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WO2025034849A1 - Pyridazines fusionnées pour le traitement du cancer et autres indications - Google Patents

Pyridazines fusionnées pour le traitement du cancer et autres indications Download PDF

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Publication number
WO2025034849A1
WO2025034849A1 PCT/US2024/041276 US2024041276W WO2025034849A1 WO 2025034849 A1 WO2025034849 A1 WO 2025034849A1 US 2024041276 W US2024041276 W US 2024041276W WO 2025034849 A1 WO2025034849 A1 WO 2025034849A1
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WO
WIPO (PCT)
Prior art keywords
compound
independently selected
ring
sulfur
nitrogen
Prior art date
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PCT/US2024/041276
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English (en)
Inventor
Rui Xu
Bin Wang
Eli Wallace
Paul Wehn
Dhirendra Kumar SIMANSHU
David Michael Turner
Daniel J. CZYZYK
Swapnil Singh
Jayasudhan Reddy YERABOLU
Felice LIGHTSTONE
Yue Yang
Original Assignee
Theras, Inc.
Leidos Biomedical Research, Inc.
Lawrence Livermore National Security, Llc
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Application filed by Theras, Inc., Leidos Biomedical Research, Inc., Lawrence Livermore National Security, Llc filed Critical Theras, Inc.
Publication of WO2025034849A1 publication Critical patent/WO2025034849A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • PI3Ks signal downstream of receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and RAS proteins to regulate a large number of cellular activities, including metabolism, proliferation, and migration.
  • RTKs receptor tyrosine kinases
  • GPCRs G protein-coupled receptors
  • RAS proteins to regulate a large number of cellular activities, including metabolism, proliferation, and migration.
  • the present disclosure provides new therapeutic modalities for treating cancers and other indications (e.g., cancers and other indications associated with and/or characterized by aberrant activation of PI3K).
  • a therapeutic agent e.g., a therapeutic agent comprising a small molecule, e.g., a compound provided herein
  • a small GTPase e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1
  • a therapeutic agent e.g., a therapeutic agent comprising a small molecule, e.g., a compound provided herein
  • a small GTPase e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1
  • a cancer and/or other indication e.g., an indication associated with and
  • therapeutic agents provided herein may be capable of binding to a PI3K protein (e.g., PI3K ⁇ ) while displaying (i) no or minimal binding to a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and/or (ii) no substantial effect on the kinase activity of the PI3K protein (e.g., PI3K ⁇ ).
  • a small GTPase e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1
  • such therapeutic agents may provide advantages such as improved efficacy or reduced side effects as compared to, e.g., ATP-competitive PI3K kinase inhibitors, as described herein.
  • such therapeutic agents may provide reduced instances of hyperglycemia and/or hyperinsulinemia relative to PI3K kinase inhibitors.
  • the present disclosure provides compounds (including in any available form, such as salt forms) useful in disrupting, inhibiting, and/or preventing an interaction between a PI3K protein (e.g., PI3K ⁇ ) and a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1).
  • a PI3K protein e.g., PI3K ⁇
  • a small GTPase e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1
  • the present disclosure provides compounds capable of binding a PI3K ⁇ protein, such that (i) the interaction between a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and the PI3K ⁇ protein is disrupted, inhibited, and/or prevented; and/or (ii) the kinase activity of the PI3K ⁇ protein is not inhibited.
  • a small GTPase e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1
  • a small GTPase e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1
  • a small GTPase
  • the present disclosure provides a compound of Formula II: or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein each of Ring A, Ring B, J, R 1 , R 2 , X, m, and n is as defined herein.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound provided herein (e.g., a compound of Formula I or II), or a salt (e.g., a pharmaceutically acceptable salt) thereof, together with a pharmaceutically acceptable carrier.
  • the present disclosure provides a method of inhibiting, disrupting, and/or preventing an interaction between a PI3K ⁇ protein and a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) such that the kinase activity of the PI3K ⁇ protein is not inhibited.
  • a small GTPase e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1
  • the PI3K ⁇ protein is in a cell, such as in a cell of a human or animal subject (e.g., as described herein).
  • the present disclosure provides a method of treating, ameliorating, delaying the progress of, ameliorating or eliminating a symptom of, and/or inhibiting a cancer and/or other indication (e.g., an indication associated with and/or characterized by aberrant activation of PI3K) comprising administering a compound provided herein (e.g., a compound of Formula I or II), or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • a compound provided herein e.g., a compound of Formula I or II
  • a salt e.g., a pharmaceutically acceptable salt
  • the present disclosure provides a use of a compound provided herein (e.g., a compound of Formula I or II), or a salt (e.g., a pharmaceutically acceptable salt) thereof, in the manufacture of a medicament for the treatment, amelioration, or inhibition of a cancer or other indication (e.g., an indication associated with and/or characterized by aberrant activation of PI3K).
  • a compound provided herein e.g., a compound of Formula I or II
  • a salt e.g., a pharmaceutically acceptable salt
  • the present disclosure also provides a compound (e.g., a compound of Formula I or II), or a salt (e.g., a pharmaceutically acceptable salt) thereof, for use as a medicament, which medicament may be used in the treatment, amelioration, or inhibition of a cancer or other indication (e.g., an indication associated with and/or characterized by aberrant activation of PI3K).
  • a compound e.g., a compound of Formula I or II
  • a salt e.g., a pharmaceutically acceptable salt
  • each stereocenter is contemplated as part of the disclosure; and the D- and L-isomers of each compound are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomeric, atropisomeric, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure.
  • Table 1 shows one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and/or as a mixture.
  • the present disclosure includes all cis, trans, syn, anti,
  • E
  • Z sixteen
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials that contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation, such as conversion to a mixture of diastereomers followed by separation via, e.g., recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method.
  • Starting compounds of a particular stereochemistry are either commercially available or can be made and resolved by various techniques. Unless otherwise stated, all tautomeric forms (e.g., rapidly interconverting forms) of provided compounds are within the scope of the disclosure.
  • aliphatic or “aliphatic group”, as used herein, means a straight- chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation (e.g., multiple bonds, such as double or triple bonds).
  • aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • Alkyl refers to a saturated, optionally substituted straight or branched hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-4 , C 1-3 , or C 1-2 ).
  • alkyl groups include methyl, ethyl, propyl (e.g., n-propyl), isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, pentyl, isoamyl, hexyl, heptyl, octyl, and nonyl.
  • alkylene as used herein, alone or in combination, refers to a bivalent, saturated, optionally substituted straight or branched hydrocarbon, such as methylene (-CH 2 -).
  • Alkenyl refers to an optionally substituted straight or branched hydrocarbon chain having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2-12 , C 2- 10 , C 2-8 , C 2-6 , C 2-4 , or C 2-3 ).
  • alkenyl groups include ethenyl, propenyl, 2- methylpropenyl, 1,4-butadienyl, butenyl, pentenyl, hexenyl, and heptenyl.
  • Alkynyl refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C 2-3 ).
  • alkynyl groups include ethynyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, and 1,3,5-hexatriynyl.
  • Aryl refers to monocyclic or bicyclic ring systems having a total of six to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring(s).” Examples of aryl groups include phenyl, naphthyl, anthracyl and the like, which may bear one or more substituents as defined herein.
  • aryl is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl or tetrahydronaphthyl, and the like. Unless otherwise specified, “aryl” groups are hydrocarbons.
  • Carbocyclyl The terms “carbocyclyl,” “carbocycle,” and “carbocyclic ring” as used herein, refer to saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having from 3 to 14 members, wherein the aliphatic ring system is optionally substituted as described herein.
  • a carbocycle may comprise fused ring systems, bridged ring systems, and/or spiro ring systems (e.g., a system including two rings sharing a single carbon atom).
  • Carbocyclic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl.
  • “carbocyclyl” refers to an optionally substituted monocyclic C 3 -C 8 hydrocarbon, or an optionally substituted C 5 -C 10 bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic.
  • the term “cycloalkyl” refers to an optionally substituted saturated ring system of 3 to 10 ring carbon atoms. In some embodiments, cycloalkyl groups have 3–6 carbons. Examples of monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • composition refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having 3 to 10 carbon atoms. Examples of monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • Composition refers to a discrete physical entity that comprises one or more specified components (e.g., a product comprising one or more specified ingredients (e.g., in specified amounts) or a product that results, directly or indirectly, from combination of specified ingredients in specified amounts).
  • a composition may be of any form – e.g., gas, gel, liquid, solid, etc.
  • a composition may comprise one or more pharmaceutically acceptable components, such as a carrier, diluent, or excipient.
  • pharmaceutically acceptable it is generally meant the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • a “pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and absorption by a subject.
  • Halogen The term “halogen” or “halo” means F, Cl, Br, or I.
  • Heteroaryl The terms “heteroaryl”, “heteroaromatic”, and “heteroar—,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to optionally substituted groups having 5 to 14 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10- membered bicyclic heteroaryl); having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • ring atoms e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10- membered bicyclic heteroaryl
  • heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • Heteroaryl also includes groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclic rings.
  • bicyclic heteroaromatic groups include indolyl, isoindolyl, benzothienyl, benzofuranyl, indazolyl, indolizinyl, benzimidazolyl, benzthiazolyl, benzotriazolyl, benzoxazolyl, benzoxadiazolyl, benzothiadiazolyl, tetrazolopyridazinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, chromonyl, coumarinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, and 4H–quinolizinyl.
  • tricyclic heterocyclic groups examples include carbazolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenazinyl, phenanthridinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. It will be appreciated that certain tautomeric forms of a heteroaryl ring can exist and are encompassed by the term “heteroaryl.” Such tautomeric forms include, for example, pyridin-2(1H)-one.
  • Heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, without limitation, any oxidized form of nitrogen, sulfur, phosphorus, or silicon); the quaternized form of any basic nitrogen or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • a heteroatom is selected from oxygen, sulfur, and nitrogen.
  • Heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a 3- to 8-membered monocyclic or 5- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to one or more carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be unsubstituted or substituted with one or more substituents (e.g., as described herein).
  • saturated or partially unsaturated heterocyclic radicals include tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • Heterocycle also includes groups in which a heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • Partially Unsaturated As used herein, the term “partially unsaturated”, when referring to a ring moiety, means a ring moiety that includes at least one double or triple bond between ring atoms.
  • patient or Subject refers to any organism to which a provided compound or composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, hamsters, guinea pigs, cats, dogs, goats, pigs, sheep, cows, deer, horses, non-human primates, and/or humans).
  • animals e.g., mammals such as mice, rats, rabbits, hamsters, guinea pigs, cats, dogs, goats, pigs, sheep, cows, deer, horses, non-human primates, and/or humans).
  • a patient or subject is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
  • Prevent or prevention refers to reducing the risk of developing the disease, disorder, or condition; delaying onset of one or more characteristics or symptoms of the disease, disorder, or condition; and/or preventing escalation of a disease, disorder, or condition. Prevention of a disease, disorder, or condition may involve complete protection from disease and/or prevention of disease progression (e.g., to a later stage of the disease, disorder, or condition).
  • prevention of a disease may not mean complete foreclosure of any effect related to the diseases at any level, but instead may mean prevention of the symptoms of a disease, disorder, or condition to a clinically significant or detectable level. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.
  • compounds of this disclosure may contain “optionally substituted” moieties (e.g., moieties bearing one or more substituents).
  • the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • Substituted applies to one or more hydrogens that are either explicit or implicit from the structure (e.g., refers to at least ; and refers to at least , or ).
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein.
  • Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents.
  • Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.
  • Suitable monovalent substituents on R° are independently halogen, —(CH 2 ) 0–2 R ⁇ , –(haloR ⁇ ), –(CH 2 ) 0–2 OH, –(CH 2 ) 0–2 OR ⁇ , –(CH 2 ) 0–2 CH(OR ⁇ ) 2 , -O(haloR ⁇ ), –CN, –N 3 , –(CH 2 )0– 2 C(O)R ⁇ , –(CH 2 ) 0–2 C(O)OH, –(CH 2 ) 0–2 C(O)OR ⁇ , –(CH 2 ) 0–2 SR ⁇ , –(CH 2 ) 0–2 SH, –(CH 2 ) 0–2 NH 2 , – (CH 2 ) 0–
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2 ) 2–3 O–, wherein each independent occurrence of R * is selected from hydrogen, C 1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, –R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2, or –NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R ⁇ , –NR ⁇ 2 , –C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , – C(O)CH 2 C(O)R ⁇ , -S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2 , –C(S)NR ⁇ 2 , –C(NH)NR ⁇ 2 , or –N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ ,
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, – R ⁇ , -(haloR ⁇ ), –OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or -NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • treat refers to any administration of a therapy (e.g., therapeutic agent) that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition.
  • a therapy e.g., therapeutic agent
  • Treatment may also refer to any other indicia of success in the treatment or amelioration of an injury, pathology, disease, disorder, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology, disease, disorder, or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; and/or improving a patient's physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation.
  • such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition.
  • such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition.
  • treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition.
  • PI3K and Small GTPase Proteins [0039] The aberrant activation of the phosphoinositide 3-kinase (PI3K) is one of the most frequent oncogenic events across human cancers, and its inhibition is an attractive therapeutic approach in treating cancers.
  • PI3Ks signal downstream of receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and RAS proteins to regulate a large number of cellular activities, including metabolism, proliferation, and migration.
  • RTKs receptor tyrosine kinases
  • GPCRs G protein-coupled receptors
  • RAS proteins to regulate a large number of cellular activities, including metabolism, proliferation, and migration.
  • PI3K catalyzes the synthesis of the second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3) by phosphorylating phosphatidylinositol 4,5-bisphosphate (PIP2).
  • PIP3 Protein Kinase B
  • Phosphorylated AKT activates or inhibits several signaling proteins through direct phosphorylation including the mammalian target of rapamycin complex 1 (mTORC1), which acts as a regulator of cell growth and survival pathways, cyclin D1, GSK3(B), BAD, MDM2, FOXO, TSC1/2, and PRAS40.
  • mTORC1 mammalian target of rapamycin complex 1
  • PTEN Phosphatase and tensin homologue deleted on chromosome 10
  • PTEN regulates this pathway by dephosphorylating PIP3 to PIP2 and thus prevents activation of downstream kinases.
  • PI3Ks Based on the sequence homology and substrate preference, PI3Ks have been grouped into three separate classes (e.g., classes I, II, and III).
  • Class I PI3Ks are further divided into two subclasses, IA and IB depending on their modes of regulation.
  • Class IA PI3Ks are heterodimers comprising p110 catalytic and p85 regulatory subunits, and are most clearly implicated in human cancer.
  • Class IA PI3K contains p110 ⁇ , p110 ⁇ , and p110 ⁇ catalytic subunits produced from different genes (PIK3CA, PIK3CB, and PIK3CD, respectively), while p110 ⁇ produced by PIK3CG represents the only catalytic subunit in class IB PI3K.
  • PI3K isoforms e.g., PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , and PI3K ⁇
  • the expression of PI3K isoforms is specific to cell types.
  • the p110 ⁇ and ⁇ isoforms are expressed in all cell types, whereas p110 ⁇ expression is mainly confined to leukocytes.
  • the p110 ⁇ isoform is expressed primarily in the myeloid cell lineage.
  • PIK3CA gene encodes the 1068 amino acid p110 ⁇ protein that contains five domains: an N-terminal adaptor binding domain (ABD) that binds to regulatory subunit p85 ⁇ , a RAS- binding domain (RBD), a C2 domain, a helical domain, and a kinase catalytic domain.
  • ABD N-terminal adaptor binding domain
  • RAS- binding domain RAS-binding domain
  • PIK3CA Activating mutations in the KRAS and PIK3CA genes are frequently detected in cancer, making these two proteins important targets for drug discovery.
  • Somatic missense mutations in the PIK3CA gene have been reported in many human cancer types including breast, colon, liver, stomach, endometrial, bladder, and lung cancers.
  • the most frequent hotspot mutations in PIK3CA are E542K, E545K, H1047R, and H1047L, and they account for 80–90% of all PIK3CA mutations detected in human malignancies.
  • These PIK3CA mutations lead to increased catalytic activity of p110 ⁇ , which causes downstream effects such as unregulated cell growth, proliferation, and survival.
  • RAS proteins function as molecular switches that cycle between an active, GTP-bound state and an inactive, GDP-bound state.
  • RAS proteins interact with various effector proteins including PI3K, RAF kinase, and RalGDS, leading to activation of multiple downstream signaling pathways.
  • Oncogenic RAS mutations are predominantly found at amino acid positions G12, G13, and Q61, and these mutations impair GTPase activities leading to the accumulation of active RAS proteins.
  • the most common oncogenic RAS mutations are G12C, G12D, G12S, G12V, G12R, G13D, and Q61H.
  • RAS signaling through PI3K is necessary for normal lymphatic development and RAS- induced transformation, especially in lung cancer, where the interaction between mutant RAS and p110a-RBD is essential for tumor initiation and maintenance.
  • RAS interactions with p110 ⁇ -RBD have been shown to be crucial for epidermal growth factor (EGF) signaling to PI3K.
  • EGF epidermal growth factor
  • Small GTPases e.g., other than RAS are also expected to bind the RBD of PI3K ⁇ resulting in activation of signaling.
  • the small GTPases Rac1 and CDC42 have been shown to bind the RBD of PI3K ⁇ and are hypothesized to also be capable of binding the RBD of PI3K ⁇ .
  • the present disclosure encompasses the recognition that disrupting an interaction between PI3K ⁇ and any small GTPase that binds the RBD of PI3K ⁇ may be a useful therapeutic strategy for treating cancers and other indications.
  • a small GTPase is selected from Rac1, CDC42, and RAS proteins (including HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1).
  • RAS proteins including HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1.
  • PI3K inhibitors that have entered clinical development thus far are reversible, ATP-competitive kinase inhibitors.
  • the clinical outcome of PI3K inhibitor-based treatments for solid tumors has been disappointing, mainly due to intolerable toxicity and drug resistance.
  • FDA U.S. Food and Drug Administration
  • alpelisib BYL719; Novartis Pharma AG
  • fulvestrant for the treatment of patients diagnosed with HR+/HER2- PIK3CA-mutation.
  • the therapeutic window of PI3K inhibitors is mainly limited by isoform selectivity and off-tumor toxicity.
  • hyperglycemia and hyperinsulinemia have been observed as major dose-limiting toxicities for p110 ⁇ inhibitors, which prevent the use of sufficiently high doses to fully suppress PI3K ⁇ signaling in the tumor.
  • Hyperglycemia and hyperinsulinemia are considered on-target effects of PI3K ⁇ inhibition, as inhibition of the PI3K/AKT pathway reduces glucose uptake, which in turn leads to increased secretion of insulin and subsequent activation of insulin/insulin-like growth factor I receptor in tumor cells, providing a survival mechanism for tumor cells and limiting the therapeutic efficacy of the PI3K ⁇ inhibitor.
  • hyperglycemia was observed in 65% of patients in a Phase III clinical trial of alpelisib, leading to significant dose interruptions.
  • provided technologies may avoid hyperglycemia and insulin-driven resistance common to PI3K ⁇ inhibitors, e.g., because such technologies target activation of PI3K ⁇ by RAS, which is mostly present in transformed cells.
  • Provided Compounds [0047]
  • the present disclosure provides compounds useful for disrupting, inhibiting, and/or preventing the interaction between small GTPases (e.g., RAS proteins, as described herein) and PI3K ⁇ proteins.
  • the present disclosure provides compounds capable of binding PI3K ⁇ , such that (i) the interaction between the small GTPase (e.g., RAS protein, as described herein) and PI3K ⁇ is disrupted, inhibited, or prevented; and/or (ii) the kinase activity of PI3K ⁇ is not significantly inhibited.
  • such compounds bind PI3K ⁇ reversibly.
  • a compound that binds “reversibly” refers to a compound that is able to bind to and become dissociated from a target protein kinase (e.g., PI3K ⁇ ).
  • reversible inhibitors are not able to form a covalent bond with a target protein kinase.
  • such compounds bind PI3K ⁇ irreversibly.
  • a compound that binds “irreversibly” refers to a compound that is able to interact (e.g., to form a covalent bond) with a target protein kinase (e.g., PI3K ⁇ ) in a substantially non-reversible manner.
  • a reversible or irreversible inhibitor may be capable of interacting covalently with PI3K ⁇ .
  • the present disclosure provides compounds comprising an electrophilic moiety (e.g., a Michael acceptor or the like) capable of binding (e.g., reversibly or irreversibly) to, e.g., a cysteine residue in the catalytic subunit of PI3K ⁇ (e.g., C242).
  • an electrophilic moiety e.g., a Michael acceptor or the like
  • a cysteine residue in the catalytic subunit of PI3K ⁇ (e.g., C242).
  • provided compounds that interact with PI3K ⁇ covalently are compounds of Formula I or II wherein –R 1 comprises an electrophilic moiety (e.g., a Michael acceptor or the like) capable of binding (e.g., reversibly or irreversibly) to, e.g., a cysteine residue of PI3K ⁇ (e.g., C242).
  • the present disclosure provides a compound of Formula I: or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: Ring A is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 8-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered carbocyclic ring, and 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is selected from phenyl, 9- to 10-membered bicyclic aryl ring, 5- to 6-membered heteroary
  • the present disclosure provides a compound of Formula I or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula I, wherein: Ring A is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 8-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered carbocyclic ring, and 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is selected from phenyl, 9- to 10-membered aryl ring, 5- to 6-membered heteroaryl ring having 1-4 heteroatom
  • the present disclosure provides a compound of Formula IA: or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, Ring C, R 1 , R 2 , R 3 , m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IA or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula IA1: or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring B, Ring C, L, R 1 , R 2 , R 3 , R 7 , n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IA1 or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound selected from Formulae IA1-a, IA1-b, and IA1-c: or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring C, L, R 1 , R 2 , R 3 , R 7 , n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IA1-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula IA1-b, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IA1-c, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula IA2: or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, R 1 , R 2 , R 3 , m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IA2 or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound selected from Formulae IA2-a, IA2-b, and IA2-c: or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, R 1 , R 2 , R 3 , m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IA2-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula IA2-b, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IA2-c, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula IA3: or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, R 1 , R 2 , R 3 , m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IA3 or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • any R 3 group may be attached to either ring of the tetrahydroisoquinoline moiety.
  • the present disclosure provides a compound selected from Formulae IA3-a, IA3-b, and IA3-c: or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, R 1 , R 2 , R 3 , m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IA3-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula IA3-b, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula IA3-c, or a salt (e.g., a pharmaceutically acceptable salt) thereof. It will be appreciated that for a compound of Formula IA3-a, IA3-b, or IA3-c, any R 3 group may be attached to either ring of the tetrahydroisoquinoline moiety. [0058] In some embodiments, the present disclosure provides a compound selected from Formulae IA4-a, IA4-b, and IA4-c:
  • the present disclosure provides a compound of Formula IA4-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula IA4-b, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula IA4-c, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula IB: or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, Ring C, R 1 , R 2 , R 3 , R 4 , R 4’ , m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IB, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula IB1:
  • a salt e.g., a pharmaceutically acceptable salt
  • ester e.g., a pharmaceutically acceptable salt
  • prodrug e.g., a drug zwitterionic form
  • stereoisomer e.g., a pharmaceutically acceptable salt
  • Ring B, Ring C, R 1 , R 2 , R 3 , R 4 , R 4’ , m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IB1, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula IB2: or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, R 1 , R 2 , R 3 , R 4 , R 4’ , m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IB2, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula IB3:
  • a salt e.g., a pharmaceutically acceptable salt
  • ester e.g., a pharmaceutically acceptable salt
  • tautomer e.g., prodrug
  • zwitterionic form e.g., stereoisomer thereof
  • Ring B, R 1 , R 2 , R 3 , R 4 , R 4’ , m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IB3, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound selected from Formulae IB4-a, IB4-b, and IB4-c: or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring C, R 1 , R 2 , R 3 , R 4 , R 4’ , m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IB4-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula IB4-b, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IB4-c, or a salt (e.g., a pharmaceutically acceptable salt) thereof. [0064] In some embodiments, the present disclosure provides a compound of Formula II:
  • Ring A is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 8-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • Ring B is selected from a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered carbocyclic ring, and 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • J is a covalent bond or a bivalent straight or branched C1-4 hydrocarbon chain;
  • X is –OR, -N(R) 2 , -C(O)N(R) 2 , or an
  • the present disclosure provides a compound of Formula II, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula II, wherein: Ring A is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 8-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered carbocyclic ring, and 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; J is a covalent bond or a bivalent straight or branched C 1-4 hydrocarbon chain; X is –OR, -N(R) 2
  • a salt e.g., a pharmaceutically acceptable salt
  • ester e.g., a pharmaceutically acceptable salt
  • tautomer e.g., prodrug, zwitterionic form, or stereoisomer thereof
  • Ring B, J, L, R 1 , R 2 , R 7 , X, and n are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IIA or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound selected from Formulae IIA1, IIA2, and IIA3: or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein J, L, R 1 , R 2 , R 7 , X, and n are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IIA1, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula IIA2, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IIA3, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound selected from Formulae IIB1, IIB2, and IIB3: or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, J, R 1 , R 2 , X, m, and n are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IIB1, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula IIB2, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IIB3, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula IIC: or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, R 1 , R 2 , m, and n are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and wherein: X is -C(O)N(R) 2 or an optionally substituted group selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 5- to 10- membered bicyclic carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen,
  • a salt e.
  • the present disclosure provides a compound of Formula IIC, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the present disclosure provides a compound of Formula IID: or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, R 1 , R 2 , m, and n are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and wherein: J is a bivalent straight or branched C1-4 hydrocarbon chain; and X is –OR or -N(R) 2 .
  • the present disclosure provides a compound of Formula IID, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • Ring A is selected from phenyl, 3- to 7-membered carbocyclic ring, and 4- to 8-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is selected from phenyl, C5-C6 cycloalkyl, and 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is phenyl.
  • Ring A is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0077] In some embodiments of any Formulae described herein, Ring A is a 3- to 7-membered carbocyclic ring. In some embodiments, Ring A is a C 3 -C 7 cycloalkyl ring.
  • Ring A is a 5- to 6-membered carbocyclic ring. In some embodiments, Ring A is a C 5 -C 6 cycloalkyl ring. In some embodiments, Ring A is a cyclohexane ring. [0078] In some embodiments of any Formulae described herein, Ring A is a 4- to 8-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is a piperidine.
  • a R 1 is halogen (e.g., fluoro or chloro).
  • a R 1 is –L-R 7 .
  • at least one R 1 is –L-R 7 .
  • one R 1 is –L-R 7 , and any other R 1 groups are halogen (e.g., fluoro or chloro).
  • one R 1 is –L-R 7 , and one other R 1 group is halogen (e.g., fluoro or chloro).
  • one R 1 is –L-R 7 , and two other R 1 groups are halogen (e.g., fluoro or chloro).
  • halogen e.g., fluoro or chloro.
  • an L is a covalent bond.
  • an L is a bivalent straight or branched C 1-12 hydrocarbon chain, wherein the hydrocarbon chain is optionally substituted with one or more halogen, and wherein one or more methylene units are optionally and independently replaced by a group selected from –N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -OC(O)N(R)-, -N(R)C(O)O-, - SO 2 N(R)-, and –N(R)SO 2 -.
  • an L is a bivalent straight or branched C 1-8 hydrocarbon chain, wherein the hydrocarbon chain is optionally substituted with one or more halogen, and wherein one or more methylene units are optionally and independently replaced by a group selected from –N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)- , -OC(O)N(R)-, -N(R)C(O)O-, -SO 2 N(R)-, and –N(R)SO 2 -.
  • an L is a covalent bond.
  • an L is a bivalent straight or branched C1-12 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by a group selected from –N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -C(O)N(R)- , -N(R)C(O)-, -C(O)O-, -OC(O)-, -OC(O)N(R)-, -N(R)C(O)O-, -SO 2 N(R)-, and –N(R)SO 2 -.
  • an L is a bivalent straight or branched C1-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by a group selected from – N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -OC(O)N(R)-, - N(R)C(O)O-, -SO 2 N(R)-, and –N(R)SO 2 -.
  • an L is a bivalent straight or branched C 1-12 hydrocarbon chain, wherein the hydrocarbon chain is optionally substituted with one or more halogen, and wherein one or more methylene units are optionally and independently replaced by a group selected from –N(R)-, -O-, -C(O)N(R)-, -N(R)C(O)-, -OC(O)N(R)-, - N(R)C(O)O-, -SO 2 N(R)-, and –N(R)SO 2 -.
  • an L is a bivalent straight or branched C 1-8 hydrocarbon chain, wherein the hydrocarbon chain is optionally substituted with one or more halogen, and wherein one or more methylene units are optionally and independently replaced by a group selected from –N(R)-, -O-, -C(O)N(R)-, -N(R)C(O)-, -OC(O)N(R)-, - N(R)C(O)O-, -SO 2 N(R)-, and –N(R)SO 2 -.
  • an L is selected from: - (CH 2 ) x -, -O(CH 2 ) x -, -OCH(CH 3 )-, –O(CH 2 ) 2 O(CH 2 ) x -, –O(CH 2 ) 2 O-, -O(CH 2 ) 2 O(CH 2 ) 2 O-, - O(CH 2 ) 2 O(CH 2 ) 2 OC(O)N(R)-, –O(CH 2 ) 2 O(CH 2 ) 2 N(R)SO 2 -, –O(CH 2 ) 2 O(CH 2 ) 2 N(R)-, – O(CH 2 ) 2 O(CH 2 ) 2 N(R)CH(CF 3 )-, –O(CH 2 ) 2 O(CH 2 ) x N(R)C(O)(CH 2 ) x -, – O(CH 2 ) 2
  • L is selected from: -O(CH 2 ) x - , –O(CH 2 ) 2 O(CH 2 ) x N(R)C(O)(CH 2 ) x -, and –O(CH 2 ) 2 O(CH 2 ) 2 N(R)C(O)O(CH 2 ) x -.
  • each R 7 is independently selected from hydrogen, C 1-6 aliphatic optionally substituted with one or more R 8 , and –Cy 1 . In some embodiments, each R 7 is independently hydrogen or –Cy 1 .
  • each R 7 is independently hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, each R 7 is independently optionally substituted C 1-6 aliphatic or –Cy 1 . In some embodiments, a R 7 is hydrogen. In some embodiments, a R 7 is optionally substituted C 1-6 aliphatic. In some embodiments, a R 7 is C 1-6 aliphatic optionally substituted with one or more R 8 . In some embodiments, a R 7 is optionally substituted C 1-6 alkyl (e.g., C 1-6 alkyl optionally substituted with one or more R 8 ).
  • a R 7 is optionally substituted C 2-6 alkenyl (e.g., C 2-6 alkenyl optionally substituted with one or more R 8 ). In some embodiments, a R 7 is optionally substituted C 2-6 alkynyl (e.g., C 2-6 alkynyl optionally substituted with one or more R 8 ). In some embodiments, a R 7 is –Cy 1 .
  • a R 7 is selected from: , and [0084] In some embodiments of any Formulae described herein, L is selected from: -O(CH 2 ) x - , –O(CH 2 ) 2 O(CH 2 ) x N(R)C(O)(CH 2 ) x -, and –O(CH 2 ) 2 O(CH 2 ) 2 N(R)C(O)O(CH 2 ) x -; and each R 7 is independently optionally substituted C 1-6 aliphatic or -Cy 1 . [0085] In some embodiments of any Formulae described herein, m is 0, 1, or 2. In some embodiments, m is 1, 2, or 3.
  • m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. [0086] In some embodiments of any Formulae described herein, a moiety is . In some embodiments, a moiety is , or . In some embodiments, a moiety is , , , , or . In some embodiments, a moiety is selected from:
  • Ring B is selected from a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a 5- to 6-membered carbocyclic ring. In some embodiments, Ring B is selected from a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a 5-membered carbocyclic ring. In some embodiments, Ring B is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is a thiophene. In some embodiments, Ring B is 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is a 5- to 6-membered carbocyclic ring. In some embodiments, Ring B is a 5- to 6-membered cycloalkyl ring. In some embodiments, Ring B is a 5-membered carbocyclic ring (e.g., cyclopentane). In some embodiments, Ring B is a 6-membered carbocyclic ring.
  • Ring B is a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is a 5- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is a 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0088] In some embodiments of any Formulae described herein, each R 2 is independently selected from halogen, -OR, and C 1-6 aliphatic. In some embodiments, each R 2 is independently selected from halogen, -OR, and optionally substituted C 1-6 alkyl.
  • each R 2 is independently selected from halogen, -OR, and C 1-6 alkyl. In some embodiments, each R 2 is independently selected from halogen and C 1-6 alkyl. In some embodiments, an R 2 is halogen (e.g., fluoro). In some embodiments, an R is –OR (e.g., -OH). In some embodiments, an R is optionally substituted C 1-6 aliphatic. In some embodiments, an R 2 is C 1-6 aliphatic. In some embodiments, an R 2 is optionally substituted C 1-6 alkyl. In some embodiments, an R 2 is C 1-6 alkyl (e.g., methyl).
  • n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. [0090] In some embodiments of any Formulae described herein, a moiety is selected from: , and . In some embodiments, a moiety is selected from: , and . In some embodiments, a moiety is selected from: and .
  • a moiety is selected from: [0091]
  • Ring C is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring C is selected from 9- to 10-membered bicyclic aryl ring, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring C is selected from phenyl, 9- to 10-membered bicyclic aryl ring, and 3- to 7-membered carbocyclic ring.
  • Ring C is selected from 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring C is selected from phenyl and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring C is phenyl.
  • Ring C is a 9- to 10-membered bicyclic aryl ring.
  • Ring C is a 9-membered bicyclic aryl ring (e.g., an indane).
  • Ring C is a 10-membered bicyclic aryl ring (e.g., a tetrahydronaphthalene).
  • Ring C is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 5- to 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring C is a pyrazole or triazole. In some embodiments, Ring C is a 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a pyridine, pyridone, or pyrimidine.
  • Ring C is a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 9-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring C is an imidazo[1,2-a]pyridine, pyrazolo[1,5-a]pyrimidine, and [1,2,4]triazolo[4,3-a]pyridine.
  • Ring C is a 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring C is a 3- to 7-membered carbocyclic ring. In some embodiments, Ring C is a 3- to 7-membered cycloalkyl ring. In some embodiments, Ring C is a 5- to 6-membered carbocyclic ring. In some embodiments, Ring C is a 5- to 6-membered cycloalkenyl ring.
  • Ring C is a cyclohexene.
  • Ring C is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring C is a 4-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • Ring C is a 5-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a piperidine or tetrahydropyridine. In some embodiments, Ring C is a 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring C is a 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring C is a fused 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a heterocyclic ring fused to an aryl, heteroaryl, cycloalkyl, or heterocyclic ring, wherein the point of attachment to the rest of the molecule is on either ring).
  • Ring C is a 6-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring C is a 7-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring C is an 8-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 9-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 10-membered bicyclic heterocyclic ring having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is selected from: , either of which is substituted with p R 3 groups. In some embodiments, Ring C is an 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring C is selected from: , any of which is substituted with p R 3 groups.
  • each R 3 is independently selected from oxo, halogen, -(CH 2 ) x CN, -(CH 2 ) x OR, -OCH 2 CH 2 OR, - (CH 2 ) x N(R) 2 , -(CH 2 ) x C(O)N(R) 2 , -(CH 2 ) x C(O)N(R)(OH), -(CH
  • each R 3 is independently selected from oxo, halogen, - (CH 2 ) x CN, -(CH 2 ) x OR, -OCH 2 CH 2 OR, -(CH 2 ) x N(R) 2 , -(CH 2 ) x C(O)N(R) 2 , - (CH 2 ) x C(O)N(R)(OH), -(CH 2 ) x C(O)N(R)(CN), -(CH 2 ) x C(O)N(R)SO 2 R, -(CH 2 ) x C(O)OR, - (CH 2 ) x N(R)C(O)R, -(CH 2 ) x SO 2 R, -(CH 2 ) x SO 2 N(R) 2 , -(CH 2 ) x Cy 3 , -(CH 2 ) x C(O)Cy 3 , - (CH 2 ) x
  • each R 3 is independently selected from halogen, -(CH 2 ) x CN, - (CH 2 ) x OR, -OCH 2 CH 2 OR, -(CH 2 ) x N(R) 2 , -(CH 2 ) x C(O)N(R) 2 , -(CH 2 ) x C(O)N(R)(OH), - (CH 2 ) x C(O)N(R)(CN), -(CH 2 ) x C(O)N(R)SO 2 R, -(CH 2 ) x C(O)OR, -(CH 2 ) x N(R)C(O)R, - (CH 2 ) x SO 2 R, -(CH 2 ) x SO 2 N(R) 2 , -(CH 2 ) x Cy 3 , -(CH 2 ) x C(O)Cy 3 , -(CH 2 ) x C(O)N
  • each R 3 is independently selected from oxo, halogen, -(CH 2 ) x OR, -(CH 2 ) x C(O)N(R) 2 , and optionally substituted C 1-6 aliphatic.
  • an R 3 is oxo.
  • an R 3 is halogen (e.g., fluoro or chloro).
  • an R 3 is -(CH 2 ) x CN (e.g., -CH 2 CN or – CN).
  • an R 3 is -(CH 2 ) x OR (e.g., -OH, -OCH 3 , -OCH(CH 3 ) 2 , -(CH 2 ) 2 OH, - (CH 2 ) 2 OCH 3 , or -(CH 2 )3OH).
  • an R 3 is -OCH 2 CH 2 OR (e.g., - OCH 2 CH 2 OCH 3 ).
  • an R 3 is -(CH 2 ) x N(R) 2 (e.g., -N(CH 3 ) 2 , -CH 2 NH 2 , - CH 2 N(CH 3 ) 2 , or -(CH 2 ) 2 NH 2 ).
  • an R 3 is -(CH 2 ) x C(O)N(R) 2 (e.g., - C(O)NH 2 , -C(O)N(CH 3 ) 2 , -CH 2 C(O)NH 2 , -CH 2 C(O)N(H)CH 3 , or -CH 2 C(O)N(CH 3 ) 2 ).
  • an R 3 is -(CH 2 ) x C(O)N(R)(OH) (e.g., -CH 2 C(O)N(CH 3 )(OH)). In some embodiments, an R 3 is -(CH 2 ) x C(O)N(R)(CN) (e.g., -CH 2 C(O)N(H)(CN)). In some embodiments, an R 3 is -(CH 2 ) x C(O)N(R)SO 2 R (e.g., -CH 2 C(O)N(H)SO 2 CH 3 ).
  • an R 3 is - (CH 2 ) x C(O)OR (e.g., -C(O)OC(CH 3 )3, -CH 2 C(O)OH, or -(CH 2 ) 2 C(O)OH).
  • an R 3 is -(CH 2 ) x N(R)C(O)R (e.g., -CH 2 N(H)C(O)CH 3 ).
  • an R 3 is - (CH 2 ) x SO 2 R (e.g., -SO 2 CH 3 ).
  • an R 3 is -(CH 2 ) x SO 2 N(R) 2 (e.g., - SO 2 N(H)CH 3 , -SO 2 N(CH 3 ) 2 , -CH 2 SO 2 N(H)CH 3 , or -(CH 2 ) 2 SO 2 N(H)CH 3 ).
  • an R 3 is -(CH 2 ) x Cy 3 (e.g., -Cy 3 , -CH 2 Cy 3 , or -(CH 2 ) 2 Cy 3 ).
  • an R 3 is -(CH 2 ) x C(O)Cy 3 (e.g., -C(O)Cy 3 or -CH 2 C(O)Cy 3 ). In some embodiments, an R 3 is - (CH 2 ) x C(O)N(R)Cy 3 (e.g., -CH 2 C(O)N(R)Cy 3 or -(CH 2 ) 2 C(O)N(H)Cy 3 ). In some embodiments, an R 3 is -C(O)O(CH 2 ) x Cy 3 (e.g., -C(O)OCH 2 Cy 3 ). In some embodiments, an R 3 is optionally substituted C 1-6 aliphatic.
  • an R 3 is C 1-6 aliphatic optionally substituted with one or more R 8 . In some embodiments, an R 3 is optionally substituted C 1-6 alkyl. In some embodiments, an R 3 is C 1-6 alkyl optionally substituted with one or more R 8 . In some embodiments, an R 3 is C 1-6 aliphatic optionally substituted with one or more halogen (e.g., fluoro) or –OH. In some embodiments, an R 3 is C 1-6 alkyl optionally substituted with one or more halogen (e.g., fluoro) or –OH.
  • halogen e.g., fluoro
  • an R 3 is selected from –CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 C ⁇ CH, and –CH 2 CH(OH)CF3.
  • p is 0, 1, or 2.
  • p is 1, 2, or 3. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 2 or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.
  • a moiety is selected from:
  • each x is independently 1, 2, or 3. In some embodiments, each x is independently 0, 1, or 2. In some embodiments, each x is independently 2 or 3. In some embodiments, each x is independently 1 or 2. In some embodiments, each x is independently 0 or 1. In some embodiments, each x is 0. In some embodiments, each x is 1. In some embodiments, each x is 2. In some embodiments, each x is 3. [0104] In some embodiments of any Formulae described herein, each R is independently hydrogen or optionally substituted C 1-6 alkyl. In some embodiments, each R is independently hydrogen or optionally substituted C 1-4 alkyl.
  • each R is independently hydrogen or C 1-6 aliphatic optionally substituted with one or more R 8 . In some embodiments, each R is independently hydrogen or C 1-6 alkyl optionally substituted with one or more R 8 . In some embodiments, each R is hydrogen or C 1-6 alkyl optionally substituted with one or more halogen (e.g., fluoro). In some embodiments, an R is hydrogen. In some embodiments, an R is optionally substituted C 1-6 aliphatic (e.g., optionally substituted C 1-6 alkyl). In some embodiments, an R is C 1-6 aliphatic optionally substituted with one or more R 8 (e.g., C 1-6 alkyl optionally substituted with one or more R 8 ).
  • an R is C 1-6 aliphatic (e.g., C 1-6 alkyl).
  • each Cy 1 is independently selected from phenyl, 3- to 7-membered carbocyclic ring, and 5- to 10-membered bicyclic carbocyclic ring, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • each Cy 1 is independently selected from 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 10-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • each Cy 1 is independently selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7- membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • each Cy 1 is independently selected from 9- to 10- membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered bicyclic carbocyclic ring, and 6- to 10-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • each Cy 1 is selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • each Cy 1 is selected from 3- to 7-membered carbocyclic ring, and 5- to 10-membered bicyclic carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 10-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is phenyl, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is an imidazole, pyrazole, or thiazole, any of which is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a pyridine, pyridone, pyrazine, or pyrimidine, any of which is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a 9- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a 9-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 is substituted with 0-3 instances of R 5 (e.g., an indole or a 9-membered bicyclic ring system comprising a heteroaryl ring fused to a carbocyclic ring).
  • a Cy 1 is a 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 is substituted with 0-3 instances of R 5 (e.g., a 10-membered bicyclic ring system comprising a heteroaryl ring fused to a carbocyclic ring).
  • a Cy 1 is a 3- to 7-membered carbocyclic ring, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a C3-7 cycloalkyl ring, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a 3-membered carbocyclic ring (e.g., a cyclopropane), wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a 4-membered carbocyclic ring (e.g., a cyclobutane), wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a 5-membered carbocyclic ring (e.g., a cyclopentane), wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a 6-membered carbocyclic ring (e.g., a cyclohexane), wherein Cy is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a 7-membered carbocyclic ring (e.g., a cycloheptane), wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a 5- to 10-membered bicyclic carbocyclic ring, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a fused 5- to 10-membered bicyclic carbocyclic ring (e.g., a carbocyclic ring fused to an aryl, heteroaryl, carbocyclic, or heterocyclic ring, wherein the point of attachment to the rest of the molecule is on either ring), wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a bridged 5- to 10-membered bicyclic carbocyclic ring, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a spirocyclic 5- to 10- membered bicyclic carbocyclic ring (e.g., a carbocyclic ring spirofused to a carbocyclic or heterocyclic ring, wherein the point of attachment to the rest of the molecule is on either ring), wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a 5-membered bicyclic carbocyclic ring, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a 6-membered bicyclic carbocyclic ring, wherein Cy 1 is substituted with 0- 3 instances of R 5 .
  • a Cy 1 is a 7-membered bicyclic carbocyclic ring, wherein Cy 1 is substituted with 0-3 instances of R 5 . In some embodiments, a Cy 1 is a 8-membered bicyclic carbocyclic ring, wherein Cy 1 is substituted with 0-3 instances of R 5 . In some embodiments, a Cy 1 is a 9-membered bicyclic carbocyclic ring, wherein Cy 1 is substituted with 0-3 instances of R 5 . In some embodiments, a Cy 1 is a 10-membered bicyclic carbocyclic ring, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a 4-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., an azetidine), wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a 5-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., a pyrrolidine or a tetrahydrofuran), wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a 6-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., a piperidine, piperazine, tetrahydropyran, morpholine, or dioxane), wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • a Cy 1 is a 7-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 is substituted with 0-3 instances of R 5 .
  • each R 5 is independently selected from oxo, halogen, -CN, -OR, -N(R) 2 , -N(R)Cy 2 , -C(O)R, -C(O)Cy 2 , -C(O)N(R) 2 , - C(O)OR, -C(O)OCy 2 , -(CH 2 ) x N(R)C(O)R, -N(R)C(O)(CH 2 ) x Cy 2 , -(CH 2 ) x N(R)C(O)OR, - N(R)C(O)OCy 2 , -SO 2 R, -Cy 2 , and optionally substitute
  • each R 5 is independently selected from oxo, halogen, -CN, -OR, -N(R) 2 , -N(R)Cy 2 , -C(O)R, -C(O)Cy 2 , -C(O)N(R) 2 , -C(O)OR, -C(O)OCy 2 , -(CH 2 ) x N(R)C(O)R, -N(R)C(O)(CH 2 ) x Cy 2 , - (CH 2 ) x N(R)C(O)OR, -N(R)C(O)OCy 2 , -SO 2 R, -Cy 2 , and C 1-6 aliphatic optionally substituted with one or more R 8 .
  • each R 5 is independently selected from halogen, -CN, - OR, -N(R) 2 , -N(R)Cy 2 , -C(O)R, -C(O)Cy 2 , -C(O)N(R) 2 , -C(O)OR, -C(O)OCy 2 , - (CH 2 ) x N(R)C(O)R, -N(R)C(O)(CH 2 ) x Cy 2 , -(CH 2 ) x N(R)C(O)OR, -N(R)C(O)OCy 2 , -SO 2 R, -Cy 2 , and optionally substituted C 1-6 aliphatic.
  • an R 5 is oxo. In some embodiments, an R 5 is halogen (e.g., fluoro). In some embodiments, an R 5 is –CN. In some embodiments, an R 5 is –OR (e.g., -OCH 3 or -OCH(CH 3 ) 2 ). In some embodiments, an R 5 is -N(R) 2 . In some embodiments, an R 5 is -N(R)Cy 2 (e.g., -N(H)Cy 2 ).
  • an R 5 is -C(O)Cy 2 .
  • an R 5 is - C(O)N(R) 2 .
  • an R 5 is -C(O)OR (e.g., -C(O)OC(CH 3 )3).
  • an R 5 is -C(O)OCy 2 .
  • an R 5 is - N(R)C(O)(CH 2 ) x Cy 2 (e.g., -N(H)C(O)Cy 2 or -N(H)C(O)CH 2 Cy 2 ).
  • an R 5 is -(CH 2 ) x N(R)C(O)OR (e.g., -N(H)C(O)OC(CH 3 )3 or - CH 2 N(H)C(O)OC(CH 3 )3).
  • an R 5 is -N(R)C(O)OCy 2 (e.g., -N(H)C(O)OCy 2 ).
  • an R 5 is -Cy 2 .
  • an R 5 is optionally substituted C 1-6 aliphatic.
  • an R 5 is C 1-6 aliphatic optionally substituted with one or more R 8 . In some embodiments, an R 5 is optionally substituted C 1-6 alkyl. In some embodiments, an R 5 is C 1-6 alkyl optionally substituted with one or more R 8 . In some embodiments, an R 5 is C 1-6 alkyl optionally substituted with one or more halogen, -OH, or –NH 2 . In some embodiments, an R 5 is selected from –CH 3 , -CF3, -CH 2 OH, -CH 2 NH2, -CH 2 CF3, - CH(CH 3 ) 2 , and –C(CH 3 )3. [0113] In some embodiments of any Formulae described herein, each Cy 1 substituted with 0- 3 instances of R 5 is independently selected from:
  • each Cy 2 is independently selected from 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 2 is substituted with 0-3 instances of R 6 .
  • each Cy 2 is independently selected from phenyl and 3- to 7-membered carbocyclic ring, wherein Cy 2 is substituted with 0-3 instances of R 6 .
  • each Cy 2 is independently selected from 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 2 is substituted with 0-3 instances of R 6 .
  • a Cy is phenyl, wherein Cy is substituted with 0-3 instances of R 6 .
  • a Cy 2 is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 2 is substituted with 0-3 instances of R 6 .
  • a Cy 2 is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 2 is substituted with 0-3 instances of R 6 .
  • a Cy 2 is a 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a pyridine), wherein Cy 2 is substituted with 0-3 instances of R 6 .
  • a Cy 2 is a 3- to 7-membered carbocyclic ring (e.g., a C3-7 cycloalkyl ring), wherein Cy 2 is substituted with 0-3 instances of R 6 .
  • a Cy 2 is a 5- to 6-membered carbocyclic ring (e.g., a C 5-6 cycloalkyl ring, such as a cyclohexane), wherein Cy 2 is substituted with 0-3 instances of R 6 .
  • a Cy 2 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 2 is substituted with 0-3 instances of R 6 .
  • a Cy 2 is a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 2 is substituted with 0-3 instances of R 6 .
  • a Cy 2 is a 5-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., a pyrrolidine), wherein Cy 2 is substituted with 0-3 instances of R 6 .
  • a Cy 2 is a 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a piperidine, piperazine, or tetrahydro-2H-thiopyran 1,1-dioxide), wherein Cy 2 is substituted with 0-3 instances of R 6 .
  • each Cy 2 substituted with 0- 3 instances of R 6 is selected from: [0116]
  • each R 6 is independently selected from oxo, halogen, -CN, -(CH 2 ) x OR, -(CH 2 ) x N(R) 2 , -(CH 2 ) x C(O)R, -(CH 2 ) x C(O)OR, - (CH 2 ) x C(O)N(R) 2 , -(CH 2 ) x N(R)C(O)R, and optionally substituted C 1-6 alkyl.
  • each R 6 is independently selected from oxo, halogen, -CN, -(CH 2 ) x OR, - (CH 2 ) x N(R) 2 , -(CH 2 ) x C(O)R, -(CH 2 ) x C(O)OR, -(CH 2 ) x C(O)N(R) 2 , -(CH 2 ) x N(R)C(O)R, and C 1-6 aliphatic.
  • each R 6 is independently selected from oxo, halogen, -CN, - (CH 2 ) x OR, -(CH 2 ) x N(R) 2 , -(CH 2 ) x C(O)R, -(CH 2 ) x C(O)OR, -(CH 2 ) x C(O)N(R) 2 , - (CH 2 ) x N(R)C(O)R, and C 1-6 alkyl.
  • each R 6 is independently selected from halogen, -CN, -(CH 2 ) x OR, -(CH 2 ) x N(R) 2 , -(CH 2 ) x C(O)R, -(CH 2 ) x C(O)OR, -(CH 2 ) x C(O)N(R) 2 , - (CH 2 ) x N(R)C(O)R, and optionally substituted C 1-6 aliphatic.
  • an R 6 is oxo.
  • an R 6 is halogen.
  • an R 6 is –CN.
  • an R 6 is -(CH 2 ) x C(O)N(R) 2 (e.g., -C(O)NH 2 or –C(O)N(CH 3 ) 2 ). In some embodiments, an R 6 is -(CH 2 ) x N(R)C(O)OR (e.g., -CH 2 N(H)C(O)OC(CH 3 )3). In some embodiments, an R 6 is optionally substituted C 1-6 aliphatic. In some embodiments, an R 6 is optionally substituted C 1-6 alkyl. In some embodiments, an R 6 is C 1-6 aliphatic. In some embodiments, an R 6 is C 1-6 alkyl.
  • each Cy 3 is independently selected from phenyl and 3- to 7-membered carbocyclic ring, wherein Cy 3 is substituted with 0-3 instances of R 6 .
  • each Cy 3 is independently selected from 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 3 is substituted with 0-3 instances of R 6 .
  • each Cy 3 is independently selected from phenyl and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 3 is substituted with 0-3 instances of R 6 .
  • each Cy 3 is independently selected from 3- to 7-membered carbocyclic ring and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 3 is substituted with 0-3 instances of R 6 .
  • a Cy 3 is phenyl, wherein Cy 3 is substituted with 0-3 instances of R 6 .
  • a Cy 3 is 5- to 6- membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 3 is substituted with 0-3 instances of R 6 .
  • a Cy 3 is a 5- membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a triazole or tetrazole), wherein Cy 3 is substituted with 0-3 instances of R 6 .
  • a Cy 3 is a 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a pyridine, pyridone, or pyrimidine), wherein Cy 3 is substituted with 0-3 instances of R 6 .
  • a Cy 3 is a 3- to 7-membered carbocyclic ring (e.g., a C3-7 cycloalkyl ring), wherein Cy 3 is substituted with 0-3 instances of R 6 .
  • a Cy 3 is a 4- to 6-membered carbocyclic ring (e.g., a C4-6 cycloalkyl ring, such as a cyclobutane), wherein Cy 3 is substituted with 0-3 instances of R 6 .
  • a Cy 3 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 3 is substituted with 0-3 instances of R 6 .
  • a Cy 3 is a 4-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., an oxetane), wherein Cy 3 is substituted with 0-3 instances of R 6 .
  • a Cy 3 is a 5-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., a pyrrolidine), wherein Cy 3 is substituted with 0-3 instances of R 6 .
  • a Cy 3 is a 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a piperidine, tetrahydropyran, piperazine, or morpholine), wherein Cy 3 is substituted with 0- 3 instances of R 6 .
  • a Cy 3 is a 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 3 is substituted with 0-3 instances of R 6 .
  • each Cy 3 substituted with 0-3 instances of R 6 is independently selected from: , and .
  • R 4 and R 4’ are connected with an optionally substituted C8-12 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O- or –N(R)-.
  • R 4 and R 4’ are connected with a C 8-12 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O- or –N(R)-.
  • R 4 and R 4’ are connected with an optionally substituted C9-11 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O- or – N(R)-. In some embodiments, R 4 and R 4’ are connected with an optionally substituted C8-12 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O-. In some embodiments, R 4 and R 4’ are connected with an optionally substituted C 9-11 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O-. In some embodiments, R 4 and R 4’ are connected with –O(CH 2 ) 8 O-. [0119] In some embodiments of Formula I, q is 0.
  • J is a covalent bond.
  • J is a bivalent straight or branched C 1- 4 hydrocarbon chain.
  • J is a bivalent straight or branched C1-2 hydrocarbon chain.
  • X is not –OR or –N(R) 2 .
  • X is –OR or –N(R) 2 .
  • X is an optionally substituted group selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7- membered carbocyclic ring, 5- to 10-membered bicyclic carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • X is a group selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 5- to 10-membered bicyclic carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein any ring is optionally substituted with C 1-6 alkyl and/or one or more R 8 .
  • X is a group selected from 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein any ring is optionally substituted with C 1-6 alkyl.
  • X is –OR (e.g., -OH or –OCH 3 ).
  • X is –N(R) 2 (e.g., -N(CH 3 ) 2 ).
  • X is -C(O)N(R) 2 (e.g., -C(O)N(CH 3 ) 2 ).
  • X is optionally substituted phenyl. In some embodiments, X is optionally substituted 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, X is optionally substituted 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., pyrazole optionally substituted with one or more C 1-6 alkyl). In some embodiments, X is optionally substituted 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • X is optionally substituted 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, X is optionally substituted 3- to 7-membered carbocyclic ring. In some embodiments, X is optionally substituted 5- to 10-membered bicyclic carbocyclic ring. In some embodiments, X is optionally substituted 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, X is optionally substituted 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • each R 8 is independently selected from halogen, -OR 9 , and -N(R 9 ) 2 .
  • each R 8 is independently selected from -C(O)OR 9 , -C(O)N(R 9 ) 2 , and -N(R 9 )C(O)R 9 .
  • an R 8 is halogen (e.g., fluoro).
  • an R 8 is -OR 9 (e.g., -OH or –O(C 1-6 alkyl)).
  • an R 8 is -N(R 9 ) 2 (e.g., -NH2, -NH(C 1-6 alkyl), or –N(C 1-6 alkyl) 2 ).
  • an R 8 is -C(O)OR 9 (e.g., -C(O)OH or -C(O)O(C 1-6 alkyl)).
  • an R 8 is -C(O)N(R 9 ) 2 (e.g., -C(O)NH2, -C(O)NH(C 1-6 alkyl), or -C(O)N(C 1-6 alkyl) 2 ).
  • an R 8 is -N(R 9 )C(O)R 9 (e.g., -N(H)C(O)(C 1-6 alkyl) or -N(C 1-6 alkyl)C(O)(C 1-6 alkyl)).
  • each R 9 is independently selected from hydrogen or C 1-6 alkyl.
  • an R 9 is hydrogen.
  • an R 9 is C 1-6 aliphatic (e.g., C 1-6 alkyl).
  • any embodiment described herein may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive.
  • two embodiments are “mutually exclusive” when one is defined to be something which is different than the other. For example, an embodiment wherein two groups combined to form a ring is mutually exclusive with an embodiment in which one group is ethyl and the other group is hydrogen. Similarly, an embodiment wherein one group is CH 2 is mutually exclusive with an embodiment wherein the same group is NH.
  • the present disclosure provides a compound selected from Table 1 or any of the Examples provided herein, or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof.
  • the present disclosure provides a compound selected from Table 1 or any of the Examples provided herein, or a salt (e.g., pharmaceutically acceptable salt) thereof.
  • provided compounds are provided and/or utilized in a salt form (e.g., a pharmaceutically acceptable salt form).
  • Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated. Pharmaceutically acceptable salt forms are known in the art. For example, S. M.
  • salts in detail in J. Pharmaceutical Sciences, 66:1-19(1977).
  • examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1– 4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • reference to a compound of Formula I is intended to also include Formulae IA, IA1, IA1-a, IA1- b, IA1-c, IA2, IA2-a, IA2-b, IA2-c, IA3, IA3-a, IA3-b, IA3-c, IA4-a, IA4-b, IA4-c, IB, IB1, IB2, IB3, IB4-a, IB4-b, and IB4-c, and compound species of such formulae disclosed herein, and reference to a compound of Formula II is intended to also include Formulae IIA, IIA1, IIA2, IIA3, IIB1, IIB2, IIB3, IIC, and IID, and compound species of such formulae disclosed herein.
  • compositions comprising a compound provided herein with one or more other components.
  • provided compositions comprise and/or deliver a compound described herein (e.g., compounds of Formulae I, IA, IA1, IA1-a, IA1-b, IA1-c, IA2, IA2-a, IA2-b, IA2-c, IA3, IA3-a, IA3-b, IA3-c, IA4-a, IA4-b, IA4-c, IB, IB1, IB2, IB3, IB4-a, IB4-b, IB4-c, II, IIA, IIA1, IIA2, IIA3, IIB1, IIB2, IIB3, IIC, and IID)
  • a provided composition is a pharmaceutical composition that comprises and/or delivers a compound provided herein (e.g., compounds of Formulae I, IA, IA1, IA1-a,
  • compositions typically contain an active agent (e.g., a compound described herein) in an amount effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects.
  • provided pharmaceutical compositions comprise a compound described herein and one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and/or anti-statics, etc.
  • Provided pharmaceutical compositions can be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppository, nasal spray and/or inhaler, eye drops, intraocular injection forms, depot forms, as well as injectable and infusible solutions. Methods of preparing pharmaceutical compositions are well known in the art.
  • provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage.
  • unit dosage form refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent.
  • a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect.
  • a unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined quantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.
  • a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents
  • a solid pharmaceutical composition e.g., a tablet, a capsule, or the like
  • a sustained release formulation containing a predetermined quantity of one or more active agents
  • a drug delivery device containing a predetermined amount of one or more active agents
  • the present disclosure provides uses for compounds and compositions described herein (e.g., compounds of Formulae I, IA, IA1, IA1-a, IA1-b, IA1-c, IA2, IA2-a, IA2-b, IA2-c, IA3, IA3-a, IA3-b, IA3-c, IA4-a, IA4-b, IA4-c, IB, IB1, IB2, IB3, IB4-a, IB4-b, IB4-c, II, IIA, IIA1, IIA2, IIA3, IIB1, IIB2, IIB3, IIC, and IID).
  • provided compounds and compositions are useful in medicine (e.g., as therapeutic agents for use in the treatment, amelioration, delaying progress of, amelioration or elimination of a symptom of, and/or inhibition of a disease or disorder, as described herein).
  • provided compounds and compositions are useful as medicaments.
  • provided compounds and compositions are useful in research as, for example, analytical tools and/or control compounds in biological assays.
  • provided compounds are useful for disrupting (e.g., inhibiting and/or preventing and/or modulating) an interaction between a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3K ⁇ protein.
  • a small GTPase e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1
  • a small GTPase e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1
  • the present disclosure provides methods of disrupting, interrupting, and/or preventing an interaction between a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3K ⁇ protein in a subject, comprising administering a provided compound or composition.
  • a small GTPase e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1
  • the present disclosure provides methods of disrupting, interrupting, and/or preventing an interaction between a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3K ⁇ protein in a biological sample, comprising administering a provided compound or composition.
  • a small GTPase e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1
  • the present disclosure provides methods comprising contacting a cell containing a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3K ⁇ protein with a provided compound or composition.
  • a small GTPase is capable of binding a RAS-binding domain (RBD) of a PI3K ⁇ protein.
  • RBD RAS-binding domain
  • a small GTPase is selected from Rac1, CDC42, and RAS proteins.
  • a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1.
  • a RAS protein is a wild-type RAS protein.
  • a RAS protein is a mutant RAS protein.
  • a RAS protein (e.g., HRAS, NRAS, or KRAS) comprises a mutation in codon 12 (e.g., G12), codon 13 (e.g., G13), or codon 61 (e.g., Q61).
  • a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation.
  • a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and/or Q61H mutation.
  • an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation.
  • an NRAS protein comprises a G12D, G12V, G13D, and/or Q61R mutation.
  • an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation.
  • an HRAS protein comprises a G12V, G13R, and/or Q61R mutation.
  • a PI3K ⁇ protein is a wild-type PI3K ⁇ protein.
  • a PI3K ⁇ protein is a mutant PI3K ⁇ protein.
  • a PI3K ⁇ protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and/or H1047L mutation.
  • a PI3K ⁇ protein comprises a E542K, E545K, H1047R, and/or H1047L mutation.
  • a subject has a disease, disorder, or condition associated with an interaction between a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3K ⁇ protein.
  • a subject has a disease, disorder, or condition ameliorated by disruption of an interaction between a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3K ⁇ protein.
  • a small GTPase e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1
  • RAS- binding domain RAS- binding domain
  • a small GTPase is selected from Rac1, CDC42, and RAS proteins.
  • a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1.
  • a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation.
  • a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and/or Q61H mutation.
  • an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation.
  • an NRAS protein comprises a G12D, G12V, G13D, and/or Q61R mutation.
  • an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation.
  • an HRAS protein comprises a G12V, G13R, and/or Q61R mutation.
  • a RAS protein is a wild-type RAS protein.
  • a PI3K ⁇ protein is a wild-type PI3K ⁇ protein.
  • a PI3K ⁇ protein is a mutant PI3K ⁇ protein.
  • a PI3K ⁇ protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and/or H1047L mutation.
  • a PI3K ⁇ protein comprises a E542K, E545K, H1047R, and/or H1047L mutation.
  • a subject has a cancer or other indication described herein.
  • a subject has previously undergone a treatment regimen for a cancer. In some embodiments, a subject has previously entered remission from a cancer.
  • provided methods comprise administering a provided compound or composition to a subject in need thereof, according to a regimen such that the subject does not experience hyperglycemia or insulin-driven resistance.
  • the present disclosure provides methods of treating a cancer, comprising administering to a subject a provided compound or composition.
  • a cancer is associated with and/or characterized by aberrant activation of PI3K ⁇ .
  • a cancer is characterized by a mutation in a RAS protein (e.g., HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1).
  • a cancer is characterized by a mutation in a KRAS protein.
  • a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation.
  • a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and/or Q61H mutation.
  • a cancer is characterized by a mutation in an NRAS protein.
  • an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation.
  • an NRAS protein comprises a G12D, G12V, G13D, and/or Q61R mutation.
  • a cancer is characterized by a mutation in an HRAS protein.
  • an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation.
  • an HRAS protein comprises a G12V, G13R, and/or Q61R mutation.
  • a cancer is characterized by a mutation in a PI3K ⁇ protein.
  • a PI3K ⁇ protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and/or H1047L mutation.
  • a PI3K ⁇ protein comprises a E542K, E545K, H1047R, and/or H1047L mutation.
  • cancer refers to cells that exhibit relatively abnormal, uncontrolled, and/or autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation.
  • a tumor may be or comprise cells that are precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and/or non-metastatic.
  • a cancer may be characterized by a solid tumor.
  • a cancer may be characterized by a hematologic tumor. Numerous different types of cancers are known.
  • a cancer is selected from pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; breast cancer; ovarian cancer; endometrial cancer; lung cancer; prostate cancer; cancers of the oral cavity and pharynx (lip, tongue, mouth, larynx, pharynx), esophagus, stomach, small intestine, large intestine, liver and biliary passages, bone, connective tissue, skin, cervix, uterus, corpus endometrium, testis, bladder, kidney and other urinary tissues, including renal cell carcinoma (RCC); cancers of the eye, brain, spinal cord, and other components of the central and peripheral nervous systems, as well as associated structures such as the meninges; cancers of the thyroid and other endocrine glands; Hodgkin’s disease; non-Hodgkin’s lymphomas; multiple myeloma; and hematopoietic malignancies including leukemias (Chronic Lymphoc
  • Additional exemplary types of cancer include, but are not limited to, adenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, anaplastic astrocytoma, basal cell carcinoma, blastoglioma, chondrosarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endotheliosarcoma, embryonal carcinoma, ependymoma, Ewing's tumor, epithelial carcinoma, fibrosarcoma, gastric cancer, genitourinary tract cancers, glioblastoma multiforme, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, hepatoma, Kaposi's sarcoma, large cell carcinoma, leiomyosarcoma, leukemias, liposarcoma, lymphatic system cancer, lympho
  • a cancer is selected from breast cancer, lung cancer (e.g., non-small cell lung cancer), endometrial cancer, esophageal cancer, ovarian cancer, colorectal cancer, gastric cancer, squamous cell carcinoma, prostate cancer, and pancreatic cancer.
  • a cancer is characterized by one or more mutations.
  • a subject may be diagnosed with cancer and/or selected for therapy based on the detection of one or more mutations in a biological sample obtained from the subject.
  • a cancer is characterized by a mutation in a RAS protein (e.g., KRAS, HRAS, or NRAS).
  • a cancer is characterized by a mutation in a KRAS protein.
  • a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation.
  • a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and/or Q61H mutation.
  • a cancer is characterized by a mutation in an NRAS protein.
  • an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation.
  • an NRAS protein comprises a G12D, G12V, G13D, and/or Q61R mutation.
  • a cancer is characterized by a mutation in an HRAS protein.
  • an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation.
  • an HRAS protein comprises a G12V, G13R, and/or Q61R mutation.
  • a cancer is characterized by a mutation in a PI3K ⁇ protein.
  • the PI3K ⁇ protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and/or H1047L mutation.
  • a PI3K ⁇ protein comprises a E542K, E545K, H1047R, and/or H1047L mutation.
  • a cancer is characterized by mutated, overexpressed, and/or amplified receptor tyrosine kinases (e.g., HER family (e.g., HER2 and/or HER3), Met, FGFR, Alk, PDGF, EGFR, or ROS kinases).
  • a cancer is characterized by a mutation in or a deletion of a PTEN protein.
  • a cancer has demonstrable sensitivity to Avastin.
  • a cancer may be non-small cell lung cancer (NSCLC) or colorectal cancer.
  • NSCLC non-small cell lung cancer
  • a cancer is ER positive (e.g., having estrogen receptors).
  • a cancer is PR positive (e.g., having progesterone receptors).
  • the present disclosure provides methods of treating a metabolic syndrome, comprising administering to a subject a provided compound or composition.
  • a metabolic syndrome is selected from hyperinsulinemia and type 2 diabetes.
  • the present disclosure provides methods of treating a RASopathy (e.g., a genetic syndrome caused by a germline mutation in a gene that encodes a component or regulator of the RAS/MAPK pathway), comprising administering to a subject a provided compound or composition.
  • a RASopathy is selected from the group consisting of capillary malformation-arteriovenous malformation syndrome and Legius syndrome.
  • a RASopathy is neurofibromatosis type 1 (NF1).
  • the present disclosure provides methods of treating a vascular disorder, comprising administering to a subject a provided compound or composition.
  • a vascular disorder is selected from PIK3CA-related overgrowth syndrome (PROS) and vascular malformations (e.g., venous malformations; lymphatic malformations; congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (CLOVES); Klippel-Trenaunay Syndrome; PTEN hamartoma tumor syndrome (PHTS); and fibro-adipose vascular anomaly (FAVA)).
  • PROS PIK3CA-related overgrowth syndrome
  • CMVOVES congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome
  • PHTS PTEN hamartoma tumor syndrome
  • FAVA fibro-adipose vascular anomaly
  • the present disclosure provides methods of treating pulmonary hypertension, such as pulmonary arterial hypertension, comprising administering to a subject a provided compound or composition.
  • the present disclosure provides methods of treating age-related macular degeneration or diabetic macular edema, comprising administering to a subject a provided compound or composition.
  • the present disclosure provides compounds or compositions for use in the manufacture of a medicament.
  • provided compounds or compositions are useful in the manufacture of a medicament for treating a disease, disorder, or condition associated with or ameliorated by an interaction between a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3K ⁇ protein.
  • a small GTPase e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1
  • RAS- binding domain RAS- binding domain
  • a small GTPase is selected from Rac1, CDC42, and RAS proteins.
  • a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1.
  • a RAS protein is a wild-type RAS protein.
  • a RAS protein is a mutant RAS protein.
  • a RAS protein (e.g., HRAS, NRAS, or KRAS) comprises a mutation in codon 12 (e.g., G12), codon 13 (e.g., G13), or codon 61 (e.g., Q61).
  • a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation.
  • a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and/or Q61H mutation.
  • an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation.
  • an NRAS protein comprises a G12D, G12V, G13D, and/or Q61R mutation.
  • an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation.
  • an HRAS protein comprises a G12V, G13R, and/or Q61R mutation.
  • a PI3K ⁇ protein is a wild-type PI3K ⁇ protein.
  • a PI3K ⁇ protein is a mutant PI3K ⁇ protein.
  • a PI3K ⁇ protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and/or H1047L mutation.
  • a PI3K ⁇ protein comprises a E542K, E545K, H1047R, and/or H1047L mutation.
  • provided compounds or compositions are useful in the manufacture of a medicament for treating a disease, disorder, or condition described herein. In some embodiments, provided compounds or compositions are useful in the manufacture of a medicament for treating a cancer or other indication described herein. [0148] In some embodiments, the present disclosure provides compounds or compositions for use in treating a disease, disorder, or condition in a subject in need thereof.
  • provided compounds or compositions are useful in treating a disease, disorder, or condition associated with or ameliorated by an interaction between a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3K ⁇ protein.
  • a small GTPase e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1
  • RAS-binding domain RAS-binding domain
  • a small GTPase is selected from Rac1, CDC42, and RAS proteins.
  • a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1.
  • a RAS protein is a wild-type RAS protein.
  • a RAS protein is a mutant RAS protein.
  • a RAS protein (e.g., HRAS, NRAS, or KRAS) comprises a mutation in codon 12 (e.g., G12), codon 13 (e.g., G13), or codon 61 (e.g., Q61).
  • a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation.
  • a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and/or Q61H mutation.
  • an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation.
  • an NRAS protein comprises a G12D, G12V, G13D, and/or Q61R mutation.
  • an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutation.
  • an HRAS protein comprises a G12V, G13R, and/or Q61R mutation.
  • a PI3K ⁇ protein is a wild-type PI3K ⁇ protein.
  • a PI3K ⁇ protein is a mutant PI3K ⁇ protein.
  • a PI3K ⁇ protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and/or H1047L mutation.
  • a PI3K ⁇ protein comprises a E542K, E545K, H1047R, and/or H1047L mutation.
  • provided compounds or compositions are useful for treating a disease, disorder, or condition described herein.
  • provided compounds or compositions are useful for treating a cancer or other indication as described herein.
  • a provided compound or composition is administered as part of a combination therapy.
  • the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents).
  • the two or more regimens may be administered simultaneously.
  • such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens.
  • “administration” of combination therapy may involve administration of one or more agents or modalities to a subject receiving the other agent or modality in the combination.
  • combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although, in some embodiments, two or more agents may be administered together in a combination composition.
  • a provided compound or composition is administered to a subject who is receiving or has received one or more additional therapeutic agents (e.g., an anti- cancer agent and/or a therapy to address one or more side effects of such anti-cancer therapy, or otherwise to provide palliative care).
  • anti-cancer agents include, but are not limited to, an alkylating agent, an antimitotic, a checkpoint inhibitor, an anti-metabolite, a plant alkaloid, a terpenoid, a cytotoxic agent, an antibiotic, a topoisomerase inhibitor, an aromatase inhibitor, an angiogenesis inhibitor, an anti-steroid, an anti-androgen, an mTOR inhibitor, monoclonal antibodies, a kinase inhibitor, a HIF2 ⁇ inhibitor, or a tyrosine kinase inhibitor.
  • An alkylating agent may be, for example, armustine, chlorambucil (LEUKERAN), cisplatin (PLATIN), carboplatin (PARAPLATIN), oxaliplatin (ELOXATIN), streptozocin (ZANOSAR), busulfan (MYLERAN), dacarbazine, ifosfamide, lomustine (CCNU), melphalan (ALKERAN), procarbazine (MATULAN), temozolomide (TEMODAR), thiotepa, or cyclophosphamide (ENDOXAN).
  • An anti-metabolite may be, for example, cladribine (LEUSTATIN), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (cytarabine, ARA-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEY), methotrexate (RHEUMATREX), or raltitrexed.
  • An antimitotic may be, for example, a taxane such as docetaxel (TAXITERE) or paclitaxel (ABRAXANE, TAXOL), or a vinca alkaloid such as vincristine (ONCOVIN), vinblastine, vindesine, or vinorelbine (NAVELBINE).
  • TAXITERE docetaxel
  • ABRAXANE paclitaxel
  • NAVELBINE vinca alkaloid
  • vincristine ONCOVIN
  • vinblastine vinblastine
  • vindesine vindesine
  • NAVELBINE vinorelbine
  • a checkpoint inhibitor may be an anti-PD-1 or anti-PD-L1 antibody such as pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), MEDI4736, or MPDL3280A; anti-CTLA-4 antibody ipilimumab (YERVOY); or an agent that targets LAG3 (lymphocyte activation gene 3 protein), KIR (killer cell immunoglobulin-like receptor), 4-1BB (tumor necrosis factor receptor superfamily member 9), TIM3 (T-cell immunoglobulin and mucin-domain containing-3), or 0X40 (tumor necrosis factor receptor superfamily member 4).
  • LAG3 lymphocyte activation gene 3 protein
  • KIR killer cell immunoglobulin-like receptor
  • 4-1BB tumor necrosis factor receptor superfamily member 9
  • TIM3 T-cell immunoglobulin and mucin-domain containing-3
  • 0X40 tumor necrosis factor receptor superfamily member 4
  • a topoisomerase inhibitor may be, for example, camptothecin (CTP), irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), teniposide (VUMON), or etoposide (EPOSIN).
  • a cytotoxic antibiotic may be, for example, actinomycin D (dactinomycin, COSMEGEN), bleomycin (BLENOXANE) doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin (ELLENCE), fludarabine (FLUDARA), idarubicin, mitomycin (MITOSOL), mitoxantrone (NOYANTRONE), or plicamycin.
  • An aromatase inhibitor may be, for example, aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (RIYIZOR), or exemestane (AROMASIN).
  • An angiogenesis inhibitor may be, for example, genistein, sunitinib (SUTENT), or bevacizumab (AYASTIN).
  • An anti-steroid or anti- androgen may be, for example, aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN), or nilutamide (NILANDRON).
  • a tyrosine kinase inhibitor may be, for example, imatinib (GLEEVEC), erlotinib (TARCEVA), afatinib (GILOTRIF), lapatinib (TYKERB), sorafenib (NEXAVAR), or axitinib (INLYTA).
  • An mTOR inhibitor may be, for example, everolimus, temsirolimus (TORISEL), or sirolimus.
  • Monoclonal antibody may be, for example, trastuzumab (HERCEPTIN) or rituximab (RITUXAN).
  • a kinase inhibitor may be, for example, a BRAF inhibitor, MEK inhibitor, or a KRAS inhibitor (e.g., KRAS G12C inhibitor, such as sotorasib, adagrasib, or BBO-8520).
  • KRAS G12C inhibitor such as sotorasib, adagrasib, or BBO-8520.
  • agents that may be useful in combination with a compound provided herein include, but are not limited to, amsacrine; Bacillus Calmette-Guerin (B-C-G) vaccine; buserelin (ETILAMIDE); chloroquine (ARALEN); clodronate, pamidronate, and other bisphosphonates; colchicine; demethoxyviridin; dichloroacetate; estramustine; filgrastim (NEUPOGEN); fludrocortisone (FLORINEF); goserelin (ZOLADEX); interferon; leucovorin; leuprolide (LUPRON); levamisole; lonidamine; mesna; metformin; mitotane (o,r'-DDD, LYSODREN); nocodazole; octreotide (SANDOSTATIN); perifosine; porfimer (particularly in combination with photo- and radiotherapy); suramin; tamoxifen;
  • Normal phase chromatography was performed using elution gradients of various solvents (e.g., hexane, ethyl acetate, methylene chloride, methanol, acetone, chloroform, MTBE, etc.).
  • the columns were SNAP Cartridges containing KP-SIL or SNAP Ultra (25 pm spherical particles) of various sizes (Biotage LLC). Typical loading was between 1:10 to 1:150 crude sample: SiO 2 by weight.
  • silica gel chromatography was performed on a Biotage Horizon flash chromatography system.
  • HNMR analyses of intermediates and exemplified compounds were typically performed on a Bruker Ascend TM 400 spectrometer (operating at 400 MHz), Bruker Ascend 500 MHz Avance Neo Spectrometer (Bruker-Biospin), Bruker Ascend 700 MHz Avance Neo Spectrometer (Bruker-Biospin), or Bruker Avance Neo Nanobay (operating at 400 MHz) at 298 °K following standard operating procedure suggested by manufacturer. Reference frequency was set using TMS as an internal standard. Chemical shift values ( ⁇ ) are reported in parts per million (ppm) with splitting patterns abbreviated to: s (singlet), br.
  • LCMS analyses were typically performed using one of the following conditions: [0157] (1) LCMS spectra were taken on an Agilent Technologies 6120B Quadrupole spectrometer. The mobile phase for the LC was acetonitrile (A) with 0.1% formic acid, and water (B) with 0.1% formic acid, and the eluent gradient was either from 5-95% A in 6.0 min, 5%-40% A in 6.0 min, or 80-100% A in 6.0 min.
  • MS mass spectra
  • LCMS spectra were taken on Waters Micromass-ZQ 2000 Quadrupole spectrometer.
  • the mobile phase for the LC was (A) 0.1% formic acid in water; (B) acetonitrile 100% and the eluent gradient was from 10-90% B in 10.0 min, 90% up to 12 min B, 12-13 min 90-10% B, 13-15 min 90-10% B using Phenomenex Gemini-C18 (50 mm x 4.6 mm x 5 ⁇ m); Flow Rate: 0.5 mL/min.
  • MS Mass spectra (MS) were measured by Electrospray Ion-Mass spectroscopy (ESI).
  • LC1 Agilent Technologies 1260 Infinity coupled, Column: poroshell 120 EC-C18150 mm x 4.6 mm x 4 ⁇ m; Temperature: 40 °C; Eluent: 5:95 v/v acetonitrile/water + 0.02% trifluoroacetic acid in 20 min; Flow Rate: 1.2 mL/min; Detection: VWD, 190-600 nm.
  • LC2 Shimadzu 2010 CHT, Column Waters X-select CSH C18 (150 x 4.6) mm x 3.5 ⁇ m, Temperature: 30 °C; MP-A 10 mM ammonium acetate Buffer, MP-B: Acetonitrile (100%), Flow Rate: 1.0 mL/min; Detection: VWD, 270 nm. Gradient elevation: time/B con: 0/5,2/5,20/50,25/50,30/90,35/90,37/05,40/05.
  • Preparative HPLC were carried out with one of the following conditions: [0166] Condition 1: GILSON Preparative HPLC System; Column: Ultimate XB-C18, 21.2 mm x 250 mm, 5 ⁇ m; Mobile phase: Water with 0.1% trifluoroacetic acid; MeCN with 0.1% trifluoroacetic acid; Method: 15 minutes gradient elution; Initial organic: 10% to 30%; Final organic: 60% to 80%; UV1: 240; UV2: 230; Flow: 15 mL/min.
  • Condition 1 GILSON Preparative HPLC System
  • Column Ultimate XB-C18, 21.2 mm x 250 mm, 5 ⁇ m
  • Mobile phase Water with 0.1% trifluoroacetic acid
  • MeCN with 0.1% trifluoroacetic acid
  • Method 15 minutes gradient elution
  • Initial organic 10% to 30%
  • Final organic 60% to 80%
  • UV1 240
  • UV2 UV2: 230
  • Flow 15 mL/min.
  • Condition 2 C18-Reverse phase preparative HPLC was performed using a Waters purification system with 2489 UV/Vis detector, 2545 Gradient module, and Fraction collector III controlled by Waters Chromescope v1.6.
  • the preparative HPLC column used was a Waters XBridge® Prep C185 ⁇ m OBD TM 19 x 250 mm column with a mobile phase of water / MeCN or water (0.1% TFA) / MeCN (0.1% TFA).
  • Condition 3 Shimadzu Preparative HPLC System; Column: Phenomenex Luna C18, 21.1 mm ⁇ 250 mm, 10 ⁇ m; Mobile phase; MP-A 10 mM ammonium acetate Buffer, MP-B: Methanol (100%), 35 minutes gradient elution UV: 254; Flow: 10 mL/min. Gradient elevation: time/B con:0/50,25/90,30/90,32/50,35/50. [0169] Compound names were generated with ChemDraw Professional.
  • Step B Preparation of 2-(benzyloxy)-4- fluorobenzoic acid: Benzyl 2-(benzyloxy)-4- fluorobenzoate (50.0 g, 149 mmol) was dissolved in a mixture of MeOH (100 mL) and THF (100 mL). NaOH (8.92 g, 111 mL, 2.00 M, 223 mmol) was added and the mixture was heated to 50 °C for 2 h. The mixture was cooled to room temperature and the organic solvent was removed in vacuo. The remaining solution was diluted with water (300 mL) and then solid citric acid was added until the solution reached ⁇ pH 5.
  • Step C Preparation of 2-(benzyloxy)-4-fluoro-N-methoxy-N-methylbenzamide: To a 0 °C solution of 2-(benzyloxy)-4-fluorobenzoic acid (37.5 g, 151 mmol) and triethylamine (16.8 g, 23.0 mL, 166 mmol) in DCM (400 mL) was added ethyl chloroformate (17.2 g, 15.2 mL, 158 mmol).
  • Step D Preparation of 2-(2-(benzyloxy)-4-fluorobenzoyl)thiophene-3-carboxylic acid: To a -78 °C solution of thiophene-3-carboxylic acid (21.2 g, 165 mmol) in THF (200 mL) was added n-butyllithium (2.5 M in hexanes) (127 mL, 317 mmol) dropwise over 15 minutes. The mixture was stirred at this temperature for 1 h before a solution of 2-(benzyloxy)-4-fluoro-N- methoxy-N-methylbenzamide (42.0 g, 138 mmol) in THF (200 mL) was added dropwise over 30 minutes.
  • n-butyllithium 2.5 M in hexanes
  • Step E Preparation of 7-(2-(benzyloxy)-4-fluorophenyl)thieno[2,3-d]pyridazin- 4(5H)-one: 2-(2-(benzyloxy)-4-fluorobenzoyl)thiophene-3-carboxylic acid (55 g, 0.11 mol) was dissolved in EtOH (300 mL). Hydrazine hydrate (64 wt% hydrazine) (17 mL, 0.22 mol) was added and the mixture was heated to 90 °C for 1 h. The mixture was cooled to ⁇ 10 °C in an ice bath. The precipitate formed was filtered and washed with cold EtOH (2 x 30 mL).
  • Step F Preparation of 7-(2-(benzyloxy)-4-fluorophenyl)-4-chlorothieno[2,3- d]pyridazine: 7-(2-(benzyloxy)-4-fluorophenyl)thieno[2,3-d]pyridazin-4(5H)-one (9.00 g, 25.5 mmol) was suspended in phosphoryl trichloride (33 g, 20 mL, 0.21 mol). The mixture was heated to 100 °C for 0.5 h then cooled to rt. The mixture was quenched slowly into warm (40-50 °C) water over 30 minutes.
  • Step G Preparation of 2-(4-chlorothieno[2,3-d]pyridazin-7-yl)-5- fluorophenol: 7-(2- (benzyloxy)-4-fluorophenyl)-4-chlorothieno[2,3-d]pyridazine (10.0 g, 27.0 mmol) was suspended in AcOH (20 mL). HBr (33 wt% in AcOH) (40 mL, 0.13 mol) was added and the mixture was heated to 50 °C for 90 min. The mixture was cooled to rt then poured into ice.
  • Step H Preparation of tert-butyl (2-(2-(2-(4-chlorothieno[2,3-d]pyridazin-7-yl)-5- fluorophenoxy)ethoxy)ethyl)carbamate: Cesium carbonate (4.18 g, 12.8 mmol) was added into a stirring solution of 2-(4-chlorothieno[2,3-d]pyridazin-7-yl)-5-fluorophenol (3.00 g, 10.7 mmol) and 2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate (4.23 g, 11.8 mmol) in acetonitrile (30 mL) and the mixture was heated to 60 °C for 2 h.
  • Step I Preparation of tert-butyl (2-(2-(5-fluoro-2-(4-(1-oxo-1,2,3,4- tetrahydroisoquinolin-6-yl)thieno[2,3-d]pyridazin-7-yl)phenoxy)ethoxy)ethyl)carbamate: To a reaction vessel containing 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4- dihydroisoquinolin-1(2H)-one (111 mg, 406 ⁇ mol), tert-butyl (2-(2-(2-(4-chlorothieno[2,3- d]pyridazin-7-yl)-5-fluorophenoxy)ethoxy)ethyl)carbamate (100 mg, 203 ⁇ mol), and K 2 CO 3 (112 mg, 812 ⁇ mol) in 1,4-dioxane (3
  • the resulting reaction mixture was degassed with N 2 for 10 min and then heated to 85 °C for two hours.
  • the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3 x 50 mL).
  • the organic extract was dried over magnesium sulphate and solvent removed under reduced pressure and the crude product was purified by chromatography on silica gel (24 g cartridge, 0- 100% EtOAc/isohexane) to afford tert-butyl (2-(2-(5-fluoro-2-(4-(1-oxo-1,2,3,4- tetrahydroisoquinolin-6-yl)thieno[2,3-d]pyridazin-7-yl)phenoxy)ethoxy)ethyl)carbamate (88 mg, 74% yield) as a white solid.
  • Step B Preparation of tert-butyl 4-[7-[2-(2-methoxyethoxy)phenyl]thieno[2,3- d]pyridazin-4-yl]piperidine-1-carboxylate: To a solution of tert-butyl 4-[7-[2-(2-methoxyethoxy) phenyl]thieno[2,3-d]pyridazin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (500 mg, 1.07 mmol) in methanol (5 mL) was added Pd/C (11 mg, 0.11 mmol) under H 2 . The mixture was stirred at 100 °C for 1 hour.
  • Step C Preparation of 7-[2-(2-methoxyethoxy)phenyl]-4-(4-piperidyl)thieno[2,3- d]pyridazine: To a solution of tert-butyl 4-[7-[2-(2-methoxyethoxy)phenyl]thieno[2,3- d]pyridazin-4-yl]piperidine-1-carboxylate (220 mg, 0.468 mmol) in DCM (2 mL) was added TFA (0.600 mL, 7.79 mmol). The mixture was stirred at 15 °C for 30 minutes.
  • Step D Preparation of 7-[2-(2-methoxyethoxy)phenyl]-4-(1-methylsulfonyl-4- piperidyl)thieno[2,3-d]pyridazine: To a solution of 7-[2-(2-methoxyethoxy)phenyl]-4-(4- piperidyl)thieno[2,3-d]pyridazine (25 mg, 0.068 mmol) and DIEA (0.018 mL, 0.10 mmol) in DCM (2 mL) cooled to 0 °C was added MsCl (10 mg, 0.088 mmol) under Ar. The mixture was stirred at 0 °C for 3 h.
  • Step B Preparation of 4,13-dioxa-2(7,4)-thieno[2,3-d]pyridazina-1(1,2),3(1,3)- dibenzenacyclotridecaphane: To a solution of 2-[4-(3-hydroxyphenyl)thieno[2,3-d]pyridazin-7- yl]phenol (10 mg, 0.031 mmol) in MeCN (15 mL) were added 1,8-dibromooctane (9.3 mg, 0.034 mmol), potassium carbonate (4.3 mg, 0.031 mmol) and potassium iodide (0.52 mg, 0.0031 mmol) under Ar.
  • Step A Preparation of 4-chloro-7-(4-fluoro-2-((tetrahydro-2H-pyran-4- yl)methoxy)phenyl)thieno[2,3-d]pyridazine: 2-(4-chlorothieno[2,3-d]pyridazin-7-yl)-5- fluorophenol (300 mg, 1.07 mmol), (tetrahydro-2H-pyran-4-yl)methanol (186 mg, 1.60 mmol) and triphenylphosphine (561 mg, 2.14 mmol) were dissolved in THF (3 mL) and cooled to 0 °C.
  • Step B Preparation of 7-(7-(4-fluoro-2-((tetrahydro-2H-pyran-4- yl)methoxy)phenyl)thieno[2,3-d]pyridazin-4-yl)-1,4-dihydroisoquinolin-3(2H)-one: Bis(pinacolato)diboron (235 mg, 924 ⁇ mol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (80 mg, 98 ⁇ mol) and potassium acetate (77.7 mg, 792 ⁇ mol) were added to a round bottom flask and the flask was evacuated and back-filled with N 2 (x 3).7-Bromo-1,4-dihydroisoquinolin-3(2H)-one (179 mg, 792 ⁇ mol) was added, followed by dry 1,4-dioxane (8 mL).
  • the reaction was degassed for 10 mins with an N 2 balloon. The reaction was stirred at 80 °C for 2.5 hours. The reaction was cooled to room temperature and then the reaction mixture was charged with 4-chloro-7-(4-fluoro-2- ((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)thieno[2,3- d]pyridazine (100 mg, 264 ⁇ mol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (80 mg, 98 ⁇ mol) and a solution of potassium carbonate (109 mg, 792 ⁇ mol) in water (0.5 ml). The resulting reaction mixture was degassed with N 2 for 10 mins and then heated to 85 C for two hours.
  • the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organic extract was dried over magnesium sulphate and solvent removed under reduced pressure.
  • the crude product was purified by chromatography on silica gel (12 g cartridge, 0-10% MeOH/DCM) to afford 7-(7-(4-fluoro-2- ((tetrahydro-2H-pyran-4- yl)methoxy)phenyl)thieno[2,3-d]pyridazin-4-yl)-1,4-dihydroisoquinolin- 3(2H)-one (67 mg, 51% yield) as a solid.
  • the resulting reaction mixture was stirred at room temperature for 10 minutes and then at 80 °C overnight.
  • the reaction mixture was cooled to room temperature and quenched with dilute HCl (0.1 M, 50 mL).
  • the mixture was extracted with ethyl acetate (3 x 50 mL), and the organic extract was sequentially washed with HCl (0.5 M, 50 mL), and brine (50 mL), dried over magnesium sulfate and solvent removed under reduced pressure.
  • Step B Preparation of 6-(4-chloro-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-3,4- dihydroisoquinolin-1(2H)-one: A Biotage microwave vial was charged with 1,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyridazine (100 mg, 0.50 mmol), 6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2yl)-3,4-dihydroisoquinolin-1(2H)-one (173 mg, 0.600 mmol), and Cs 2 CO 3 (340 mg, 1.00 mmol).
  • Step C Preparation of 6-(4-(2-(2-methoxyethoxy)phenyl)-6,7-dihydro-5H- cyclopenta[d]pyridazin-1-yl)-3,4-dihydroisoquinolin-1(2H)-one: A Biotage microwave vial was charged with 6-(4-chloro-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-3,4-dihydroisoquinolin- 1(2H)-one (100 mg, 0.300 mmol), (2-(2-methoxyethoxy)phenyl)boronic acid (200 mg, 1.00 mmol), and Cs 2 CO 3 (194 mg, 0.600 mmol).
  • Step A Preparation of ethyl 5-(7-(2-(2-(2-((tert- butoxycarbonyl)amino)ethoxy)ethoxy)-4-fluorophenyl)thieno[2,3-d]pyridazin-4-yl)pent-4- ynoate: To a reaction vessel containing tert-butyl (2-(2-(2-(4-chlorothieno[2,3-d]pyridazin-7-yl)- 5-fluorophenoxy)ethoxy)ethyl)carbamate (200 mg, 427 ⁇ mol), copper(I) iodide (814 ⁇ g, 4.27 ⁇ mol) in triethylamine (1.45 g, 2.00 mL, 14.3 mmol) and MeCN (0.5 mL) was added bis(triphenylphosphine)palladium(II) chloride (30.0 mg, 42.7 ⁇ mol) and the mixture was stirred
  • reaction mixture was absorbed onto silica (3 g) and the crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford ethyl 5-(7- (2-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)-4-fluorophenyl)thieno[2,3-d]pyridazin-4- yl)pent-4-ynoate (58 mg, 24% yield) as a brown solid.
  • Step B Preparation of lithium 5-(7-(2-(2-(2-((tert- butoxycarbonyl)amino)ethoxy)ethoxy)-4-fluorophenyl)thieno[2,3-d]pyridazin-4-yl)pent-4- ynoate: A solution of lithium hydroxide (4.9 mg, 0.20 mmol) in water (1 mL) was added into a stirring solution of ethyl 5-(7-(2-(2-(2-(2-(((tert-butoxycarbonyl)amino)ethoxy)ethoxy)-4- fluorophenyl)thieno[2,3-d]pyridazin-4-yl)pent-4-ynoate (60 mg, 0.10 mmol) in methanol (2 mL) and THF (2 mL) and the resulting reaction mixture was stirred at room temperature overnight.
  • Step C Preparation of tert-butyl (2-(2-(2-(4-(5-(dimethylamino)-5-oxopent-1-yn-1- yl)thieno[2,3-d]pyridazin-7-yl)-5-fluorophenoxy)ethoxy)ethyl)carbamate: To a stirred suspension of 5-(7-(2-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)-4-fluorophenyl)thieno[2,3- d]pyridazin-4-yl)pent-4-ynoic acid lithium salt (55 mg, 0.10 mmol), dimethylamine hydrochloride (25 mg, 0.31 mmol) and HATU (78 mg, 0.21 mmol) in DMF (3 mL) was added triethylamine (62 mg, 86
  • the resulting reaction mixture was stirred at ambient temperature for 1 h.
  • the mixture was quenched with saturated ammonium chloride solution (30 mL) and the resulting mixture was extracted with ethyl acetate (3 x 50 mL).
  • the organic extract was sequentially washed with water (2 x 50 mL), brine (50 mL), dried over magnesium sulfate and solvent removed under reduced pressure.
  • Step B Preparation of 2-(4-chloro-2-methoxy-benzoyl)thiophene-3-carboxylic acid: To a stirred solution of thiophene-3-carboxylic acid (6.70 g, 52.3 mmol) in THF (200 mL) was added n-butyllithium (44.0 mL, 2.5 N solution in hexanes, 110 mmol) at -78 °C. The mixture was stirred for 30 min.4-Chloro-N,2-dimethoxy-N-methyl-benzamide (12.0 g, 52.3 mmol) in THF was added. The temperature was warmed to 20 °C and stirred for an additional 2 hours.
  • Step C Preparation of 7-(4-chloro-2-methoxy-phenyl)-5H-thieno[2,3-d]pyridazin-4- one: A solution of 2-(4-chloro-2-methoxy-benzoyl)thiophene-3-carboxylic acid (13.0 g, 43.8 mmol) and hydrazine monohydrate (5.48 g, 110 mmol) in 1-butanol (200 mL) was stirred at 140 °C for 2 hours. The mixture was concentrated and diluted with water.
  • Step D Preparation of 4-chloro-7-(4-chloro-2-methoxy-phenyl)thieno[2,3- d]pyridazine: A suspension of 7-(4-chloro-2-methoxy-phenyl)-5H-thieno[2,3-d]pyridazin-4-one (8.00 g, 27.3 mmol) in phosphorus oxychloride (100 mL, 1073 mmol) was stirred at 100 °C for 2 hours. The mixture was concentrated in vacuo and diluted with DCM (100 mL). The mixture was poured into ice-water and NaHCO 3 solution was added to adjust the pH to 8.
  • Step E Preparation of 5-chloro-2-(4-chlorothieno[2,3-d]pyridazin-7-yl)phenol: To a solution of 4-chloro-7-(4-chloro-2-methoxy-phenyl)thieno[2,3-d]pyridazine (4.00 g, 12.9 mmol) in DCM (50 mL) was added boron tribromide (2.40 mL, 25.7 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 3 hours. The mixture was poured into ice-water (100 mL) and extracted with DCM (100 mL x 2).
  • Step F Preparation of 4-[[5-chloro-2-(4-chloro-7H-cyclopenta[d]pyridazin-1- yl)phenoxy]methyl]-1-methyl-piperidin-2-one: A mixture of 5-chloro-2-(4-chlorothieno[2,3- d]pyridazin-7-yl)phenol (100 mg, 0.337 mmol), Cs 2 CO 3 (329 mg, 1.01 mmol) and (1-methyl-2- oxo-4-piperidyl)methyl 4-methylbenzenesulfonate (150 mg, 0.505 mmol) in DMF (5 mL) was stirred for 16 h at 90 °C.
  • Step G Preparation of tert-butyl 6-[7-[4-chloro-2-[(1-methyl-2-oxo-4- piperidyl)methoxy]phenyl]thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2- carboxylate: To a solution of 4-[[5-chloro-2-(4-chloro-7H-cyclopenta[d]pyridazin-1- yl)phenoxy]methyl]-1-methyl-piperidin-2-one (105 mg, 0.260 mmol) in 1,4-dioxane (2.5 mL)/water (0.5 mL) were added tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4- dihydro-1H-isoquinoline-2-carboxylate (140 mg, 0.390 mmol), Na 2
  • Step H Preparation of 4-[[5-chloro-2-[4-(1,2,3,4-tetrahydroisoquinolin-6- yl)thieno[2,3-d]pyridazin-7-yl]phenoxy]methyl]-1-methyl-piperidin-2-one: To a solution of tert- butyl 6-[7-[4-chloro-2-[(1-methyl-2-oxo-4-piperidyl)methoxy]phenyl]thieno[2,3-d]pyridazin-4- yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (88 mg, 0.14 mmol) in DCM (3 mL) was added trifluoroacetic acid (1.0 mL, 13 mmol).
  • Step A Preparation of 3-bromo-4-(diethoxymethyl)thiophene: 4-bromothiophene-3- carbaldehyde (100 g, 523 mmol) was dissolved in ethanol (600 mL) and to this was added triethyl orthoformate (131 mL, 785 mmol) and NH 4 Cl (8.93 g, 167 mmol). The mixture was stirred at 70 °C for 6 h. The mixture was concentrated and extracted with EtOAc (200 mL x 4). The organic phase was washed with brine (200 mL x 1), dried over anhydrous Na 2 SO 4 and concentrated.
  • Step B Preparation of [3-bromo-4-(diethoxymethyl)-5-trimethylsilyl-2-thienyl]- trimethyl-silane: To a solution of 3-bromo-4-(diethoxymethyl)thiophene (130 g, 490 mmol) in THF (900 mL) was added LDA (2.0 M in THF) (613 mL, 1.23 mol) dropwise at -78 °C under Ar. The reaction was stirred at -78 °C for 40 min, followed by the addition of trimethylchlorosilane (175 mL, 1.37 mol) at -78 °C under Ar.
  • LDA 2.0 M in THF
  • Step C Preparation of [3-(diethoxymethyl)-4-fluoro-5-trimethylsilyl-2-thienyl]- trimethyl-silane: To the solution of [3-bromo-4-(diethoxymethyl)-5-trimethylsilyl-2-thienyl]- trimethyl-silane (55.0 g, 134 mmol) in THF (580 mL) was added n-BuLi (2.5 M in hexane) (5.09 mL, 148 mmol) dropwise at -78 °C under Ar. The mixture was stirred for 1 h at -78 °C under Ar.
  • n-BuLi 2.5 M in hexane
  • Step D Preparation of 3-(diethoxymethyl)-4-fluoro-thiophene: To a solution of [3- (diethoxymethyl)-4-fluoro-5-trimethylsilyl-2-thienyl]-trimethyl-silane (3.50 g, 10.0 mmol) in THF (50 mL) was added tetrabutylammonium fluoride trihydrate (7.80 g, 24.7 mmol) in THF (20 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min. The mixture was poured into water (100 mL), and the product was extracted with petroleum ether/EtOAc (5/1, 100 mL).
  • Step E and Step F Preparation of 4-fluorothiophene-3-carboxylic acid: To a solution of 3-(diethoxymethyl)-4-fluoro-thiophene (520 mg, 2.55 mmol) in acetone (9 mL) and water (3 mL) was added 4-methylbenzenesulfonic acid (530 mg, 3.08 mmol). The mixture was stirred at 30 °C for 1 h.
  • Step G Preparation of 4-fluoro-2-(4-fluoro-2-methoxy-benzoyl)thiophene-3- carboxylic acid: To a solution of 4-fluorothiophene-3-carboxylic acid (180 mg, 1.23 mmol) in THF (3 mL) was added n-butyllithium (2.5 M in hexanes, 1.20 mL, 3.00 mmol) at -70 °C. The mixture was stirred at -70 °C for 15 min, and then 4-fluoro-N,2-dimethoxy-N-methyl-benzamide (532 mg, 2.50 mmol) was added.
  • Step H Preparation of 3-fluoro-7-(4-fluoro-2-methoxy-phenyl)-5H-thieno[2,3- d]pyridazin-4-one: To a solution of 4-fluoro-2-(4-fluoro-2-methoxy-benzoyl)thiophene-3- carboxylic acid (230 mg, 0.771 mmol) in n-BuOH (10 mL) was added hydrazine hydrate (115 mg, 2.30 mmol). The mixture was stirred at 140 °C for 1 h.
  • Step I Preparation of 4-chloro-3-fluoro-7-(4-fluoro-2-methoxy-phenyl)thieno[2,3- d]pyridazine: A mixture of 3-fluoro-7-(4-fluoro-2-methoxy-phenyl)-5H-thieno[2,3-d]pyridazin-4- one (230 mg, 0.782 mmol) in phosphorus oxychloride (10 mL, 107 mmol) was stirred at 100 °C for 2 h. The mixture was concentrated and diluted with DCM. The mixture was poured into ice- water, and NaHCO 3 aqueous solution was added to adjust the pH to 7-8.
  • Step J Preparation of 2-(4-chloro-3-fluoro-thieno[2,3-d]pyridazin-7-yl)-5-fluoro- phenol: To a solution of 4-chloro-3-fluoro-7-(4-fluoro-2-methoxy-phenyl)thieno[2,3-d]pyridazine (136 mg, 0.435 mmol) in DCM (3 mL) was added boron tribromide (0.083 mL, 0.88 mmol) at -30 °C. The mixture was stirred at 0 °C for 2 h.
  • Step K Preparation of tert-butyl N-[2-[2-[2-(4-chloro-3-fluoro-thieno[2,3- d]pyridazin-7-yl)-5-fluoro-phenoxy]ethoxy]ethyl]carbamate: To a solution of 2-(4-chloro-3- fluoro-thieno[2,3-d]pyridazin-7-yl)-5-fluoro-phenol (126 mg, 0.422 mmol) and 2-[2-(tert- butoxycarbonylamino)ethoxy]ethyl 4-methylbenzenesulfonate (182 mg, 0.506 mmol) in DMF (5 mL) was added NaH (20 mg, 0.50 mmol, 60% dispersion in mineral oil) at 0 °C.
  • Step L Preparation of tert-butyl N-[2-[5-fluoro-2-[3-fluoro-4-(1,2,3,4- tetrahydroisoquinolin-6-yl)thieno[2,3-d]pyridazin-7-yl]phenoxy]ethoxy]ethyl]carbamate: To a solution of tert-butyl N-[2-[2-[2-(4-chloro-3-fluoro-thieno[2,3-d]pyridazin-7-yl)-5-fluoro- phenoxy]ethoxy]ethyl]carbamate (10 mg, 0.021 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (15 mg, 0.058 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL)
  • Step A Preparation of 5-bromo-1,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyridazine: A solution of 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine (1.26 g, 6.67 mmol), 2,2'-azobis(2-methylpropionitrile) (109 mg, 0.667 mmol) and N- bromosuccinimide (1.19 g, 6.67 mmol) in 1,2-dichloroethane (15 mL) was sparged with nitrogen for 3 min. The mixture was stirred at 60 °C for 2.5 h.
  • Step B Preparation of 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazin-5-ol: To a solution of 5-bromo-1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine (1060 mg, 3.96 mmol) in 1,2-dimethoxyethane (11.4 mL) and water (0.6 mL) at 25 °C was added silver perchlorate (1340 mg, 5.93 mmol). The mixture was stirred at 60 °C for 2.5 h. Volatiles were removed by concentration under reduced pressure.
  • Step C Preparation of tert-butyl (2-(2-(2-(4-chloro-5-hydroxy-6,7-dihydro-5H- cyclopenta[d]pyridazin-1-yl)-5-fluorophenoxy)ethoxy)ethyl)carbamate: A mixture of 1,4- dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazin-5-ol (310 mg, 1.51 mmol), tert-butyl N-[2-[2-[5- fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethoxy]ethyl]carbamate (1290 mg, 3.02 mmol), Pd(dppf)Cl 2 (55.3 mg, 0.0755 mmol) and Na 2 CO 3 (400 mg, 3.78 mmol) in 1,4- dioxane (10 mL) and water (0.5
  • reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine solution, dried over anhydrous Na 2 SO 4 and concentrated in vacuo.
  • Step D Preparation of tert-butyl N-[2-[2-[2-(4-chloro-5-fluoro-6,7-dihydro-5H- cyclopenta[d]pyridazin-1-yl)-5-fluoro-phenoxy]ethoxy]ethyl]carbamate: To a stirred solution of tert-butyl N-[2-[2-[2-(4-chloro-5-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5- fluoro-phenoxy]ethoxy]ethyl]carbamate (30 mg, 0.064 mmol) in DCM (1.5 mL) was added diethylaminosulfur trifluoride (0.013 mL, 0.096 mmol) at 0 °C under nitrogen.
  • Step E Preparation of tert-butyl N-[2-[5-fluoro-2-[7-fluoro-1-(1,2,3,4- tetrahydroisoquinolin-6-yl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-4- yl]phenoxy]ethoxy]ethyl]carbamate: A mixture of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1,2,3,4-tetrahydroisoquinoline (17 mg, 0.064 mmol), tert-butyl N-[2-[2-[2-[2-(4-chloro-5-fluoro- 6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-fluoro-phenoxy]ethoxy]ethyl]carbamate (15 mg, 0.032 mmol), Pd(dppf)
  • Step B Preparation of benzyl 6-(7-oxo-6H-thieno[2,3-d]pyridazin-4-yl)-3,4-dihydro- 1H-isoquinoline-2-carboxylate: A solution of crude benzyl 6-(2-methoxycarbonylthiophene-3- carbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (6.8 g) and hydrazine hydrate (1.13 g, 22.5 mmol) in n-BuOH (50 mL) was stirred at 140 °C for 4 hours.
  • Step C Preparation of benzyl 6-(7-chlorothieno[2,3-d]pyridazin-4-yl)-3,4-dihydro- 1H-isoquinoline-2-carboxylate: A suspension of benzyl 6-(7-oxo-6H-thieno[2,3-d]pyridazin-4- yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (2.60 g, 6.23 mmol) in phosphorus oxychloride (20 mL, 215 mmol) was stirred at 95 °C for 6 h.
  • Step D Preparation of benzyl 6-[7-(4-phenylcyclohexen-1-yl)thieno[2,3-d]pyridazin- 4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: A mixture of 4,4,5,5-tetramethyl-2-(4- phenylcyclohexen-1-yl)-1,3,2-dioxaborolane (209 mg, 0.734 mmol), benzyl 6-(7- chlorothieno[2,3-d]pyridazin-4-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (160 mg, 0.367 mmol), Pd(dppf)Cl 2 (39 mg, 0.055 mmol) and Na 2 CO 3 (97 mg, 0.92 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was stirred at 95
  • Step E Preparation of benzyl 6-[7-(4-phenylcyclohexyl)thieno[2,3-d]pyridazin-4-yl]- 3,4-dihydro-1H-isoquinoline-2-carboxylate: To a stirred solution of benzyl 6-[7-(4- phenylcyclohexen-1-yl)thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (76 mg, 0.14 mmol) in methanol (10 mL) was added 10% Pd/C (100 mg).
  • Step F Preparation of Isomer 1 of 7-(4-phenylcyclohexyl)-4-(1,2,3,4- tetrahydroisoquinolin-6-yl)thieno[2,3-d]pyridazine: To a solution of Isomer 1 of benzyl 6-[7-(4- phenylcyclohexyl)thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (25 mg, 0.045 mmol) in dichloromethane (1 mL) was added hydrobromic acid acetic acid solution (0.5 ml).
  • Step B Preparation of benzyl 6-[7-(1-phenyl-4-piperidyl)thieno[2,3-d]pyridazin-4- yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: To a solution of benzyl 6-[7-(1-phenyl-3,6- dihydro-2H-pyridin-4-yl)thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2- carboxylate (25 mg, 0.045 mmol) in THF (2 mL)/isobutyl alcohol (2 mL) was added Pd/C (4.7 mg, 0.045 mmol).
  • Step C Preparation of 7-(1-phenyl-4-piperidyl)-4-(1,2,3,4-tetrahydroisoquinolin-6- yl)thieno[2,3-d]pyridazine: A mixture of benzyl 6-[7-(1-phenyl-4-piperidyl)thieno[2,3- d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (28 mg, 0.050 mmol) in HBr/CH 3 COOH (1.0 mL) was stirred at 25 °C for 0.5 hour. The mixture was diluted with water (5 mL).
  • Step A Preparation of (2,2,2-trifluoro-1,1-dimethyl-ethyl)imidazole-1-carboxylate: A solution of 1,1,1-trifluoro-2-methyl-propan-2-ol (401 mg, 3.13 mmol) and di(imidazol-1- yl)methanone (254 mg, 1.57 mmol) in chloroform (3 mL) was placed under argon and stirred at rt for 13 h. The reaction mixture was poured into water (5 mL) and the resulting mixture was extracted with DCM (2 x 5 mL).
  • Step B Preparation of (2,2,2-trifluoro-1,1-dimethyl-ethyl)3-methylimidazol-3-ium-1- carboxylate iodide: A mixture of (2,2,2-trifluoro-1,1-dimethyl-ethyl)imidazole-1-carboxylate (298 mg, 1.34 mmol) and iodomethane (895 mg, 6.30 mmol) in MeCN (5 mL) was stirred at rt overnight.
  • Step C Preparation of 2-[2-[(2,2,2-trifluoro-1,1-dimethyl- ethoxy)carbonylamino]ethoxy]ethyl 4-methylbenzenesulfonate: To a solution of (2,2,2-trifluoro- 1,1-dimethyl-ethyl)3-methylimidazol-3-ium-1-carboxylate iodide (316 mg, 0.870 mmol) in chloroform (1.2 mL) was added a mixture of 2-(2-aminoethoxy)ethyl 4-methylbenzenesulfonate (225 mg, 0.870 mmol) and Et 3 N (0.250 mL, 1.74 mmol) in chloroform (1 mL).
  • Step D Preparation of 7-(2,2,2-trifluoro-1,1-dimethyl-ethyl)N-[2-[2-[2-(4- chlorothieno[2,3-d]pyridazin-7-yl)-5-fluoro-phenoxy]ethoxy]ethyl]carbamate: To a solution of 2- (4-chlorothieno[2,3-d]pyridazin-7-yl)-5-fluoro-phenol (50 mg, 0.18 mmol) and 2-[2-[(2,2,2- trifluoro-1,1-dimethyl-ethoxy)carbonylamino]ethoxy]ethyl 4-methylbenzenesulfonate (89 mg, 0.22 mmol) in MeCN (2 mL) was added Cs 2 CO 3 (173 mg, 0.530 mmol).
  • the reaction mixture was heated to 60 °C for 3 h then cooled to rt.
  • the product was extracted with EtOAc (2 x 5 mL), and the organic fractions were pooled, washed with brine (10 mL), dried (Na 2 SO 4 ), filtered and concentrated.
  • Step E Preparation of (2,2,2-trifluoro-1,1-dimethyl-ethyl) N-[2-[5-fluoro-2-[4- (1,2,3,4-tetrahydroisoquinolin-6-yl)thieno[2,3-d]pyridazin-7- yl]phenoxy]ethoxy]ethyl]carbamate: A Biotage microwave vial was charged with (2,2,2-trifluoro- 1,1-dimethyl-ethyl) N-[2-[2-[2-[2-(4-chlorothieno[2,3-d]pyridazin-7-yl)-5-fluoro- phenoxy]ethoxy]ethyl]carbamate (40 mg, 0.070 mmol), 6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (34 mg, 0.12 m
  • Step B Preparation of tert-butyl 6-[7-[4-fluoro-2-[2-[2-[[1- (trifluoromethyl)cyclopropyl]methoxycarbonylamino]ethoxy]ethoxy]phenyl]thieno[2,3- d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: To a solution of tert-butyl 6-[7-[2- [2-(2-aminoethoxy)ethoxy]-4-fluoro-phenyl]thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H- isoquinoline-2-carboxylate (From Synthetic Example 23 Step B, 65 mg, 0.12 mmol) and triethylamine (0.048 mL, 0.35 mmol) in DCM (3 mL) was added (4-nitrophenyl) [1-
  • Step C Preparation of [1-(trifluoromethyl)cyclopropyl]methyl N-[2-[2-[5-fluoro-2-[4- (1,2,3,4-tetrahydroisoquinolin-6-yl)thieno[2,3-d]pyridazin-7- yl]phenoxy]ethoxy]ethyl]carbamate: To a solution of tert-butyl 6-[7-[4-fluoro-2-[2-[2-[[[1- (trifluoromethyl)cyclopropyl]methoxycarbonylamino]ethoxy]ethoxy]phenyl]thieno[2,3- d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (40 mg, 0.055 mmol) in DCM (3 mL) was added TFA (1 mL).
  • Step B Preparation of tert-butyl 6-[7-(4-fluoro-2-hydroxy-phenyl)thieno[2,3- d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: To a solution of tert-butyl 6-[7-(4- fluoro-2-methoxy-phenyl)thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2- carboxylate (3.10 g, 6.31 mmol) in DCM (30 mL) was added boron tribromide (3.00 mL, 31.5 mmol) dropwise at 0 °C.
  • Step C Preparation of tert-butyl 6-[7-[2-[2-(3-ethoxy-3-oxo-propoxy)ethoxy]-4- fluoro-phenyl]thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: To a stirred solution of tert-butyl 6-[7-(4-fluoro-2-hydroxy-phenyl)thieno[2,3-d]pyridazin-4-yl]-3,4- dihydro-1H-isoquinoline-2-carboxylate (300 mg, 0.628 mmol), ethyl 3-(2- hydroxyethoxy)propanoate (153 mg, 0.942 mmol), and triphenylphosphine (412 mg, 1.57 mmol) in THF (3 mL) was added diisopropyl azodicarboxylate (0.310 mL
  • Step D Preparation of 3-[2-[2-[4-(2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinolin- 6-yl)thieno[2,3-d]pyridazin-7-yl]-5-fluoro-phenoxy]ethoxy]propanoic acid: To a solution of tert- butyl 6-[7-[2-[2-(3-ethoxy-3-oxo-propoxy)ethoxy]-4-fluoro-phenyl]thieno[2,3-d]pyridazin-4-yl]- 3,4-dihydro-1H-isoquinoline-2-carboxylate (110 mg, 0.177 mmol) in THF (3 mL)/water (1 mL)/methanol (1 mL) was added LiOH.H 2 O (150 mg, 3.54 mmol) at 20 °C.
  • the mixture was stirred at 20 °C for 14 h.
  • the mixture was diluted with water (10 mL) and 1 N HCl was added to adjust the pH to 3-4.
  • the mixture was extracted with EtOAc (20 mL x 2).
  • the combined organic phase was washed with saturated brine solution (20 mL), dried (Na 2 SO 4 ) and filtered before concentrating to dryness.
  • Step E Preparation of tert-butyl 6-[7-[4-fluoro-2-[2-[3-oxo-3-(1- piperidyl)propoxy]ethoxy]phenyl]thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2- carboxylate: To a solution of 3-[2-[2-[4-(2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinolin-6- yl)thieno[2,3-d]pyridazin-7-yl]-5-fluoro-phenoxy]ethoxy]propanoic acid (40 mg, 0.067 mmol), HATU (38 mg, 0.10 mmol) and DIEA (35 mg, 0.27 mmol) in DMF (2 mL) was added piperidine (6.9 mg, 0.081) at 0 °C.
  • Step F Preparation of 3-[2-[5-fluoro-2-[4-(1,2,3,4-tetrahydroisoquinolin-6- yl)thieno[2,3-d]pyridazin-7-yl]phenoxy]ethoxy]-1-(1-piperidyl)propan-1-one: To a solution of tert-butyl 6-[7-[4-fluoro-2-[2-[3-oxo-3-(1-piperidyl)propoxy]ethoxy]phenyl]thieno[2,3- d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (30 mg, 0.045 mmol) in DCM (3 mL) was added trifluoroacetic acid (1.1 mL, 15 mmol) at room temperature.
  • Step B Preparation of tert-butyl 6-(7-(4-fluoro-2-(2-(2-(((pyrrolidin-3- yloxy)carbonyl)amino)ethoxy)ethoxy)phenyl)thieno[2,3-d]pyridazin-4-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate: A solution of tert-butyl 6-[7-[4-fluoro-2-[2-[2- (pyrrolidin-3-yloxycarbonylamino)ethoxy]ethoxy]phenyl]thieno[2,3-d]pyridazin-4-yl]-3,4- dihydro-1H-isoquinoline-2-carboxylate (100 mg, 0.11 mmol) and diethylamine (1 mL) in DCM (2 mL) was stirred at 20 °C for 3 h.
  • Step C Preparation of tert-butyl 6-(7-(2-(2-(2-(2-((((1-acryloylpyrrolidin-3- yl)oxy)carbonyl)amino)ethoxy)ethoxy)-4-fluorophenyl)thieno[2,3-d]pyridazin-4-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate: To a solution of tert-butyl 6-[7-[4-fluoro-2-[2-[2- (pyrrolidin-3-yloxycarbonylamino)ethoxy]ethoxy]phenyl]thieno[2,3-d]pyridazin-4-yl]-3,4- dihydro-1H-isoquinoline-2-carboxylate (50 mg, 0.074 mmol) in DCM (5 mL) were added N,N- diisopropylethylamine (0.026 mL, 0.15
  • Step D Preparation of 1-acryloylpyrrolidin-3-yl (2-(2-(5-fluoro-2-(4-(1,2,3,4- tetrahydroisoquinolin-6-yl)thieno[2,3-d]pyridazin-7-yl)phenoxy)ethoxy)ethyl)carbamate: To a solution of tert-butyl 6-[7-[4-fluoro-2-[2-[2-[(1-prop-2-enoylpyrrolidin-3- yl)oxycarbonylamino]ethoxy]ethoxy]phenyl]thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H- isoquinoline-2-carboxylate (30 mg, 0.041 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (0
  • Triphenylphosphine 101 mg, 0.390 mmol
  • 2-(4-chlorothieno[2,3-d]pyridazin-7- yl)-5-fluoro-phenol 109 mg, 0.390 mmol
  • DIAD 73 ⁇ L, 0.39 mmol
  • Step B Preparation of tert-butyl (3S,4R)-3-[5-fluoro-2-[4-(1,2,3,4- tetrahydroisoquinolin-6-yl)thieno[2,3-d]pyridazin-7-yl]phenoxy]-4-methoxy-pyrrolidine-1- carboxylate: A Biotage microwave vial was charged with tert-butyl (4R)-3-[2-(4-chlorothieno[2,3- d]pyridazin-7-yl)-5-fluoro-phenoxy]-4-methoxy-pyrrolidine-1-carboxylate (50 mg, 0.10 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (46 mg, 0.16 mmol), Cs 2 CO 3 (136 mg, 0.42 mmol), and Pd(dppf)C
  • Step B Preparation of 4-chloro-5,5-difluoro-1-[2-(2-methoxyethoxy)phenyl]-6,7- dihydrocyclopenta[d]pyridazine: A solution of 1,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyridazin-5-one (243 mg, 1.90 mmol) in DCM (4 mL) was cooled to 0 °C. DAST (483 mg, 3.60 mmol) was added and the reaction was warmed to RT over 18 h.
  • Step C Preparation of 5,5-difluoro-1,4-bis(2-(2-methoxyethoxy)phenyl)-6,7-dihydro- 5H-cyclopenta[d]pyridazine: A Biotage microwave vial was charged with 6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (51 mg, 0.20 mmol), 4-chloro-5,5- difluoro-1-[2-(2-methoxyethoxy)phenyl]-6,7-dihydrocyclopenta[d]pyridazine (45 mg, 0.11 mmol), and Cs 2 CO 3 (86 mg, 0.26 mmol).
  • Step B Preparation of tert-butyl N-[2-[2-[7,7-difluoro-1-(1,2,3,4- tetrahydroisoquinolin-6-yl)-5,6-dihydrocyclopenta[d]pyridazin-4-yl]-5-fluoro- phenoxy]ethoxy]ethyl]carbamate: A Biotage microwave vial was charged with tert-butyl N-[2-[2- [2-(4-chloro-5,5-difluoro-6,7-dihydrocyclopenta[d]pyridazin-1-yl)-5-fluoro- phenoxy]ethoxy]ethyl]carbamate (89 mg, 0.18 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1,2,3,4-tetrahydroisoquinoline (71 mg, 0.27 mmol
  • reaction mixture was filtered through a pad of Celite® and the filtrate was purified by C18 reverse phase preparative HPLC ( 0-100% MeCN/water) to give tert-butyl N-[2-[2-[7,7-difluoro-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-5,6- dihydrocyclopenta[d]pyridazin-4-yl]-5-fluoro-phenoxy]ethoxy]ethyl]carbamate (10 mg, 9% yield) as a solid.
  • Step A Preparation of tert-butyl 6-[7-[2-[2-[2-(1,3-dioxoisoindolin-2- yl)ethoxy]ethoxy]-4-fluoro-phenyl]thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2- carboxylate: To a stirred solution of tert-butyl 6-[7-(4-fluoro-2-hydroxy-phenyl)thieno[2,3- d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (102 mg, 0.213 mmol), 2-[2-(2- hydroxyethoxy)ethyl]isoindoline-1,3-dione (50.0 mg, 0.213 mmol) and PPh3 (67 mg, 0.26 mmol) in THF (4 mL) was added
  • Step B Preparation of tert-butyl 6-[7-[2-[2-(2-aminoethoxy)ethoxy]-4-fluoro- phenyl]thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: A mixture of tert-butyl 6-[7-[2-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]ethoxy]-4-fluoro-phenyl]thieno[2,3- d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (730 mg, 1.05 mmol) and hydrazine monohydrate (105 mg, 2.10 mmol) in ethanol (10 mL) was stirred at 70 °C for 2
  • Step C Preparation of tert-butyl 6-[7-[2-[2-[(E)- benzylideneamino]ethoxy]ethoxy]-4-fluoro-phenyl]thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H- isoquinoline-2-carboxylate: A solution of tert-butyl 6-[7-[2-[2-(2-aminoethoxy)ethoxy]-4-fluoro- phenyl]thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (20 mg, 0.035 mmol), benzaldehyde (0.0054 mL, 0.053 mmol) and 3 ⁇ molecular sieve (100 mg) in DCM (3 mL) was stirred at 20 °C for 16 h.
  • Step D Preparation of tert-butyl 6-[7-[4-fluoro-2-[2-[2-[(2,2,2-trifluoro-1-phenyl- ethyl)amino]ethoxy]ethoxy]phenyl]thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2- carboxylate: To a solution of tert-butyl 6-[7-[2-[2-[2-[2-[(E)-benzylideneamino]ethoxy]ethoxy]-4- fluoro-phenyl]thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (43 mg, 0.066 mmol) in MeCN (3 mL) was added trifluoroacetic acid (0.0066 mL, 0.086 mmol) and potassium hydrogen fluoride (4.6
  • Step E Preparation of 2,2,2-trifluoro-N-[2-[2-[5-fluoro-2-[4-(1,2,3,4- tetrahydroisoquinolin-6-yl)thieno[2,3-d]pyridazin-7-yl]phenoxy]ethoxy]ethyl]-1-phenyl- ethanamine: To a solution of tert-butyl 6-[7-[4-fluoro-2-[2-[2-[(2,2,2-trifluoro-1-phenyl- ethyl)amino]ethoxy]ethoxy]phenyl]thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2- carboxylate (9.0 mg, 0.013 mmol) in DCM (2 mL) was added trifluoroacetic acid (0.70 mL, 9.1 mmol) at 20 C.
  • Step B Preparation of 2-(2-((benzyloxy)carbonyl)-1,2,3,4-tetrahydroisoquinoline-6- carbonyl)-4-methylthiophene-3-carboxylic acid: 4-methylthiophene-3-carboxylic acid (500 mg, 3.52 mmol) was dissolved in THF (10 mL) and cooled to -78 °C under Ar. To this was added n- butyllithium (2.5 M in hexanes, 3.10 mL, 7.74 mmol) dropwise at -78 °C under Ar.
  • Step C Preparation of benzyl 6-(3-methyl-4-oxo-5H-thieno[2,3-d]pyridazin-7-yl)- 3,4-dihydro-1H-isoquinoline-2-carboxylate: To a solution of 2-(2-benzyloxycarbonyl-3,4- dihydro-1H-isoquinoline-6-carbonyl)-4-methyl-thiophene-3-carboxylic acid (2.50 g, 2.30 mmol) in 1-butanol (8 mL) was added hydrazine monohydrate (431 mg, 6.89 mmol). The mixture was stirred at 140 °C for 2 h.
  • Step D Preparation of benzyl 6-(4-chloro-3-methyl-thieno[2,3-d]pyridazin-7-yl)-3,4- dihydro-1H-isoquinoline-2-carboxylate: A suspension of benzyl 6-(3-methyl-4-oxo-5H- thieno[2,3-d]pyridazin-7-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (660 mg, 1.53 mmol) in phosphorus oxychloride (6.80 mL, 72.6 mmol) was stirred at 110 °C for 20 min. POCl 3 was removed under vacuum and the residue was dissolved in DCM.
  • phosphorus oxychloride 6.80 mL, 72.6 mmol
  • Step E Preparation of benzyl 6-[4-[2-[2-[2-(tert- butoxycarbonylamino)ethoxy]ethoxy]-4-fluoro-phenyl]-3-methyl-thieno[2,3-d]pyridazin-7-yl]- 3,4-dihydro-1H-isoquinoline-2-carboxylate: A suspension of benzyl 6-(4-chloro-3-methyl- thieno[2,3-d]pyridazin-7-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (50 mg, 0.11 mmol), [2- [2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]-4-fluoro-phenyl]boronic acid (57 mg, 0.17 mmol), Na 2 CO 3 (35 mg, 0.33 mmol) and Pd(dppf)Cl 2 (8.1 mg, 0.011 mmol) in
  • Step F Preparation of tert-butyl N-[2-[2-[5-fluoro-2-[3-methyl-7-(1,2,3,4- tetrahydroisoquinolin-6-yl)thieno[2,3-d]pyridazin-4-yl]phenoxy]ethoxy]ethyl]carbamate: Benzyl 6-[4-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]-4-fluoro-phenyl]-3-methyl-thieno[2,3- d]pyridazin-7-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (55 mg, 0.077 mmol) and LiOH monohydrate (130 mg, 3.09 mmol) were dissolved in 1,4-dioxane (3 mL) and water (1 mL).
  • Step A Preparation of 2-(2-((benzyloxy)carbonyl)-1,2,3,4-tetrahydroisoquinoline-6- carbonyl)-4-fluorothiophene-3-carboxylic acid: 4-Fluorothiophene-3-carboxylic acid (500 mg, 3.42 mmol) was dissolved in THF (10 mL) and cooled to -78 °C under Ar. n-Butyllithium (2.5 M in hexanes, 3.0 mL, 7.5 mmol) was added dropwise at -78 °C under Ar.
  • Step B Preparation of benzyl 6-(3-fluoro-4-oxo-5H-thieno[2,3-d]pyridazin-7-yl)-3,4- dihydro-1H-isoquinoline-2-carboxylate: To the solution of 2-(2-benzyloxycarbonyl-3,4-dihydro- 1H-isoquinoline-6-carbonyl)-4-fluoro-thiophene-3-carboxylic acid (1.01 g, 1.38 mmol) in 1- butanol (8 mL) was added hydrazine monohydrate (259 mg, 4.14 mmol).
  • Step C Preparation of benzyl 6-(4-chloro-3-fluoro-thieno[2,3-d]pyridazin-7-yl)-3,4- dihydro-1H-isoquinoline-2-carboxylate: A mixture of benzyl 6-(3-fluoro-4-oxo-5H-thieno[2,3- d]pyridazin-7-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (410 mg, 0.772 mmol) in phosphorus oxychloride (5.0 mL, 54 mmol) was stirred at 110 °C for 20 min. POCl 3 was removed under vacuum and the residue was dissolved in DCM.
  • phosphorus oxychloride 5.0 mL, 54 mmol
  • Step D Preparation of benzyl 6-[4-[2-[2-[2-(tert- butoxycarbonylamino)ethoxy]ethoxy]-4-fluoro-phenyl]-3-fluoro-thieno[2,3-d]pyridazin-7-yl]- 3,4-dihydro-1H-isoquinoline-2-carboxylate: A mixture of benzyl 6-(4-chloro-3-fluoro-thieno[2,3- d]pyridazin-7-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (50 mg, 0.080 mmol), tert-butyl (2- (2-(5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethoxy)ethyl)carbamate (51 mg, 0.12 mmol), Na 2 CO 3 (26 mg, 0.24
  • Step E Preparation of tert-butyl N-[2-[2-[5-fluoro-2-[3-fluoro-7-(1,2,3,4- tetrahydroisoquinolin-6-yl)thieno[2,3-d]pyridazin-4-yl]phenoxy]ethoxy]ethyl]carbamate: A mixture of benzyl 6-[4-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]-4-fluoro-phenyl]-3- fluoro-thieno[2,3-d]pyridazin-7-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (37 mg, 0.052 mmol) and LiOH.H 2 O (87 mg, 2.1 mmol) in 1,4-dioxane (1.5 mL) and
  • Step B Preparation of 6-[7-[2-[2-(2-aminoethoxy)ethoxy]-4-fluoro-phenyl]-3-fluoro- thieno[2,3-d]pyridazin-4-yl]-N,N-dimethyl-tetralin-2-amine: To a solution of tert-butyl N-[2-[2- [2-[4-[2-(dimethylamino)tetralin-6-yl]-3-fluoro-thieno[2,3-d]pyridazin-7-yl]-5-fluoro- phenoxy]ethoxy]ethyl]carbamate (35 mg, 0.056 mmol) in DCM (3 mL) was added TFA (1 mL).
  • Step C Preparation of (S)-1-acryloylpyrrolidin-3-yl (2-(2-(2-(4-(6-(dimethylamino)- 5,6,7,8-tetrahydronaphthalen-2-yl)-3-fluorothieno[2,3-d]pyridazin-7-yl)-5- fluorophenoxy)ethoxy)ethyl)carbamate: A solution of 6-[7-[2-[2-(2-aminoethoxy)ethoxy]-4- fluoro-phenyl]-3-fluoro-thieno[2,3-d]pyridazin-4-yl]-N,N-dimethyl-tetralin-2-amine (27 mg, 0.052 mmol), (4-nitrophenyl) (1-prop-2-enoylpyrrolidin-3-yl) carbonate (16 mg, 0.052 mmol) and triethylamine (0.0072 mL, 0.052 m
  • Step B Preparation of tert-butyl 6-[7-[2-[2-[2-(1,3-dioxoisoindolin-2- yl)ethoxy]ethoxy]-4-fluoro-phenyl]-3-fluoro-thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H- isoquinoline-2-carboxylate: To a solution of tert-butyl 6-[3-fluoro-7-(4-fluoro-2-hydroxy- phenyl)thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (370 mg, 0.747 mmol), 2-[2-(2-hydroxyethoxy)ethyl]isoindoline-1,3-dione (228 mg, 0.971 mmol) and triphenylphosphine (979 mg, 3.73
  • Step C Preparation of tert-butyl 6-[7-[2-[2-(2-aminoethoxy)ethoxy]-4-fluoro-phenyl]- 3-fluoro-thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: To a solution of tert-butyl 6-[7-[2-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]ethoxy]-4-fluoro-phenyl]-3-fluoro- thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (300 mg, 0.421 mmol) in ethanol (5 mL) was added hydrazine monohydrate (42 mg, 0.84 mmol).
  • Step D Preparation of tert-butyl 6-[3-fluoro-7-[4-fluoro-2-[2-[2-[[(3S)-1-prop-2- enoylpyrrolidin-3-yl]oxycarbonylamino]ethoxy]ethoxy]phenyl]thieno[2,3-d]pyridazin-4-yl]-3,4- dihydro-1H-isoquinoline-2-carboxylate: To a solution of tert-butyl 6-[7-[2-[2-(2- aminoethoxy)ethoxy]-4-fluoro-phenyl]-3-fluoro-thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H- isoquinoline-2-carboxylate (100 mg, 0.172 mmol) and (4-nitrophenyl) [(3S)-1-prop-2- enoylpyrrolidin-3-yl]carbonate (
  • Step E Preparation of [(3S)-1-prop-2-enoylpyrrolidin-3-yl] N-[2-[2-[5-fluoro-2-[3- fluoro-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)thieno[2,3-d]pyridazin-7- yl]phenoxy]ethoxy]ethyl]carbamate: To a solution of tert-butyl 6-[3-fluoro-7-[4-fluoro-2-[2-[2- [[(3S)-1-prop-2-enoylpyrrolidin-3-yl]oxycarbonylamino]ethoxy]ethoxy]phenyl]thieno[2,3- d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (35 mg, 0.0
  • Step F Preparation of (S)-1-acryloylpyrrolidin-3-yl (2-(2-(5-fluoro-2-(3-fluoro-4-(2- methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)thieno[2,3-d]pyridazin-7- yl)phenoxy)ethoxy)ethyl)carbamate: To a solution of [(3S)-1-prop-2-enoylpyrrolidin-3-yl] N-[2- [2-[5-fluoro-2-[3-fluoro-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)thieno[2,3-d]pyridazin-7- yl]phenoxy]ethoxy]ethyl]carbamate (12 mg, 0.019 mmol) in methanol (1 mL) was added paraformaldehyde (1.1 mg, 0.037 mmol).
  • Step B Preparation of [1-prop-2-enoyl-3-(trifluoromethyl)pyrrolidin-3-yl] N-[2-[2-[5- fluoro-2-[4-(1,2,3,4-tetrahydroisoquinolin-6-yl)thieno[2,3-d]pyridazin-7- yl]phenoxy]ethoxy]ethyl]carbamate: To a solution of tert-butyl 6-[7-[4-fluoro-2-[2-[2-[[[1-prop-2- enoyl-3-(trifluoromethyl)pyrrolidin-3-yl]oxycarbonylamino]ethoxy]ethoxy]phenyl]thieno[2,3- d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (10 mg, 0.013 mmol) in DCM (1 mL) was added TFA (40 mg,
  • Step B Preparation of (4-nitrophenyl) [1-prop-2-enoyl-3-(trifluoromethyl)pyrrolidin- 3-yl] carbonate: To a solution of (4-nitrophenyl)carbonochloridate (125 mg, 0.622 mmol) in DCM (0.5 mL) was added 1-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]prop-2-en-1-one (65 mg, 0.31 mmol) and Et 3 N (130 ⁇ l, 0.930 mmol).
  • Step C Preparation of [1-prop-2-enoyl-3-(trifluoromethyl)pyrrolidin-3-yl]N-[2-[2-[5- fluoro-2-[4-(2-methyl-3,4-dihydro-1H-isoquinolin-6-yl)thieno[2,3-d]pyridazin-7- yl]phenoxy]ethoxy]ethyl]carbamate: To a solution of 2-[2-[5-fluoro-2-[4-(2-methyl-3,4-dihydro- 1H-isoquinolin-6-yl)thieno[2,3-d]pyridazin-7-yl]phenoxy]ethoxy]ethanamine (42 mg, 0.088 mmol) in anhydrous DCM (0.5 mL) was added (4-nitrophenyl)[1-prop-2-enoyl-3- (trifluoromethyl)pyrrolidin-3-yl]carbonate (99 mg,
  • Step A Preparation of 2-(1,2-dimethylbenzimidazole-5-carbonyl)-4-fluoro-thiophene- 3-carboxylic acid: To a solution of 4-fluorothiophene-3-carboxylic acid (2.48 g, 17.0 mmol) in THF (15 mL) was added n-BuLi (2.5 M in hexanes, 7.10 mL, 17.7 mmol). The mixture was stirred at -65 °C for 0.5 h, then N- methoxy-N,1,2-trimethyl-benzimidazole-5-carboxamide (0.900 g, 3.86 mmol) in THF (1 mL) was added.
  • Step B Preparation of 7-(1,2-dimethylbenzimidazol-5-yl)-3-fluoro-5H-thieno[2,3- d]pyridazin-4-one: To a solution of 2-(1,2-dimethylbenzimidazole-5-carbonyl)-4-fluoro- thiophene-3-carboxylic acid (185 mg, 0.581 mmol) in 1-butanol (2 mL) was added hydrazine monohydrate (58 mg, 1.2 mmol). The mixture was stirred at 140 °C for 2 h.
  • Step C Preparation of 4-chloro-7-(1,2-dimethylbenzimidazol-5-yl)-3-fluoro- thieno[2,3-d]pyridazine: A suspension of 7-(1,2-dimethylbenzimidazol-5-yl)-3-fluoro-5H- thieno[2,3-d]pyridazin-4-one (145 mg, 0.461 mmol) in POCl 3 (2 mL) was stirred at 90 °C for 2 hours. The mixture was concentrated under reduced pressure. The crude was diluted with EtOAc (30 mL) and washed with saturated NaHCO 3 aqueous solution (30 mL) followed by brine (30 mL).
  • Step D Preparation of 4-(2-(((1s,3s)-3-((tert- butyldimethylsilyl)oxy)cyclobutyl)methoxy)-4-fluorophenyl)-7-(1,2-dimethyl-1H- benzo[d]imidazol-5-yl)-3-fluorothieno[2,3-d]pyridazine: A mixture of 4-chloro-7-(1,2- dimethylbenzimidazol-5-yl)-3-fluoro-thieno[2,3-d]pyridazine (15 mg, 0.045 mmol), tert-butyl-[3- [[5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy] methyl]cyclobutoxy]- dimethyl-silane (23 mg, 0.054 mmol), Na 2 CO 3 (9.6 mg, 0.090 mmol) and P
  • Step E Preparation of (1s,3s)-3-((2-(7-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-3- fluorothieno[2,3-d]pyridazin-4-yl)-5-fluorophenoxy)methyl)cyclobutan-1-ol: To a solution of 4- (2-(((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)methoxy)-4-fluorophenyl)-7-(1,2- dimethyl-1H-benzo[d]imidazol-5-yl)-3-fluorothieno[2,3-d]pyridazine (8.0 mg, 0.013 mmol) in THF (1 mL) was added TBAF/THF solution (0.50 mL, 1.0 M in THF, 0.50 mmol).
  • Biological Assays Biological Example 1 Binding affinity of compounds to PI3K ⁇ using isothermal titration calorimetry (ITC) assay [0292] The binding affinities of the full-length and RAS-binding domain (RBD) of PI3K ⁇ with compounds were measured using isothermal titration calorimetry (ITC). Protein samples were prepared by dialyzing them in a filtered and degassed buffer containing 20 mM HEPES (pH 7.3), 150 mM NaCl, 5 mM MgCl 2 , and 1 mM TCEP. Before titration, all proteins were centrifuged at 14,000 ⁇ g for 5 minutes to remove any debris and air bubbles.
  • ITC isothermal titration calorimetry
  • Protein concentration was measured using absorbance at 280 nm. The tested compounds were dissolved in the dialysis buffer. Protein and compounds were prepared with a final DMSO concentration of 5%.
  • ITC experiments were performed using a MicroCal PEAQ-ITC (Malvern) at 25 °C, with 19 injections of 2.2 ⁇ L administered at 150-second intervals. Typically, an ITC experiment consisted of 30-50 ⁇ M of protein in the cell and 300-500 ⁇ M of compound (10 times excess) in the syringe. Data analysis was conducted based on a binding model containing "one set of sites," using a nonlinear least-squares algorithm incorporated in the MicroCal PEAQ-ITC analysis software (Malvern).
  • Binding affinities of selected compounds measured using this assay are provided in Table 2.
  • “A” means K D ⁇ 5 ⁇ M
  • “B” means K D ⁇ 5 ⁇ M and ⁇ 25 ⁇ M
  • “C” means K D > 25 ⁇ M.
  • Table 2 KD of selected compounds of the present disclosure to full-length PI3K ⁇ as measured by ITC Biological
  • Example 2 Binding affinity of compounds to PI3K ⁇ using surface plasmon resonance (SPR) assay
  • SPR binding experiments were performed on a Biacore 8K Instrument (Cytiva).
  • Neutravidin was amine coupled to the carboxymethylated dextran surface of a CM5 sensor chip (Cytiva) using standard amine coupling chemistry.
  • the CM5 chip surface was first activated with 0.1 M N-hydroxy succinimide and 0.4 M N-ethyl-N'-(3-dimethyl aminopropyl) carbodiimide at a flow rate of 20 ⁇ L/min using 20 mM HEPES pH 7.4, 150 mM NaCl as the running buffer.
  • neutravidin was diluted to 20 ⁇ g/mL in 10 mM sodium acetate (pH 4.5) and injected on all flow cells until a density of approximately 10,000 response units (RU) was immobilized.
  • Activated amine groups were quenched with an injection of 1 M ethanolamine (pH 8.0).10,000 RU of avi- tagged full-length PI3K ⁇ was captured on all flow cells in 20 mM HEPES pH 7.4, 150 mM NaCl, 5 mM MgCl 2 , 1 mM TCEP, 0.05% tween 20, 5% DMSO buffer. A dilution series of 8 concentrations of each compound was prepared and injected over the PI3K ⁇ surface at 30 ⁇ L/min and 25 °C. The K D for each compound was determined using the Steady State affinity fit in the Cytiva software. [0295] Binding affinities of selected compounds measured using this assay are provided in Table 3.
  • Example 3 Disrupting KRAS PI3K ⁇ interaction by SPR inhibition assay
  • SPR binding experiments were performed on a Biacore 8K Instrument (Cytiva). Neutravidin (Pierce) was amine coupled to the carboxymethylated dextran surface of a CM5 sensor chip (Cytiva) using standard amine coupling chemistry.
  • the CM5 chip surface was first activated with 0.1 M N-hydroxy succinimide and 0.4 M N-ethyl-N'-(3-dimethyl aminopropyl) carbodiimide at a flow rate of 20 ⁇ L/min using 20 mM HEPES pH 7.4, 150 mM NaCl as the running buffer.
  • neutravidin was diluted to 20 ⁇ g/mL in 10 mM sodium acetate (pH 4.5) and injected on all flow cells until a density of approximately 10,000 response units (RU) was immobilized.
  • Activated amine groups were quenched with an injection of 1 M ethanolamine (pH 8.0).300–500 RU of avi- tagged full length PI3K ⁇ was captured on all flow cells in 20 mM HEPES pH 7.4, 150 mM NaCl, 5 mM MgCl 2 , 1 mM TCEP, 0.05% tween 20, 5% DMSO buffer. KRAS-Q25A at 20 ⁇ M was mixed with 8 concentrations of compound (50 nM – 100 ⁇ M) and injected over the full-length PI3K ⁇ at 30 ⁇ L/min and 25 o C. Steady-state levels of KRAS binding were recorded and fit with a 4-parameter inhibition model to determine the IC 50 values.
  • IC 50 values of selected compounds measured using this assay are provided in Table 4.
  • A means IC 50 ⁇ 5 ⁇ M
  • B means IC 50 ⁇ 5 ⁇ M and ⁇ 25 ⁇ M
  • C means IC 50 > 25 ⁇ M. Table 4.
  • Biological Example 4 Covalent modification assay using MALDI-TOF MS
  • MALDI-TOF MS Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) analysis of covalent modification of Cys242 in human PIK3CA (157-299) was performed using 3.33 ⁇ M protein target, and 1:7.5 protein to compound ratio.
  • Target pretreatment Before each assay, MALDI target (Bruker MPT 384 ground steel BC) was pre-treated by pipetting on each spot 0.75 ⁇ L of saturated sinapinic acid in acetonitrile (ACN). This step significantly improves the uniformity of sample crystallization across the plate resulting in enhanced sensitivity.
  • Sample preparation At collection time point, 2 ⁇ L of reaction mixtures were pipetted out into 20 ⁇ L MALDI matrix solution (saturated solution of sinapinic acid in 1:1 ACN: water solution containing 0.15% trifluoroacetic acid (TFA)) deposited on 384 well polypropylene plate.
  • MALDI matrix solution saturated solution of sinapinic acid in 1:1 ACN: water solution containing 0.15% trifluoroacetic acid (TFA)
  • Detector gain was set to 0.64 ⁇ (459 V), sample rate to 5 GS/s, real-time smoothing to medium (175 MHz), laser smart beam pattern was set to “Custom” single smartbeam beam scan with a scan range of 40 ⁇ m on both X and Y axis, and the laser frequency was 10000 Hz. Spectra were automatically collected using the custom AutoXecute method. Laser power was auto adjusted using fuzzy control. The peak selection range was set to be between 16.0 and 18.5 kDa.
  • Peak evaluation used a half-width parameter set to be smaller than 40 Da for processed spectrograms (centroid peak detection; smoothed by SavitzkyGolay algorithm using 7 m/z width and 2 cycles; baseline was subtracted using a median algorithm with flatness 1 and median level 0).
  • Fuzzy control used Proteins/Oligonucleotides protocol with minimum half-width 1/10 times above threshold. Up to 40000 satisfactory shots were collected in 10000 short steps. Dynamic termination was implemented to finish data collection when the peak signal/noise ratio reached a value of 1000.
  • Spectra processing Spectra were smoothed by SavitzkyGolay algorithm using 7 m/z width and three cycles.
  • Centroid peak detection algorithm was used with signal to noise threshold set to 6, relative intensity threshold 3%, peak width 10 m/z, and median baseline subtraction using flatness of 1 and a median level of 0.1. Peak intensity and area under the peak were evaluated and recorded for all peaks between 16.0 and 19.5 kDa.
  • Calculation of percent modification was calculated as a ratio of the peak height for protein modified by a compound to the sum of the peak height of the remaining protein plus the peak height for protein modified by a compound. If multiple modifications were observed, each was calculated as a ratio of peak height for a given modification versus the sum of peak heights for all observed protein species.
  • Percent of modification (%mod) of selected compounds measured using this assay is provided in Table 5.
  • Plates were harvested after 30 min and 4 h incubation by aspirating media and adding kit- supplied 1x supplemented lysis buffer to all wells (50 ⁇ L per well). For compounds with an electrophilic moiety, plates were harvested after 4 h only. Plates were then placed on a plate shaker and incubated at 850 rpm for an additional 30 min.
  • the antibody mixture solution was prepared by diluting aliquoted d2 and Eu Cryptate antibodies 1:20 in kit-supplied detection buffer, then mixed the diluted antibodies solutions (1:1 v:v).4 ⁇ L of this solution was then added to a 384-well detection plate (Perkin Elmer; 6008230).
  • Samples were homogenized by pipetting up and down and then transferred (16 ⁇ L of cell lysates) from the 96-well cell culture plate to two wells of the HTRF 384-well detection plate containing the antibody solution. Plates were centrifuged (524 g for 1 min) and allowed to incubate between 4 h and 24 h at room temperature. The maximum signal was reached after 4 h incubation time and remained stable over a period of 24 hours. Therefore, readings could be made between 4 h and 24 h of incubation.
  • IC 50 values of selected compounds measured using this assay are provided in Table 6.
  • IC 50 values shown in Table 6 “A” means IC 50 ⁇ 5 ⁇ M; “B” means IC 50 ⁇ 5 ⁇ M and ⁇ 25 ⁇ M; and “C” means IC 50 > 25 ⁇ M. Table 6.
  • Biological Example 6 Cell-based pAKT HTRF assay in BT474 cells [0310] On Day 1, cells were seeded into 96-well plates at 2.5x104 cells/well in complete growth media (DMEM, 10% FBS). On Day 2, cells were treated with compounds at 0.25% DMSO. The source plate was created with compounds diluted in media at 5-fold the final assay concentration. The compounds were run in a 9-point concentration curve starting at 3 ⁇ M, with a 3-fold dilution between concentrations.20 ⁇ L was transferred onto the cell plates (final volume in wells was 100 ⁇ L). Plates were harvested after 4 h incubation by aspirating media and adding kit- supplied 1x supplemented lysis buffer to all wells (75 ⁇ L per well).
  • the antibody mixture solution was prepared by diluting aliquoted d2 and Eu Cryptate antibodies 1:20 in kit-supplied detection buffer, then mixed the diluted antibodies solutions (1:1 v:v).4 ⁇ L of this solution was then added to a 384-well detection plate (Perkin Elmer; 6008230). Samples were homogenized by pipetting up and down and then transferred (16 ⁇ L of cell lysates) from the 96-well cell culture plate to two wells of the HTRF 384-well detection plate containing the antibody solution.
  • pAKT inhibition IC 50 values shown in Table 7 “A” means IC 50 ⁇ 0.1 mM; “B” means IC 50 ⁇ 0.1 ⁇ M and ⁇ 1 ⁇ M; “C” means IC 50 ⁇ 1 ⁇ M and ⁇ 3 ⁇ M; and “D” means IC 50 > 3 ⁇ M. Table 7.
  • pAKT inhibition IC 50 of selected compounds in BT474 cells Biological Example 7: Cell-based pAKT HTRF assay in SKUT-1 cells. [0312] On Day 1, cells were seeded into 96-well plates at 2x104 cells/well in complete growth media (DMEM, 10% FBS). On Day 2, cells were treated with compounds at 0.25% DMSO.
  • the source plate was created with compounds diluted in media at 5-fold the final assay concentration.
  • the compounds are run in a 9-point concentration curve starting at 1 ⁇ M, with a half-log dilution between concentrations.20 ⁇ L was transferred onto the cell plates (the final volume in wells was 100 ⁇ L). Plates were harvested after 4hr incubation by aspirating media and adding kit-supplied 1x supplemented lysis buffer to all wells (50 ⁇ l per well). Plates were then placed on a plate shaker and incubated at 850 rpm for an additional 30 min.
  • the antibody mixture solution was prepared by diluting aliquoted d2 and Eu Cryptate antibodies 1:20 in kit supplied detection buffer, then mixed the diluted antibodies solutions (1:1 v:v).4 ⁇ L of this solution was then added to a 384-well detection plate (Perkin Elmer; 6008230). Samples were homogenized by pipetting up and down and then transferred (16 ⁇ L of cell lysates) from the 96-well cell culture plate to two wells of the HTRF 384-well detection plate containing the antibody solution. Plates were centrifuged (524 g for 1min) and allowed to incubate between 4 and 24 h at room temperature. The maximum signal is reached after 4 h incubation time and remains stable over a period of 24 hours.

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Abstract

L'invention concerne des composés de formule (I) et de formule (II) et des compositions associées qui peuvent perturber, interrompre et/ou prévenir une interaction entre une petite protéine GTPase et une protéine PI3K (par exemple, PI3Kα). La présente divulgation concerne également des méthodes de traitement de cancers et autres indications avec de tels composés ou des compositions associées.
PCT/US2024/041276 2023-08-08 2024-08-07 Pyridazines fusionnées pour le traitement du cancer et autres indications WO2025034849A1 (fr)

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WO2023116763A1 (fr) * 2021-12-23 2023-06-29 上海优理惠生医药有限公司 Composé pyridazine, composition pharmaceutique et leur utilisation
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