, less than about 5%, or less than about 2%of the enantiomer.
  • a substantially purified enantiomer has an enantiomeric excess of S enantiomer of at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%or at least about 99.9%.
  • a substantially purified enantiomer has an enantiomeric excess of R enantiomer of at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%or at least about 99.9%.
  • Stepoisomers can also include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof.
  • a compound described herein is isolated as either the E or Z isomer.
  • a compound described herein is a mixture of the E and Z isomers.
  • Tautomers refers to isomeric forms of a compound that are in equilibrium with each other.
  • concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution.
  • pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
  • the term “pharmaceutically acceptable salt” includes both acid and base addition salts.
  • Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glu
  • Examples of pharmaceutically acceptable base addition salt include, but are not limited to, salts prepared from addition of an inorganic base or an organic base to a free acid compound.
  • Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • the inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • the organic bases are isopropyl
  • the term “subject” refers to an animal, including, but not limited to, a primate (e.g., human) , cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • a primate e.g., human
  • the terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.
  • the subject is a mammal.
  • the subject is a human.
  • the terms “treat, ” “treating, ” and “treatment” refer to the eradication or amelioration of a disease or disorder, or of one or more symptoms associated with the disease or disorder. In general, treatment occurs after the onset of the disease or disorder. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease or disorder resulting from the administration of one or more prophylactic or therapeutic agents to a subject with such a disease or disorder.
  • prevention refers to the prevention of the onset, recurrence or spread of a disease or disorder, or of one or more symptoms thereof. In general, prevention occurs prior to the onset of the disease or disorder.
  • the terms “manage, ” “managing, ” and “management” refer to preventing or slowing the progression, spread or worsening of a disease or disorder, or of one or more symptoms thereof. Sometimes, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disease or disorder.
  • the term “therapeutically effective amount” are meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated.
  • therapeutically effective amount also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • IC 50 refers an amount, concentration, or dosage of a compound that is required for 50%inhibition of a maximal response in an assay that measures such response.
  • the term “pharmaceutically acceptable carrier, ” “pharmaceutically acceptable excipient, ” “physiologically acceptable carrier, ” or “physiologically acceptable excipient” refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • isotopes that can be incorporated into compounds provided herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • provided herein are compounds having the present structures except for the replacement or enrichment of a hydrogen by deuterium or tritium at one or more atoms in the molecule, or the replacement or enrichment of a carbon by 13 C or 14 C at one or more atoms in the molecule.
  • isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by deuterium.
  • isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by tritium In one embodiment, provided herein are isotopically labeled compounds having one or more carbon atoms replaced or enriched by 13 C. In one embodiment, provided herein are isotopically labeled compounds having one or more carbon atoms replaced or enriched by 14 C.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05%of a given value or range.
  • heteroaromatic compounds as ubiquitin-specific-processing protease 1 (USP1) inhibitors.
  • the compounds have a pyrimidine core structure.
  • X 1 is N or CR a1 ;
  • R a1 is hydrogen or C 1 -C 6 alkyl;
  • X 2 is N or CR a2 ;
  • R a2 is hydrogen or C 1 -C 6 alkyl;
  • X 3 is N or CR a3 ;
  • R a3 is hydrogen or C 1 -C 6 alkyl;
  • L is NR b , O or S;
  • R b is hydrogen or C 1 -C 6 alkyl;
  • R c and R d are each independently hydrogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; and each alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl in R c or R d is independently optionally substituted;
  • R 2 and R 3 are each independently halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino) alkyl, (dialkylamino) alkyl, cyanoalkyl, (carboxamido) alkyl, mercaptoalkyl, (cycloalkylamino) alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalky
  • R 4 is hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or (C 1 -C 6 alkoxy) - (C 1 -C 6 alkyl) ;
  • R 4’ is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or (C 1 -C 6 alkoxy) - (C 1 -C 6 alkyl) ;
  • R 7 is hydrogen or C 1 -C 6 alkyl
  • Ring A is aryl, heteroaryl, cycloalkyl, or heterocyclyl; and Ring A is optionally substituted;
  • R is hydrogen, halogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, or amido; and each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl moiety in R is independently optionally substituted.
  • the compound is a compound of Formula (I-A) :
  • the compound is a compound of Formula (I-B) :
  • R 1 is C 1 -C 6 alkoxy. In one embodiment, R 1 is C 1 -C 6 alkyl. In one embodiment, R 1 is N (C 1 -C 6 alkyl) 2 . In one embodiment, R 1 is -CONH (C 1 -C 6 alkyl) . In one embodiment, R 1 is -CON (C 1 -C 6 alkyl) 2 . In one embodiment, R 1 is -CONH (C 3 -C 8 cycloalkyl) . In one embodiment, R 1 is -CONH (C 1 -C 6 alkylene) - (C 1 -C 6 alkoxy) .
  • R 1 is -CONH (C 1 -C 6 alkylene) - (C 3 -C 8 heterocyclyl) . In one embodiment, R 1 is C 3 -C 8 cycloalkyl. In one embodiment, R 1 is 3-to 8-membered heterocyclyl. In one embodiment, R 1 is 5-to 10-membered aryl. In one embodiment, R 1 is 5-to 10-membered heteroaryl.
  • R 1 is methoxy. In one embodiment, R 1 is ethoxy. In one embodiment, R 1 is methoxymethoxy. In one embodiment, R 1 is 2-methoxyethoxy. In one embodiment, R 1 is methyl. In one embodiment, R 1 is ethyl. In one embodiment, R 1 is propyl or isopropyl. In one embodiment, R 1 is n-butyl, iso-butyl, or tert-butyl. In one embodiment, R 1 is pentyl. In one embodiment, R 1 is hexyl. In one embodiment, R 1 is fluoro. In one embodiment, R 1 is bromo. In one embodiment, R 1 is chloro. In one embodiment, R 1 is NH 2 . In one embodiment, R 1 is NHCH 3 . In one embodiment, R 1 is NHC 2 H 5 . In one embodiment, R 1 is -CONH 2 .
  • R c is hydrogen. In one embodiment, R c is alkyl. In one embodiment, R c is alkoxy. In one embodiment, R c is cycloalkyl. In one embodiment, R c is heterocyclyl. In one embodiment, R c is aryl. In one embodiment, R c is heteroaryl.
  • R c is C 1 -C 6 alkyl. In one embodiment, R c is C 1 -C 6 alkoxy. In one embodiment, R c is C 3 -C 8 cycloalkyl. In one embodiment, R c is 3-to 8-membered heterocyclyl. In one embodiment, R c is 5-to 10-membered aryl. In one embodiment, R c is 5-to 10-membered heteroaryl. In one embodiment, R c is C 1 -C 6 alkyl substituted with alkoxy. In one embodiment, R c is C 1 -C 6 alkyl substituted with heterocyclyl. In one embodiment, R c is C 1 -C 6 alkyl substituted with alkylamine. In one embodiment, R c is C 1 -C 6 alkyl substituted with dialkylamine.
  • R d is hydrogen. In one embodiment, R d is alkyl. In one embodiment, R d is alkoxy. In one embodiment, R d is cycloalkyl. In one embodiment, R d is heterocyclyl. In one embodiment, R d is aryl. In one embodiment, R d is heteroaryl.
  • R d is C 1 -C 6 alkyl. In one embodiment, R d is C 1 -C 6 alkoxy. In one embodiment, R d is C 3 -C 8 cycloalkyl. In one embodiment, R d is 3-to 8-membered heterocyclyl. In one embodiment, R d is 5-to 10-membered aryl. In one embodiment, R d is 5-to 10-membered heteroaryl. In one embodiment, R d is C 1 -C 6 alkyl substituted with alkoxy. In one embodiment, R d is C 1 -C 6 alkyl substituted with heterocyclyl. In one embodiment, R d is C 1 -C 6 alkyl substituted with alkylamine. In one embodiment, R d is C 1 -C 6 alkyl substituted with dialkylamine.
  • R c and R d are both hydrogen. In one embodiment, R c and R d are both alkyl. In one embodiment, R c and R d are both C 1 -C 6 alkyl. In one embodiment, R c and R d are both methyl.
  • L is NR b . In one embodiment, L is NH. In one embodiment, L is O. In one embodiment, L is S.
  • R b is hydrogen. In one embodiment, R b is C 1 -C 6 alkyl. In one embodiment, R b is methyl. In one embodiment, R b is ethyl. In one embodiment, R b is propyl (e.g. n-propyl or isopropyl) . In one embodiment, R b is butyl (e.g. n-butyl, iso-butyl, or tert-butyl) . In one embodiment, R b is pentyl. In one embodiment, R b is hexyl.
  • R 7 is hydrogen. In one embodiment, R 7 is alkyl. In one embodiment, R 7 is C 1 -C 6 alkyl. In one embodiment, R 7 is methyl. In one embodiment, R 7 is ethyl. In one embodiment, R 7 is propyl (e.g. n-propyl or isopropyl) . In one embodiment, R 7 is butyl (e.g. n-butyl, iso-butyl, or tert-butyl) . In one embodiment, R 7 is pentyl. In one embodiment, R b is hexyl.
  • Ring A is aryl. In one embodiment, Ring A is C 6 -C 10 aryl. In one embodiment, Ring A is phenyl. In one embodiment, Ring A is
  • Ring A is heteroaryl. In one embodiment, Ring A is a 5-to 10-membered heteroaryl. In one embodiment, Ring A is a 5-or 6-membered heteroaryl. In one embodiment, nitrogen is the only type of heteroatom contained in the heteroaryl. In one embodiment, Ring A is pyridyl. In one embodiment, Ring A is In one embodiment, Ring A is
  • Ring A is cycloalkyl. In one embodiment, Ring A is C 3 -C 8 cycloalkyl. In one embodiment, Ring A is C 5 -C 6 cycloalkyl. In one embodiment, Ring A is cyclopentyl. In one embodiment, Ring A is cyclohexyl.
  • Ring A is heterocyclyl. In one embodiment, Ring A is a 5-to 10-membered heterocyclyl. In one embodiment, Ring A is a 5-or 6-membered heterocyclyl. In one embodiment, nitrogen is the only type of heteroatom contained in the heterocyclyl. In one embodiment, Ring A is pyrrolidinyl. In one embodiment, Ring A is In one embodiment, Ring A is piperidinyl. In one embodiment, Ring A is piperidyl. In one embodiment, Ring A is
  • Ring A is optionally substituted with one or more R 5 ; and wherein each R 5 is independently halogen, cyano, alkyl, amino, alkylamino, dialkylamino, hydroxy, or alkoxy; and wherein each alkyl moiety is independently optionally substituted with one or more halogen, hydroxy, or alkoxy.
  • Ring A is unsubstituted.
  • Ring A is substituted with one R 5 .
  • Ring A is substituted with two R 5 . Unless otherwise specified, the substitution status for Ring A as described herein does not take the R group into consideration.
  • each R 5 is independently fluoro, chloro, cyano, methoxy, difluoromethoxy, hydroxyethoxy, or methoxyethoxy.
  • Ring A is selected from the group consisting of:
  • the point of attachment at left side of a Ring A structure is to carbon atom bearing R 4 group and the point of attachment at right side is to the R group.
  • R is hydrogen. In one embodiment, R is halogen. In one embodiment, R is alkyl. In one embodiment, R is cycloalkyl. In one embodiment, R is heterocyclyl. In one embodiment, R is aryl. In one embodiment, R is heteroaryl. In one embodiment, R is alkoxy. In one embodiment, R is cycloalkyloxy. In one embodiment, R is heterocyclyloxy. In one embodiment, R is aryloxy. In one embodiment, R is heteroaryloxy. In one embodiment, R is cycloalkylalkyl. In one embodiment, R is heterocyclylalkyl. In one embodiment, R is aralkyl. In one embodiment, R is heteroarylalkyl.
  • R is cycloalkylalkyloxy. In one embodiment, R is heterocyclylalkyloxy. In one embodiment, R is aralkyloxy. In one embodiment, R is heteroarylalkyloxy. In one embodiment, R is amido;
  • R is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-to 8-membered heterocyclyl, C 6 -C 10 aryl, 5-to 10-membered heteroaryl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyloxy, 4-to 8-membered heterocyclyloxy, C 6 -C 10 aryloxy, 5-to 10-membered heteroaryloxy, (C 3 -C 8 cycloalkyl) - (C 1 -C 2 alkyl) -, (4-to 8-membered heterocyclyl) - (C 1 -C 2 alkyl) -, (C 6 -C 10 aryl) - (C 1 -C 2 alkyl) -, (5-to 10-membered heteroaryl) - (C 1 -C 2 alkyl) -, (C 3 -C 8 cycloalkyl) - (C 1 -C 1 -
  • R is a 5-to 10-membered heteroaryl. In one embodiment, R is a 5-or 6-membered heteroaryl. In one embodiment, R is a 5-or 6-membered nitrogen- containing heteroaryl. In one embodiment, R is a 5-or 6-membered nitrogen-containing heteroaryl, and nitrogen is the only type of heteroatom contained in the heteroaryl. In one embodiment, R is imidazolyl. In one embodiment, R is pyridyl. In one embodiment, R is pyrazolyl. In one embodiment, R is pyridazinyl. In one embodiment, R is pyrimidinyl. In one embodiment, R is triazinyl. In one embodiment, R is pyrazinyl.
  • R is triazolyl. In one embodiment, R is a 5-or 6-membered nitrogen-containing heteroaryl, and the heteroaryl contains at least one heteroatom other than nitrogen. In one embodiment, R is oxazolyl. In one embodiment, R is thiazolyl.
  • R is optionally substituted with one or more R 6 ; and each R 6 is independently halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino) alkyl, (dialkylamino) alkyl, cyanoalkyl, (carboxamido) alkyl, mercaptoalkyl, (cycloalkylamino) alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkyl,
  • R is optionally substituted with one or more R 6 ; and wherein each R 6 is independently cyano, nitro, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, l-fluoropropan-2-yl, 2-fluoroethyl, amino, methylamino, ethylamino, dimethylamino, 2, 2-difluoroethoxy, cyclopropoxy, morpholino, tetrahydropyranyl, oxetanyl, methoxymethyl, N, N-dimethylsulfonamido, cyclopropyl, cyclobutyl, methylaminomethyl, deuteromethyl, deutero
  • R is substituted with one R 6 . In one embodiment, R is substituted with R 6 at a position adjacent to the point of attachment of R to Ring A. In one embodiment, R is substituted with R 6 at a position that is separated by one ring atom to the point of attachment of R to Ring A.
  • R is substituted with two R 6 .
  • R is substituted with R 6 at (i) a position adjacent to the point of attachment of R to Ring A, and (ii) a position that is separated by one ring atom to the point of attachment of R to Ring A.
  • the two positions are on the same side of the point of attachment of R to Ring A. In one embodiment, the two positions are on the opposite side of the point of attachment of R to Ring A.
  • R is In one embodiment, R is In one embodiment, R is In one embodiment, R is In one embodiment, R is In one embodiment, R is In one embodiment, R is In one embodiment, R is In one embodiment, R is In one embodiment, R is In one embodiment, R is In one embodiment, R is In one embodiment, R is In one embodiment, R is In one embodiment, R is In one embodiment, R is In one embodiment, R is In one embodiment, R is In one embodiment, R is in one embodiment, R is In one embodiment, R is
  • R is selected from the group consisting of:
  • R is selected from the group consisting of:
  • X 1 is CR a1 . In one embodiment, X 1 is CH. In one embodiment, X 1 is N. In one embodiment, R a1 is hydrogen. In one embodiment, R a1 is C 1 -C 6 alkyl. In one embodiment, R a1 is methyl. In one embodiment, R a1 is ethyl. In one embodiment, R a1 is propyl (e.g. n-propyl or isopropyl) . In one embodiment, R a1 is butyl (e.g. n-butyl, iso-butyl, or tert-butyl) . In one embodiment, R a1 is pentyl. In one embodiment, R a1 is hexyl.
  • X 2 is CR a2 . In one embodiment, X 2 is CH. In one embodiment, X 2 is N. In one embodiment, R a2 is hydrogen. In one embodiment, R a2 is C 1 -C 6 alkyl. In one embodiment, R a2 is methyl. In one embodiment, R a2 is ethyl. In one embodiment, R a2 is propyl or isopropyl. In one embodiment, R a2 is n-butyl, iso-butyl, or tert-butyl. In one embodiment, R a2 is pentyl. In one embodiment, R a2 is hexyl.
  • X 3 is CR a3 . In one embodiment, X 3 is CH. In one embodiment, X 3 is N. In one embodiment, R a3 is hydrogen. In one embodiment, R a3 is C 1 - C 6 alkyl. In one embodiment, R a3 is methyl. In one embodiment, R a3 is ethyl. In one embodiment, R a3 is propyl or isopropyl. In one embodiment, R a3 is n-butyl, iso-butyl, or tert-butyl. In one embodiment, R a3 is pentyl. In one embodiment, R a3 is hexyl.
  • X 1 is CR a1
  • X 2 is CR a2 .
  • X 1 is CR a1
  • X 2 is N.
  • X 1 is N
  • X 2 is CR a2 .
  • X 1 is N
  • X 2 is N.
  • X 1 is CR a1
  • X 3 is CR a3 .
  • X 1 is CR a1
  • X 3 is N.
  • X 1 is N, and X 3 is CR a3 .
  • X 1 is N, and X 3 is N.
  • X 2 is CR a2
  • X 3 is CR a3
  • X 2 is CR a2
  • X 3 is N
  • X 2 is N
  • X 3 is CR a3
  • X 2 is N
  • X 3 is N.
  • X 1 is N, X 2 is N, and X 3 is CR a3 . In one embodiment, X 1 is N, X 2 is N, and X 3 is CH. In one embodiment, X 1 is CR a1 , X 2 is CR a2 , and X 3 is CR a3 . In one embodiment, X 1 is CH, X 2 is CH, and X 3 is CH.
  • R 4’ is hydrogen. In one embodiment, R 4’ is halogen. In one embodiment, R 4’ is C 1 -C 6 alkyl. In one embodiment, R 4’ is C 1 -C 6 alkoxy. In one embodiment, R 4’ is (C 1 -C 6 alkoxy) - (C 1 -C 6 alkyl) .
  • R 4 is hydroxyl. In one embodiment, R 4 is C 1 -C 6 alkyl. In one embodiment, R 4 is methyl. In one embodiment, R 4 is ethyl. In one embodiment, R 4 is propyl (e.g. n-propyl or isopropyl) . In one embodiment, R 4 is butyl (e.g. n-butyl, iso-butyl, or tert-butyl) . In one embodiment, R 4 is pentyl. In one embodiment, R 4 is hexyl.
  • R 4 is C 1 -C 6 alkoxy. In one embodiment, R 4 is methoxy. In one embodiment, R 4 is ethoxy. In one embodiment, R 4 is -O-propyl. In one embodiment, R 4 is -O-butyl. In one embodiment, R 4 is -O-pentyl. In one embodiment, R 4 is -O-hexyl.
  • R 4 is (C 1 -C 6 alkoxy) - (C 1 -C 6 alkyl) . In one embodiment, R 4 is methoxymethyl. In one embodiment, R 4 is ethoxymethyl. In one embodiment, R 4 is ethoxyethyl.
  • R 4 and R 4’ are the same. In one embodiment, R 4 and R 4’ are different. In one embodiment, R 4’ is hydrogen and R 4 is hydroxyl. In one embodiment, R 4’ is hydrogen and R 4 is C 1 -C 6 alkyl. In one embodiment, R 4’ is hydrogen and R 4 is methyl. In one embodiment, R 4’ is hydrogen and R 4 is C 1 -C 6 alkoxy. In one embodiment, R 4’ is hydrogen and R 4 is methoxy. In one embodiment, R 4’ is hydrogen and R 4 is (C 1 -C 6 alkoxy) - (C 1 -C 6 alkyl) . In one embodiment, R 4’ is hydrogen and R 4 is methoxymethyl.
  • X 4 is CR a4 or N
  • X 5 is CR a5 or N
  • X 6 is CR a6 or N
  • X 7 is CR a7 or N
  • X 8 is CR a8 , N, NR a8 , O, or S;
  • X 9 is CR a9 , N, NR a9 , O, or S;
  • X 10 is CR a10 , N, NR a10 , O, or S;
  • X 11 is CR a11 , N, NR a11 , O, or S;
  • X 12 is C or N
  • X 13 is CR a13 or N
  • X 14 is CR a14 or N
  • X 15 is CR a15 or N
  • X 16 is CR a16 or N
  • X 17 is CR a17 or N
  • each R a4 , R a5 , R a6 , R a7 is independently hydrogen or R 5 ;
  • each R a8 , R a9 , R a10 , R a11 , R a13 , R a14 , R a15 , R a16 and R a17 is independently hydrogen or R 6 ;
  • each R 5 is independently halogen, cyano, alkyl, amino, alkylamino, dialkylamino, hydroxy, or alkoxy; and wherein each alkyl moiety is independently optionally substituted with one or more halogen, hydroxy, or alkoxy; and
  • each R 6 is independently halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino) alkyl, (dialkylamino) alkyl, cyanoalkyl, (carboxamido) alkyl, mercaptoalkyl, (cycloalkylamino) alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl) amino
  • X 4 is CR a4 . In one embodiment, X 4 is CH. In one embodiment, X 4 is CR 5 . In one embodiment, X 4 is N. In one embodiment, X 5 is CR a5 . In one embodiment, X 5 is CH. In one embodiment, X 5 is CR 5 . In one embodiment, X 5 is N. In one embodiment, X 6 is CR a6 . In one embodiment, X 6 is CH. In one embodiment, X 6 is CR 5 . In one embodiment, X 6 is N. In one embodiment, X 7 is CR a7 . In one embodiment, X 7 is CH. In one embodiment, X 7 is CR 5 . In one embodiment, X 7 is N.
  • X 4 is N, and X 5 is CR a5 . In one embodiment, X 4 is CR a4 , and X 5 is N. In one embodiment, X 6 is N, and X 7 is CR a7 . In one embodiment, X 6 is CR a6 , and X 7 is N. In one embodiment, X 4 is N, and X 5 is N. In one embodiment, X 4 is N, and X 6 is N. In one embodiment, X 4 is N, and X 7 is N. In one embodiment, X 5 is N, and X 6 is N. In one embodiment, X 5 is N, and X 7 is N. In one embodiment, X 5 is N, and X 6 is N. In one embodiment, X 5 is N, and X 7 is N.
  • X 4 is N, X 5 is CR a5 , X 6 is CR a6 , and X 7 is CR a7 .
  • X 4 is CR a4 , X 5 is N, X 6 is CR a6 , and X 7 is CR a7 .
  • X 4 is CR a4 , X 5 is CR a5 , X 6 is N, and X 7 is CR a7 .
  • X 4 is CR a4 , X 5 is CR a5 , X 6 is CR a6 , and X 7 is N.
  • X 4 is CR a4
  • X 5 is CR a5
  • X 6 is CR a6
  • X 7 is CR a7 .
  • R a4 , R a5 , R a6 and R a7 are all hydrogen.
  • X 8 is CR a8 . In one embodiment, X 8 is CH. In one embodiment, X 8 is CR 6 . In one embodiment, X 8 is N. In one embodiment, X 8 is NR a8 . In one embodiment, X 8 is NH. In one embodiment, X 8 is NR 6 . In one embodiment, X 8 is O. In one embodiment, X 8 is S. In one embodiment, X 9 is CR a9 . In one embodiment, X 9 is CH. In one embodiment, X 9 is CR 6 . In one embodiment, X 9 is N. In one embodiment, X 9 is NR a9 . In one embodiment, X 9 is NH.
  • X 9 is NR 6 . In one embodiment, X 9 is O. In one embodiment, X 9 is S. In one embodiment, X 10 is CR a10 . In one embodiment, X 10 is CH. In one embodiment, X 10 is CR 6 . In one embodiment, X 10 is N. In one embodiment, X 10 is NR a10 . In one embodiment, X 10 is NH. In one embodiment, X 10 is NR 6 . In one embodiment, X 10 is O. In one embodiment, X 10 is S. In one embodiment, X 11 is CR a11 . In one embodiment, X 11 is CH. In one embodiment, X 11 is CR 6 . In one embodiment, X 11 is N.
  • X 11 is NR a11 . In one embodiment, X 11 is NH. In one embodiment, X 11 is NR 6 . In one embodiment, X 11 is O. In one embodiment, X 11 is S. In one embodiment, X 12 is C. In one embodiment, X 12 is N.
  • X 8 is N, and X 9 is CR 6 . In one embodiment, X 9 is CR 6 or NR 6 , and X 11 is CR 6 or NR 6 . In one embodiment, X 8 is CH or N, and X 10 is CH or N. In one embodiment, X 8 is CH or N, X 9 is CH or N, and X 10 is CH or N. In one embodiment, X 8 is N, X 9 is CR 6 and X 11 is NR 6 . In one embodiment, X 8 is CH or N, X 10 is CH or N, and X 11 is CH or N.
  • one of X 8 , X 9 , X 10 , X 11 and X 12 is N. In one embodiment, two of X 8 , X 9 , X 10 , X 11 and X 12 are N. In one embodiment, three of X 8 , X 9 , X 10 , X 11 and X 12 are N.
  • X 13 is CR a13 . In one embodiment, X 13 is CH. In one embodiment, X 13 is CR 6 . In one embodiment, X 13 is N. In one embodiment, X 14 is CR a14 . In one embodiment, X 14 is CH. In one embodiment, X 14 is CR 6 . In one embodiment, X 14 is N. In one embodiment, X 15 is CR a15 . In one embodiment, X 15 is CH. In one embodiment, X 15 is CR 6 . In one embodiment, X 15 is N. In one embodiment, X 16 is CR a16 . In one embodiment, X 16 is CH. In one embodiment, X 16 is CR 6 . In one embodiment, X 16 is N. In one embodiment, X 17 is CR a17 . In one embodiment, X 17 is CH. In one embodiment, X 17 is CR 6 . In one embodiment, X 17 is N. In one embodiment, X 17 is CR a17 . In one embodiment
  • X 13 is N, and X 14 is CR 6 . In one embodiment, X 13 is N, and X 14 is N. In one embodiment, X 13 is N, and X 15 is N. In one embodiment, X 13 is N, and X 17 is CR 6 . In one embodiment, X 13 is N, and X 16 is N. In one embodiment, X 13 is CR 6 , and X 17 is N. In one embodiment, X 14 is N, and X 17 is CR 6 .
  • X 14 is N, X 17 is CR 6 and X 16 is CH. In one embodiment, X 14 is N, X 17 is CR 6 and X 16 is CH. In one embodiment, X 13 is N, X 14 is N and X 15 is CR 6 . In one embodiment, X 13 is N, X 14 is N and X 17 is CR 6 . In one embodiment, X 13 is N, X 16 is N, and X 17 is CR 6 . In one embodiment, X 13 is N, X 16 is N, and X 14 is CR 6 . In one embodiment, X 13 is N, X 14 is CR 6 , and X 17 is CR 6 . In one embodiment, X 13 is N, X 14 is CR 6 , and X 17 is CR 6 . In one embodiment, X 13 is N, X 15 is CR 6 , and X 17 is CR 6 . In one embodiment, X 13 is N, X 15 is CH, and X 16 is
  • one of X 13 , X 14 , X 15 , X 16 and X 17 is N. In one embodiment, two of X 13 , X 14 , X 15 , X 16 and X 17 are N. In one embodiment, three of X 13 , X 14 , X 15 , X 16 and X 17 are N.
  • each R 6 is independently halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, alkylamino, dialkylamino, and wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl moiety is independently optionally substituted with one or more C 1 -C 6 alkyl, acyl, halogen, or deuterium.
  • each R 6 is independently cyano, nitro, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, l-fluoropropan-2-yl, 2-fluoroethyl, acetyl, amino, methylamino, ethylamino, dimethylamino, 2, 2-difluoroethoxy, cyclopropoxy, morpholino, tetrahydropyranyl, oxetanyl, methoxymethyl, N, N-dimethylsulfonamido, cyclopropyl, cyclobutyl, methylaminomethyl, deuteromethyl, deuteroethyl,
  • each R 6 is independently fluoro, methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, methoxy, dimethylamine, acetylmethylamine or 1-acetylpiperidin-4-yl.
  • the R 6 at a position that is separated by one ring atom to the point of attachment of R to Ring A is trifluoromethyl.
  • one R 6 trifluoromethyl and the other R 6 is alkyl. In one embodiment, one R 6 trifluoromethyl and the other R 6 is alkoxy. In one embodiment, one R 6 trifluoromethyl and the other R 6 is cycloalkyl. In one embodiment, one R 6 alkyl and the other R 6 is alkoxy. In one embodiment, one R 6 halogen and the other R 6 is alkoxy. In one embodiment, one R 6 halogen and the other R 6 is alkyl. In one embodiment, one R 6 alkoxy and the other R 6 is cycloalkyl. In one embodiment, one R 6 alkyl and the other R 6 is cycloalkyl. In one embodiment, one R 6 alkyl and the other R 6 is dialkylamino.
  • R 2 and R 3 are each independently halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino) alkyl, (dialkylamino) alkyl, cyanoalkyl, (carboxamido) alkyl, mercaptoalkyl, (cycloalkylamino) alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (
  • R 2 and R 3 are each independently halogen, nitro, cyano, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3-to 8-membered heterocyclyl, 5-to 10-membered aryl, 5-to 10-membered heteroaryl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyloxy, 3-to 8-membered heterocyclyloxy, 5-to 10-membered aryloxy, 5-to 10-membered heteroaryloxy, (C 3 -C 8 cycloalkyl) (C 1 -C 6 alkyl) , or (3-to 8-membered heterocyclyl) (C 1 -C 6 alkyl) .
  • R 2 is cyano, amino, methylamino, dimethylamino, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, cyclopropoxy, cyclobutoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, chloro, fluoro, l-fluoropropan-2-yl, (S) -1-fluoropropan-2-yl, (R) -l-fluoropropan-2-yl, hydroxyethyl, l-methoxy-2-methylpropan-2-yl, 1-methoxypropan-2-yl, (S) -1-methoxypropan-2-yl, (R) -l-methoxypropan-2-
  • R 2 is cycloalkyl. In one embodiment, R 2 is C 3 -C 8 cycloalkyl. In one embodiment, R 2 is cyclopropyl. In one embodiment, R 2 is cyclobutyl.
  • R 3 is cyano, amino, methylamino, dimethylamino, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, cyclopropoxy, cyclobutoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, chloro, fluoro, l-fluoropropan-2-yl, (S) -1-fluoropropan-2-yl, (R) -l-fluoropropan-2-yl, hydroxyethyl, l-methoxy-2-methylpropan-2-yl, 1-methoxypropan-2-yl, (S) -1-methoxypropan-2-yl, (R) -l-methoxypropan-2-
  • R 3 is alkoxy. In one embodiment, R 3 is C 1 -C 6 alkoxy. In one embodiment, R 3 is methoxy. In one embodiment, R 3 is ethoxy.
  • R 2 is cycloalkyl and R 3 is alkoxy. In one embodiment, R 2 is C 3 -C 8 cycloalkyl and R 3 is C 1 -C 6 alkoxy. In one embodiment, R 2 is cyclopropyl and R 3 is methoxy.
  • X 1 is CR a1
  • X 2 is CR a2
  • X 3 is CR a3
  • R 2 is cycloalkyl
  • R 3 is alkoxy.
  • X 1 , X 2 , and X 3 are CH, R 2 is cycloalkyl, and R 3 is alkoxy.
  • X 1 is N, X 2 is CR a2 , X 3 is CR a3 , R 2 is cycloalkyl, and R 3 is alkoxy.
  • X 2 is N, X 1 is CR a1 , X 3 is CR a3 , R 2 is cycloalkyl, and R 3 is alkoxy.
  • X 3 is N, X 1 is CR a1 , X 2 is CR a2 , R 2 is cycloalkyl, and R 3 is alkoxy.
  • X 1 is N, X 2 is N, X 3 is CR a3 , R 2 is cycloalkyl, and R 3 is alkoxy.
  • X 1 is N, X 2 is N, X 3 is CH, R 2 is cycloalkyl, and R 3 is alkoxy.
  • X 1 is N
  • X 2 is CR a2
  • X 3 is N
  • R 2 is cycloalkyl
  • R 3 is alkoxy
  • X 2 is N
  • X 3 is N
  • X 1 is CR a1
  • R 2 is cycloalkyl
  • R 3 is alkoxy
  • R 1 is alkoxy.
  • R 2 is cycloalkyl.
  • R 3 is methoxy.
  • R 4 is methyl.
  • the compounds provided herein are single enantiomers. In one embodiment, the compounds provided herein are single diastereoisomers. In one embodiment, the compounds provided herein are mixtures of enantiomers. In one embodiment, the compounds provided herein are mixtures of diastereoisomers. In one embodiment, the compounds provided herein are racemic compounds.
  • a compound provided herein has enantiomeric excess of at least about 10%, at least about 20%, at least about 30%, at least about 40%, 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%, at least about 98%, at least about 99%, at least about 99.5%, or at least about 99.9%.
  • the compound is a substantially purified enantiomer.
  • the compound is a substantially purified enantiomer of S-configuration.
  • the compound is a substantially purified enantiomer of R-configuration.
  • the compound has enantiomeric excess of S-configuration of at least about 80%. In one embodiment, the compound has enantiomeric excess of S-configuration of at least about 90%. In one embodiment, the compound has enantiomeric excess of S-configuration of at least about 92%. In one embodiment, the compound has enantiomeric excess of S-configuration of at least about 94%. In one embodiment, the compound has enantiomeric excess of S-configuration of at least about 96%. In one embodiment, the compound has enantiomeric excess of S-configuration of at least about 98%. In one embodiment, the compound has enantiomeric excess of S-configuration of at least about 99%. In one embodiment, the compound has enantiomeric excess of S-configuration of at least about 99.5%. In one embodiment, the compound has enantiomeric excess of S-configuration of at least about 99.9%.
  • the compound has enantiomeric excess of R-configuration of at least about 80%. In one embodiment, the compound has enantiomeric excess of R-configuration of at least about 90%. In one embodiment, the compound has enantiomeric excess of R-configuration of at least about 92%. In one embodiment, the compound has enantiomeric excess of R-configuration of at least about 94%. In one embodiment, the compound has enantiomeric excess of R-configuration of at least about 96%. In one embodiment, the compound has enantiomeric excess of R-configuration of at least about 98%. In one embodiment, the compound has enantiomeric excess of R-configuration of at least about 99%. In one embodiment, the compound has enantiomeric excess of R-configuration of at least about 99.5%. In one embodiment, the compound has enantiomeric excess of R-configuration of at least about 99.9%.
  • the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof.
  • stereochemical configuration for a chiral center in a compound provided herein is drawn stereo specifically (e.g., with widget and/or dash bonds) , either without additional designation or being designated “R” (or “ (R) ” ) or “S’ (or “ (S) ” ) , it means the absolute stereochemistry is known.
  • the stereochemical configuration at indicated centers has been designated as “*R” (first eluted from the column in case the column conditions of the separation are described in the synthesis protocol and when only one stereocenter present or indicated) or “*S” (second eluted from the column in case the column conditions of the separation are described in the synthesis protocol and when only one stereocenter present or indicated) when the absolute stereochemistry is undetermined (even if the bonds are drawn stereo specifically) although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure.
  • the “*R” indication of the resulting compound is derived from its starting material.
  • the compounds provided herein are USP1 inhibitors that reduce the level of USP1 protein and/or inhibit or reduce at least one biological activity of USP1 protein.
  • the compounds provided herein specifically bind to USP1 protein. In one embodiment, the compounds provided herein specifically bind to USP1 protein in a USP1-UAF1 complex. In one embodiment, the compounds provided herein specifically bind to USP1 mRNA. In one embodiment, the compounds provided herein specifically bind to USP1 protein (alone or in a USP1-UAF1 complex) or USP1 mRNA. In one embodiment, the compounds provided herein specifically bind to UAF1 (alone or in a USP1-UAF1 complex) and inhibit or reduces formation or activity of the USP1-UAF1 complex.
  • the S enantiomer of a compound provided herein has a higher binding affinity to USP1 protein than the R enantiomer. In one embodiment, the S enantiomer has a binding affinity to USP1 protein of at least 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 8 times, 10 times, 20 times, 30 times, 50 times or 100 times higher than the R enantiomer.
  • the R enantiomer of a compound provided herein has a higher binding affinity to USP1 protein than the S enantiomer. In one embodiment, the R enantiomer has a binding affinity to USP1 protein of at least 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 8 times, 10 times, 20 times, 30 times, 50 times or 100 times higher than the S enantiomer.
  • the compounds provided herein decrease the formation of the USP1-UAF1 complex. In one embodiment, the compounds provided herein decrease the activity of the USP1-UAF1 complex. In one embodiment, the compounds provided herein decrease the deubiquitinase activity of USP1. In one embodiment, the compounds provided herein increase mono-ubiquitinated PCNA. In one embodiment, the compounds provided herein increase mono-ubiquitinated FANCD2.
  • the compounds provided herein increase mono-ubiquitinated FANCI.
  • the compounds provided herein do not bind to other deubiquitinases, other USP proteins, or other UAFl complexes (e.g., USP46-UAF1) .
  • the compounds provided herein bind to deubiquitinases, other USP proteins, or other UAFl complexes (e.g., USP46-UAF1) with at least about 5-fold, at least about 10-fold, at least about 20-fold, or at least about 100-fold reduced affinity compared to the affinity for USP1 (i.e., the K D of the compounds provided herein for other deubiquitinases, other USP proteins, or other UAFl complexes (e.g., USP46-UAF1) is at least about 5-fold, at least about 10-fold, at least about 20-fold, or at least about 100-fold higher than the KD for USP1) .
  • the compounds provided herein inhibit USP1 deubiquitinase activity with an IC 50 of less than about 50 nM, between about 50 nM and about 200 nM, between about 200 nM and about 2 ⁇ M, or greater than 2 ⁇ M, e.g., as measured using the assay described in US Patent Application Publication No. 2017/0145012, or IC 50 of 50 nM to 1000 nM, e.g., as measured using the assay disclosed in Liang et al., Nat Chem Biol 10: 289-304 (2014) .
  • the compounds provided herein inhibit USP1 deubiquitinase activity with an IC 50 as measured using the assay disclosed in Chen, et al., Chem Biol., 18 (11) : 1390-1400 (2011) .
  • the compounds provided herein do not inhibit the activity of other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) , or the compounds provided herein inhibit the activity of other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) with at least about 5-fold, at least about 10-fold, at least about 20-fold, or at least about 100-fold higher IC 50 compared to the IC 50 for inhibition of USP1 deubiquitinase activity.
  • the compounds provided herein bind to a USP1 protein with an affinity in the range of about 1 pM to about 100 ⁇ M, about 1 pM to about 1 ⁇ M, about 1 pM to about 500 nM, or about 1 pM to about 100 nM.
  • the compounds provided herein bind to a USP1 protein with an affinity of about 1 pM to about 100 ⁇ M, about 1 nM to about 100 ⁇ M, about 1 ⁇ M to about 100 ⁇ M, about 1 ⁇ M to about 50 ⁇ M, about 1 ⁇ M to about 40 ⁇ M, about 1 ⁇ M to about 30 ⁇ M, about 1 ⁇ M to about 20 ⁇ M, or about 1 ⁇ M to about 10 ⁇ M, about 1 ⁇ M, about 5 ⁇ M, about 10 ⁇ M, about 15 ⁇ M, about 20 ⁇ M, about 25 ⁇ M, about 30 ⁇ M, about 35 ⁇ M, about 40 ⁇ M, about 45 ⁇ M, about 50 ⁇ M, about 60 ⁇ M, about 70 ⁇ M, about 80 ⁇ M, about 90 ⁇ M, or about 100 ⁇ M.
  • the compounds provided herein bind to a USP1 protein with an affinity of about 100 nM to about 1 ⁇ M, about 100 nM to about 900 nM, about 100 nM to about 800 nM, about 100 nM to about 700 nM, about 100 nM to about 600 nM, about 100 nM to about 500 nM, about 100 nM to about 400 nM, about 100 nM to about 300 nM, about 100 nM to about 200 nM, about 200 nM to about 1 ⁇ M, about 300 nM to about 1 ⁇ M, about 400 nM to about 1 ⁇ M, about 500 nM to about 1 ⁇ M, about 600 nM to about 1 ⁇ M, about 700 nM to about 1 ⁇ M, about 800 nM to about 1 ⁇ M, about 900 nM to about 1 ⁇ M, about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM to
  • the compounds provided herein bind to a USP1 protein with an affinity of about 1 nM to about 100 nM, about 1 nM to about 90 nM, about 1 nM to about 80 nM, about 1 nM to about 70 nM, about 1 nM to about 60 nM, about 1 nM to about 50 nM, about 1 nM to about 40 nM, about 1 nM to about 30 nM, about 1 nM to about 20 nM, about 1 nM to about 10 nM, about 10 nM to about 100 nM, about 20 nM to about 100 nM, about 30 nM to about 100 nM, about 40 nM to about 100 nM, about 50 nM to about 100 nM, about 60 nM to about 100 nM, about 70 nM to about 100 nM, about 80 nM to about 100 nM, about 90 nM to about 100 nM, about 1 nM, about 1
  • the compounds provided herein bind to a USP1 protein with an affinity of less than about 1 ⁇ M, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. In one embodiment, the compounds provided herein bind to a USP1 protein with an affinity of less than 1 nM.
  • the compounds provided herein inhibit USP1 activity with an IC 50 of about 1 pM to about 100 ⁇ M, or about 1 pM to about 1 ⁇ M, or about 1 pM to about 500 nM, or about 1 pM to about 100 nM.
  • the compounds provided herein inhibit USP1 activity with an IC 50 of about 1 pM to about 100 ⁇ M, about 1 nM to about 100 ⁇ M, about 1 ⁇ M to about 100 ⁇ M, about 1 ⁇ M to about 50 ⁇ M, about 1 ⁇ M to about 40 ⁇ M, about 1 ⁇ M to about 30 ⁇ M, about 1 ⁇ M to about 20 ⁇ M, or about 1 ⁇ M to about 10 ⁇ M, about 1 ⁇ M, about 5 ⁇ M, about 10 ⁇ M, about 15 ⁇ M, about 20 ⁇ M, about 25 ⁇ M, about 30 ⁇ M, about 35 ⁇ M, about 40 ⁇ M, about 45 ⁇ M, about 50 ⁇ M, about 60 ⁇ M, about 70 ⁇ M, about 80 ⁇ M, about 90 ⁇ M, or about 100 ⁇ M.
  • the compounds provided herein inhibit USP1 activity with an IC 50 of about 100 nM to about 1 ⁇ M, about 100 nM to about 900 nM, about 100 nM to about 800 nM, about 100 nM to about 700 nM, about 100 nM to about 600 nM, about 100 nM to about 500 nM, about 100 nM to about 400 nM, about 100 nM to about 300 nM, about 100 nM to about 200 nM, about 200 nM to about 1 ⁇ M, about 300 nM to about 1 ⁇ M, about 400 nM to about 1 ⁇ M, about 500 nM to about 1 ⁇ M, about 600 nM to about 1 ⁇ M, about 700 nM to about 1 ⁇ M, about 800 nM to about 1 ⁇ M, about 900 nM to about 1 ⁇ M, about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, about 200
  • the compounds provided herein inhibit USP1 activity with an IC 50 of about 1 nM to about 100 nM, about 1 nM to about 90 nM, about 1 nM to about 80 nM, about 1 nM to about 70 nM, about 1 nM to about 60 nM, about 1 nM to about 50 nM, about 1 nM to about 40 nM, about 1 nM to about 30 nM, about 1 nM to about 20 nM, about 1 nM to about 10 nM, about 10 nM to about 100 nM, about 20 nM to about 100 nM, about 30 nM to about 100 nM, about 40 nM to about 100 nM, about 50 nM to about 100 nM, about 60 nM to about 100 nM, about 70 nM to about 100 nM, about 80 nM to about 100 nM, about 90 nM to about 100 nM, about 1 nM, about
  • the compounds provided herein inhibit USP1 activity with an ICso of less than 1 ⁇ M, less than 500 nM, less than 100 nM, less than 10 nM, or less than 1 nM. In one embodiment, the compounds provided herein inhibit USP1 activity with an IC 50 of less than 1 nM.
  • the IC 50 of the S enantiomer of a compound provided herein is lower than the IC 50 of the R enantiomer for inhibiting USP1 activity.
  • the IC 50 of the R enantiomer is at least 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 8 times, 10 times, 20 times, 30 times, 50 times or 100 times higher than the IC 50 of the S enantiomer for inhibiting USP1 activity.
  • the IC 50 of the R enantiomer of a compound provided herein is lower than the IC 50 of the S enantiomer for inhibiting USP1 activity.
  • the IC 50 of the S enantiomer is at least 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 8 times, 10 times, 20 times, 30 times, 50 times or 100 times higher than the IC 50 of the R enantiomer for inhibiting USP1 activity.
  • the compounds provided herein can be used to inhibit the activity of a USP1 protein.
  • a method of inhibiting a USP1 protein comprises contacting the USP1 protein with a compound provided herein. The contacting can occur in vitro or in vivo. In one embodiment, the contacting occurs in a subject suffering from a USP1 protein mediated disorder.
  • the compounds provided herein can be used to treat a USP1 protein mediated disorder.
  • a method of treating a USP1 protein mediated disorder or cancer comprising administering to a subject having the disorder or cancer a therapeutically effective amount of a compound provided herein or a pharmaceutical composition provided herein.
  • a USP1 protein mediated disorder is any pathological condition in which a USP1 protein is known to play a role.
  • a USP1 protein mediated disorder is a proliferative disease such as cancer.
  • provided herein are methods of treating diseases and disorders with the compounds provided herein.
  • Exemplary diseases and disorders that may be treated with the compounds provided herein include, but are not limited to, cancer.
  • provided herein is a method of treating a cancer, comprising administering to a subject having the cancer a therapeutically effective amount of a compound provided herein or a pharmaceutical composition provided herein.
  • the cancer is a hematological cancer, a lymphatic cancer, a DNA damage repair pathway deficient cancer, a homologous-recombination deficient cancer, a cancer comprising cancer cells with a mutation in a gene encoding p53, or a cancer comprising cancer cells with a loss of function mutation in a gene encoding p53.
  • the cancer is a cancer that comprises cancer cells with a mutation in a gene encoding p53.
  • the cancer is a cancer that comprises cancer cells with a loss of function mutation in a gene encoding p53.
  • the cancer is a cancer that comprises cancer cells with a mutation in a gene encoding BRCA1.
  • the cancer is a cancer that comprises cancer cells with a mutation in a gene encoding BRCA2.
  • the cancer is a cancer that comprises cancer cells with a loss of function mutation in a gene encoding ATM.
  • the cancer is a solid tumor.
  • the cancer is lung cancer, non-small cell lung cancer (NSCLC) , colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, or breast cancer.
  • the cancer is non-small cell lung cancer (NSCLC) , osteosarcoma, ovarian cancer, or breast cancer.
  • the cancer is ovarian cancer.
  • the cancer is breast cancer.
  • the cancer is a triple negative breast cancer.
  • the cancer to be treated with a compound provided herein is selected from the group consisting of bone cancer, including osteosarcoma and chondrosarcoma; brain cancer, including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma; soft tissue cancer, including rhabdoid and sarcoma; kidney cancer; bladder cancer; skin cancer, including melanoma; and lung cancer, including non-small cell lung cancer; colon cancer, uterine cancer; nervous system cancer; head and neck cancer; pancreatic cancer; and cervical cancer.
  • bone cancer including osteosarcoma and chondrosarcoma
  • brain cancer including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma
  • soft tissue cancer including rhabdoid and sarcoma
  • kidney cancer including melanoma
  • lung cancer including non-small cell lung cancer
  • colon cancer
  • a method of treating cancer comprising administering to a subject having the cancer a therapeutically effective amount of a compound provided herein, wherein the cancer comprises cancer cells with elevated levels of RAD18.
  • the elevated levels of RAD 18 are elevated RAD 18 protein levels.
  • the elevated levels of RAD 18 are elevated RAD 18 mRNA levels.
  • the elevated levels of RAD18 e.g., RAD18 protein and/or RAD18 mRNA
  • the elevated levels of RAD18 have been detected (e.g., in a cancer sample obtained from the subject) prior to the administration. That is, in one embodiment, the cancer in the subject has been tested for RAD 18 protein or mRNA prior to beginning treatment with a USP1 inhibitor, such as a compound provided herein.
  • such methods comprise (a) identifying a cancer in a subject as a USP1 inhibitor-sensitive cancer, and then (b) administering a therapeutically effective amount of a compound provided herein to the subject.
  • such methods comprise (a) detecting levels of RAD 18 (e.g., RAD 18 protein and/or RAD 18 mRNA) in cancer cells (e.g., in a cancer sample obtained from the subject) and then (b) administering a therapeutically effective amount of a compound provided herein to a subject having a cancer comprising the cancer cells with elevated levels of RAD18.
  • RAD 18 e.g., RAD 18 protein and/or RAD 18 mRNA
  • such methods comprise administering to a subject having triple negative breast cancer a therapeutically effective amount of a compound provided herein.
  • a compound provided herein is used to treat a cancer, wherein the cancer is a homologous-recombination deficient cancer. In one embodiment, a compound provided herein is used to treat a cancer, wherein the cancer comprises cancer cells with a mutation in a gene encoding p53. In one embodiment, a compound provided herein is used to treat a cancer, wherein the cancer comprises cancer cells with a loss of function mutation in a gene encoding p53. In one embodiment, a compound provided herein is used to treat a cancer that does not have a defect in the homologous recombination pathway.
  • a compound provided herein is used to treat a cancer, wherein the cancer is a BRCA1 mutant cancer. In one embodiment, a compound provided herein is used to treat a cancer, wherein the cancer is a BRCA2 mutant cancer. In one embodiment, a compound provided herein is used to treat a cancer, wherein the cancer is a BRCA1 mutant cancer and a BRCA2 mutant cancer. In one embodiment, the cancer is not a BRCA1 mutant cancer or a BRCA2 mutant cancer. In one embodiment, the cancer is a BRCA1 deficient cancer. In one embodiment, the cancer is a BRCA2 deficient cancer. In one embodiment, the cancer is a BRCA1 deficient cancer and a BRCA2 deficient cancer.
  • a compound provided herein is used to treat a cancer, wherein the cancer is an ATM mutant cancer. In one embodiment, the cancer is not an ATM mutant cancer. In one embodiment, the cancer is an ATM deficient cancer.
  • a compound provided herein is used to treat a cancer, wherein the cancer is a PARP inhibitor resistant or refractory cancer.
  • the cancer is a PARP inhibitor resistant or refractory BRCA1 mutant cancer.
  • the cancer is a PARP inhibitor resistant or refractory BRCA1 deficient cancer.
  • the cancer is a PARP inhibitor resistant or refractory BRCA2 mutant cancer.
  • the cancer is a PARP inhibitor resistant or refractory BRCA2 deficient cancer.
  • the cancer is a BRCA1 and/or BRCA2 mutant cancer, wherein the cancer comprises cells with elevated levels of RAD18.
  • the elevated levels of RAD18 are at least as high as the RAD18 protein and/or mRNA levels in ES2 cells.
  • the elevated levels of RAD18 are higher than the RAD18 protein and/or mRNA levels in HEP3B217 cells.
  • a triple negative breast cancer is a BRCA1 and/or BRCA2 mutant cancer.
  • the cancer is a solid cancer. In one embodiment, the cancer is a hematological/lymphatic cancer. In one embodiment, the cancer is a DNA damage repair pathway deficient cancer. In one embodiment, the cancer is a homologous-recombination deficient cancer. In one embodiment, the cancer comprises cancer cells with a mutation in a gene encoding p53. In one embodiment, the cancer comprises cancer cells with a loss of function mutation in a gene encoding p53. In one embodiment, the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC) , osteosarcoma, ovarian cancer, and breast cancer (including triple negative breast cancer) . In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is triple negative breast cancer.
  • NSCLC non-small cell lung cancer
  • the cancer is ovarian cancer. In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is triple negative breast cancer.
  • a compound provided herein is used in combination with one or more additional therapeutic agents to treat cancer. It has been reported that p53 status determines PARP inhibitor sensitization (Sa et al., Genome Biology, (2019) 20: 253) and that BRCAl/2 status predicts the efficacy of PARP inhibitors in the clinic (Audeh et al., Lancet (2010) 376 (9737) , 245-51) . In one embodiment, without being bound by a particular theory, p53 mutant cancers and BRCA mutant cancers have increased sensitivity to USP1 inhibitors. Accordingly, in one embodiment, a compound provided herein is used in combination with a PARP inhibitor to treat cancer.
  • compounds provided herein are provided for use as a medicament or are provided for use in preparing a medicament, e.g., for the treatment of cancer. In one embodiment, compounds provided herein are provided for use in a method for the treatment of cancer.
  • compositions comprising a compound provided herein and a pharmaceutically acceptable excipient.
  • compounds provided herein are administered to a mammal in the form of a raw chemical without any other components present.
  • compounds provided herein are administered to a mammal as part of a pharmaceutical composition containing the compound combined with a suitable pharmaceutically acceptable carrier (see, for example, Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th ed. (2003) ; Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippencott Williams and Wilkins (2004) ; Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press (2000) ) .
  • a carrier can be selected from pharmaceutically acceptable excipients and auxiliaries.
  • a pharmaceutical composition provided herein may be prepared as liquid suspensions or solutions using a liquid, such as an oil, water, an alcohol, and combinations of these.
  • a pharmaceutical composition provided herein may be prepared as a sterile injectable, which may be aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art.
  • a pharmaceutical composition provided herein may be orally administered in any orally acceptable dosage form including capsules, tablets, aqueous suspensions or solutions.
  • a pharmaceutical composition provided herein may be administered in the form of suppositories for rectal administration.
  • a pharmaceutical composition provided herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract.
  • Topical application for the lower intestinal tract is affected in a rectal suppository formulation or in a suitable enema formulation.
  • Topically-transdermal patches may also be used.
  • the pharmaceutical compositions is formulated in a suitable ointment, lotion, or cream containing the active component suspended or dissolved in one or more carriers.
  • a pharmaceutical composition provided herein may also be administered ophthalmically and formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzyl alkonium chloride.
  • the pharmaceutical compositions is formulated in an ointment such as petrolatum.
  • a pharmaceutical composition provided herein may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • the pharmaceutical compositions to be used for in vivo administration can be sterile. In one embodiment, this is accomplished by filtration through, e.g., sterile filtration membranes.
  • compositions provided herein include all compositions where a compound provided herein is combined with one or more pharmaceutically acceptable carriers.
  • the compound provided herein is present in the composition in an amount that is effective to achieve its intended therapeutic purpose.
  • a pharmaceutical composition provided herein can be administered to any patient that may experience the beneficial effects of a compound provided herein.
  • the patients are mammals, e.g., humans and companion animals.
  • the patient is a human.
  • kits which comprise a compound provided herein (or a composition comprising a compound provided herein) packaged in a manner that facilitates their use to practice methods provided herein.
  • the kit includes a compound provided herein (or a composition comprising a compound provided herein) packaged in a container, such as a sealed vial, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method provided herein.
  • the compound or composition is packaged in a unit dosage form.
  • the kit further includes a device suitable for administering the compound or composition according to the intended route of administration.
  • the kit comprises a compound provided herein, and instructions for administering the compound to a patient having cancer.
  • Method 1 for the preparation of a compound provided herein comprising the following steps:
  • X is a halogen, such as Br, Cl or F.
  • Step 1 is performed at a suitable temperature such as from room temperature to 120 °C, in the presence of a suitable inorganic base such as triethyl amine or diisopropylethylamine, and in a suitable organic solvent such as THF, ethanol or isopropanol.
  • a suitable inorganic base such as triethyl amine or diisopropylethylamine
  • a suitable organic solvent such as THF, ethanol or isopropanol.
  • Step 2 is performed at a suitable temperature such as from 50 to 120 °C, in the presence of a suitable inorganic base such as sodium carbonate or potassium phosphate, in the presence of a suitable palladium catalyst such as for example CATACXIUMI A Pd G3 or Pd (dppf) Cl 2 , and in a suitable solvent combination such as dimethoxyethane/water or dioxane/water.
  • a suitable inorganic base such as sodium carbonate or potassium phosphate
  • a suitable palladium catalyst such as for example CATACXIUMI A Pd G3 or Pd (dppf) Cl 2
  • a suitable solvent combination such as dimethoxyethane/water or dioxane/water.
  • stereochemical configuration for a chiral center in a compound provided herein is drawn stereo specifically (e.g., with widget and/or dash bonds) , either without additional designation or being designated “R” (or “ (R) ” ) or “S’ (or “ (S) ” ) , it means the mixture (s) was separated and absolute stereochemistry was known, or only one enantiomer was obtained and absolute stereochemistry was known.
  • the stereochemical configuration at indicated centers has been designated as “*R” (first eluted from the column in case the column conditions of the separation are described in the synthesis protocol and when only one stereocenter present or indicated) or “*S” (second eluted from the column in case the column conditions of the separation are described in the synthesis protocol and when only one stereocenter present or indicated) when the absolute stereochemistry is undetermined (even if the bonds are drawn stereo specifically) although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure.
  • the “*R” indication of the resulting compound is derived from its starting material.
  • intermediate 81 140 mg, 201.51 ⁇ mol, 1 eq
  • DCM DCM
  • TFA 7.68 g, 67.31 mmol, 5 mL, 334.03 eq
  • the reaction mixture was stirred at 25 °C for 0.5 h.
  • the reaction mixture was concentrated under reduced pressure to give intermediate 82 (150 mg, crude, TFA salt) as yellow solid, which was used for next step without further purification.
  • HPLC High-Performance Liquid Chromatography
  • MS Mass Spectrometer
  • Mobile phase Ramp from 30%ACN (0.018%TFA) in water (0.037%TFA) to 90%ACN in 2.00 min, Flow rate is set at 1.5 mL/min; then ramp from 90%ACN in water to 100%ACN in 1.70 min. Flow rate is set at 1.5 mL/min; return back to 30%ACN in water and hold for 0.30 min. Flow rate is set at 2.0 mL/min.
  • Column temperature at 50°C and detector wavelength from 210 nm to 265 nm .
  • the column is of EVO C18 4.6 x 50 mm, 5 ⁇ m.
  • Mobile phase Ramp from 5%ACN (0.01875%TFA) in water (0.0375% TFA) to 95%ACN in 2.40 min, Flow rate is set at 2.0 mL/min; then hold at 95%ACN for 0.30 minutes. Flow rate is set at 2.0 mL/min; return back to 5%ACN in water and hold for 0.30 min. Flow rate is set at 2.0 mL/min.
  • Mobile phase Ramp from 5%ACN (0.01875%TFA) in water (0.0375% TFA) to 95%ACN in 3.20 min, Flow rate is set at 1.5 mL/min; then hold at 95%ACN for 0.30 minutes. Flow rate is set at 1.5 mL/min; return back to 5%ACN in water and hold for 0.30 min. Flow rate is set at 2.0 mL/min.
  • Mobile phase Ramp from 5%ACN in water (0.025%NH 3 ⁇ H 2 O) to 95%ACN in 3.00 min, Flow rate is set at 0.6 mL/min; then hold at 95%ACN for 0.70 minutes Flow rate is set at 0.6 mL/min; return back to 5%ACN in water and hold for 0.30 min. Flow rate is set at 1.2 mL/min.
  • Column temperature at 40°C and detector wavelength from 210 nm to 265 nm.
  • the column is XBridge C18 2.1 x 30 mm, 3.5 ⁇ m.
  • Mobile phase Ramp from 5%ACN (0.01875%TFA) in water (0.0375% TFA) to 95%ACN in 4.8min, Flow rate is set at 0.6 mL/min; then hold at 95%ACN for 0.60 minutes. Flow rate is set at 1.0 mL/min; return back to 5%ACN in water and hold for 0.60 min. Flow rate is set at 1.0 mL/min. Column temperature at 50°C. The column is Kinetex EVO C18 2.1*50mm, 1.7 ⁇ m.
  • Mobile phase Ramp from 5%ACN (0.01875%TFA) in water (0.0375% TFA) to 95%ACN in 3.20 min, Flow rate is set at 1.5 mL/min; then hold at 95%ACN for 0.30 minutes. Flow rate is set at 1.5 mL/min; return back to 5%ACN in water and hold for 0.30 min. Flow rate is set at 2.0 mL/min.
  • Column temperature at 50°C. The column is of EVO C18 4.6 x50 mm, 5 ⁇ m.
  • Mobile phase Ramp from 5%ACN (0.01875%TFA) in water (0.0375%TFA) to 95%ACN in 2.40 min, Flow rate is set at 2.0 mL/min; then hold at 95%ACN for 0.30 minutes Flow rate is set at 2.0 mL/min; return back to 5%ACN in water and hold for 0.30 min. Flow rate is set at 2.0 mL/min.
  • Column temperature at 50 °C. The column is of EVO C18 4.6 x 50 mm, 5 ⁇ m.
  • Mobile phase Ramp from 5%ACN (0.01875%TFA) in water (0.0375%TFA) to 95%ACN in 3.20 min, Flow rate is set at 1.5 mL/min; then hold at 95%ACN for 0.30 minutes. Flow rate is set at 1.5 mL/min; return back to 5%ACN in water and hold for 0.30 min. Flow rate is set at 2.0 mL/min.
  • Mobile phase Ramp from 5%ACN (0.018%TFA) in water (0.037%TFA) to 95%ACN in 3.0 min, Flow rate is set at 1.0 mL/min; then hold at 95%ACN for 0.60 minutes. Flow rate is set from 1.0 mL/min to 1.5 mL/min; return back to 5%ACN in water and hold for 0.40 min. Flow rate is set at 1.5 mL/min.
  • Mobile phase Ramp from 5%ACN in water (0.025%NH 3 ⁇ H 2 O) to 95%ACN in 2.60 min, Flow rate is set at 0.6 mL/min; then hold at 95%ACN for 0.25 minutes. Flow rate is set at 0.8 mL/min; return back to 5%ACN in water and hold for 0.15 min. Flow rate is set at 1.2 mL/min.
  • Column temperature at 40°C and detector wavelength from 210 nm to 265 nm. The column is of XBridge C18 2.1 x 30 mm, 3.5 ⁇ m.
  • Mobile phase Ramp from 5%ACN (0.01875%TFA) in water (0.0375%TFA) to 95%ACN in water in 0.60 min, Flow rate is set at 2.0 mL/min; then hold at 95%ACN for 0.18 minutes. Flow rate is set at 2.0 mL/min; return back to 5%ACN in water and hold for 0.02 min. Flow rate is set at 2.0 mL/min.
  • Mobile phase Ramp from 5%ACN in water (0.025%NH 3 ⁇ H 2 O) to 95%ACN in 3.00 min, Flow rate is set at 0.9 mL/min; then hold at 95%ACN for 0.70 minutes. Flow rate is set at 0.9 mL/min; return back to 5%ACN in water and hold for 0.30 min. Flow rate is set at 1.2 mL/min.
  • Column temperature at 40°C and detector wavelength from 210 nm to 265 nm. The column is of XBridge C18 3.0 x 50 mm, 5 ⁇ m.
  • NMR experiments were carried out using a Bruker Advance III 400 spectrometer at ambient temperature (298.6 K) , using internal deuterium lock, and equipped with BBO 400 MHz S1 5 mm probe head with z gradients and operating at 400 MHz for the proton and 100 MHz for carbon. Chemical shifts ( ⁇ ) are reported in parts per million (ppm) . J values are expressed in Hz.
  • Assay was conducted at a total 15 ⁇ l of reaction volume, including 0.05 nM USP1-UAF1 enzyme and assay buffer (50 mM HEPES pH 7.8, 0.5 mM EDTA, 100 mM NaCl, 0.1 mg/ml bovine serum albumin, I mM DTT, and 0.01%Tween-20) , and was commenced by adding a final concentration of 150 nM ubiquitin-rhodamine 110 substrate.
  • assay buffer 50 mM HEPES pH 7.8, 0.5 mM EDTA, 100 mM NaCl, 0.1 mg/ml bovine serum albumin, I mM DTT, and 0.01%Tween-20
  • Deubiquitinase inhibitory assay was conducted with compounds dissolved in DMSO at a starting concentration of 10 ⁇ M. Dissolved compounds were added to 384-well microplate and premixed with USP1-UAF1 enzyme for 20 min incubation. Intrinsic fluorescence provided by compounds were measured as control prior to the addition of ubiquitin-rhodamine 110. Enzymatic reactions were started by adding ubiquitin-rhodamine 110 to the mixtures, and each well was read at 30 min by microplate reader ( TECAN) to detect the fluorescence intensity at 480 nm excitation/530 nm emission.
  • TECAN microplate reader

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Abstract

Provided herein are certain heteroaromatic compounds, such as a compound of Formula (I), as ubiquitin-specific-processing protease 1 (USP1) inhibitors, pharmaceutical compositions comprising the compounds, and method of use of the compounds or pharmaceutical compositions in the treatment of diseases or disorders.

Description

HETEROAROMATIC COMPOUNDS AND THEIR USE AS USP1 INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to International Patent Application No. PCT/CN2023/073113 filed on January 19, 2023, the entirely of which is incorporated herein by reference.
FIELD
Provided herein are certain heteroaromatic compounds, such as a compound of Formula (I) , as ubiquitin-specific-processing protease 1 (USP1) inhibitors, pharmaceutical compositions comprising the compounds, and method of use of the compounds or pharmaceutical compositions in the treatment of diseases or disorders.
BACKGROUND
Ubiquitin (Ub) is a highly conserved 76–amino acid peptide that is post-transcriptionally attached to target proteins. The ubiquitin–proteasome system (UPS) is the major proteolytic system that controls protein degradation, and it also regulates many cellular processes in eukaryotic cells. Poly-ubiquitination via surface Lysine-48 (K48) or Lysine-11 (K11) residues of ubiquitin often leads to protein proteolysis through the 26S proteasome. In contrast, mono-ubiquitination or poly-ubiquitin chains linked through other lysines are always involved in DNA damage and repair, cell cycle progression, apoptosis, receptor-mediated endocytosis, and signal transduction. Similar to other posttranslational modifications, ubiquitination is a reversible process, and there is a family of enzymes, termed deubiquitinases (DUBs) , that act on ubiquitinated substrates to catalyze the removal of ubiquitin moieties.
One of the best-characterized human DUBs is ubiquitin-specific protease 1 (USP1) , which plays an important role in the cellular response to DNA damage. USP1, together with the cofactor UAF1 (USP1-associated factor 1) , acts during DNA repair processes to specifically to remove mono-ubiquitin signals. The mono-ubiquitinated FANCI-FANCD2 heterodimer is one such substrate and is involved in the repair of DNA interstrand crosslinks via the Fanconi Anemia pathway. A second DNA repair-related process, translesion synthesis (TLS) , is also regulated by USP1, further supporting the crucial role of this DUB in the DNA damage response. The critical USP1 substrate in TLS is mono- ubiquitinated PCNA (Proliferating Cell Nuclear Antigen) . By reverting PCNA monoubiquitination, USP1 contributes to prevent unscheduled recruitment of TLS polymerases, and may thus help maintaining genome stability. Knockdown of USP1 results in elevated levels of FANCD2-Ub and PCNA-Ub and in increased cellular sensitivity to interstrand cross-linking agents, such as mitomycin C (MMC) . Mutations and altered expression of deubiquitinases have been found associated with many human diseases including cancers. There is a need for development of safe and effective treatments targeting deubiquitinases.
SUMMARY
In one embodiment, provided herein are certain heteroaromatic compounds as ubiquitin-specific-processing protease 1 (USP1) inhibitors. In one embodiment, the compounds have a pyrimidine core structure.
In one embodiment, provided herein is a compound of Formula (I) :
or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, R, R1, R2, R3, R4, R4’, R7, L and Ring A are as defined herein or elsewhere.
Also provided herein are pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable excipient.
Also provided herein are methods of inhibiting a USP1 protein, comprising contacting the USP1 protein with a compound provided herein or a pharmaceutical composition provided herein.
Also provided herein are methods of treating a USP1 protein mediated disorder or cancer, comprising administering to a subject having the disorder or cancer a therapeutically effective amount of a compound provided herein or a pharmaceutical composition provided herein.
DETAILED DESCRIPTION
DEFINITIONS
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
As used herein, and in the specification and the accompanying claims, the indefinite articles “a” and “an” and the definite article “the” include plural as well as single referents, unless the context clearly indicates otherwise.
As used herein, the terms “comprising” and “including” can be used interchangeably. The terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of” . Consequently, the term “consisting of” can be used in place of the terms “comprising” and “including” to provide for more specific embodiments.
As used herein, the term “or” is to be interpreted as an inclusive “or” meaning any one or any combination. Therefore, “A, B or C” means any of the following: “A; B; C; A and B; A and C; B and C; A, B and C” . An exception to this definition will occur only when a combination of elements, functions, steps or acts are in some way inherently mutually exclusive.
As used herein, the phrase “and/or” as used in a phrase such as “A and/or B” herein is intended to include both A and B; A or B; A (alone) ; and B (alone) . Likewise, the phrase “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone) ; B (alone) ; and C (alone) .
It should be noted that if there is a discrepancy between a depicted structure and a name for that structure, the depicted structure is to be accorded more weight.
As used herein, and unless otherwise specified, the term “alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen  atoms, which is saturated. In one embodiment, the alkyl group has, for example, from one to twenty-four carbon atoms (C1-C24 alkyl) , four to twenty carbon atoms (C4-C20 alkyl) , six to sixteen carbon atoms (C6-C16 alkyl) , six to nine carbon atoms (C6-C9 alkyl) , one to fifteen carbon atoms (C1-C15 alkyl) , one to twelve carbon atoms (C1-C12 alkyl) , one to eight carbon atoms (C1-C8 alkyl) or one to six carbon atoms (C1-C6 alkyl) and which is attached to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl) , n-butyl, n-pentyl, 1, 1-dimethylethyl (t-butyl) , 3-methylhexyl, 2-methylhexyl, and the like. Unless otherwise specified, an alkyl group is optionally substituted.
As used herein, and unless otherwise specified, the term “alkenyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbon double bonds. The term “alkenyl” also embraces radicals having “cis” and “trans” configurations, or alternatively, “E” and “Z” configurations, as appreciated by those of ordinary skill in the art. In one embodiment, the alkenyl group has, for example, from two to twenty-four carbon atoms (C2-C24 alkenyl) , four to twenty carbon atoms (C4-C20 alkenyl) , six to sixteen carbon atoms (C6-C16 alkenyl) , six to nine carbon atoms (C6-C9 alkenyl) , two to fifteen carbon atoms (C2-C15 alkenyl) , two to twelve carbon atoms (C2-C12 alkenyl) , two to eight carbon atoms (C2-C8 alkenyl) or two to six carbon atoms (C2-C6 alkenyl) and which is attached to the rest of the molecule by a single bond. Examples of alkenyl groups include, but are not limited to, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1, 4-dienyl, and the like. Unless otherwise specified, an alkenyl group is optionally substituted.
As used herein, and unless otherwise specified, the term “alkynyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbon triple bonds. In one embodiment, the alkynyl group has, for example, from two to twenty-four carbon atoms (C2-C24 alkynyl) , four to twenty carbon atoms (C4-C20 alkynyl) , six to sixteen carbon atoms (C6-C16 alkynyl) , six to nine carbon atoms (C6-C9 alkynyl) , two to fifteen carbon atoms (C2-C15 alkynyl) , two to twelve carbon atoms (C2-C12 alkynyl) , two to eight carbon atoms (C2-C8 alkynyl) or two to six carbon atoms (C2-C6 alkynyl) and which is attached to the rest of the molecule by a single bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like. Unless otherwise specified, an alkynyl group is optionally substituted.
As used herein, and unless otherwise specified, the term “cycloalkyl” refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, and which is saturated. Cycloalkyl group may include fused, bridged, or spiro ring systems. In one embodiment, the cycloalkyl has, for example, from 3 to 15 ring carbon atoms (C3-C15 cycloalkyl) , from 3 to 10 ring carbon atoms (C3-C10 cycloalkyl) , or from 3 to 8 ring carbon atoms (C3-C8 cycloalkyl) . The cycloalkyl is attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl radicals include, but are not limited to, adamantyl, norbornyl, decalinyl, 7, 7-dimethyl-bicyclo [2.2.1] heptanyl, and the like. Unless otherwise specified, a cycloalkyl group is optionally substituted.
As used herein, and unless otherwise specified, the term “cycloalkenyl” refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, and which includes one or more carbon-carbon double bonds. Cycloalkenyl may include fused, bridged, or spiro ring systems. In one embodiment, the cycloalkenyl has, for example, from 3 to 15 ring carbon atoms (C3-C15 cycloalkenyl) , from 3 to 10 ring carbon atoms (C3-C10 cycloalkenyl) , or from 3 to 8 ring carbon atoms (C3-C8 cycloalkenyl) . The cycloalkenyl is attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyl radicals include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like. Unless otherwise specified, a cycloalkenyl group is optionally substituted. Similarly, as used herein, and unless otherwise specified, the term “cycloalkynyl” refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, and which includes one or more carbon-carbon triple bonds.
As used herein, and unless otherwise specified, the term “heteroalkyl” refers to an alkyl radical that has one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, and phosphorus, or combinations thereof. A numerical range can be given to refer to the chain length in total. For example, a -CH2OCH2CH3 radical is referred to as a “C4” heteroalkyl. Connection to the parent molecular structure can be through either a heteroatom or a carbon in the heteroalkyl chain. One or more heteroatom (s) in the heteroalkyl radical can be optionally oxidized. One or more nitrogen atoms, if present, can also be optionally quaternized. Unless otherwise specified, a heteroalkyl group is optionally substituted.
As used herein, and unless otherwise specified, the term “aryl” refers to a monocyclic aromatic group and/or multicyclic aromatic group that contain at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 18 ring carbon atoms (C6-C18 aryl) , from 6 to 14 ring carbon atoms (C6-C14 aryl) , or from 6 to 10 ring carbon atoms (C6-C10 aryl) . Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. The term “aryl” also refers to bicyclic, tricyclic, or other multicyclic hydrocarbon rings, where at least one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl) . Unless otherwise specified, an aryl group is optionally substituted.
As used herein, and unless otherwise specified, the term “heteroaryl” refers to a monocyclic aromatic group and/or multicyclic aromatic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more (e.g., one, one or two, one to three, or one to four) heteroatoms independently selected from O, S, and N. The heteroaryl may be attached to the main structure at any heteroatom or carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. The term “heteroaryl” also refers to bicyclic, tricyclic, or other multicyclic rings, where at least one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N. Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, and xanthenyl. Unless otherwise specified, a heteroaryl group is optionally substituted.
As used herein, and unless otherwise specified, the term “heterocyclyl” refers to a monocyclic and/or multicyclic non-aromatic group that contains one or more (e.g., one,  one or two, one to three, or one to four) heteroatoms independently selected from nitrogen, oxygen, phosphorous, and sulfur. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom. A heterocyclyl group can be a monocyclic, bicyclic, tricyclic, tetracyclic, or other multicyclic ring system, wherein the multicyclic ring systems can be a fused, bridged or spiro ring system. Heterocyclyl multicyclic ring systems can include one or more heteroatoms in one or more rings. A heterocyclyl group can be saturated or partially unsaturated. Saturated heterocycloalkyl groups can be termed “heterocycloalkyl” . Partially unsaturated heterocycloalkyl groups can be termed “heterocycloalkenyl” if the heterocyclyl contains at least one double bond, or “heterocycloalkynyl” if the heterocyclyl contains at least one triple bond. In one embodiment, the heterocyclyl has, for example, 3 to 18 ring atoms (3-to 18-membered heterocyclyl) , 4 to 18 ring atoms (4-to 18-membered heterocyclyl) , 5 to 18 ring atoms (5-to 18-membered heterocyclyl) , 4 to 8 ring atoms (4-to 8-membered heterocyclyl) , or 5 to 8 ring atoms (5-to 8-membered heterocyclyl) . Examples of heterocyclyl groups include, but are not limited to, imidazolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, isoxazolidinyl, isothiazolidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuryl, and piperidinyl. Unless otherwise specified, a heterocyclyl group is optionally substituted.
Whenever it appears herein, a numerical range such as “3 to 18” refers to each integer in the given range; e.g., a heterocyclyl with “3 to 18 ring atoms” means that the heterocyclyl group can consist of 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, etc., up to and including 18 ring atoms. Similarly, a C1-C6 alkyl means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms.
As used herein and unless otherwise specified, a “cycloalkylalkyl” group is a radical of the formula: -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined above. Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl, or both the alkyl and the cycloalkyl portions of the group. Representative cycloalkylalkyl groups include but are not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl and the like.
As used herein and unless otherwise specified, an “aralkyl” group is a radical of the formula: -alkyl-aryl, wherein alkyl and aryl are defined above. Substituted aralkyl groups may be substituted at the alkyl, the aryl, or both the alkyl and the aryl portions of the  group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and aralkyl groups wherein the aryl group is fused to a cycloalkyl group such as indan-4-yl ethyl.
As used herein and unless otherwise specified, other similar composite terms mirror the above description for “cycloalkylalkyl” and “aralkyl” . For example, a “heterocyclylalkyl” group is a radical of the formula: -alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above. A “heteroarylalkyl” group is a radical of the formula: -alkyl-heteroaryl, wherein alkyl and heteroaryl are defined above. A “heterocycloalkylalkyl” group is a radical of the formula: -alkyl-heterocycloalkyl, wherein alkyl and heterocycloalkyl are defined above.
As used herein, and unless otherwise specified, the term “halogen” , “halide” or “halo” refers to fluorine, chlorine, bromine, and/or iodine. As used herein, and unless otherwise specified, the terms “haloalkyl, ” “haloalkenyl, ” “haloalkynyl, ” and “haloalkoxy” refer to alkyl, alkenyl, alkynyl, and alkoxy structures that are substituted with one or more halo groups or with combinations thereof.
As used herein, and unless otherwise specified, the term “alkoxy” refers to -O- (alkyl) , wherein alkyl is defined above. As used herein, and unless otherwise specified, the term “aryloxy” refers to -O- (aryl) , wherein aryl is defined above.
As used herein, and unless otherwise specified, the term “alkyl sulfonyl” refers to –SO2-alkyl, wherein alkyl is defined above.
As used herein, and unless otherwise specified, the term “carboxyl” and “carboxy” refers to -COOH.
As used herein, and unless otherwise specified, the term “alkoxycarbonyl” refers to -C (=O) O- (alkyl) , wherein alkyl is defined above. As used herein, and unless otherwise specified, the term “arylalkyloxy” refers to -O- (alkyl) - (aryl) , wherein alkyl and aryl are defined above. As used herein, and unless otherwise specified, the term “cycloalkyloxy” refers to -O- (cycloalkyl) , wherein cycloalkyl is defined above. As used herein, and unless otherwise specified, the term “cycloalkylalkyloxy” refers to -O- (alkyl) - (cycloalkyl) , wherein cycloalkyl and alkyl are defined above.
As used herein, and unless otherwise specified, the term “acyl” refers to –C (O) -Ra, wherein Ra can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl,  alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. In certain embodiments, Ra may be unsubstituted or substituted with one or more substituents.
As used herein, and unless otherwise specified, the term “acyloxy” refers to –O-C (O) -Ra, wherein Ra can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. In certain embodiments, Ra may be unsubstituted or substituted with one or more substituents.
As used herein, and unless otherwise specified, the term “amino” refers to –N (R#) (R#) , wherein each R#independently can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. When a -N (R#) (R#) group has two R#other than hydrogen, they can be combined with the nitrogen atom to form a ring. In one embodiment, the ring is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In one embodiment, one or more ring atoms are heteroatoms independently selected from O, S, or N. The term “amino” also includes N-oxide (–N+ (R#) (R#) O-) . In certain embodiments, each R#or the ring formed by -N (R#) (R#) independently may be unsubstituted or substituted with one or more substituents.
As used herein, and unless otherwise specified, the term “amide” or “amido” refers to –C (O) N (R#) 2 or –NR#C (O) R#, wherein each R#independently can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. When a –C (O) N (R#) 2 group has two R#other than hydrogen, they can be combined with the nitrogen atom to form a ring. In one embodiment, the ring is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In one embodiment, one or more ring atoms are heteroatoms independently selected from O, S, or N. In certain embodiments, each R#or the ring formed by -N (R#) (R#) independently may be unsubstituted or substituted with one or more substituents.
As used herein, and unless otherwise specified, the term “aminoalkyl” refers to - (alkyl) - (amino) , wherein alkyl and amino are defined above. As used herein, and unless otherwise specified, the term “aminoalkoxy” refers to -O- (alkyl) - (amino) , wherein alkyl and amino are defined above.
As used herein, and unless otherwise specified, the term “alkylamino” refers to -NH (alkyl) or -N (alkyl) (alkyl) , wherein alkyl is defined above. Examples of such alkylamino groups include, but are not limited to, -NHCH3, -NHCH2CH3, -NH (CH2) 2CH3, - NH (CH2) 3CH3, -NH (CH2) 4CH3, -NH (CH2) 5CH3, -N (CH3) 2, -N (CH2CH3) 2, -N ( (CH2) 2CH3) 2, -N (CH3) (CH2CH3) , and the like.
As used herein, and unless otherwise specified, the term “arylamino” refers to -NH (aryl) or -N (aryl) (aryl) , wherein aryl is defined above. As used herein, and unless otherwise specified, similar composite terms such as “arylalkylamino” and “cycloalkylamino” mirrors the descriptions above for “alkylamino” and “arylamino” .
As used herein, and unless otherwise specified, the term “sulfanyl” , “sulfide” , or “thio” refers to -S-Ra, wherein Ra can be, but is not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. In certain embodiments, Ra may be unsubstituted or substituted with one or more substituents.
As used herein, and unless otherwise specified, the term “sulfoxide” refers to –S (O) -Ra, wherein Ra can be, but is not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. In certain embodiments, Ra may be unsubstituted or substituted with one or more substituents.
As used herein, and unless otherwise specified, the term “sulfonyl” or “sulfone” refers to –S (O) 2-Ra, wherein Ra can be, but is not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. In certain embodiments, Ra may be unsubstituted or substituted with one or more substituents.
As used herein, and unless otherwise specified, the term “sulfonamido” or “sulfonamide” refers to –S (=O) 2–N (R#) 2 or –N (R#) –S (=O) 2–R#, wherein each R#independently can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. When a –S (=O) 2–N (R#) 2 group has two R#other than hydrogen, they can be combined with the nitrogen atom to form a ring. In one embodiment, the ring is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In one embodiment, one or more ring atoms are heteroatoms independently selected from O, S, or N. In certain embodiments, each R#or the ring formed by -N (R#) (R#) independently may be unsubstituted or substituted with one or more substituents.
“Azide” refers to a –N3 radical.
“Cyano” refers to a –CN radical.
“Nitro” refers to the –NO2 radical.
“Oxa” refers to the –O–radical.
“Oxo” refers to the =O radical.
As used herein, and unless otherwise specified, the term “optional” or “optionally” (e.g., optionally substituted) means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means that the alkyl radical may or may not be substituted and that the description includes both substituted alkyl radicals and alkyl radicals having no substitution.
When the groups described herein are said to be “substituted, ” they may be substituted with any appropriate substituent or substituents. Illustrative examples of substituents include, but are not limited to, those found in the exemplary compounds and embodiments provided herein, as well as halogen (chloro, iodo, bromo, or fluoro) ; alkyl; alkenyl; alkynyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aryloxyamine, aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxo (═O) ; B (OH) 2, O (alkyl) aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) , or a heterocyclyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl) ; monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy.
As used herein, and unless otherwise specified, the term “isomer” refers to different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Atropisomers” are stereoisomers from hindered rotation about single bonds. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any proportion can be known as a “racemic” mixture. “Diastereoisomers” are stereoisomers that  have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry can be specified according to the Cahn-Ingold-Prelog R-S system. When a compound is an enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro-or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. However, the sign of optical rotation, (+) and (-) , is not related to the absolute configuration of the molecule, R and S. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry at each asymmetric atom, as (R) -or (S) -. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically substantially pure forms and intermediate mixtures. Optically active (R) -and (S) -isomers can be prepared, for example, using chiral synthons or chiral reagents, or resolved using conventional techniques.
As used herein, and unless otherwise specified, the term “enantiomeric purity” or “enantiomer purity” refers to a qualitative or quantitative measure of a purified enantiomer. The enantiomeric purity of compounds described herein may be described in terms of enantiomeric excess (ee) , which indicates the degree to which a sample contains one enantiomer in greater amounts than the other. A racemic mixture has an ee of 0%, while a single completely pure enantiomer has an ee of 100%. Examples of the enantiomeric purity include an ee of at least about 10%, at least about 12%, at least about 14%, at least about 16%, at least about 18%, at least about 20%, at least about 22%, at least about 24%, at least about 26%, at least about 28%, at least about 30%, at least about 32%, at least about 34%, at least about 36%, at least about 38%, at least about 40%, at least about 42%, at least about 44%, at least about 46%, at least about 48%, at least about 50%, at least about 52%, at least about 54%, at least about 56%, at least about 58%, at least about 60%, at least about 62%, at least about 64%, at least about 66%, at least about 68%, at least about 70%, at least about 72%, at least about 74%, at least about 76%, at least about 78%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about or at least about 99%. Similarly, “diastereomeric purity” may be described in terms of  diasteriomeric excess (de) , which indicates the degree to which a sample contains one diastereoisomers in greater amounts than the other (s) .
As used herein, and unless otherwise specified, the term “substantially purified enantiomer” refers to a compound wherein one enantiomer has been enriched over the other. In one embodiment, the other enantiomer represents less than about 20%, less than about 10%, less than about 5%, or less than about 2%of the enantiomer. In one embodiment, a substantially purified enantiomer has an enantiomeric excess of S enantiomer of at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%or at least about 99.9%. In one embodiment, a substantially purified enantiomer has an enantiomeric excess of R enantiomer of at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%or at least about 99.9%.
“Stereoisomers” can also include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof. In certain embodiments, a compound described herein is isolated as either the E or Z isomer. In other embodiments, a compound described herein is a mixture of the E and Z isomers.
Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
As used herein, and unless otherwise specified, the term “pharmaceutically acceptable salt” includes both acid and base addition salts.
Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1, 5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.
Examples of pharmaceutically acceptable base addition salt include, but are not limited to, salts prepared from addition of an inorganic base or an organic base to a free acid compound. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. In one embodiment, the inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. In one embodiment, the organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
As used herein, and unless otherwise specified, the term “subject” refers to an animal, including, but not limited to, a primate (e.g., human) , cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. In one embodiment, the subject is a mammal. In one embodiment, the subject is a human.
As used herein, and unless otherwise specified, the terms “treat, ” “treating, ” and “treatment” refer to the eradication or amelioration of a disease or disorder, or of one or more symptoms associated with the disease or disorder. In general, treatment occurs after the onset of the disease or disorder. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease or disorder resulting from the administration of one or more prophylactic or therapeutic agents to a subject with such a disease or disorder.
As used herein, and unless otherwise specified, the terms “prevent, ” “preventing, ” and “prevention” refer to the prevention of the onset, recurrence or spread of a disease or disorder, or of one or more symptoms thereof. In general, prevention occurs prior to the onset of the disease or disorder.
As used herein, and unless otherwise specified, the terms “manage, ” “managing, ” and “management” refer to preventing or slowing the progression, spread or worsening of a disease or disorder, or of one or more symptoms thereof. Sometimes, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disease or disorder.
As used herein, and unless otherwise specified, the term “therapeutically effective amount” are meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term “therapeutically effective amount” also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
As used herein, and unless otherwise specified, the term “IC50” refers an amount, concentration, or dosage of a compound that is required for 50%inhibition of a maximal response in an assay that measures such response.
As used herein, and unless otherwise specified, the term “pharmaceutically acceptable carrier, ” “pharmaceutically acceptable excipient, ” “physiologically acceptable  carrier, ” or “physiologically acceptable excipient” refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams &Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004.
Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. Examples of isotopes that can be incorporated into compounds provided herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, e.g., 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. For example, provided herein are compounds having the present structures except for the replacement or enrichment of a hydrogen by deuterium or tritium at one or more atoms in the molecule, or the replacement or enrichment of a carbon by 13C or 14C at one or more atoms in the molecule. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by deuterium. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by tritium. In one embodiment, provided herein are isotopically labeled compounds having one or more carbon atoms replaced or enriched by 13C. In one embodiment, provided herein are isotopically labeled compounds having one or more carbon atoms replaced or enriched by 14C.
As used herein, and unless otherwise specified, the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means  within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05%of a given value or range.
COMPOUNDS
In one embodiment, provided herein are certain heteroaromatic compounds as ubiquitin-specific-processing protease 1 (USP1) inhibitors. In one embodiment, the compounds have a pyrimidine core structure.
In one embodiment, provided herein is a compound of Formula (I) :
or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein:
X1 is N or CRa1; Ra1 is hydrogen or C1-C6 alkyl;
X2 is N or CRa2; Ra2 is hydrogen or C1-C6 alkyl;
X3 is N or CRa3; Ra3 is hydrogen or C1-C6 alkyl;
L is NRb, O or S; Rb is hydrogen or C1-C6 alkyl;
R1 is alkyl, alkoxy, halogen, cyano, NRcRd, -C (=O) NHRd, -NHC (=O) Rc, cycloalkyl, heterocyclyl, aryl, heteroaryl; and each alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl in R1 is optionally substituted;
Rc and Rd are each independently hydrogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; and each alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl in Rc or Rd is independently optionally substituted;
R2 and R3 are each independently halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino) alkyl, (dialkylamino) alkyl, cyanoalkyl, (carboxamido) alkyl, mercaptoalkyl, (cycloalkylamino) alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl) amino, carboxy, amido, carboxamido, sulfonamido,  alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, or alkylthio; and each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl moiety in R2 or R3 is independently optionally substituted with one or more C1-C6 alkyl, halogen, or deuterium;
R4 is hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, or (C1-C6 alkoxy) - (C1-C6 alkyl) ;
R4’ is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, or (C1-C6 alkoxy) - (C1-C6 alkyl) ;
R7 is hydrogen or C1-C6 alkyl;
Ring A is aryl, heteroaryl, cycloalkyl, or heterocyclyl; and Ring A is optionally substituted;
R is hydrogen, halogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, or amido; and each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl moiety in R is independently optionally substituted.
In one embodiment, the compound is a compound of Formula (I-A) :
or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound is a compound of Formula (I-B) :
or a pharmaceutically acceptable salt thereof.
In one embodiment, R1 is alkoxy. In one embodiment, R1 is alkyl. In one embodiment, R1 is halogen. In one embodiment, R1 is cyano. In one embodiment, R1 is  NRcRd. In one embodiment, R1 is -C (=O) NHRd. In one embodiment, R1 is -NHC (=O) Rc. In one embodiment, R1 is cycloalkyl. In one embodiment, R1 is heterocyclyl. In one embodiment, R1 is aryl. In one embodiment, R1 is heteroaryl;
In one embodiment, R1 is C1-C6 alkoxy. In one embodiment, R1 is C1-C6 alkyl. In one embodiment, R1 is N (C1-C6 alkyl) 2. In one embodiment, R1 is -CONH (C1-C6 alkyl) . In one embodiment, R1 is -CON (C1-C6 alkyl) 2. In one embodiment, R1 is -CONH (C3-C8 cycloalkyl) . In one embodiment, R1 is -CONH (C1-C6 alkylene) - (C1-C6 alkoxy) . In one embodiment, R1 is -CONH (C1-C6 alkylene) - (C3-C8 heterocyclyl) . In one embodiment, R1 is C3-C8 cycloalkyl. In one embodiment, R1 is 3-to 8-membered heterocyclyl. In one embodiment, R1 is 5-to 10-membered aryl. In one embodiment, R1 is 5-to 10-membered heteroaryl.
In one embodiment, R1 is methoxy. In one embodiment, R1 is ethoxy. In one embodiment, R1 is methoxymethoxy. In one embodiment, R1 is 2-methoxyethoxy. In one embodiment, R1 is methyl. In one embodiment, R1 is ethyl. In one embodiment, R1 is propyl or isopropyl. In one embodiment, R1 is n-butyl, iso-butyl, or tert-butyl. In one embodiment, R1 is pentyl. In one embodiment, R1 is hexyl. In one embodiment, R1 is fluoro. In one embodiment, R1 is bromo. In one embodiment, R1 is chloro. In one embodiment, R1 is NH2. In one embodiment, R1 is NHCH3. In one embodiment, R1 is NHC2H5. In one embodiment, R1 is -CONH2.
In one embodiment, Rc is hydrogen. In one embodiment, Rc is alkyl. In one embodiment, Rc is alkoxy. In one embodiment, Rc is cycloalkyl. In one embodiment, Rc is heterocyclyl. In one embodiment, Rc is aryl. In one embodiment, Rc is heteroaryl.
In one embodiment, Rc is C1-C6 alkyl. In one embodiment, Rc is C1-C6 alkoxy. In one embodiment, Rc is C3-C8 cycloalkyl. In one embodiment, Rc is 3-to 8-membered heterocyclyl. In one embodiment, Rc is 5-to 10-membered aryl. In one embodiment, Rc is 5-to 10-membered heteroaryl. In one embodiment, Rc is C1-C6 alkyl substituted with alkoxy. In one embodiment, Rc is C1-C6 alkyl substituted with heterocyclyl. In one embodiment, Rc is C1-C6 alkyl substituted with alkylamine. In one embodiment, Rc is C1-C6 alkyl substituted with dialkylamine.
In one embodiment, Rd is hydrogen. In one embodiment, Rd is alkyl. In one embodiment, Rd is alkoxy. In one embodiment, Rd is cycloalkyl. In one embodiment, Rd is heterocyclyl. In one embodiment, Rd is aryl. In one embodiment, Rd is heteroaryl.
In one embodiment, Rd is C1-C6 alkyl. In one embodiment, Rd is C1-C6 alkoxy. In one embodiment, Rd is C3-C8 cycloalkyl. In one embodiment, Rd is 3-to 8-membered heterocyclyl. In one embodiment, Rd is 5-to 10-membered aryl. In one embodiment, Rd is 5-to 10-membered heteroaryl. In one embodiment, Rd is C1-C6 alkyl substituted with alkoxy. In one embodiment, Rd is C1-C6 alkyl substituted with heterocyclyl. In one embodiment, Rd is C1-C6 alkyl substituted with alkylamine. In one embodiment, Rd is C1-C6 alkyl substituted with dialkylamine.
In one embodiment, Rc and Rd are both hydrogen. In one embodiment, Rc and Rd are both alkyl. In one embodiment, Rc and Rd are both C1-C6 alkyl. In one embodiment, Rc and Rd are both methyl.
In one embodiment, L is NRb. In one embodiment, L is NH. In one embodiment, L is O. In one embodiment, L is S.
In one embodiment, Rb is hydrogen. In one embodiment, Rb is C1-C6 alkyl. In one embodiment, Rb is methyl. In one embodiment, Rb is ethyl. In one embodiment, Rb is propyl (e.g. n-propyl or isopropyl) . In one embodiment, Rb is butyl (e.g. n-butyl, iso-butyl, or tert-butyl) . In one embodiment, Rb is pentyl. In one embodiment, Rb is hexyl.
In one embodiment, R7 is hydrogen. In one embodiment, R7 is alkyl. In one embodiment, R7 is C1-C6 alkyl. In one embodiment, R7 is methyl. In one embodiment, R7 is ethyl. In one embodiment, R7 is propyl (e.g. n-propyl or isopropyl) . In one embodiment, R7 is butyl (e.g. n-butyl, iso-butyl, or tert-butyl) . In one embodiment, R7 is pentyl. In one embodiment, Rb is hexyl.
In one embodiment, Ring A is aryl. In one embodiment, Ring A is C6-C10 aryl. In one embodiment, Ring A is phenyl. In one embodiment, Ring A is 
In one embodiment, Ring A is heteroaryl. In one embodiment, Ring A is a 5-to 10-membered heteroaryl. In one embodiment, Ring A is a 5-or 6-membered heteroaryl. In one embodiment, nitrogen is the only type of heteroatom contained in the heteroaryl. In  one embodiment, Ring A is pyridyl. In one embodiment, Ring A isIn one embodiment, Ring A is
In one embodiment, Ring A is cycloalkyl. In one embodiment, Ring A is C3-C8 cycloalkyl. In one embodiment, Ring A is C5-C6 cycloalkyl. In one embodiment, Ring A is cyclopentyl. In one embodiment, Ring A is cyclohexyl.
In one embodiment, Ring A is heterocyclyl. In one embodiment, Ring A is a 5-to 10-membered heterocyclyl. In one embodiment, Ring A is a 5-or 6-membered heterocyclyl. In one embodiment, nitrogen is the only type of heteroatom contained in the heterocyclyl. In one embodiment, Ring A is pyrrolidinyl. In one embodiment, Ring A is In one embodiment, Ring A is piperidinyl. In one embodiment, Ring A is piperidyl. In one embodiment, Ring A is
In one embodiment, Ring A is optionally substituted with one or more R5; and wherein each R5 is independently halogen, cyano, alkyl, amino, alkylamino, dialkylamino, hydroxy, or alkoxy; and wherein each alkyl moiety is independently optionally substituted with one or more halogen, hydroxy, or alkoxy. In one embodiment, Ring A is unsubstituted. In one embodiment, Ring A is substituted with one R5. In one embodiment, Ring A is substituted with two R5. Unless otherwise specified, the substitution status for Ring A as described herein does not take the R group into consideration.
In one embodiment, each R5 is independently fluoro, chloro, cyano, methoxy, difluoromethoxy, hydroxyethoxy, or methoxyethoxy.
In one embodiment, Ring A is selected from the group consisting of:

As shown herein and unless otherwise specified, the point of attachment at left side of a Ring A structure is to carbon atom bearing R4 group and the point of attachment at right side is to the R group.
In one embodiment, R is hydrogen. In one embodiment, R is halogen. In one embodiment, R is alkyl. In one embodiment, R is cycloalkyl. In one embodiment, R is heterocyclyl. In one embodiment, R is aryl. In one embodiment, R is heteroaryl. In one embodiment, R is alkoxy. In one embodiment, R is cycloalkyloxy. In one embodiment, R is heterocyclyloxy. In one embodiment, R is aryloxy. In one embodiment, R is heteroaryloxy. In one embodiment, R is cycloalkylalkyl. In one embodiment, R is heterocyclylalkyl. In one embodiment, R is aralkyl. In one embodiment, R is heteroarylalkyl. In one embodiment, R is cycloalkylalkyloxy. In one embodiment, R is heterocyclylalkyloxy. In one embodiment, R is aralkyloxy. In one embodiment, R is heteroarylalkyloxy. In one embodiment, R is amido;
In one embodiment, R is C1-C6 alkyl, C3-C8 cycloalkyl, 4-to 8-membered heterocyclyl, C6-C10 aryl, 5-to 10-membered heteroaryl, C1-C6 alkoxy, C3-C8 cycloalkyloxy, 4-to 8-membered heterocyclyloxy, C6-C10 aryloxy, 5-to 10-membered heteroaryloxy, (C3-C8 cycloalkyl) - (C1-C2 alkyl) -, (4-to 8-membered heterocyclyl) - (C1-C2 alkyl) -, (C6-C10 aryl) - (C1-C2 alkyl) -, (5-to 10-membered heteroaryl) - (C1-C2 alkyl) -, (C3-C8 cycloalkyl) - (C1-C2 alkyloxy) -, (4-to 8-membered heterocyclyl) - (C1-C2 alkyloxy) -, (C6-C10 aryl) - (C1-C2 alkyloxy) -, or (5-to 10-membered heteroaryl) - (C1-C2 alkyloxy) -; wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl moiety in R is independently optionally substituted.
In one embodiment, R is a 5-to 10-membered heteroaryl. In one embodiment, R is a 5-or 6-membered heteroaryl. In one embodiment, R is a 5-or 6-membered nitrogen- containing heteroaryl. In one embodiment, R is a 5-or 6-membered nitrogen-containing heteroaryl, and nitrogen is the only type of heteroatom contained in the heteroaryl. In one embodiment, R is imidazolyl. In one embodiment, R is pyridyl. In one embodiment, R is pyrazolyl. In one embodiment, R is pyridazinyl. In one embodiment, R is pyrimidinyl. In one embodiment, R is triazinyl. In one embodiment, R is pyrazinyl. In one embodiment, R is triazolyl. In one embodiment, R is a 5-or 6-membered nitrogen-containing heteroaryl, and the heteroaryl contains at least one heteroatom other than nitrogen. In one embodiment, R is oxazolyl. In one embodiment, R is thiazolyl.
In one embodiment, R is optionally substituted with one or more R6; and each R6 is independently halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino) alkyl, (dialkylamino) alkyl, cyanoalkyl, (carboxamido) alkyl, mercaptoalkyl, (cycloalkylamino) alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl) amino, carboxy, amido, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, or alkylthio; and wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl moiety is independently optionally substituted with one or more C1-C6 alkyl, acyl, halogen, or deuterium.
In one embodiment, R is optionally substituted with one or more R6; and wherein each R6 is independently cyano, nitro, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, l-fluoropropan-2-yl, 2-fluoroethyl, amino, methylamino, ethylamino, dimethylamino, 2, 2-difluoroethoxy, cyclopropoxy, morpholino, tetrahydropyranyl, oxetanyl, methoxymethyl, N, N-dimethylsulfonamido, cyclopropyl, cyclobutyl, methylaminomethyl, deuteromethyl, deuteroethyl, deuteroisopropyl, deuteromethoxy, or deuteroethoxy.
In one embodiment, R is substituted with one R6. In one embodiment, R is substituted with R6 at a position adjacent to the point of attachment of R to Ring A. In one embodiment, R is substituted with R6 at a position that is separated by one ring atom to the point of attachment of R to Ring A.
In one embodiment, R is substituted with two R6. In one embodiment, R is substituted with R6 at (i) a position adjacent to the point of attachment of R to Ring A, and (ii) a position that is separated by one ring atom to the point of attachment of R to Ring A. In one embodiment, the two positions are on the same side of the point of attachment of R to Ring A. In one embodiment, the two positions are on the opposite side of the point of attachment of R to Ring A.
In one embodiment, R isIn one embodiment, R is In one embodiment, R isIn one embodiment, R is In one embodiment, R isIn one embodiment, R is In one embodiment, R isIn one embodiment, R is
In one embodiment, R is selected from the group consisting of:


In one embodiment, R is selected from the group consisting of:
In one embodiment, X1 is CRa1. In one embodiment, X1 is CH. In one embodiment, X1 is N. In one embodiment, Ra1 is hydrogen. In one embodiment, Ra1 is C1-C6 alkyl. In one embodiment, Ra1 is methyl. In one embodiment, Ra1 is ethyl. In one embodiment, Ra1 is propyl (e.g. n-propyl or isopropyl) . In one embodiment, Ra1 is butyl (e.g. n-butyl, iso-butyl, or tert-butyl) . In one embodiment, Ra1 is pentyl. In one embodiment, Ra1 is hexyl.
In one embodiment, X2 is CRa2. In one embodiment, X2 is CH. In one embodiment, X2 is N. In one embodiment, Ra2 is hydrogen. In one embodiment, Ra2 is C1-C6 alkyl. In one embodiment, Ra2 is methyl. In one embodiment, Ra2 is ethyl. In one embodiment, Ra2 is propyl or isopropyl. In one embodiment, Ra2 is n-butyl, iso-butyl, or tert-butyl. In one embodiment, Ra2 is pentyl. In one embodiment, Ra2 is hexyl.
In one embodiment, X3 is CRa3. In one embodiment, X3 is CH. In one embodiment, X3 is N. In one embodiment, Ra3 is hydrogen. In one embodiment, Ra3 is C1- C6 alkyl. In one embodiment, Ra3 is methyl. In one embodiment, Ra3 is ethyl. In one embodiment, Ra3 is propyl or isopropyl. In one embodiment, Ra3 is n-butyl, iso-butyl, or tert-butyl. In one embodiment, Ra3 is pentyl. In one embodiment, Ra3 is hexyl.
In one embodiment, X1 is CRa1, and X2 is CRa2. In one embodiment, X1 is CRa1, and X2 is N. In one embodiment, X1 is N, and X2 is CRa2. In one embodiment, X1 is N, and X2 is N. In one embodiment, X1 is CRa1, and X3 is CRa3. In one embodiment, X1 is CRa1, and X3 is N. In one embodiment, X1 is N, and X3 is CRa3. In one embodiment, X1 is N, and X3 is N. In one embodiment, X2 is CRa2, and X3 is CRa3. In one embodiment, X2 is CRa2, and X3 is N. In one embodiment, X2 is N, and X3 is CRa3. In one embodiment, X2 is N, and X3 is N.
In one embodiment, X1 is N, X2 is N, and X3 is CRa3. In one embodiment, X1 is N, X2 is N, and X3 is CH. In one embodiment, X1 is CRa1, X2 is CRa2, and X3 is CRa3. In one embodiment, X1 is CH, X2 is CH, and X3 is CH.
In one embodiment, R4’ is hydrogen. In one embodiment, R4’ is halogen. In one embodiment, R4’ is C1-C6 alkyl. In one embodiment, R4’ is C1-C6 alkoxy. In one embodiment, R4’ is (C1-C6 alkoxy) - (C1-C6 alkyl) .
In one embodiment, R4 is hydroxyl. In one embodiment, R4 is C1-C6 alkyl. In one embodiment, R4 is methyl. In one embodiment, R4 is ethyl. In one embodiment, R4 is propyl (e.g. n-propyl or isopropyl) . In one embodiment, R4 is butyl (e.g. n-butyl, iso-butyl, or tert-butyl) . In one embodiment, R4 is pentyl. In one embodiment, R4 is hexyl.
In one embodiment, R4 is C1-C6 alkoxy. In one embodiment, R4 is methoxy. In one embodiment, R4 is ethoxy. In one embodiment, R4 is -O-propyl. In one embodiment, R4 is -O-butyl. In one embodiment, R4 is -O-pentyl. In one embodiment, R4 is -O-hexyl.
In one embodiment, R4 is (C1-C6 alkoxy) - (C1-C6 alkyl) . In one embodiment, R4 is methoxymethyl. In one embodiment, R4 is ethoxymethyl. In one embodiment, R4 is ethoxyethyl.
In one embodiment, R4 and R4’ are the same. In one embodiment, R4 and R4’ are different. In one embodiment, R4’ is hydrogen and R4 is hydroxyl. In one embodiment, R4’ is hydrogen and R4 is C1-C6 alkyl. In one embodiment, R4’ is hydrogen and R4 is methyl. In one embodiment, R4’ is hydrogen and R4 is C1-C6 alkoxy. In one embodiment, R4’ is hydrogen and R4 is methoxy. In one embodiment, R4’ is hydrogen and R4 is (C1-C6 alkoxy) - (C1-C6 alkyl) . In one embodiment, R4’ is hydrogen and R4 is methoxymethyl.
In one embodiment, provided herein is a compound of Formula (II-A) , (II-B) , (II-C) , (II-D) , (II-E) , (II-F) , (II-G) , or (II-H) :

or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:
X4 is CRa4 or N;
X5 is CRa5 or N;
X6 is CRa6 or N;
X7 is CRa7 or N;
X8 is CRa8, N, NRa8, O, or S;
X9 is CRa9, N, NRa9, O, or S;
X10 is CRa10, N, NRa10, O, or S;
X11 is CRa11, N, NRa11, O, or S;
X12 is C or N;
X13 is CRa13 or N;
X14 is CRa14 or N;
X15 is CRa15 or N;
X16 is CRa16 or N;
X17 is CRa17 or N;
each Ra4, Ra5, Ra6, Ra7 is independently hydrogen or R5;
each Ra8, Ra9, Ra10, Ra11, Ra13, Ra14, Ra15, Ra16 and Ra17 is independently hydrogen or R6;
each R5 is independently halogen, cyano, alkyl, amino, alkylamino, dialkylamino, hydroxy, or alkoxy; and wherein each alkyl moiety is independently optionally substituted with one or more halogen, hydroxy, or alkoxy; and
each R6 is independently halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino) alkyl, (dialkylamino) alkyl, cyanoalkyl, (carboxamido) alkyl, mercaptoalkyl, (cycloalkylamino) alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl) amino, carboxy, amido, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, or alkylthio; and wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl moiety is independently optionally substituted with one or more C1-C6 alkyl, acyl, halogen, or deuterium.
In one embodiment, X4 is CRa4. In one embodiment, X4 is CH. In one embodiment, X4 is CR5. In one embodiment, X4 is N. In one embodiment, X5 is CRa5. In one embodiment, X5 is CH. In one embodiment, X5 is CR5. In one embodiment, X5 is N. In one embodiment, X6 is CRa6. In one embodiment, X6 is CH. In one embodiment, X6 is CR5. In one embodiment, X6 is N. In one embodiment, X7 is CRa7. In one embodiment, X7 is CH. In one embodiment, X7 is CR5. In one embodiment, X7 is N.
In one embodiment, X4 is N, and X5 is CRa5. In one embodiment, X4 is CRa4, and X5 is N. In one embodiment, X6 is N, and X7 is CRa7. In one embodiment, X6 is CRa6, and X7 is N. In one embodiment, X4 is N, and X5 is N. In one embodiment, X4 is N, and X6 is N. In one embodiment, X4 is N, and X7 is N. In one embodiment, X5 is N, and X6 is N. In one embodiment, X5 is N, and X7 is N.
In one embodiment, X4 is N, X5 is CRa5, X6 is CRa6, and X7 is CRa7. In one embodiment, X4 is CRa4, X5 is N, X6 is CRa6, and X7 is CRa7. In one embodiment, X4 is CRa4, X5 is CRa5, X6 is N, and X7 is CRa7. In one embodiment, X4 is CRa4, X5 is CRa5, X6 is CRa6, and X7 is N. In one embodiment, X4 is CRa4, X5 is CRa5, X6 is CRa6, and X7 is CRa7. In one embodiment, Ra4, Ra5, Ra6 and Ra7 are all hydrogen.
In one embodiment, X8 is CRa8. In one embodiment, X8 is CH. In one embodiment, X8 is CR6. In one embodiment, X8 is N. In one embodiment, X8 is NRa8. In one embodiment, X8 is NH. In one embodiment, X8 is NR6. In one embodiment, X8 is O. In one embodiment, X8 is S. In one embodiment, X9 is CRa9. In one embodiment, X9 is CH. In one embodiment, X9 is CR6. In one embodiment, X9 is N. In one embodiment, X9 is NRa9. In one embodiment, X9 is NH. In one embodiment, X9 is NR6. In one embodiment, X9 is O. In one embodiment, X9 is S. In one embodiment, X10 is CRa10. In one embodiment, X10 is CH. In one embodiment, X10 is CR6. In one embodiment, X10 is N. In one embodiment, X10 is NRa10. In one embodiment, X10 is NH. In one embodiment, X10 is NR6. In one embodiment, X10 is O. In one embodiment, X10 is S. In one embodiment, X11 is CRa11. In one embodiment, X11 is CH. In one embodiment, X11 is CR6. In one embodiment, X11 is N. In one embodiment, X11 is NRa11. In one embodiment, X11 is NH. In one embodiment, X11 is NR6. In one embodiment, X11 is O. In one embodiment, X11 is S. In one embodiment, X12 is C. In one embodiment, X12 is N.
In one embodiment, X8 is N, and X9 is CR6. In one embodiment, X9 is CR6 or NR6, and X11 is CR6 or NR6. In one embodiment, X8 is CH or N, and X10 is CH or N. In one  embodiment, X8 is CH or N, X9 is CH or N, and X10 is CH or N. In one embodiment, X8 is N, X9 is CR6 and X11 is NR6. In one embodiment, X8 is CH or N, X10 is CH or N, and X11 is CH or N.
In one embodiment, one of X8, X9, X10, X11 and X12 is N. In one embodiment, two of X8, X9, X10, X11 and X12 are N. In one embodiment, three of X8, X9, X10, X11 and X12 are N.
In one embodiment, X13 is CRa13. In one embodiment, X13 is CH. In one embodiment, X13 is CR6. In one embodiment, X13 is N. In one embodiment, X14 is CRa14. In one embodiment, X14 is CH. In one embodiment, X14 is CR6. In one embodiment, X14 is N. In one embodiment, X15 is CRa15. In one embodiment, X15 is CH. In one embodiment, X15 is CR6. In one embodiment, X15 is N. In one embodiment, X16 is CRa16. In one embodiment, X16 is CH. In one embodiment, X16 is CR6. In one embodiment, X16 is N. In one embodiment, X17 is CRa17. In one embodiment, X17 is CH. In one embodiment, X17 is CR6. In one embodiment, X17 is N.
In one embodiment, X13 is N, and X14 is CR6. In one embodiment, X13 is N, and X14 is N. In one embodiment, X13 is N, and X15 is N. In one embodiment, X13 is N, and X17 is CR6. In one embodiment, X13 is N, and X16 is N. In one embodiment, X13 is CR6, and X17 is N. In one embodiment, X14 is N, and X17 is CR6.
In one embodiment, X14 is N, X17 is CR6 and X16 is CH. In one embodiment, X14 is N, X17 is CR6 and X16 is CH. In one embodiment, X13 is N, X14 is N and X15 is CR6. In one embodiment, X13 is N, X14 is N and X17 is CR6. In one embodiment, X13 is N, X16 is N, and X17 is CR6. In one embodiment, X13 is N, X16 is N, and X14 is CR6. In one embodiment, X13 is N, X14 is CR6, and X17 is CR6. In one embodiment, X13 is N, X15 is CR6, and X17 is CR6. In one embodiment, X13 is N, X15 is CH, and X16 is CH.
In one embodiment, one of X13, X14, X15, X16 and X17 is N. In one embodiment, two of X13, X14, X15, X16 and X17 are N. In one embodiment, three of X13, X14, X15, X16 and X17 are N.
In one embodiment, each R6 is independently halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, alkylamino, dialkylamino, and wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl moiety is independently optionally substituted with one or more C1-C6 alkyl, acyl, halogen, or deuterium.
In one embodiment, each R6 is independently cyano, nitro, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, l-fluoropropan-2-yl, 2-fluoroethyl, acetyl, amino, methylamino, ethylamino, dimethylamino, 2, 2-difluoroethoxy, cyclopropoxy, morpholino, tetrahydropyranyl, oxetanyl, methoxymethyl, N, N-dimethylsulfonamido, cyclopropyl, cyclobutyl, methylaminomethyl, deuteromethyl, deuteroethyl, deuteroisopropyl, deuteromethoxy, or deuteroethoxy.
In one embodiment, each R6 is independently fluoro, methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, methoxy, dimethylamine, acetylmethylamine or 1-acetylpiperidin-4-yl. In one embodiment, the R6 at a position that is separated by one ring atom to the point of attachment of R to Ring A is trifluoromethyl.
In one embodiment, when R is substituted with two R6, one R6 trifluoromethyl and the other R6 is alkyl. In one embodiment, one R6 trifluoromethyl and the other R6 is alkoxy. In one embodiment, one R6 trifluoromethyl and the other R6 is cycloalkyl. In one embodiment, one R6 alkyl and the other R6 is alkoxy. In one embodiment, one R6 halogen and the other R6 is alkoxy. In one embodiment, one R6 halogen and the other R6 is alkyl. In one embodiment, one R6 alkoxy and the other R6 is cycloalkyl. In one embodiment, one R6 alkyl and the other R6 is cycloalkyl. In one embodiment, one R6 alkyl and the other R6 is dialkylamino.
In one embodiment, R2 and R3 are each independently halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino) alkyl, (dialkylamino) alkyl, cyanoalkyl, (carboxamido) alkyl, mercaptoalkyl, (cycloalkylamino) alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl) amino, carboxy, amido, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, or alkylthio; and each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl moiety in R2 or R3 is independently optionally substituted with one or more C1-C6 alkyl, halogen, or deuterium.
In one embodiment, R2 and R3 are each independently halogen, nitro, cyano, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-to 8-membered  heterocyclyl, 5-to 10-membered aryl, 5-to 10-membered heteroaryl, C1-C6 alkoxy, C3-C8 cycloalkyloxy, 3-to 8-membered heterocyclyloxy, 5-to 10-membered aryloxy, 5-to 10-membered heteroaryloxy, (C3-C8 cycloalkyl) (C1-C6 alkyl) , or (3-to 8-membered heterocyclyl) (C1-C6 alkyl) .
In one embodiment, R2 is cyano, amino, methylamino, dimethylamino, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, cyclopropoxy, cyclobutoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, chloro, fluoro, l-fluoropropan-2-yl, (S) -1-fluoropropan-2-yl, (R) -l-fluoropropan-2-yl, hydroxyethyl, l-methoxy-2-methylpropan-2-yl, 1-methoxypropan-2-yl, (S) -1-methoxypropan-2-yl, (R) -l-methoxypropan-2-yl, 1- (methoxymethyl) cyclopropyl, l-hydroxypropan-2-yl, oxetan-3-yl, tetrahydrofuran-3-yl, 1-methylcyclopropyl, deuteromethyl, deuteroethyl, deuteroisopropyl, deuteromethoxy, or deuteroethoxy.
In one embodiment, R2 is cycloalkyl. In one embodiment, R2 is C3-C8 cycloalkyl. In one embodiment, R2 is cyclopropyl. In one embodiment, R2 is cyclobutyl.
In one embodiment, R3 is cyano, amino, methylamino, dimethylamino, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, cyclopropoxy, cyclobutoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, chloro, fluoro, l-fluoropropan-2-yl, (S) -1-fluoropropan-2-yl, (R) -l-fluoropropan-2-yl, hydroxyethyl, l-methoxy-2-methylpropan-2-yl, 1-methoxypropan-2-yl, (S) -1-methoxypropan-2-yl, (R) -l-methoxypropan-2-yl, 1- (methoxymethyl) cyclopropyl, l-hydroxypropan-2-yl, oxetan-3-yl, tetrahydrofuran-3-yl, 1-methylcyclopropyl, deuteromethyl, deuteroethyl, deuteroisopropyl, deuteromethoxy, or deuteroethoxy.
In one embodiment, R3 is alkoxy. In one embodiment, R3 is C1-C6 alkoxy. In one embodiment, R3 is methoxy. In one embodiment, R3 is ethoxy.
In one embodiment, R2 is cycloalkyl and R3 is alkoxy. In one embodiment, R2 is C3-C8 cycloalkyl and R3 is C1-C6 alkoxy. In one embodiment, R2 is cyclopropyl and R3 is methoxy.
In one embodiment, X1 is CRa1, X2 is CRa2, X3 is CRa3, R2 is cycloalkyl, and R3 is alkoxy. In one embodiment, X1, X2, and X3 are CH, R2 is cycloalkyl, and R3 is alkoxy. In one embodiment, X1 is N, X2 is CRa2, X3 is CRa3, R2 is cycloalkyl, and R3 is alkoxy. In  one embodiment, X2 is N, X1 is CRa1, X3 is CRa3, R2 is cycloalkyl, and R3 is alkoxy. In one embodiment, X3 is N, X1 is CRa1, X2 is CRa2, R2 is cycloalkyl, and R3 is alkoxy. In one embodiment, X1 is N, X2 is N, X3 is CRa3, R2 is cycloalkyl, and R3 is alkoxy. In one embodiment, X1 is N, X2 is N, X3 is CH, R2 is cycloalkyl, and R3 is alkoxy. In one embodiment, X1 is N, X2 is CRa2, X3 is N, R2 is cycloalkyl, and R3 is alkoxy. In one embodiment, X2 is N, X3 is N, X1 is CRa1, R2 is cycloalkyl, and R3 is alkoxy.
In one embodiment, provided herein is a compound of Formula (III-A) , (III-B) , (III-C) , (III-D) , (III-E) , (III-F) , (III-G) , or (III-H) :

or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.
In one embodiment of Formula (III-A) , (III-B) , (III-C) , (III-D) , (III-E) , (III-F) , (III-G) , or (III-H) , R1 is alkoxy. In one embodiment of Formula (III-A) , (III-B) , (III-C) , (III-D) , (III-E) , (III-F) , (III-G) , or (III-H) , R2 is cycloalkyl. In one embodiment of Formula (III-A) , (III-B) , (III-C) , (III-D) , (III-E) , (III-F) , (III-G) , or (III-H) , R3 is methoxy. In one embodiment of Formula (III-A) , (III-B) , (III-C) , (III-D) , (III-E) , (III-F) , (III-G) , or (III-H) , R4 is methyl.
In one embodiment, when the carbon connected to R4 and R4’ is a chiral center, it has the S-configuration.
In one embodiment, when the carbon connected to R4 and R4’ is a chiral center, it has the R-configuration.
In one embodiment, the compounds provided herein are single enantiomers. In one embodiment, the compounds provided herein are single diastereoisomers. In one embodiment, the compounds provided herein are mixtures of enantiomers. In one embodiment, the compounds provided herein are mixtures of diastereoisomers. In one embodiment, the compounds provided herein are racemic compounds.
In one embodiment, a compound provided herein has enantiomeric excess of at least about 10%, at least about 20%, at least about 30%, at least about 40%, 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%, at least about 98%, at least about 99%, at least about 99.5%, or at least about 99.9%. In one embodiment, the compound is a substantially purified enantiomer. In one embodiment, the compound is a substantially purified enantiomer of S-configuration. In one embodiment, the compound is a substantially purified enantiomer of R-configuration.
In one embodiment, the compound has enantiomeric excess of S-configuration of at least about 80%. In one embodiment, the compound has enantiomeric excess of S-configuration of at least about 90%. In one embodiment, the compound has enantiomeric excess of S-configuration of at least about 92%. In one embodiment, the compound has enantiomeric excess of S-configuration of at least about 94%. In one embodiment, the compound has enantiomeric excess of S-configuration of at least about 96%. In one embodiment, the compound has enantiomeric excess of S-configuration of at least about 98%. In one embodiment, the compound has enantiomeric excess of S-configuration of at least about 99%. In one embodiment, the compound has enantiomeric excess of S-configuration of at least about 99.5%. In one embodiment, the compound has enantiomeric excess of S-configuration of at least about 99.9%.
In one embodiment, the compound has enantiomeric excess of R-configuration of at least about 80%. In one embodiment, the compound has enantiomeric excess of R-configuration of at least about 90%. In one embodiment, the compound has enantiomeric excess of R-configuration of at least about 92%. In one embodiment, the compound has enantiomeric excess of R-configuration of at least about 94%. In one embodiment, the compound has enantiomeric excess of R-configuration of at least about 96%. In one embodiment, the compound has enantiomeric excess of R-configuration of at least about 98%. In one embodiment, the compound has enantiomeric excess of R-configuration of at least about 99%. In one embodiment, the compound has enantiomeric excess of R-configuration of at least about 99.5%. In one embodiment, the compound has enantiomeric excess of R-configuration of at least about 99.9%.
In one embodiment, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof.
Table 1.


As used herein and unless otherwise specified, when the stereochemical configuration for a chiral center in a compound provided herein is drawn stereo specifically (e.g., with widget and/or dash bonds) , either without additional designation or being designated “R” (or “ (R) ” ) or “S’ (or “ (S) ” ) , it means the absolute stereochemistry is known. For some compounds, the stereochemical configuration at indicated centers has been  designated as “*R” (first eluted from the column in case the column conditions of the separation are described in the synthesis protocol and when only one stereocenter present or indicated) or “*S” (second eluted from the column in case the column conditions of the separation are described in the synthesis protocol and when only one stereocenter present or indicated) when the absolute stereochemistry is undetermined (even if the bonds are drawn stereo specifically) although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure. In case a compound designated as “*R” is converted into another compound, the “*R” indication of the resulting compound is derived from its starting material.
In one embodiment, the compounds provided herein are USP1 inhibitors that reduce the level of USP1 protein and/or inhibit or reduce at least one biological activity of USP1 protein.
In one embodiment, the compounds provided herein specifically bind to USP1 protein. In one embodiment, the compounds provided herein specifically bind to USP1 protein in a USP1-UAF1 complex. In one embodiment, the compounds provided herein specifically bind to USP1 mRNA. In one embodiment, the compounds provided herein specifically bind to USP1 protein (alone or in a USP1-UAF1 complex) or USP1 mRNA. In one embodiment, the compounds provided herein specifically bind to UAF1 (alone or in a USP1-UAF1 complex) and inhibit or reduces formation or activity of the USP1-UAF1 complex.
In one embodiment, without being bound by a particular theory, the S enantiomer of a compound provided herein has a higher binding affinity to USP1 protein than the R enantiomer. In one embodiment, the S enantiomer has a binding affinity to USP1 protein of at least 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 8 times, 10 times, 20 times, 30 times, 50 times or 100 times higher than the R enantiomer.
In one embodiment, without being bound by a particular theory, the R enantiomer of a compound provided herein has a higher binding affinity to USP1 protein than the S enantiomer. In one embodiment, the R enantiomer has a binding affinity to USP1 protein of at least 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 8 times, 10 times, 20 times, 30 times, 50 times or 100 times higher than the S enantiomer.
In one embodiment, the compounds provided herein decrease the formation of the USP1-UAF1 complex. In one embodiment, the compounds provided herein decrease the  activity of the USP1-UAF1 complex. In one embodiment, the compounds provided herein decrease the deubiquitinase activity of USP1. In one embodiment, the compounds provided herein increase mono-ubiquitinated PCNA. In one embodiment, the compounds provided herein increase mono-ubiquitinated FANCD2.
In one embodiment, the compounds provided herein increase mono-ubiquitinated FANCI.
In one embodiment, the compounds provided herein do not bind to other deubiquitinases, other USP proteins, or other UAFl complexes (e.g., USP46-UAF1) . In one embodiment, the compounds provided herein bind to deubiquitinases, other USP proteins, or other UAFl complexes (e.g., USP46-UAF1) with at least about 5-fold, at least about 10-fold, at least about 20-fold, or at least about 100-fold reduced affinity compared to the affinity for USP1 (i.e., the KD of the compounds provided herein for other deubiquitinases, other USP proteins, or other UAFl complexes (e.g., USP46-UAF1) is at least about 5-fold, at least about 10-fold, at least about 20-fold, or at least about 100-fold higher than the KD for USP1) .
In one embodiment, the compounds provided herein inhibit USP1 deubiquitinase activity with an IC50 of less than about 50 nM, between about 50 nM and about 200 nM, between about 200 nM and about 2 μM, or greater than 2 μM, e.g., as measured using the assay described in US Patent Application Publication No. 2017/0145012, or IC50 of 50 nM to 1000 nM, e.g., as measured using the assay disclosed in Liang et al., Nat Chem Biol 10: 289-304 (2014) . In one embodiment, the compounds provided herein inhibit USP1 deubiquitinase activity with an IC50 as measured using the assay disclosed in Chen, et al., Chem Biol., 18 (11) : 1390-1400 (2011) . In one embodiment, the compounds provided herein do not inhibit the activity of other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) , or the compounds provided herein inhibit the activity of other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) with at least about 5-fold, at least about 10-fold, at least about 20-fold, or at least about 100-fold higher IC50 compared to the IC50 for inhibition of USP1 deubiquitinase activity.
In one embodiment, the compounds provided herein bind to a USP1 protein with an affinity in the range of about 1 pM to about 100 μM, about 1 pM to about 1 μM, about 1 pM to about 500 nM, or about 1 pM to about 100 nM. In some embodiment, the compounds provided herein bind to a USP1 protein with an affinity of about 1 pM to about 100 μM, about 1 nM to about 100 μM, about 1 μM to about 100 μM, about 1 μM to about 50  μM, about 1 μM to about 40 μM, about 1 μM to about 30 μM, about 1 μM to about 20 μM, or about 1 μM to about 10 μM, about 1 μM, about 5 μM, about 10 μM, about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM, about 40 μM, about 45 μM, about 50 μM, about 60 μM, about 70 μM, about 80 μM, about 90 μM, or about 100 μM. In some embodiment, the compounds provided herein bind to a USP1 protein with an affinity of about 100 nM to about 1 μM, about 100 nM to about 900 nM, about 100 nM to about 800 nM, about 100 nM to about 700 nM, about 100 nM to about 600 nM, about 100 nM to about 500 nM, about 100 nM to about 400 nM, about 100 nM to about 300 nM, about 100 nM to about 200 nM, about 200 nM to about 1 μM, about 300 nM to about 1 μM, about 400 nM to about 1 μM, about 500 nM to about 1 μM, about 600 nM to about 1 μM, about 700 nM to about 1 μM, about 800 nM to about 1 μM, about 900 nM to about 1 μM, about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, about 600 nM, about 700 nM, about 800 nM, or about 900 nM. In some embodiment, the compounds provided herein bind to a USP1 protein with an affinity of about 1 nM to about 100 nM, about 1 nM to about 90 nM, about 1 nM to about 80 nM, about 1 nM to about 70 nM, about 1 nM to about 60 nM, about 1 nM to about 50 nM, about 1 nM to about 40 nM, about 1 nM to about 30 nM, about 1 nM to about 20 nM, about 1 nM to about 10 nM, about 10 nM to about 100 nM, about 20 nM to about 100 nM, about 30 nM to about 100 nM, about 40 nM to about 100 nM, about 50 nM to about 100 nM, about 60 nM to about 100 nM, about 70 nM to about 100 nM, about 80 nM to about 100 nM, about 90 nM to about 100 nM, about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 20 nM, about 30 nM, about 40 nM, about 50 nM, about 60 nM, about 70 nM, about 80 nM, about 90 nM, or about 100 nM. In some embodiment, the compounds provided herein bind to a USP1 protein with an affinity of less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. In one embodiment, the compounds provided herein bind to a USP1 protein with an affinity of less than 1 nM.
In one embodiment, the compounds provided herein inhibit USP1 activity with an IC50 of about 1 pM to about 100 μM, or about 1 pM to about 1 μM, or about 1 pM to about 500 nM, or about 1 pM to about 100 nM. In one embodiment, the compounds provided herein inhibit USP1 activity with an IC50 of about 1 pM to about 100 μM, about 1 nM to about 100 μM, about 1 μM to about 100 μM, about 1 μM to about 50 μM, about 1 μM to about 40 μM, about 1 μM to about 30 μM, about 1 μM to about 20 μM, or about 1 μM to about 10 μM, about 1 μM, about 5 μM, about 10 μM, about 15 μM, about 20 μM, about 25  μM, about 30 μM, about 35 μM, about 40 μM, about 45 μM, about 50 μM, about 60 μM, about 70 μM, about 80 μM, about 90 μM, or about 100 μM. In some embodiment, the compounds provided herein inhibit USP1 activity with an IC50 of about 100 nM to about 1 μM, about 100 nM to about 900 nM, about 100 nM to about 800 nM, about 100 nM to about 700 nM, about 100 nM to about 600 nM, about 100 nM to about 500 nM, about 100 nM to about 400 nM, about 100 nM to about 300 nM, about 100 nM to about 200 nM, about 200 nM to about 1 μM, about 300 nM to about 1 μM, about 400 nM to about 1 μM, about 500 nM to about 1 μM, about 600 nM to about 1 μM, about 700 nM to about 1 μM, about 800 nM to about 1 μM, about 900 nM to about 1 μM, about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, about 600 nM, about 700 nM, about 800 nM, or about 900 nM. In some embodiment, the compounds provided herein inhibit USP1 activity with an IC50 of about 1 nM to about 100 nM, about 1 nM to about 90 nM, about 1 nM to about 80 nM, about 1 nM to about 70 nM, about 1 nM to about 60 nM, about 1 nM to about 50 nM, about 1 nM to about 40 nM, about 1 nM to about 30 nM, about 1 nM to about 20 nM, about 1 nM to about 10 nM, about 10 nM to about 100 nM, about 20 nM to about 100 nM, about 30 nM to about 100 nM, about 40 nM to about 100 nM, about 50 nM to about 100 nM, about 60 nM to about 100 nM, about 70 nM to about 100 nM, about 80 nM to about 100 nM, about 90 nM to about 100 nM, about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 20 nM, about 30 nM, about 40 nM, about 50 nM, about 60 nM, about 70 nM, about 80 nM, about 90 nM, or about 100 nM. In one embodiment, the compounds provided herein inhibit USP1 activity with an ICso of less than 1 μM, less than 500 nM, less than 100 nM, less than 10 nM, or less than 1 nM. In one embodiment, the compounds provided herein inhibit USP1 activity with an IC50 of less than 1 nM.
In one embodiment, without being bound by a particular theory, the IC50 of the S enantiomer of a compound provided herein is lower than the IC50 of the R enantiomer for inhibiting USP1 activity. In one embodiment, the IC50 of the R enantiomer is at least 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 8 times, 10 times, 20 times, 30 times, 50 times or 100 times higher than the IC50 of the S enantiomer for inhibiting USP1 activity.
In one embodiment, without being bound by a particular theory, the IC50 of the R enantiomer of a compound provided herein is lower than the IC50 of the S enantiomer for inhibiting USP1 activity. In one embodiment, the IC50 of the S enantiomer is at least 1.5  times, 2 times, 3 times, 4 times, 5 times, 6 times, 8 times, 10 times, 20 times, 30 times, 50 times or 100 times higher than the IC50 of the R enantiomer for inhibiting USP1 activity.
METHODS OF USE
In one embodiment, the compounds provided herein can be used to inhibit the activity of a USP1 protein. In one embodiment, provided herein is a method of inhibiting a USP1 protein comprises contacting the USP1 protein with a compound provided herein. The contacting can occur in vitro or in vivo. In one embodiment, the contacting occurs in a subject suffering from a USP1 protein mediated disorder.
In one embodiment, the compounds provided herein can be used to treat a USP1 protein mediated disorder. In one embodiment, provided herein is a method of treating a USP1 protein mediated disorder or cancer, comprising administering to a subject having the disorder or cancer a therapeutically effective amount of a compound provided herein or a pharmaceutical composition provided herein. A USP1 protein mediated disorder is any pathological condition in which a USP1 protein is known to play a role. In one embodiment, a USP1 protein mediated disorder is a proliferative disease such as cancer.
In one embodiment, provided herein are methods of treating diseases and disorders with the compounds provided herein. Exemplary diseases and disorders that may be treated with the compounds provided herein include, but are not limited to, cancer.
In one embodiment, provided herein is a method of treating a cancer, comprising administering to a subject having the cancer a therapeutically effective amount of a compound provided herein or a pharmaceutical composition provided herein.
In one embodiment, the cancer is a hematological cancer, a lymphatic cancer, a DNA damage repair pathway deficient cancer, a homologous-recombination deficient cancer, a cancer comprising cancer cells with a mutation in a gene encoding p53, or a cancer comprising cancer cells with a loss of function mutation in a gene encoding p53. In one embodiment, the cancer is a cancer that comprises cancer cells with a mutation in a gene encoding p53. In one embodiment, the cancer is a cancer that comprises cancer cells with a loss of function mutation in a gene encoding p53. In one embodiment, the cancer is a cancer that comprises cancer cells with a mutation in a gene encoding BRCA1. In one embodiment, the cancer is a cancer that comprises cancer cells with a mutation in a gene encoding BRCA2. In one embodiment, the cancer is a cancer that comprises cancer cells with a loss of function mutation in a gene encoding ATM.
In one embodiment, the cancer is a solid tumor. In one embodiment, the cancer is lung cancer, non-small cell lung cancer (NSCLC) , colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, or breast cancer. In one embodiment, the cancer is non-small cell lung cancer (NSCLC) , osteosarcoma, ovarian cancer, or breast cancer. In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is a triple negative breast cancer.
In one embodiment, the cancer to be treated with a compound provided herein is selected from the group consisting of bone cancer, including osteosarcoma and chondrosarcoma; brain cancer, including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma; soft tissue cancer, including rhabdoid and sarcoma; kidney cancer; bladder cancer; skin cancer, including melanoma; and lung cancer, including non-small cell lung cancer; colon cancer, uterine cancer; nervous system cancer; head and neck cancer; pancreatic cancer; and cervical cancer.
In one embodiment, provided herein is a method of treating cancer, comprising administering to a subject having the cancer a therapeutically effective amount of a compound provided herein, wherein the cancer comprises cancer cells with elevated levels of RAD18. In one embodiment, the elevated levels of RAD 18 are elevated RAD 18 protein levels. In one embodiment, the elevated levels of RAD 18 are elevated RAD 18 mRNA levels. In one embodiment, the elevated levels of RAD18 (e.g., RAD18 protein and/or RAD18 mRNA) have been detected (e.g., in a cancer sample obtained from the subject) prior to the administration. That is, in one embodiment, the cancer in the subject has been tested for RAD 18 protein or mRNA prior to beginning treatment with a USP1 inhibitor, such as a compound provided herein.
In one embodiment, such methods comprise (a) identifying a cancer in a subject as a USP1 inhibitor-sensitive cancer, and then (b) administering a therapeutically effective amount of a compound provided herein to the subject.
In one embodiment, such methods comprise (a) detecting levels of RAD 18 (e.g., RAD 18 protein and/or RAD 18 mRNA) in cancer cells (e.g., in a cancer sample obtained from the subject) and then (b) administering a therapeutically effective amount of a compound provided herein to a subject having a cancer comprising the cancer cells with elevated levels of RAD18.
In one embodiment, such methods comprise administering to a subject having triple negative breast cancer a therapeutically effective amount of a compound provided herein.
In one embodiment, a compound provided herein is used to treat a cancer, wherein the cancer is a homologous-recombination deficient cancer. In one embodiment, a compound provided herein is used to treat a cancer, wherein the cancer comprises cancer cells with a mutation in a gene encoding p53. In one embodiment, a compound provided herein is used to treat a cancer, wherein the cancer comprises cancer cells with a loss of function mutation in a gene encoding p53. In one embodiment, a compound provided herein is used to treat a cancer that does not have a defect in the homologous recombination pathway.
In one embodiment, a compound provided herein is used to treat a cancer, wherein the cancer is a BRCA1 mutant cancer. In one embodiment, a compound provided herein is used to treat a cancer, wherein the cancer is a BRCA2 mutant cancer. In one embodiment, a compound provided herein is used to treat a cancer, wherein the cancer is a BRCA1 mutant cancer and a BRCA2 mutant cancer. In one embodiment, the cancer is not a BRCA1 mutant cancer or a BRCA2 mutant cancer. In one embodiment, the cancer is a BRCA1 deficient cancer. In one embodiment, the cancer is a BRCA2 deficient cancer. In one embodiment, the cancer is a BRCA1 deficient cancer and a BRCA2 deficient cancer.
In one embodiment, a compound provided herein is used to treat a cancer, wherein the cancer is an ATM mutant cancer. In one embodiment, the cancer is not an ATM mutant cancer. In one embodiment, the cancer is an ATM deficient cancer.
In one embodiment, a compound provided herein is used to treat a cancer, wherein the cancer is a PARP inhibitor resistant or refractory cancer. In one embodiment, the cancer is a PARP inhibitor resistant or refractory BRCA1 mutant cancer. In one embodiment, the cancer is a PARP inhibitor resistant or refractory BRCA1 deficient cancer. In one embodiment, the cancer is a PARP inhibitor resistant or refractory BRCA2 mutant cancer. In one embodiment, the cancer is a PARP inhibitor resistant or refractory BRCA2 deficient cancer.
In one embodiment, the cancer is a BRCA1 and/or BRCA2 mutant cancer, wherein the cancer comprises cells with elevated levels of RAD18. In one embodiment, the elevated levels of RAD18 are at least as high as the RAD18 protein and/or mRNA levels in  ES2 cells. In one embodiment, the elevated levels of RAD18 are higher than the RAD18 protein and/or mRNA levels in HEP3B217 cells. In one embodiment, a triple negative breast cancer is a BRCA1 and/or BRCA2 mutant cancer.
In one embodiment, the cancer is a solid cancer. In one embodiment, the cancer is a hematological/lymphatic cancer. In one embodiment, the cancer is a DNA damage repair pathway deficient cancer. In one embodiment, the cancer is a homologous-recombination deficient cancer. In one embodiment, the cancer comprises cancer cells with a mutation in a gene encoding p53. In one embodiment, the cancer comprises cancer cells with a loss of function mutation in a gene encoding p53. In one embodiment, the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC) , osteosarcoma, ovarian cancer, and breast cancer (including triple negative breast cancer) . In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is triple negative breast cancer.
In one embodiment, a compound provided herein is used in combination with one or more additional therapeutic agents to treat cancer. It has been reported that p53 status determines PARP inhibitor sensitization (Sa et al., Genome Biology, (2019) 20: 253) and that BRCAl/2 status predicts the efficacy of PARP inhibitors in the clinic (Audeh et al., Lancet (2010) 376 (9737) , 245-51) . In one embodiment, without being bound by a particular theory, p53 mutant cancers and BRCA mutant cancers have increased sensitivity to USP1 inhibitors. Accordingly, in one embodiment, a compound provided herein is used in combination with a PARP inhibitor to treat cancer.
In one embodiment, compounds provided herein are provided for use as a medicament or are provided for use in preparing a medicament, e.g., for the treatment of cancer. In one embodiment, compounds provided herein are provided for use in a method for the treatment of cancer.
PHARMACEUTICAL COMPOSITIONS
Also provided herein are pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable excipient.
In one embodiment, compounds provided herein are administered to a mammal in the form of a raw chemical without any other components present. In one embodiment, compounds provided herein are administered to a mammal as part of a pharmaceutical composition containing the compound combined with a suitable  pharmaceutically acceptable carrier (see, for example, Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th ed. (2003) ; Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippencott Williams and Wilkins (2004) ; Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press (2000) ) . Such a carrier can be selected from pharmaceutically acceptable excipients and auxiliaries.
In one embodiment, a pharmaceutical composition provided herein may be prepared as liquid suspensions or solutions using a liquid, such as an oil, water, an alcohol, and combinations of these.
In one embodiment, a pharmaceutical composition provided herein may be prepared as a sterile injectable, which may be aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art.
In one embodiment, a pharmaceutical composition provided herein may be orally administered in any orally acceptable dosage form including capsules, tablets, aqueous suspensions or solutions.
In one embodiment, a pharmaceutical composition provided herein may be administered in the form of suppositories for rectal administration.
In one embodiment, a pharmaceutical composition provided herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Topical application for the lower intestinal tract is affected in a rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches may also be used. For topical applications, the pharmaceutical compositions is formulated in a suitable ointment, lotion, or cream containing the active component suspended or dissolved in one or more carriers.
In one embodiment, a pharmaceutical composition provided herein may also be administered ophthalmically and formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzyl alkonium chloride. In one embodiment, for ophthalmic uses, the pharmaceutical compositions is formulated in an ointment such as petrolatum.
In one embodiment, a pharmaceutical composition provided herein may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to  techniques known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
In one embodiment, the pharmaceutical compositions to be used for in vivo administration can be sterile. In one embodiment, this is accomplished by filtration through, e.g., sterile filtration membranes.
In one embodiment, pharmaceutical compositions provided herein include all compositions where a compound provided herein is combined with one or more pharmaceutically acceptable carriers. In one embodiment, the compound provided herein is present in the composition in an amount that is effective to achieve its intended therapeutic purpose.
In one embodiment, a pharmaceutical composition provided herein can be administered to any patient that may experience the beneficial effects of a compound provided herein. In one embodiment, the patients are mammals, e.g., humans and companion animals. In one embodiment, the patient is a human.
In one embodiment, also provided herein are kits which comprise a compound provided herein (or a composition comprising a compound provided herein) packaged in a manner that facilitates their use to practice methods provided herein. In one embodiment, the kit includes a compound provided herein (or a composition comprising a compound provided herein) packaged in a container, such as a sealed vial, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method provided herein. In one embodiment, the compound or composition is packaged in a unit dosage form. In one embodiment, the kit further includes a device suitable for administering the compound or composition according to the intended route of administration. In one embodiment, the kit comprises a compound provided herein, and instructions for administering the compound to a patient having cancer.
EXAMPLES
SYNTHETIC METHODS
In one embodiment, provided herein is a process (Method 1) for the preparation of a compound provided herein comprising the following steps:
Wherein X is a halogen, such as Br, Cl or F.
Step 1 is performed at a suitable temperature such as from room temperature to 120 ℃, in the presence of a suitable inorganic base such as triethyl amine or diisopropylethylamine, and in a suitable organic solvent such as THF, ethanol or isopropanol.
Step 2 is performed at a suitable temperature such as from 50 to 120 ℃, in the presence of a suitable inorganic base such as sodium carbonate or potassium phosphate, in the presence of a suitable palladium catalyst such as for example CATACXIUMI A Pd G3 or Pd (dppf) Cl2, and in a suitable solvent combination such as dimethoxyethane/water or dioxane/water.
Several methods for preparing the compounds provided herein are illustrated in the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively can be synthesized by a skilled person by using well-known methods.


As used herein and unless otherwise specified, when the stereochemical configuration for a chiral center in a compound provided herein is drawn stereo specifically (e.g., with widget and/or dash bonds) , either without additional designation or being designated “R” (or “ (R) ” ) or “S’ (or “ (S) ” ) , it means the mixture (s) was separated and absolute stereochemistry was known, or only one enantiomer was obtained and absolute stereochemistry was known. For some compounds, the stereochemical configuration at indicated centers has been designated as “*R” (first eluted from the column in case the column conditions of the separation are described in the synthesis protocol and when only  one stereocenter present or indicated) or “*S” (second eluted from the column in case the column conditions of the separation are described in the synthesis protocol and when only one stereocenter present or indicated) when the absolute stereochemistry is undetermined (even if the bonds are drawn stereo specifically) although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure. In case a compound designated as “*R” is converted into another compound, the “*R” indication of the resulting compound is derived from its starting material.
Preparation of intermediates
For intermediates that were used in a next reaction step as a crude or as a partially purified intermediate, in some cases no mol amounts are mentioned for such intermediate in the next reaction step or alternatively estimated mol amounts or theoretical mol amounts for such intermediate in the next reaction step are indicated in the reaction protocols described below.
Preparation of intermediate 1
To a solution of tert-butyl N- [ (1S) -1- (4-bromophenyl) ethyl] carbamate (2 g, 6.66 mmol, 1 eq) in THF (20 mL) was added n-BuLi (2.5 M, 7.99 mL, 3.00 eq) dropwise at -78 ℃ under N2 atmosphere. After addition, the reaction mixture was stirred at this temperature for 1 hr. Then DMF (486.98 mg, 6.66 mmol, 512.61 uL, 1 eq) was added to the mixture dropwise at -78 ℃, which was stirred for 1 hr while gradually heating back to 25 ℃. The reaction mixture was quenched with NH4Cl (sat. aq. 50 mL) at 0 ℃, the mixture was poured into H2O (50 mL) and extracted with ethyl acetate (100 mL x 3) . The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (20 gSilica Flash Column, Eluent of 0～14%Ethyl acetate/Petroleum ether gradient @45 mL/min) to afford intermediate 1 (680 mg, 38.69%yield, 94.5%purity) as colorless oil.
The following intermediate was synthesized by an analogous method as described above for intermediate 1.
Preparation of intermediate 3
A mixture of 3, 3-dibromo-1, 1, 1-trifluoro-propan-2-one (1.10 g, 4.09 mmol, 1.5 eq) , NaOAc (447.51 mg, 5.46 mmol, 2 eq) in H2O (1.4 mL) was stirred at 95 ℃ for 30 min. After cooled to 0 ℃, a cold solution of intermediate 1 (680 mg, 2.73 mmol, 1 eq) in NH3. H2O (1.75 mL) and MeOH (5.25 mL) was added and then the mixture was stirred at 25 ℃ for 4 h. The mixture was concentrated under reduced pressure to give a residue which was then diluted with H2O (50 mL) and extracted with EtOAc (50 mL *3) . The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0～30 %Ethyl acetate/Petroleum ether gradient @40 mL/min) to afford intermediate 3 (450 mg, 33.57%yield, 72.3%purity) as a light-yellow solid.
The following intermediate was synthesized by an analogous method as described above for intermediate 3.
Preparation of intermediate 5
A mixture of intermediate 3 (450 mg, 1.27 mmol, 1 eq) , 2-iodopropane (322.90 mg, 1.90 mmol, 189.61 uL, 1.5 eq) and Cs2CO3 (1.24 g, 3.80 mmol, 3 eq) in MeCN (5 mL) was stirred at 50 ℃ for 12 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0～20 %Ethyl acetate/Petroleum ether gradient @40 mL/min) to afford intermediate 5 (330 mg, 64.13%yield, 97.8%purity) as white solid.
The following intermediates were synthesized by an analogous method as described above for intermediate 5.
Preparation of intermediate 8
A solution of 2-cyclopropyl-2-oxo-acetaldehyde (786.99 mg, 8.02 mmol, 2 eq) in MeOH (10 mL) was added dropwise to a stirring solution of the tert-butyl N- [ (1S) -1- (4- formylphenyl) ethyl] carbamate (1 g, 4.01 mmol, 1 eq) and NH4OAc (1.55 g, 20.06 mmol, 5 eq) in MeOH (10 mL) and stirred at 25 ℃ for 16 h. The solution was quenched with saturated NaHCO3 (aq. ) solution (20 mL) and stirred for 30 min. MeOH was removed in vacuum and EtOAc (20 mL) was added. The organic layer was separated, and the aqueous layer was extracted with EtOAc (20 mL x 3) . The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1/0 to 0/1, TLC (PE: EA=0: 1, Rf=0.3) ) to afford intermediate 8 (720 mg, 52.63%yield, 96%purity) as a yellow solid.
Preparation of intermediate 9
To a solution of intermediate 8 (550 mg, 1.68 mmol, 1 eq) in MeCN (8 mL) was added 2-iodopropane (856.66 mg, 5.04 mmol, 503.03 μL, 3 eq) and Cs2CO3 (1.64 g, 5.04 mmol, 3 eq) and stirred at 70 ℃ for 16 h. H2O (50 mL) was added, the mixture was extracted with ethyl acetate (50 mL x 3) . The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 3/1) to afford intermediate 9 (90 mg, crude) as colorless oil.
Preparation of intermediate 10
To a solution of 1- (4-bromophenyl) ethanol (3 g, 14.92 mmol, 1 eq) in DMSO (40 mL) added KOAc (4.39 g, 44.76 mmol, 3 eq) and BIS (PINACOLATO) DIBORON (4.17 g, 16.41 mmol, 1.1 eq) . The mixture was degassed under vacuum and purged with N2 atmosphere for three times, and then Pd (dppf) Cl2 (2.18 g, 2.98 mmol, 0.2 eq) was added. The mixture was degassed under vacuum and purged with N2 atmosphere for three times and stirred at 85 ℃ for 18 h. The reaction mixture was diluted with H2O (50 mL) and extracted  with EtOAc (50mL *3) . The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=5/1 to 2/1) to afford intermediate 10 (2.18 g, 51.82%yield, 88%purity) as yellow oil.
Preparation of intermediate 11
To a solution of 2-chloro-3-methoxy-6- (trifluoromethyl) pyridine (1.04 g, 4.92 mmol, 1 eq) and intermediate 10 (1.22 g, 4.92 mmol, 1 eq) in dioxane (24 mL) and H2O (6 mL) was added Cs2CO3 (3.20 g, 9.83 mmol, 2 eq) , the suspension was degassed under vacuum and purged with N2 atmosphere for three times, and then [1, 1'-bis (di-tert-butylphosphino) ferrocene] palladium (II) dichloride (320.40 mg, 491.57 μmol, 0.1 eq) was added. The mixture was degassed under vacuum and purged with N2 atmosphere for three times and stirred at 100 ℃ for 12 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50mL *3) . The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to get a residue. The residue was purified by flash silica gel chromatography (12 gSilica Flash Column, Eluent of 0～20%Ethyl acetate/Petroleum ether gradient @35 mL/min) to afford intermediate 11 (1.41 g, 66.97%yield, 95%purity) as yellow oil.
The following intermediate was synthesized by an analogous method as described above for intermediate 11.
Preparation of intermediate 13
To a solution of intermediate 11 (1.41 g, 4.74 mmol, 1 eq) in DCM (15 mL) was added MnO2 (6.19 g, 71.15 mmol, 15 eq) . The mixture was stirred at 20 ℃ for 16 hr. The reaction was filtered, and the filtrate was concentrated under reduced pressure to afford intermediate 13 (906 mg, crude) as a white solid, which was used to the next step without further purification.
The following intermediate was synthesized by an analogous method as described above for intermediate 13.
Preparation of intermediate 15
To a solution of intermediate 13 (856 mg, 2.90 mmol, 1 eq) and AMMONIUM ACETATE (2.23 g, 28.99 mmol, 10 eq) in EtOH (15 mL) was added NaBH3CN (188 mg, 2.99 mmol, 1.03 eq) . The mixture was stirred at 20 ℃ for 16 hr. The reaction was quenched with water (5 mL) and the residue was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0～10%MeOH/DCM @35 mL/min) to afford intermediate 15 (784 mg, 73.00%yield, 80%purity) as a white solid.
The following intermediate was synthesized by an analogous method as described above for intermediate 15.
Preparation of intermediate 17
A mixture of tert-butyl N- [ (1S) -1- (4-bromophenyl) ethyl] carbamate (500.00 mg, 1.67 mmol, 1 eq) and 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (634.44 mg, 2.50 mmol, 1.5 eq) in dioxane (5 mL) was degassed an purged with N2 for 3 times, and then added KOAc (490.39 mg, 5.00 mmol, 3 eq) and Pd (dppf) Cl2 (121.87 mg, 166.56 μmol, 0.1 eq) to the mixture was stirred at 100 ℃ for 12 hr under N2 atmosphere. H2O (30 mL) was added, the mixture was extracted with ethyl acetate (20 mL x 3) . The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH = 1: 0 to 10: 1) to afford intermediate 17 (510 mg, 83.77%yield, 95%purity) as a brown oil.
Preparation of intermediate 18
A mixture of intermediate 17 (505.68 mg, 1.46 mmol, 1.5 eq) and 2-bromo-6-fluoro-3-methoxy-pyridine (200 mg, 970.82 μmol, 1 eq) in dioxane (8 mL) and H2O (2 mL) was degassed and purged with N2 for 3 times, and then [1, 1'-bis (di-tert-butylphosphino) ferrocene] palladium (II) dichloride (63.27 mg, 97.08 μmol, 0.1 eq) and Cs2CO3 (632.62 mg, 1.94 mmol, 2 eq) was added, the mixture was stirred at 100 ℃ for 12 hr under N2 atmosphere. The reaction mixture was partitioned between H2O 30 mL and EtOAc  20 mL. The organic phase was separated, extracted with EtOAc (20 mL x 3) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 3/1, Rf =0.4) to afford intermediate 18 (326 mg, 96.94%yield) as a yellow solid.
The following intermediates were synthesized by an analogous method as described above for intermediate 18.

Preparation of intermediate 30
To a solution of 6-bromo-5-methoxy-pyridine-2-carbaldehyde (2 g, 9.26 mmol, 1 eq) in DCM (40 mL) was added N-ethyl-N- (trifluoro-sulfanyl) ethanamine (4.48 g, 27.77 mmol, 3.67 mL, 3 eq) , and the mixture was stirred at 25 ℃ for 12 hr. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3) . The combined organic layers were washed with saturated NaCl (50 mL) , dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 gSilica Flash Column, Eluent of 1/0～95/5 Petroleum ether/Ethyl acetate @30 mL/min) TLC (PE: EA= 10: 1, Rf=0.3) to afford intermediate 30 (1.95 g, 73.11%yield, 82.62%purity) as a light yellow solid.
Preparation of intermediate 31
To a solution of 2-chloro-6- (trifluoromethyl) pyridin-3-amine (1 g, 5.09 mmol, 1 eq) was dissolved in AcOH (7 mL) was added acetyl acetate (545.35 mg, 5.34 mmol, 501.70 μL, 1.05 eq) dropwise. The reaction mixture was stirred at 28 ℃ for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the organic phase was washed with 10%aqueous K2CO3 and brine. The organic layer was dried anhydrous Na2SO4, filtered and concentrated under reduced pressure to give intermediate 31 as a light-yellow solid (1.87 g, crude) , which was used for next step without further purification.
Preparation of intermediate 32
To a solution of intermediate 31 (600 mg, 2.51 mmol, 1 eq) in THF (6 mL) was added NaH (150.88 mg, 3.77 mmol, 60%purity, 1.5 eq) dropwise at 0 ℃, the resulting mixture was stirred at 0 ℃ for 30 min and then iodomethane (428.32 mg, 3.02 mmol, 187.86 μL, 1.2 eq) was added dropwise. After addition, the reaction mixture was warmed to 25 ℃slowly and stirred at 25 ℃ for 1 hr. The mixture was quenched with 1N aq. hydrochloric acid (40 mL) and water (100 mL) . The mixture was extracted with ethyl acetate (120 mL * 3) . The combined organic layers were dried anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 3/1) to afford intermediate 32 (307 mg, 44.55%yield, 92.1%purity) as a yellow oil.
Preparation of intermediate 35
A mixture of 3, 3-dibromo-1, 1, 1-trifluoro-propan-2-one (21.37 g, 79.19 mmol) and NaOAc (9.99 g, 121.83 mmol) in H2O (40 mL) was heated at 95 ℃ for 30 min. After cooling to 0 ℃, a cold solution of methyl 4-formylbenzoate (10 g, 60.92 mmol) in a mixture of NH3·H2O (50 mL, 28%purity) and MeOH (150 mL) was added. The reaction mixture was stirred at 25 ℃ for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (silica gel, petroleum ether /ethyl acetate=1/0 to 75/25) to afford intermediate 35 (13.2 g, 78.66%yield, 98.09%purity) as a yellow solid.
Preparation of intermediate 36
To a solution of intermediate 35 (1 g, 3.70 mmol) , cyclopropylboronic acid (635.7 mg, 7.40 mmol) and Na2CO3 (784.5 mg, 7.40 mmol) in DCE (5 mL) was added a solution of Cu (OAc) 2 (336.10 mg, 1.85 mmol) and 2- (2-pyridyl) pyridine (578.02 mg, 3.70 mmol) in DCE (10 mL) . The reaction mixture was heated and stirred at 70 ℃ under an atmosphere of O2 for 12 h. The reaction mixture was cooled to room temperature and diluted with H2O (80 mL) and extracted with dichloromethane (60 mL x 3) . The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (silica gel, Petroleum Ether/Ethyl Acetate=1/0 to 5/1) to afford intermediate 36 (810 mg, 65.26%yield, 92.51%purity) as a yellow solid.
Preparation of intermediate 37
To a mixture of intermediate 36 (1024 mg, 3.300 mmol) in THF (10 mL) was added KOH (1110 mg, 19.800 mmol) dissolved in MeOH (10 mL) and water (10 mL) and the resulting mixture was stirred at r.t. for 1 hr. The mixture was adjusted to pH 2 -3 with 2 M hydrochloride aqueous solution (5 mL) and extracted with dichloromethane (10 mL) for three times. The combined organic layers were washed with brine (10 mL) twice, dried over anhydrous Na2SO4, filtered, and concentrated to give intermediate 37 (841 mg, 2.39 mmol, 72.41%) as a crude product which was used in the next step without further purification.
Preparation of intermediate 38
To a solution of intermediate 37 (7 g, 22.56 mmol, 1 eq) and N-methoxymethanamine hydrochloride (4.40 g, 45.12 mmol, 2 eq) in anhydrous THF (70 mL) was added chloro (isopropyl) magnesium (2 M, 45.12 mL, 4 eq) dropwise at 0 ℃ under N2 atmosphere. The reaction mixture was stirred at 0 ℃ for 1 hr. The reaction mixture was quenched with NH4Cl (sat. aq. 40 mL) at 0 ℃, the mixture was poured into H2O (200 mL) and extracted with ethyl acetate (100 mL x 3) . The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, DCM: MeOH = 1: 0 to 9: 1) to afford intermediate 38 (7.62 g, 82.63%yield, 83%purity) as a yellow solid.
Preparation of intermediate 39
To a solution of intermediate 38 (7.62 g, 22.46 mmol, 1 eq) in THF (100 mL) was added bromo (methyl) magnesium (3 M, 14.97 mL, 2 eq) dropwise at 0 ℃. After addition, the reaction mixture was allowed to warm to 25 ℃ and stirred for 2 hr. The reaction mixture was quenched with NH4Cl (sat. aq. 20 mL) at 0 ℃, the mixture was poured into H2O (100 mL) and extracted with ethyl acetate (50 mL x 3) . The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 3/1) to afford intermediate 39 (4.9 g, 73.41%yield, 99%purity) as a yellow oil.
Preparation of intermediate 40
The mixture of intermediate 39 (1.3 g, 4.42 mmol, 1 eq) , NH4OAc (2.89 g, 37.55 mmol, 8.5 eq) in MeOH (10 mL) and MeCN (10 mL) was stirred at 65 ℃ for 30 min. After cooled to 25 ℃, sodium cyanoborohydride (610.76 mg, 9.72 mmol, 2.2 eq) was added to the resulting mixture. The reaction was heated at 65℃ for another 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH = 1: 0 to 17: 1) to afford intermediate 40 (1.20 g, 90.69%yield, 99%purity) as a yellow oil.
Preparation of intermediate 41
To a solution of intermediate 5 (330 mg, 830.33 μmol, 1 eq) in DCM (1.5 mL) was added TFA (2.30 g, 20.19 mmol, 1.5 mL, 24.32 eq) . The mixture was stirred at 25 ℃for 1 hr. The mixture was concentrated to afford intermediate 41 (340 mg, crude, TFA salt) as crude product, which was used in next step without further purification.
The following intermediates were synthesized by an analogous method as described above for intermediate 41.


Preparation of intermediate 59
Intermediate 41 (340 mg, crude, TFA) , 2, 4-dichloro-5-methoxy-pyrimidine (147.96 mg, 826.56 μmol, 1 eq) , DIEA (320.48 mg, 2.48 mmol, 431.92 μL, 3 eq) was added into EtOH (5 mL) at 25℃, and then the mixture was stirred at 80 ℃ for 6 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 gSilica Flash Column, Eluent of 0～40%Ethyl acetate/Petroleum ether gradient @35 mL/min) to afford intermediate 59 (280 mg, 72.78%yield, 94.5%purity) as white solid.
The following intermediates were synthesized by an analogous method as described above for intermediate 59.



Preparation of intermediate 80
A mixture of intermediate 74 (1.90 g, 4.78 mmol, 1 eq) , 4-cyclopropyl-6-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (3.30 g, 11.94 mmol, 2.5 eq) , K3PO4 (3.04 g, 14.33 mmol, 3 eq) in a solution of H2O (10 mL) and 1, 4-dioxane (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was added CATACXIUM (R) A PD G3 (347.86 mg, 477.65 μmol, 0.1 eq) in one portion. The resulting mixture was stirred at 100 C for 1 hour under N2 atmosphere. The mixture was filtered and concentrated to afford a residue which was purified by flash silica gel chromatography (20 gSilica Flash Column, Eluent of 0～90%Ethyl acetate/Petroleum ether gradient @40mL/min) to give intermediate 81 (600 mg, 23.21%yield, 94.5%purity) as yellow solid.
Preparation of intermediate 81
To a solution of intermediate 80 (300 mg, 586.51 μmol, 1 eq) in DMF (3 mL) was added K2CO3 (243.18 mg, 1.76 mmol, 3 eq) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (491.53 mg, 1.76 mmol, 3 eq) . The mixture was stirred at 110 ℃ for 12 h. The mixture was cooled to 25 ℃ and diluted with H2O (50 mL) , extracted with ethyl acetate (60 mL *3) . The combined organic layers were washed with aqueous 4%LiCl (80 mL) and sat. NaCl (80 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 gSilica Flash Column, Eluent of 0/1～75/25 Ethyl acetate/Petroleum ether gradient @40 mL/min) to afford intermediate 81 (140 mg, 12.15%yield, 70.7%purity) as light-yellow solid.
Preparation of intermediate 82
To a solution of intermediate 81 (140 mg, 201.51 μmol, 1 eq) in DCM (5 mL) was added TFA (7.68 g, 67.31 mmol, 5 mL, 334.03 eq) . The mixture was stirred at 25 ℃ for 0.5 h. The reaction mixture was concentrated under reduced pressure to give intermediate 82 (150 mg, crude, TFA salt) as yellow solid, which was used for next step without further purification.
Preparation of intermediate 83
A mixture of intermediate 41 &42 (1: 1, 940 mg, 2.29 mmol, 1 eq, TFA) , 2, 4-dichloro-5-methoxypyrimidine (409.06 mg, 2.29 mmol, 1 eq) , DIEA (886.04 mg, 6.86 mmol, 1.19 mL, 3 eq) in THF (9 mL) was stirred at 25 ℃ for 5 hr. The mixture was concentrated under reduced pressure to afford the crude. The crude was purified by FCC (40g Silica Flash Column, EA of 40%, PE/EA@50mL/min) , PE/EA=1: 1, Rf=0.5) to afford intermediate 83 (1.1 g, 80.98%yield, 74%purity) as a white solid.
Preparation of intermediate 84
A mixture of intermediate 83 (420 mg, 954.85 μmol, 1 eq) in DCM (3 mL) was degassed and purged with N2 for 3 times, and then BBr3 (1.20 g, 4.77 mmol, 460.02 uL,  5 eq) was added at 0 ℃ and the mixture was stirred at 25 ℃ for 2 hours under N2 atmosphere. The reaction mixture was quenched by addition warm water 10 mL, and then concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 gSilica Flash Column, Eluent of 0～8% Methanol /Dichloromethane @30 mL/min) to afford intermediate 84 (500 mg, crude) as a yellow solid.
Preparation of intermediate 85
A mixture of intermediate 84 (200 mg, 469.67 μmol, 1 eq) , K2CO3 (194.74 mg, 1.41 mmol, 3 eq) in DMF (0.5 mL) was added 1-iodo-2-methoxy-ethane (104.82 mg, 563.60 μmol, 1.2 eq) , then the mixture was stirred at 110 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 gSilica Flash Column, Eluent of 0～50%Ethyl acetate/Petroleum ether gradient @30 mL/min) to afford intermediate 85 (122 mg, 53.68%yield) as a white solid.
Preparation of intermediate 86
To a solution of 2, 4-dichloro-N-methyl-pyrimidin-5-amine (170 mg, 276.94 μmol, 1 eq) in EtOH (5 mL) was added DIEA (107.38 mg, 830.81 μmol, 144.71 μL, 3 eq) and intermediate 41 (227.83 mg, 553.87 μmol, 2 eq, TFA) . The mixture was stirred at 70 ℃for 12 hr. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by FCC ( (4gSilica Flash  Column, EA of 38%, PE/EA@35mL/min) , PE/EA=1: 1, Rf=0.5) to afford intermediate 86 (50 mg, 113.93 μmol, 41.14%yield) as a black-brown oil.
Preparation of Compounds
Preparation of Compound 1
A mixture of intermediate 59 (230 mg, 522.89 μmol, 1 eq) , 4-cyclopropyl-6-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (433.17 mg, 1.57 mmol, 3 eq) , K3PO4 (332.98 mg, 1.57 mmol, 3 eq) in a solution of H2O (1 mL) and dioxane (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was added CATACXIUM (R) A Pd G3 (38.08 mg, 52.29 μmol, 0.1 eq) in one portion. The resulting mixture was stirred at 100 ℃ for 1 hr under N2 atmosphere. The mixture was filtered and concentrated to afford the crude. The crude was purified by prep. HPLC (Column: Phenomenex luna C18 150*25mm*10μm, Mobile Phase A: water (FA) , Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 29%B to 59%) . The pure fractions were collected, and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (8 mL) and water (80 mL) . The solution was lyophilized to dryness to give Compound 1 (75.48 mg, 25.32%yield, 97.1%purity) as white solid.
The following Compounds were synthesized by an analogous method as described above for Compound 1.





Preparation of Compound 19
To a solution of intermediate 82 (150 mg, 211.67 μmol, 1 eq, TFA) and TEA (64.26 mg, 635.01 μmol, 88.38 μL, 3 eq) in DCM (3 mL) was added acetyl chloride (49.85 mg, 635.01 μmol, 45.15 μL, 3 eq) dropwise at 0℃. Then the mixture was stirred at 25℃ for 1 hour. Then the mixture was filtered and concentrated to afford a residue which was purified by prep-TLC (SiO2, Dichloromethane: Methanol=10: 1, Rf = 0.5) to give Compound 19 (48.39 mg, 34.25%yield, 95.39%purity) as white solid.
LCMS (Liquid chromatography/Mass spectrometry)
General procedure
The High-Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g., scanning range, dwell time…) in order to obtain ions to allow the identification of the compound’s nominal monoisotopic molecular weight (MW) . Data acquisition was performed with appropriate software.
Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H] + (protonated molecule) and/or [M-H] - (deprotonated molecule) . All results were obtained with experimental uncertainties that are commonly associated with the method used.
Method 1
Mobile phase: Ramp from 30%ACN (0.018%TFA) in water (0.037%TFA) to 90%ACN in 2.00 min, Flow rate is set at 1.5 mL/min; then ramp from 90%ACN in water to 100%ACN in 1.70 min. Flow rate is set at 1.5 mL/min; return back to 30%ACN in water and hold for 0.30 min. Flow rate is set at 2.0 mL/min. Column temperature at 50℃ and detector wavelength from 210 nm to 265 nm . The column is ofEVO C18 4.6 x 50 mm, 5 μm.
Method 2
Mobile phase: Ramp from 5%ACN (0.01875%TFA) in water (0.0375% TFA) to 95%ACN in 2.40 min, Flow rate is set at 2.0 mL/min; then hold at 95%ACN for 0.30 minutes. Flow rate is set at 2.0 mL/min; return back to 5%ACN in water and hold for 0.30 min. Flow rate is set at 2.0 mL/min. Column temperature at 50℃. The column is of EVO C18 4.6x50mm, 5 μm.
Method 3
Mobile phase: Ramp from 5%ACN (0.01875%TFA) in water (0.0375% TFA) to 95%ACN in 3.20 min, Flow rate is set at 1.5 mL/min; then hold at 95%ACN for 0.30 minutes. Flow rate is set at 1.5 mL/min; return back to 5%ACN in water and hold for  0.30 min. Flow rate is set at 2.0 mL/min. Column temperature at 50℃. The column is of EVO C18 4.6 x 50 mm, 5 μm.
Method 4
Mobile phase: Ramp from 5%ACN in water (0.025%NH3·H2O) to 95%ACN in 3.00 min, Flow rate is set at 0.6 mL/min; then hold at 95%ACN for 0.70 minutes Flow rate is set at 0.6 mL/min; return back to 5%ACN in water and hold for 0.30 min. Flow rate is set at 1.2 mL/min. Column temperature at 40℃ and detector wavelength from 210 nm to 265 nm. The column isXBridge C18 2.1 x 30 mm, 3.5 μm.
Method 5
Mobile phase: Ramp from 5%ACN (0.01875%TFA) in water (0.0375% TFA) to 95%ACN in 4.8min, Flow rate is set at 0.6 mL/min; then hold at 95%ACN for 0.60 minutes. Flow rate is set at 1.0 mL/min; return back to 5%ACN in water and hold for 0.60 min. Flow rate is set at 1.0 mL/min. Column temperature at 50℃. The column is Kinetex EVO C18 2.1*50mm, 1.7 μm.
Method 6
Mobile phase: Ramp from 5%ACN (0.01875%TFA) in water (0.0375% TFA) to 95%ACN in 3.20 min, Flow rate is set at 1.5 mL/min; then hold at 95%ACN for 0.30 minutes. Flow rate is set at 1.5 mL/min; return back to 5%ACN in water and hold for 0.30 min. Flow rate is set at 2.0 mL/min. Column temperature at 50℃. The column is of EVO C18 4.6 x50 mm, 5 μm.
Method 7
Mobile phase: Ramp from 5%ACN (0.01875%TFA) in water (0.0375%TFA) to 95%ACN in 2.40 min, Flow rate is set at 2.0 mL/min; then hold at 95%ACN for 0.30 minutes Flow rate is set at 2.0 mL/min; return back to 5%ACN in water and hold for 0.30 min. Flow rate is set at 2.0 mL/min. Column temperature at 50 ℃. The column is of EVO C18 4.6 x 50 mm, 5 μm.
Method 8
Mobile phase: Ramp from 5%ACN (0.01875%TFA) in water (0.0375%TFA) to 95%ACN in 3.20 min, Flow rate is set at 1.5 mL/min; then hold at 95%ACN for 0.30 minutes. Flow rate is set at 1.5 mL/min; return back to 5%ACN in water and hold for  0.30 min. Flow rate is set at 2.0 mL/min. Column temperature at 50℃. The column is of EVO C18 4.6 x 50 mm, 5 μm.
Method 9
Mobile phase: Ramp from 5%ACN (0.018%TFA) in water (0.037%TFA) to 95%ACN in 3.0 min, Flow rate is set at 1.0 mL/min; then hold at 95%ACN for 0.60 minutes. Flow rate is set from 1.0 mL/min to 1.5 mL/min; return back to 5%ACN in water and hold for 0.40 min. Flow rate is set at 1.5 mL/min. Column temperature at 50℃. The column is of Shim-pack Velox SP-C18 3.0 x 30 mm, 2.7 μm.
Method 10
Mobile phase: Ramp from 5%ACN in water (0.025%NH3·H2O) to 95%ACN in 2.60 min, Flow rate is set at 0.6 mL/min; then hold at 95%ACN for 0.25 minutes. Flow rate is set at 0.8 mL/min; return back to 5%ACN in water and hold for 0.15 min. Flow rate is set at 1.2 mL/min. Column temperature at 40℃ and detector wavelength from 210 nm to 265 nm. The column is ofXBridge C18 2.1 x 30 mm, 3.5 μm.
Method 11
Mobile phase: Ramp from 5%ACN (0.01875%TFA) in water (0.0375%TFA) to 95%ACN in water in 0.60 min, Flow rate is set at 2.0 mL/min; then hold at 95%ACN for 0.18 minutes. Flow rate is set at 2.0 mL/min; return back to 5%ACN in water and hold for 0.02 min. Flow rate is set at 2.0 mL/min. Column temperature at 50℃. The column is ofEVO C18 2.1 x 30 mm, 5 μm.
Method 12
Mobile phase: Ramp from 5%ACN in water (0.025%NH3·H2O) to 95%ACN in 3.00 min, Flow rate is set at 0.9 mL/min; then hold at 95%ACN for 0.70 minutes. Flow rate is set at 0.9 mL/min; return back to 5%ACN in water and hold for 0.30 min. Flow rate is set at 1.2 mL/min. Column temperature at 40℃ and detector wavelength from 210 nm to 265 nm. The column is ofXBridge C18 3.0 x 50 mm, 5 μm.
Analytical data
The LCMS analytical information in the Table below.

NMR Methods:
NMR experiments were carried out using a Bruker Advance III 400 spectrometer at ambient temperature (298.6 K) , using internal deuterium lock, and equipped with BBO 400 MHz S1 5 mm probe head with z gradients and operating at 400 MHz for the proton and 100 MHz for carbon. Chemical shifts (δ) are reported in parts per million (ppm) . J values are expressed in Hz.
The NMR analytical information in the Tables below.

USP1-UAF1 deubiquitination assay
Certain compounds provided herein were assessed by USP1-UAF1 deubiquitination assay. Deubiquitinase was measured by detecting the fluorescent signal generated when the amide bond between rhodamine and the C-terminal glycine of ubiquitin is hydrolyzed by USP1 using Ubiquitin-Rhodamine 110 (catalog U-555-050, R&D Systems) as an active substrate. Assay was conducted at a total 15 μl of reaction volume, including 0.05 nM USP1-UAF1 enzyme and assay buffer (50 mM HEPES pH 7.8, 0.5 mM EDTA, 100 mM NaCl, 0.1 mg/ml bovine serum albumin, I mM DTT, and 0.01%Tween-20) , and was commenced by adding a final concentration of 150 nM ubiquitin-rhodamine 110 substrate.
Deubiquitinase inhibitory assay was conducted with compounds dissolved in DMSO at a starting concentration of 10 μM. Dissolved compounds were added to 384-well microplate and premixed with USP1-UAF1 enzyme for 20 min incubation. Intrinsic fluorescence provided by compounds were measured as control prior to the addition of ubiquitin-rhodamine 110. Enzymatic reactions were started by adding ubiquitin-rhodamine  110 to the mixtures, and each well was read at 30 min by microplate reader (TECAN) to detect the fluorescence intensity at 480 nm excitation/530 nm emission.
All measured data were subtracted with control well, and IC50 values were calculated using four parameters dose-response inhibition model in GraphPad Prism 8.0.2 (La Jolla California USA, www. graphpad. com) .
Cell proliferation assay
For USP1i sensitivity, exponentially growing cells were seed in 96 or 384-well plates at very low density with the goal of not splitting for at least 7 days (typically 0.3k-1.2k cells/well) . Cells were plated on day-1 and treated with DMSO or increasing concentrations of USP1 inhibitors on Day 0. At the end of the experiment, cell viability was estimated using Cell-Titer Glo (Promega) .
Biological data
The embodiments described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the invention and are encompassed by the appended claims.

Claims (59)

  1. A compound of Formula (I) :
    or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein:
    X1 is N or CRa1; Ra1 is hydrogen or C1-C6 alkyl;
    X2 is N or CRa2; Ra2 is hydrogen or C1-C6 alkyl;
    X3 is N or CRa3; Ra3 is hydrogen or C1-C6 alkyl;
    L is NRb, O or S; Rb is hydrogen or C1-C6 alkyl;
    R1 is alkyl, alkoxy, halogen, cyano, NRcRd, -NHC (=O) Rc, -C (=O) NHRd, cycloalkyl, heterocyclyl, aryl, heteroaryl; and each alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl in R1 is optionally substituted;
    Rc and Rd are each independently hydrogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; and each alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl in Rc or Rd is independently optionally substituted;
    R2 and R3 are each independently halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino) alkyl, (dialkylamino) alkyl, cyanoalkyl, (carboxamido) alkyl, mercaptoalkyl, (cycloalkylamino) alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl) amino, carboxy, amido, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, or alkylthio; and each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl moiety in R2 or R3 is independently optionally substituted with one or more C1-C6 alkyl, halogen, or deuterium;
    R4 is hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, or (C1-C6 alkoxy) - (C1-C6 alkyl) ;
    R4’ is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, or (C1-C6 alkoxy) - (C1-C6 alkyl) ;
    R7 is hydrogen or C1-C6 alkyl;
    Ring A is aryl, heteroaryl, cycloalkyl, or heterocyclyl; and Ring A is optionally substituted;
    R is hydrogen, halogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, or amido; and each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl moiety in R is independently optionally substituted.
  2. The compound of claim 1, wherein L is NRb.
  3. The compound of claim 1 or 2, wherein Ring A is phenyl, 5-or 6-membered heteroaryl, or 5-or 6-membered heterocyclyl.
  4. The compound of claim 3, wherein Ring A is phenyl.
  5. The compound of claim 3, wherein Ring A is pyridyl.
  6. The compound of any one of claims 1 to 5, wherein Ring A is optionally substituted with one or more R5; and wherein each R5 is independently halogen, cyano, alkyl, amino, alkylamino, dialkylamino, hydroxy, or alkoxy; and wherein each alkyl moiety is independently optionally substituted with one or more halogen, hydroxy, or alkoxy.
  7. The compound of claim 1 or 2, wherein Ring A is selected from the group consisting of:
    wherein the point of attachment at left side is to the carbon atom bearing R4 group and the point of attachment at right side is to the R group.
  8. The compound of any one of claims 1 to 7, wherein R is hydrogen, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4-to 8-membered heterocyclyl, C6-C10 aryl, 5-to 10-membered heteroaryl, C1-C6 alkoxy, C3-C8 cycloalkyloxy, 4-to 8-membered heterocyclyloxy, C6-C10 aryloxy, 5-to 10-membered heteroaryloxy, (C3-C8 cycloalkyl) - (C1-C2 alkyl) -, (4-to 8-membered heterocyclyl) - (C1-C2 alkyl) -, (C6-C10 aryl) - (C1-C2 alkyl) -, (5-to 10-membered heteroaryl) - (C1-C2 alkyl) -, (C3-C8 cycloalkyl) - (C1-C2 alkyloxy) -, (4-to 8-membered heterocyclyl) - (C1-C2 alkyloxy) -, (C6-C10 aryl) - (C1-C2 alkyloxy) -, or (5-to 10-membered heteroaryl) - (C1-C2 alkyloxy) -; wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl moiety in R is independently optionally substituted.
  9. The compound of claim 8, wherein R is a 5-or 6-membered heteroaryl.
  10. The compound of claim 9, wherein R is a 5-or 6-membered nitrogen-containing heteroaryl.
  11. The compound of claim 10, wherein R is a 5-or 6-membered nitrogen-containing heteroaryl, and nitrogen is the only type of heteroatom contained in the heteroaryl.
  12. The compound of claim 10, wherein R is imidazolyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, pyrazinyl, triazolyl, oxazolyl, or thiazolyl.
  13. The compound of any one of claims 1 to 12, wherein R is optionally substituted with one or more R6; and each R6 is independently halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino) alkyl, (dialkylamino) alkyl, cyanoalkyl, (carboxamido) alkyl, mercaptoalkyl, (cycloalkylamino) alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl) amino, carboxy, amido, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, or alkylthio; and wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl moiety is independently optionally substituted with one or more C1-C6 alkyl, acyl, halogen, or deuterium.
  14. The compound of any one of claims 1 to 7, wherein R is selected from the group consisting of:

  15. The compound of any one of claims 1 to 7, wherein R is selected from the group consisting of:
  16. The compound of any one of claims 1 to 15, wherein X1 is N.
  17. The compound of any one of claims 1 to 16, wherein X2 is N.
  18. The compound of any one of claims 1 to 17, wherein X3 is CRa3.
  19. The compound of any one of claims 1 to 18, wherein R4’ is hydrogen.
  20. The compound of claim 1, which is a compound of Formula (II-A) , (II-B) , (II-C) , (II-D) , (II-E) , (II-F) , (II-G) , or (II-H) :

    or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:
    X4 is CRa4 or N;
    X5 is CRa5 or N;
    X6 is CRa6 or N;
    X7 is CRa7 or N;
    X8 is CRa8, N, NRa8, O, or S;
    X9 is CRa9, N, NRa9, O, or S;
    X10 is CRa10, N, NRa10, O, or S;
    X11 is CRa11, N, NRa11, O, or S;
    X12 is C or N;
    X13 is CRa13 or N;
    X14 is CRa14 or N;
    X15 is CRa15 or N;
    X16 is CRa16 or N;
    X17 is CRa17 or N;
    each Ra4, Ra5, Ra6, Ra7 is independently hydrogen or R5;
    each Ra8, Ra9, Ra10, Ra11, Ra13, Ra14, Ra15, Ra16 and Ra17 is independently hydrogen or R6;
    each R5 is independently halogen, cyano, alkyl, amino, alkylamino, dialkylamino, hydroxy, or alkoxy; and wherein each alkyl moiety is independently optionally substituted with one or more halogen, hydroxy, or alkoxy; and
    each R6 is independently halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl,  carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino) alkyl, (dialkylamino) alkyl, cyanoalkyl, (carboxamido) alkyl, mercaptoalkyl, (cycloalkylamino) alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl) amino, carboxy, amido, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, or alkylthio; and wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl moiety is independently optionally substituted with one or more C1-C6 alkyl, acyl, halogen, or deuterium.
  21. The compound of any one of claims 1 to 20, wherein R7 is hydrogen.
  22. The compound of any one of claims 1 to 20, wherein R7 is C1-C6 alkyl.
  23. The compound of any one of claims 20 to 22, wherein X4 is CRa4, X5 is CRa5, X6 is CRa6, and X7 is CRa7.
  24. The compound of claim 23, wherein Ra4, Ra5, Ra6 and Ra7 are all hydrogen.
  25. The compound of claim 20, which is a compound of Formula (III-A) , (III-B) , (III-C) , (III-D) , (III-E) , (III-F) , (III-G) , or (III-H) :

    or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.
  26. The compound of any one of claims 20 to 25, wherein X8 is N, and X9 is CR6.
  27. The compound of claim 26, wherein X11 is NR6.
  28. The compound of any one of claims 20 to 25, wherein X13 is N, and X17 is CR6.
  29. The compound of claim 28, wherein X14 is CR6.
  30. The compound of any one of claims 20 to 29, wherein each R6 is independently halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, alkylamino, dialkylamino, and wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl moiety is independently optionally substituted with one or more C1-C6 alkyl, acyl, halogen, or deuterium.
  31. The compound of any one of claims 20 to 29, wherein each R6 is independently cyano, nitro, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, l-fluoropropan-2-yl, 2-fluoroethyl, acetyl, amino, methylamino, ethylamino, dimethylamino, 2, 2-difluoroethoxy, cyclopropoxy, morpholino, tetrahydropyranyl, oxetanyl, methoxymethyl, N, N-dimethylsulfonamido, cyclopropyl, cyclobutyl, methylaminomethyl, deuteromethyl, deuteroethyl, deuteroisopropyl, deuteromethoxy, or deuteroethoxy.
  32. The compound of any one of claims 1 to 31, wherein R2 is cyano, amino, methylamino, dimethylamino, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, cyclopropoxy, cyclobutoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, chloro, fluoro, l-fluoropropan-2-yl, (S) -1-fluoropropan-2-yl, (R) -l-fluoropropan-2-yl, hydroxyethyl, l-methoxy-2-methylpropan-2-yl, 1-methoxypropan-2-yl, (S) -1-methoxypropan-2-yl, (R) -l-methoxypropan-2-yl, 1- (methoxymethyl) cyclopropyl, l-hydroxypropan-2-yl, oxetan-3-yl, tetrahydrofuran-3-yl, 1-methylcyclopropyl, deuteromethyl, deuteroethyl, deuteroisopropyl, deuteromethoxy, or deuteroethoxy.
  33. The compound of claim 32, wherein R2 is cyclopropyl.
  34. The compound of any one of claims 1 to 33, wherein R3 is cyano, amino, methylamino, dimethylamino, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, cyclopropoxy, cyclobutoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, chloro, fluoro, l-fluoropropan-2-yl, (S) -1-fluoropropan-2-yl, (R) -l-fluoropropan-2-yl, hydroxyethyl, l-methoxy-2-methylpropan-2-yl, 1-methoxypropan-2-yl, (S) -1-methoxypropan-2-yl, (R) -l-methoxypropan-2-yl, 1- (methoxymethyl) cyclopropyl, l-hydroxypropan-2-yl, oxetan-3-yl, tetrahydrofuran-3-yl, 1-methylcyclopropyl, deuteromethyl, deuteroethyl, deuteroisopropyl, deuteromethoxy, or deuteroethoxy.
  35. The compound of claim 34, wherein R3 is methoxy.
  36. The compound of any one of claims 1 to 35, wherein when the carbon connected to R4 and R4’ is a chiral center, it has the S-configuration.
  37. The compound of any one of claims 1 to 35, wherein when the carbon connected to R4 and R4’ is a chiral center, it has the R-configuration.
  38. The compound of any one of claims 1 to 37, wherein R1 is alkoxy.
  39. The compound of claim 38, wherein R1 is methoxy.
  40. The compound of any one of claims 1 to 39, wherein R4 is C1-C6 alkyl.
  41. The compound of claim 40, wherein R4 is methyl.
  42. A compound in Table 1, or a pharmaceutically acceptable salt thereof.
  43. A pharmaceutical composition, comprising a compound of any one of claims 1 to 42 and a pharmaceutically acceptable excipient.
  44. A method of inhibiting a USP1 protein, comprising contacting the USP1 protein with a compound of any one of claims 1 to 42 or a pharmaceutical composition of claim 43.
  45. The method of claim 44, wherein the contacting occurs in a subject suffering from a USP1 protein mediated disorder.
  46. A method of treating a USP1 protein mediated disorder, comprising administering to a subject having the disorder a therapeutically effective amount of a compound of any one of claims 1 to 42 or a pharmaceutical composition of claim 43.
  47. The method of claim 45 or 46, wherein the USP1 protein mediated disorder is a cancer.
  48. A method of treating a cancer, comprising administering to a subject having the cancer a therapeutically effective amount of a compound of any one of claims 1 to 42 or a pharmaceutical composition of claim 43.
  49. The method of claim 47 or 48, wherein the cancer is a hematological cancer, a lymphatic cancer, a DNA damage repair pathway deficient cancer, a homologous-recombination deficient cancer, a cancer comprising cancer cells with a mutation in a gene encoding p53, or a cancer comprising cancer cells with a loss of function mutation in a gene encoding p53.
  50. The method of any one of claims 47 to 49, wherein the cancer is a solid tumor.
  51. The method of claim 50, wherein the cancer is lung cancer, non-small cell lung cancer (NSCLC) , colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, or breast cancer.
  52. The method of claim 51, wherein the cancer is ovarian cancer.
  53. The method of claim 51, wherein the cancer is triple negative breast cancer.
  54. The method of claim 47 or 48, wherein the cancer comprises cancer cells with elevated levels of RAD18.
  55. The method of claim 54, wherein the elevated levels of RAD 18 are elevated RAD 18 protein levels.
  56. The method of claim 54, wherein the elevated levels of RAD 18 are elevated RAD 18 mRNA levels.
  57. The method of claim 47 or 48, wherein the cancer is a BRCA1 mutant cancer, a BRCA2 mutant cancer, or both a BRCA1 mutant cancer and a BRCA2 mutant cancer.
  58. The method of claim 57, wherein the BRCA1 or BRCA2 mutant cancer is a BRCA1 or BRCA2 deficient cancer.
  59. The method of claim 47 or 48, wherein the cancer is a PARP inhibitor resistant or refractory cancer or a PARP inhibitor resistant or refractory BRCA1 or BRCA2 mutant cancer.
PCT/CN2024/072984 2023-01-19 2024-01-18 Heteroaromatic compounds and their use as usp1 inhibitors WO2024153175A1 (en)

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