Fused pyridazines for the treatment of cancer and other indications

Abstract

Provided herein are compounds of Formula (I) and Formula (II) and compositions thereof that capable of disrupting, interrupting, and / or preventing an interaction between a small GTPase protein and a PI3K protein (e.g., PI3Kα). The present disclosure also provides methods of treating cancers and other indications with such compounds or compositions thereof. (I) (II)

Description

FUSED PYRIDAZINES FOR THE TREATMENT OF CANCER AND OTHER INDICATIONS GOVERNMENT SUPPORT

[0001] This invention was made with government support under 75N91019D00024 awarded by the National Institutes of Health and under DE-AC52-07NA27344 awarded by the United States Department of Energy. The government has certain rights in the invention. CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and benefit of U.S. Application No.63 / 518,249, filed August 8, 2023, the entire contents of which are hereby incorporated by reference. BACKGROUND

[0003] An estimated over 600,000 Americans will have died from cancer in 2021, corresponding to more than 1600 deaths per day (Cancer Facts and Figures 2021). The greatest number of deaths are from cancers of the lung, prostate, and colorectum in men, and cancers of the lung, breast, and colorectum in women. Almost one-quarter of all cancer deaths are due to lung cancer, 82% of which is directly caused by cigarette smoking. The 5-year survival rate for lung cancer patients is only about 20%.

[0004] 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.

[0005] The frequency of PI3K oncogenic events has fueled the development and testing of PI3K inhibitors. Most PI3K inhibitors that have entered clinical development thus far are reversible, ATP-competitive kinase inhibitors. Despite considerable efforts, the clinical outcome of PI3K inhibitor-based treatments for solid tumors has been disappointing, mainly due to intolerable toxicity and drug resistance.SUMMARY

[0006] 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). The present disclosure encompasses the recognition that a therapeutic agent (e.g., a therapeutic agent comprising a small molecule, e.g., a compound provided herein) that disrupts, inhibits, and / or prevents an interaction between a PI3K protein (e.g., PI3Kα) and a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) may be particularly useful for 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). Without wishing to be bound by theory, therapeutic agents provided herein (e.g., therapeutic agents comprising small molecules, e.g., compounds provided herein) may be capable of binding to a PI3K protein (e.g., PI3Kα) 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., PI3Kα). In some embodiments, 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. For example, in some embodiments, such therapeutic agents may provide reduced instances of hyperglycemia and / or hyperinsulinemia relative to PI3K kinase inhibitors.

[0007] 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., PI3Kα) and a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1). In some embodiments, the present disclosure provides compounds capable of binding a PI3Kα 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 PI3Kα protein is disrupted, inhibited, and / or prevented; and / or (ii) the kinase activity of the PI3Kα protein is not inhibited. In some embodiments, such compounds are useful for treating a cancer or other indication, as described herein.

[0008] In some embodiments, the present disclosure provides a compound of Formula I:or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein each of Ring A, Ring B, Ring C, R1, R2, R3, R4, R4’, m, n, p, and q is as defined herein.

[0009] In some embodiments, 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, R1, R2, X, m, and n is as defined herein.

[0010] In some embodiments, the present disclosure provides 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.

[0011] In some embodiments, the present disclosure provides a method of inhibiting, disrupting, and / or preventing an interaction between a PI3Kα 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 PI3Kα protein is not inhibited. In some embodiments, the PI3Kα protein is in a cell, such as in a cell of a human or animal subject (e.g., as described herein).

[0012] In some embodiments, 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 byaberrant 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.

[0013] In some embodiments, 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). 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). DETAILED DESCRIPTION Compounds and Definitions

[0014] Compounds of this disclosure include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001.

[0015] Unless otherwise stated, structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric, diastereomeric, atropisomeric, or epimeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are 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. For example, in some cases, 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, entgegen (E), and zusammen (Z) isomers, as well asmixtures thereof. 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.

[0016] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0017] Aliphatic: The term “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). Unless otherwise specified, 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.

[0018] Alkyl: The term “alkyl”, used alone or as part of a larger moiety, 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., C1-12, C1-10, C1-8, C1-6, C1-4, C1-3, or C1-2). Examples of 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. The term “alkylene,” as used herein, alone or in combination, refers to a bivalent, saturated, optionally substituted straight or branched hydrocarbon, such as methylene (-CH2-).

[0019] Alkenyl: The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched hydrocarbon chain having at least one double bond andhaving (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Examples of alkenyl groups include ethenyl, propenyl, 2- methylpropenyl, 1,4-butadienyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0020] Alkynyl: The term “alkynyl”, used alone or as part of a larger moiety, 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., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Examples of 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.

[0021] Aryl: The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” 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. The term “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. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl or tetrahydronaphthyl, and the like. Unless otherwise specified, “aryl” groups are hydrocarbons.

[0022] 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. In some embodiments, “carbocyclyl” (or “cycloaliphatic”) refers to an optionally substituted monocyclic C3-C8hydrocarbon, or an optionally substituted C5-C10bicyclic 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. The term “cycloalkenyl” 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.

[0023] Composition: As used herein, the term “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). Unless otherwise specified, 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. By “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. For example, a “pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and absorption by a subject.

[0024] Halogen: The term “halogen” or “halo” means F, Cl, Br, or I.

[0025] 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 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Examples of 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”, as used herein, also includes groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclic rings. Examples of 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. Examples of tricyclic heterocyclic groups 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.

[0026] Heteroatom: The term “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)). In some embodiments, a heteroatom is selected from oxygen, sulfur, and nitrogen.

[0027] 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. When used in reference to a ring atom of a heterocycle, the term "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). Examples of such 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,” as used herein, 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.

[0028] 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. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0029] Patient or Subject: As used herein, the term “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 orsubjects 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). In some embodiments, 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.

[0030] Prevent or prevention: As used herein, when used in connection with the occurrence of a disease, disorder, and / 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). For example, 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.

[0031] Substituted or Optionally Substituted: As described herein, compounds of this disclosure may contain “optionally substituted” moieties (e.g., moieties bearing one or more substituents). In general, 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; andrefers to at least,or). Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when morethan 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. The term “stable,” as used herein, 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.

[0032] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0-4R°, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; – (CH2)0–4O(CH2)0 1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0–4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°; - N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°; – C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; -(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; – OC(O)(CH2)0–4SR°; –(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; – SC(S)SR°, -(CH2)0–4OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; – C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; – S(O)2NR°2; -(CH2)0–4S(O)R°; -N(R°)S(O)2NR°2; –N(R°)S(O)2R°; –N(OR°)R°; –C(NH)NR°2; – P(O)2R°; -P(O)R°2; -OP(O)R°2; –OP(O)(OR°)2; –SiR°3; –(C1–4 straight or branched alkylene)O– N(R°)2; or –(C1–4straight or branched alkylene)C(O)O–N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1–6aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 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°, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or arylmono– or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0033] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, –(CH2)0–2R●, –(haloR●), –(CH2)0–2OH, –(CH2)0–2OR●, –(CH2)0–2CH(OR●)2, -O(haloR●), –CN, –N3, –(CH2)0–2C(O)R●, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR●, –(CH2)0–2SR●, –(CH2)0–2SH, –(CH2)0–2NH2, – (CH2)0–2NHR●, –(CH2)0–2NR●2, –NO2, –SiR●3, –OSiR●3, -C(O)SR●, –(C1–4straight or branched alkylene)C(O)OR●, or –SSR●wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, – CH2Ph, –O(CH2)0–1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0034] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O (“oxo”), =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from 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. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic 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.

[0035] Suitable substituents on the aliphatic group of R*include halogen, –R●, -(haloR●), -OH, –OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR●2, or –NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0036] 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)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; 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†, taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] Suitable substituents on the aliphatic group of R†are independently halogen, – R●, -(haloR●), –OH, –OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR●2, or -NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] Treat: As used herein, the term “treat” (also “treatment” or “treating”) 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. 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. In some embodiments, 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. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and / or condition. In some embodiments, 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. Upon activation, PI3K catalyzes the synthesis of the second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3) by phosphorylating phosphatidylinositol 4,5-bisphosphate (PIP2). Signaling proteins such as Ser / Thr kinase AKT (e.g., Protein Kinase B (PKB)) can bind to PIP3 and thereby localize to the cell membrane. 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. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) regulates this pathway by dephosphorylating PIP3 to PIP2 and thus prevents activation of downstream kinases.

[0040] 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 p110α, p110β, and p110δ catalytic subunits produced from different genes (PIK3CA, PIK3CB, and PIK3CD, respectively), while p110γ produced by PIK3CG represents the only catalytic subunit in class IB PI3K. The expression of PI3K isoforms (e.g., PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ) is specific to cell types. The p110α and β isoforms are expressed in all cell types, whereas p110δ expression is mainly confined to leukocytes. The p110γ isoform is expressed primarily in the myeloid cell lineage.

[0041] PIK3CA gene encodes the 1068 amino acid p110α protein that contains five domains: an N-terminal adaptor binding domain (ABD) that binds to regulatory subunit p85α, a RAS- binding domain (RBD), a C2 domain, a helical domain, and a kinase catalytic domain. RAS contributes directly to the activation of the PI3K pathway through direct binding of RAS proteins (e.g., HRAS, NRAS, and KRAS) to a RAS-binding domain (RBD) in the p110α catalytic subunit of PI3Kα. 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 p110α, which causes downstream effects such as unregulated cell growth, proliferation, and survival.

[0042] Mutations in RAS proteins are found in over 20% of all human cancers. RAS proteins function as molecular switches that cycle between an active, GTP-bound state and an inactive, GDP-bound state. In the active 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.

[0043] 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 p110α-RBD have been shown to be crucial for epidermal growth factor (EGF) signaling to PI3K. Recent studies have shown that disrupting the RAS-PI3K interaction inhibits AKT and RAC1 activation in EGFR-mutant lung cancer cells, leading to reduced growth and survival and inhibiting EGFR- mutant-induced tumor onset. These results suggest that the binding of p110α to endogenous RAS proteins in EGFR-driven lung adenocarcinoma is critical in tumors driven by upstream activators of the RAS pathways and not just those in which RAS is mutationally activated.

[0044] Small GTPases (e.g., other than RAS) are also expected to bind the RBD of PI3Kα resulting in activation of signaling. The small GTPases Rac1 and CDC42 have been shown to bind the RBD of PI3Kβ and are hypothesized to also be capable of binding the RBD of PI3Kα. Accordingly, in some embodiments, the present disclosure encompasses the recognition that disrupting an interaction between PI3Kα and any small GTPase that binds the RBD of PI3Kα may be a useful therapeutic strategy for treating cancers and other indications. In some embodiments,a small GTPase is selected from Rac1, CDC42, and RAS proteins (including HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1).

[0045] The frequency of oncogenic PIK3CA hotspot mutations across cancers has fueled the development and testing of numerous PI3K (e.g., PI3Kα) inhibitors. Most PI3K inhibitors that have entered clinical development thus far are reversible, ATP-competitive kinase inhibitors. Despite considerable efforts, the clinical outcome of PI3K inhibitor-based treatments for solid tumors has been disappointing, mainly due to intolerable toxicity and drug resistance. In 2019, the U.S. Food and Drug Administration (FDA) approved alpelisib (BYL719; Novartis Pharma AG), an inhibitor specific to the PI3Kα isoform, combined with 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. Moreover, hyperglycemia and hyperinsulinemia have been observed as major dose-limiting toxicities for p110α inhibitors, which prevent the use of sufficiently high doses to fully suppress PI3Kα signaling in the tumor. Hyperglycemia and hyperinsulinemia are considered on-target effects of PI3Kα 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 PI3Kα inhibitor. Indeed, hyperglycemia was observed in 65% of patients in a Phase III clinical trial of alpelisib, leading to significant dose interruptions.

[0046] To overcome the limitations of current PI3Kα inhibitors, novel strategies to target PI3Kα need to be explored. Previous studies have suggested that inhibiting the RAS-p110α(RBD) interaction has minimal toxicity in adult animals while effectively causing tumor regression. The present disclosure encompasses the recognition that this therapeutic approach may be effective in various cancers including RAS-mutant-driven cancers and / or those driven by mutations or amplification of receptor tyrosine kinases (RTKs). The present disclosure also appreciates that this therapeutic modality may provide certain advantages over known PI3Kα inhibitors (e.g., those that target the ATP binding pocket of PI3Kα). For example, provided technologies may avoid hyperglycemia and insulin-driven resistance common to PI3Kα inhibitors, e.g., because such technologies target activation of PI3Kα by RAS, which is mostly present in transformed cells. Provided Compounds

[0047] In some embodiments, 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 PI3Kα proteins. In some embodiments, the present disclosure provides compounds capable of binding PI3Kα, such that (i) the interaction between the small GTPase (e.g., RAS protein, as described herein) and PI3Kα is disrupted, inhibited, or prevented; and / or (ii) the kinase activity of PI3Kα is not significantly inhibited. In some embodiments, such compounds bind PI3Kα reversibly. As used herein, 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., PI3Kα). Often, but not always, reversible inhibitors are not able to form a covalent bond with a target protein kinase. In some embodiments, such compounds bind PI3Kα irreversibly. As used herein, 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., PI3Kα) in a substantially non-reversible manner. In some embodiments, a reversible or irreversible inhibitor may be capable of interacting covalently with PI3Kα. For example, in some embodiments 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 PI3Kα (e.g., C242). In some embodiments, provided compounds that interact with PI3Kα covalently are compounds of Formula I or II wherein –R1comprises 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 PI3Kα (e.g., C242).

[0048] In some embodiments, 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 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, 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; each R1is independently selected from halogen and –L-R7; each L is independently a covalent bond or a bivalent straight or branched C1-12hydrocarbon 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)-, -SO2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, - OC(O)-, -OC(O)N(R)-, -N(R)C(O)O-, -SO2N(R)-, and –N(R)SO2-; each R7is independently selected from hydrogen, optionally substituted C1-6aliphatic, and – Cy1; each R2is independently selected from halogen, -OR, and optionally substituted C1-6aliphatic; each R3is independently selected from oxo, halogen, -(CH2)xCN, -(CH2)xOR, -OCH2CH2OR, -(CH2)xN(R)2, -(CH2)xC(O)N(R)2, -(CH2)xC(O)N(R)(OH), -(CH2)xC(O)N(R)(CN), - (CH2)xC(O)N(R)SO2R, -(CH2)xC(O)OR, -(CH2)xN(R)C(O)R, -(CH2)xSO2R, - (CH2)xSO2N(R)2, -(CH2)xCy3, -(CH2)xC(O)Cy3, -(CH2)xC(O)N(R)Cy3, -C(O)O(CH2)xCy3, and optionally substituted C1-6aliphatic; R4and R4’are connected with an optionally substituted C8-12hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O- or –N(R)-;m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0 or 1; each x is independently 0, 1, 2, or 3; each R is independently selected from hydrogen and optionally substituted C1-6aliphatic; each Cy1is independently selected from phenyl, 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, 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 10-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with 0-3 instances of R5; each R5is independently selected from oxo, halogen, -CN, -OR, -N(R)2, -N(R)Cy2, -C(O)R, - C(O)Cy2, -C(O)N(R)2, -C(O)OR, -C(O)OCy2, -(CH2)xN(R)C(O)R, -N(R)C(O)(CH2)xCy2, -(CH2)xN(R)C(O)OR, -N(R)C(O)OCy2, -SO2R, -Cy2, and optionally substituted C1-6aliphatic; each Cy2is 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 Cy2is substituted with 0-3 instances of R6; each R6is independently selected from oxo, halogen, -CN, -(CH2)xOR, -(CH2)xN(R)2, - (CH2)xC(O)R, -(CH2)xC(O)OR, -(CH2)xC(O)N(R)2, -(CH2)xN(R)C(O)OR, and optionally substituted C1-6aliphatic; and each Cy3is 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 Cy3is substituted with 0-3 instances of R6.

[0049] In some embodiments, the present disclosure provides a compound of Formula I or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0050] In some embodiments, 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 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, 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; each R1is independently selected from halogen and –L-R7; each L is independently a covalent bond or a bivalent straight or branched C1-12hydrocarbon 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)-, -SO2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, - OC(O)-, -OC(O)N(R)-, -N(R)C(O)O-, -SO2N(R)-, and –N(R)SO2-; each R7is independently selected from hydrogen, C1-6aliphatic optionally substituted with one or more R8, and –Cy1; each R2is independently selected from halogen, -OR, and C1-6aliphatic; each R3is independently selected from oxo, halogen, -(CH2)xCN, -(CH2)xOR, -OCH2CH2OR, -(CH2)xN(R)2, -(CH2)xC(O)N(R)2, -(CH2)xC(O)N(R)(OH), -(CH2)xC(O)N(R)(CN), - (CH2)xC(O)N(R)SO2R, -(CH2)xC(O)OR, -(CH2)xN(R)C(O)R, -(CH2)xSO2R, -(CH2)xSO2N(R)2, -(CH2)xCy3, -(CH2)xC(O)Cy3, -(CH2)xC(O)N(R)Cy3, -C(O)O(CH2)xCy1, and C1-6aliphatic optionally substituted with one or more R8; R4and R4’are connected with a C8-12hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O- or –N(R)-; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0 or 1; each x is independently 0, 1, 2, or 3; each R is independently selected from hydrogen and C1-6aliphatic optionally substituted with one or more R8; each Cy1is independently selected from phenyl, 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, 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 10-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with 0-3 instances of R5; each R5is independently selected from oxo, halogen, -CN, -OR, -N(R)2, -N(R)Cy2, -C(O)R, - C(O)Cy2, -C(O)N(R)2, -C(O)OR, -C(O)OCy2, -(CH2)xN(R)C(O)R, -N(R)C(O)(CH2)xCy2, -(CH2)xN(R)C(O)OR, -N(R)C(O)OCy2, -SO2R, -Cy2, and C1-6aliphatic optionally substituted with one or more R8; each Cy2is 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 Cy2is substituted with 0-3 instances of R6; each R6is independently selected from oxo, halogen, -CN, -(CH2)xOR, -(CH2)xN(R)2, - (CH2)xC(O)R, -(CH2)xC(O)OR, -(CH2)xC(O)N(R)2, -(CH2)xN(R)C(O)OR, and C1-6aliphatic;each Cy3is 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 Cy3is substituted with 0-3 instances of R6; each R8is independently selected from halogen, -OR9, -N(R9)2, -C(O)OR9, -C(O)N(R9)2, and -N(R9)C(O)R9; and each R9is independently hydrogen or C1-6aliphatic.

[0051] In some embodiments, 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, R1, R2, R3, m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IA or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0052] In some embodiments, 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, R1, R2, R3, R7, n, and p are as defined above forFormula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IA1 or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0053] In some embodiments, 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, R1, R2, R3, R7, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IA1-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, 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.

[0054] In some embodiments, 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, R1, R2, R3, m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In someembodiments, the present disclosure provides a compound of Formula IA2 or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0055] In some embodiments, 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, R1, R2, R3, m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IA2-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, 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.

[0056] In some embodiments, 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, R1, R2, R3, m, n, and p are as defined above forFormula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IA3 or a salt (e.g., a pharmaceutically acceptable salt) thereof. It will be appreciated that for a compound of Formula IA3, any R3group may be attached to either ring of the tetrahydroisoquinoline moiety.

[0057] In some embodiments, 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, R1, R2, R3, m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IA3-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IA3-b, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, 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 R3group 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:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring C, R1, R2, R3, m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IA4-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IA4-b, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IA4-c, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0059] In some embodiments, 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, R1, R2, R3, R4, R4’, m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IB, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0060] In some embodiments, the present disclosure provides a compound of Formula IB1:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring B, Ring C, R1, R2, R3, R4, R4’, m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IB1, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0061] In some embodiments, 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, R1, R2, R3, R4, R4’, m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IB2, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0062] In some embodiments, the present disclosure provides a compound of Formula IB3:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring B, R1, R2, R3, R4, R4’, m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IB3, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0063] In some embodiments, 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, R1, R2, R3, R4, R4’, m, n, and p are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IB4-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, 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: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; 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 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; each R1is independently halogen and –L-R7; each L is independently a covalent bond or a bivalent straight or branched C1-12 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 agroup selected from –N(R)-, -O-, -S-, -C(O)-, -SO2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, - OC(O)-, -OC(O)N(R)-, -N(R)C(O)O-, -SO2N(R)-, and –N(R)SO2-; each R7is independently selected from hydrogen, optionally substituted C1-6aliphatic, and – Cy1; each R2is independently selected from halogen, -OR, and optionally substituted C1-6aliphatic; m is 0, 1, 2, or 3; n is 0, 1, or 2; each x is independently 0, 1, 2, or 3; each R is independently selected from hydrogen and optionally substituted C1-6aliphatic; each Cy1is independently selected from phenyl, 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, 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 10-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with 0-3 instances of R5; each R5is independently selected from oxo, halogen, -CN, -OR, -N(R)2, -N(R)Cy2, -C(O)R, - C(O)Cy2, -C(O)N(R)2, -C(O)OR, -C(O)OCy2, -(CH2)xN(R)C(O)R, -N(R)C(O)(CH2)xCy2, -(CH2)xN(R)C(O)OR, -N(R)C(O)OCy2, -SO2R, -Cy2, and optionally substituted C1-6aliphatic; each Cy2is 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 Cy2is substituted with 0-3 instances of R6; and each R6is independently selected from oxo, halogen, -CN, -(CH2)xOR, -(CH2)xN(R)2, - (CH2)xC(O)R, -(CH2)xC(O)OR, -(CH2)xC(O)N(R)2, -(CH2)xN(R)C(O)OR, and optionally substituted C1-6aliphatic.

[0065] In some embodiments, the present disclosure provides a compound of Formula II, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0066] In some embodiments, 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 C1-4hydrocarbon chain; X is –OR, -N(R)2, -C(O)N(R)2, or 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 C1-6alkyl and / or one or more R8; each R1is independently halogen and –L-R7; each L is independently a covalent bond or a bivalent straight or branched C1-12 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)-, -SO2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, - OC(O)-, -OC(O)N(R)-, -N(R)C(O)O-, -SO2N(R)-, and –N(R)SO2-; each R7is independently selected from hydrogen, C1-6aliphatic optionally substituted with one or more R8, and –Cy1; each R2is independently selected from halogen, -OR, and C1-6aliphatic; m is 0, 1, 2, or 3; n is 0, 1, or 2;each x is independently 0, 1, 2, or 3; each R is independently selected from hydrogen and C1-6aliphatic optionally substituted with one or more R8; each Cy1is independently selected from phenyl, 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, 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 10-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with 0-3 instances of R5; each R5is independently selected from oxo, halogen, -CN, -OR, -N(R)2, -N(R)Cy2, -C(O)R, - C(O)Cy2, -C(O)N(R)2, -C(O)OR, -C(O)OCy2, -(CH2)xN(R)C(O)R, -N(R)C(O)(CH2)xCy2, -(CH2)xN(R)C(O)OR, -N(R)C(O)OCy2, -SO2R, -Cy2, and C1-6aliphatic optionally substituted with one or more R8; each Cy2is 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 Cy2is substituted with 0-3 instances of R6; each R6is independently selected from oxo, halogen, -CN, -(CH2)xOR, -(CH2)xN(R)2, - (CH2)xC(O)R, -(CH2)xC(O)OR, -(CH2)xC(O)N(R)2, -(CH2)xN(R)C(O)OR, and C1-6aliphatic; each R8is independently selected from halogen, -OR9, -N(R9)2, -C(O)OR9, -C(O)N(R9)2, and -N(R9)C(O)R9; and each R9is independently hydrogen or C1-6aliphatic.

[0067] In some embodiments, the present disclosure provides a compound of Formula IIA:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring B, J, L, R1, R2, R7, X, and n are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IIA or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0068] In some embodiments, 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, R1, R2, R7, X, and n are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IIA1, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, 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.

[0069] In some embodiments, 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, R1, R2, X, m, and n are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IIB1, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, 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.

[0070] In some embodiments, 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, R1, R2, 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)2or an optionally substituted group selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, 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.

[0071] In some embodiments, the present disclosure provides a compound of Formula IIC, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0072] In some embodiments, 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, R1, R2, 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.

[0073] In some embodiments, the present disclosure provides a compound of Formula IID, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0074] In some embodiments of any Formulae described herein, 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. In some embodiments, 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.

[0075] In some embodiments of any Formulae described herein, Ring A is phenyl.

[0076] In some embodiments of any Formulae described herein, 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 C3-C7cycloalkyl ring. In some embodiments, a 5- to 6-membered carbocyclic ring. In some embodiments, Ring A is a C5-C6cycloalkyl 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. In some embodiments, Ring A is a piperidine.

[0079] In some embodiments of any Formulae described herein, a R1is halogen (e.g., fluoro or chloro). In some embodiments, a R1is –L-R7. In some embodiments, at least one R1is –L-R7. In some embodiments, one R1is –L-R7, and any other R1groups are halogen (e.g., fluoro or chloro). In some embodiments, one R1is –L-R7, and one other R1group is halogen (e.g., fluoro or chloro). In some embodiments, one R1is –L-R7, and two other R1groups are halogen (e.g., fluoro or chloro).

[0080] In some embodiments of any Formulae described herein, an L is a covalent bond. In some embodiments, an L is a bivalent straight or branched C1-12hydrocarbon 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)-, -SO2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -OC(O)N(R)-, -N(R)C(O)O-, - SO2N(R)-, and –N(R)SO2-. In some embodiments, an L is a bivalent straight or branched C1-8hydrocarbon 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)-, -SO2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -OC(O)N(R)-, -N(R)C(O)O-, -SO2N(R)-, and –N(R)SO2-. In some embodiments of any Formulae described herein, an L is a covalent bond. In some embodiments, 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)-, -SO2-, -C(O)N(R)- , -N(R)C(O)-, -C(O)O-, -OC(O)-, -OC(O)N(R)-, -N(R)C(O)O-, -SO2N(R)-, and –N(R)SO2-. In some embodiments, 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)-, -SO2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -OC(O)N(R)-, - N(R)C(O)O-, -SO2N(R)-, and –N(R)SO2-. In some embodiments, an L is a bivalent straight or branched C1-12hydrocarbon 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-, -SO2N(R)-, and –N(R)SO2-. In some embodiments, an L is a bivalent straight or branched C1-8hydrocarbon 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-, -SO2N(R)-, and –N(R)SO2-.

[0081] In some embodiments of any Formulae described herein, an L is selected from: - (CH2)x-, -O(CH2)x-, -OCH(CH3)-, –O(CH2)2O(CH2)x-, –O(CH2)2O-, -O(CH2)2O(CH2)2O-, - O(CH2)2O(CH2)2OC(O)N(R)-, –O(CH2)2O(CH2)2N(R)SO2-, –O(CH2)2O(CH2)2N(R)-, – O(CH2)2O(CH2)2N(R)CH(CF3)-, –O(CH2)2O(CH2)xN(R)C(O)(CH2)x-, – O(CH2)2O(CH2)2N(R)C(O)O(CH2)x-, –O(CH2)2O(CH2)2N(R)C(O)O(CH2)2N(R)C(O)-, – O(CH2)2O(CH2)2N(R)C(O)OCH(CH3)CH2N(R)C(O)-, –O(CH2)2O(CH2)2N(R)C(O)N(R)-, – O(CH2)2O(CH2)xC(O)N(R)-, –O(CH2)2O(CH2)xC(O)-, -N(R)(CH2)2O-, -N(R)(CH2)x-, - N(R)C(O)(CH2)x-, -N(R)(CH2)2O(CH2)2N(R)-, -N(R)(CH2)2O(CH2)2N(R)C(O)O-, and - N(R)C(O)CH2O(CH2)2N(R)C(O)O-, wherein each x is independently 0, 1, 2, or 3.

[0082] In some embodiments of any Formulae described herein, L is selected from: -O(CH2)x- , –O(CH2)2O(CH2)xN(R)C(O)(CH2)x-, and –O(CH2)2O(CH2)2N(R)C(O)O(CH2)x-.

[0083] In some embodiments of any Formulae described herein, each R7is independently selected from hydrogen, C1-6aliphatic optionally substituted with one or more R8, and –Cy1. In some embodiments, each R7is independently hydrogen or –Cy1. In some embodiments, each R7is independently hydrogen or optionally substituted C1-6aliphatic. In some embodiments, each R7is independently optionally substituted C1-6aliphatic or –Cy1. In some embodiments, a R7is hydrogen. In some embodiments, a R7is optionally substituted C1-6aliphatic. In some embodiments, a R7is C1-6aliphatic optionally substituted with one or more R8. In some embodiments, a R7is optionally substituted C1-6alkyl (e.g., C1-6alkyl optionally substituted with one or more R8). In some embodiments, a R7is optionally substituted C2-6alkenyl (e.g., C2-6alkenyl optionally substituted with one or more R8). In some embodiments, a R7is optionally substituted C2-6alkynyl (e.g., C2-6alkynyl optionally substituted with one or more R8). In some embodiments, a R7is –Cy1. In some embodiments, a R7is selected from:, and

[0084] In some embodiments of any Formulae described herein, L is selected from: -O(CH2)x- , –O(CH2)2O(CH2)xN(R)C(O)(CH2)x-, and –O(CH2)2O(CH2)2N(R)C(O)O(CH2)x-; and each R7is independently optionally substituted C1-6aliphatic or -Cy1.

[0085] In some embodiments of any Formulae described herein, m is 0, 1, or 2. In some embodiments, m is 1, 2, or 3. In some embodiments, 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 moietyis. In some embodiments, a moietyis, or. In some embodiments, a moietyis,, , , or. In some embodiments, a moietyis selected from:and. In some embodiments, a moietyis selected from:

[0087] In some embodiments of any Formulae described herein, 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. In some embodiments, 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. In some embodiments, 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 R2is independently selected from halogen, -OR, and C1-6aliphatic. In some embodiments, each R2is independently selected from halogen, -OR, and optionally substituted C1-6alkyl. In some embodiments, each R2is independently selected from halogen, -OR, and C1-6alkyl. In some embodiments, each R2is independently selected from halogen and C1-6alkyl. In some embodiments, an R2is halogen (e.g.,fluoro). In some embodiments, an R is –OR (e.g., -OH). In some embodiments, an R is optionally substituted C1-6aliphatic. In some embodiments, an R2is C1-6aliphatic. In some embodiments, an R2is optionally substituted C1-6alkyl. In some embodiments, an R2is C1-6alkyl (e.g., methyl).

[0089] In some embodiments of any Formulae described herein, 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 moietyis selected from:, and. In some embodiments, a moietyis selected from:,and. In some embodiments, a moietyis selected from:and. In some embodiments, a moietyis selected from:

[0091] In some embodiments of any of Formulae I, IA, IA1, IA1-a, IA1-b, IA1-c, IA4-a, IA4- b, IA4-c, IB, IB1, IB4-a, IB4-b, and IB4-c, 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. In some embodiments, 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. In some embodiments, Ring C is selected from phenyl, 9- to 10-membered bicyclic aryl ring, and 3- to 7-membered carbocyclic ring. In some embodiments, 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. In some embodiments, 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.

[0092] In some embodiments of any of Formulae I, IA, IA1, IA1-a, IA1-b, IA1-c, IA4-a, IA4- b, IA4-c, IB, IB1, IB4-a, IB4-b, and IB4-c, Ring C is phenyl.

[0093] In some embodiments of any of Formulae I, IA, IA1, IA1-a, IA1-b, IA1-c, IA4-a, IA4- b, IA4-c, IB, IB1, IB4-a, IB4-b, and IB4-c, Ring C is a 9- to 10-membered bicyclic aryl ring. In some embodiments, Ring C is a 9-membered bicyclic aryl ring (e.g., an indane). In some embodiments, Ring C is a 10-membered bicyclic aryl ring (e.g., a tetrahydronaphthalene).

[0094] In some embodiments of any of Formulae I, IA, IA1, IA1-a, IA1-b, IA1-c, IA4-a, IA4- b, IA4-c, IB, IB1, IB4-a, IB4-b, and IB4-c, 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. In some embodiments, 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.

[0095] In some embodiments of any of Formulae I, IA, IA1, IA1-a, IA1-b, IA1-c, IA4-a, IA4- b, IA4-c, IB, IB1, IB4-a, IB4-b, and IB4-c, 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. In some embodiments, Ring C is an imidazo[1,2-a]pyridine, pyrazolo[1,5-a]pyrimidine, and [1,2,4]triazolo[4,3-a]pyridine. In some embodiments, Ring C is a 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0096] In some embodiments of any of Formulae I, IA, IA1, IA1-a, IA1-b, IA1-c, IA4-a, IA4- b, IA4-c, IB, IB1, IB4-a, IB4-b, and IB4-c, 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. In some embodiments, Ring C is a cyclohexene.

[0097] In some embodiments of any of Formulae I, IA, IA1, IA1-a, IA1-b, IA1-c, IA4-a, IA4- b, IA4-c, IB, IB1, IB4-a, IB4-b, and IB4-c, Ring C is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 4-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, 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 ortetrahydropyridine. In some embodiments, Ring C is a 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0098] In some embodiments of any of Formulae I, IA, IA1, IA1-a, IA1-b, IA1-c, IA4-a, IA4- b, IA4-c, IB, IB1, IB4-a, IB4-b, and IB4-c, Ring C is a 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, 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). In some embodiments, Ring C is a 6-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 7-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, 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 R3groups. In some embodiments, Ring C is an 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is selected from:, any of which is substituted with p R3groups.

[0099] In some embodiments of any 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, IB4-a, IB4-b, and IB4-c, each R3is independently selected from oxo, halogen, -(CH2)xCN, -(CH2)xOR, -OCH2CH2OR, -(CH2)xN(R)2, -(CH2)xC(O)N(R)2, -(CH2)xC(O)N(R)(OH), -(CH2)xC(O)N(R)(CN), - (CH2)xC(O)N(R)SO2R, -(CH2)xC(O)OR, -(CH2)xN(R)C(O)R, -(CH2)xSO2R, -(CH2)xSO2N(R)2, - (CH2)xCy3, -(CH2)xC(O)Cy3, -(CH2)xC(O)N(R)Cy3, -C(O)O(CH2)xCy3, and optionally substituted C1-6alkyl. In some embodiments, each R3is independently selected from oxo, halogen, - (CH2)xCN, -(CH2)xOR, -OCH2CH2OR, -(CH2)xN(R)2, -(CH2)xC(O)N(R)2, - (CH2)xC(O)N(R)(OH), -(CH2)xC(O)N(R)(CN), -(CH2)xC(O)N(R)SO2R, -(CH2)xC(O)OR, - (CH2)xN(R)C(O)R, -(CH2)xSO2R, -(CH2)xSO2N(R)2, -(CH2)xCy3, -(CH2)xC(O)Cy3, - (CH2)xC(O)N(R)Cy3, -C(O)O(CH2)xCy3, and C1-6aliphatic optionally substituted with one or more R8. In some embodiments, each R3is independently selected from halogen, -(CH2)xCN, - (CH2)xOR, -OCH2CH2OR, -(CH2)xN(R)2, -(CH2)xC(O)N(R)2, -(CH2)xC(O)N(R)(OH), - (CH2)xC(O)N(R)(CN), -(CH2)xC(O)N(R)SO2R, -(CH2)xC(O)OR, -(CH2)xN(R)C(O)R, - (CH2)xSO2R, -(CH2)xSO2N(R)2, -(CH2)xCy3, -(CH2)xC(O)Cy3, -(CH2)xC(O)N(R)Cy3, - C(O)O(CH2)xCy3, and optionally substituted C1-6aliphatic. In some embodiments, each R3is independently selected from oxo, halogen, -(CH2)xOR, -(CH2)xC(O)N(R)2, and optionally substituted C1-6aliphatic. In some embodiments, an R3is oxo. In some embodiments, an R3is halogen (e.g., fluoro or chloro). In some embodiments, an R3is -(CH2)xCN (e.g., -CH2CN or – CN). In some embodiments, an R3is -(CH2)xOR (e.g., -OH, -OCH3, -OCH(CH3)2, -(CH2)2OH, - (CH2)2OCH3, or -(CH2)3OH). In some embodiments, an R3is -OCH2CH2OR (e.g., - OCH2CH2OCH3). In some embodiments, an R3is -(CH2)xN(R)2(e.g., -N(CH3)2, -CH2NH2, - CH2N(CH3)2, or -(CH2)2NH2). In some embodiments, an R3is -(CH2)xC(O)N(R)2(e.g., - C(O)NH2, -C(O)N(CH3)2, -CH2C(O)NH2, -CH2C(O)N(H)CH3, or -CH2C(O)N(CH3)2). In some embodiments, an R3is -(CH2)xC(O)N(R)(OH) (e.g., -CH2C(O)N(CH3)(OH)). In some embodiments, an R3is -(CH2)xC(O)N(R)(CN) (e.g., -CH2C(O)N(H)(CN)). In some embodiments, an R3is -(CH2)xC(O)N(R)SO2R (e.g., -CH2C(O)N(H)SO2CH3). In some embodiments, an R3is - (CH2)xC(O)OR (e.g., -C(O)OC(CH3)3, -CH2C(O)OH, or -(CH2)2C(O)OH). In some embodiments, an R3is -(CH2)xN(R)C(O)R (e.g., -CH2N(H)C(O)CH3). In some embodiments, an R3is - (CH2)xSO2R (e.g., -SO2CH3). In some embodiments, an R3is -(CH2)xSO2N(R)2(e.g., - SO2N(H)CH3, -SO2N(CH3)2, -CH2SO2N(H)CH3, or -(CH2)2SO2N(H)CH3). In some embodiments, an R3is -(CH2)xCy3(e.g., -Cy3, -CH2Cy3, or -(CH2)2Cy3). In some embodiments, an R3is -(CH2)xC(O)Cy3(e.g., -C(O)Cy3or -CH2C(O)Cy3). In some embodiments, an R3is - (CH2)xC(O)N(R)Cy3(e.g., -CH2C(O)N(R)Cy3or -(CH2)2C(O)N(H)Cy3). In some embodiments,an R3is -C(O)O(CH2)xCy3(e.g., -C(O)OCH2Cy3). In some embodiments, an R3is optionally substituted C1-6aliphatic. In some embodiments, an R3is C1-6aliphatic optionally substituted with one or more R8. In some embodiments, an R3is optionally substituted C1-6alkyl. In some embodiments, an R3is C1-6alkyl optionally substituted with one or more R8. In some embodiments, an R3is C1-6aliphatic optionally substituted with one or more halogen (e.g., fluoro) or –OH. In some embodiments, an R3is C1-6alkyl optionally substituted with one or more halogen (e.g., fluoro) or –OH. In some embodiments, an R3is selected from –CH3, -CH2CH3, -CH(CH3)2, -CH2C≡CH, and –CH2CH(OH)CF3.

[0100] In some embodiments of any 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, IB4-a, IB4-b, and IB4-c, p is 0, 1, or 2. In some embodiments, 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.

[0101] In some embodiments of any 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, IB4-a, IB4-b, and IB4-c, a moietyis selected from:, and

[0102] In some embodiments of any 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, IB4-a, IB4-b, and IB4-c, a moietyis selected from:

[0103] In some embodiments of any Formulae described herein, 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 C1-6alkyl. In some embodiments, each R is independently hydrogen or optionally substituted C1-4alkyl. In some embodiments, each R is independently hydrogen or C1-6aliphatic optionally substituted with one or more R8. In some embodiments, eachR is independently hydrogen or C1-6alkyl optionally substituted with one or more R8. In some embodiments, each R is hydrogen or C1-6alkyl 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 C1-6aliphatic (e.g., optionally substituted C1-6alkyl). In some embodiments, an R is C1-6aliphatic optionally substituted with one or more R8(e.g., C1-6alkyl optionally substituted with one or more R8). In some embodiments, an R is C1-6aliphatic (e.g., C1-6alkyl).

[0105] In some embodiments of any Formulae described herein, each Cy1is independently selected from phenyl, 3- to 7-membered carbocyclic ring, and 5- to 10-membered bicyclic carbocyclic ring, wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, each Cy1is 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 Cy1is substituted with 0-3 instances of R5. In some embodiments, each Cy1is 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 Cy1is substituted with 0-3 instances of R5. In some embodiments, each Cy1is 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 Cy1is substituted with 0-3 instances of R5. In some embodiments, each Cy1is 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 Cy1is substituted with 0-3 instances of R5. In some embodiments, each Cy1is 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-memberedbicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with 0-3 instances of R5.

[0106] In some embodiments of any Formulae described herein, a Cy1is phenyl, wherein Cy1is substituted with 0-3 instances of R5.

[0107] In some embodiments of any Formulae described herein, a Cy1is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is an imidazole, pyrazole, or thiazole, any of which is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a pyridine, pyridone, pyrazine, or pyrimidine, any of which is substituted with 0-3 instances of R5.

[0108] In some embodiments of any Formulae described herein, a Cy1is a 9- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a 9-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with 0-3 instances of R5(e.g., an indole or a 9-membered bicyclic ring system comprising a heteroaryl ring fused to a carbocyclic ring). In some embodiments, a Cy1is a 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with 0-3 instances of R5(e.g., a 10-membered bicyclic ring system comprising a heteroaryl ring fused to a carbocyclic ring).

[0109] In some embodiments of any Formulae described herein, a Cy1is a 3- to 7-membered carbocyclic ring, wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a C3-7 cycloalkyl ring, wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a 3-membered carbocyclic ring (e.g., a cyclopropane), wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a 4-membered carbocyclic ring (e.g., a cyclobutane), wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a 5-membered carbocyclic ring (e.g., a cyclopentane), wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a 6-membered carbocyclicring (e.g., a cyclohexane), wherein Cy is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a 7-membered carbocyclic ring (e.g., a cycloheptane), wherein Cy1is substituted with 0-3 instances of R5.

[0110] In some embodiments of any Formulae described herein, a Cy1is a 5- to 10-membered bicyclic carbocyclic ring, wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is 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 Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a bridged 5- to 10-membered bicyclic carbocyclic ring, wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is 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 Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a 5-membered bicyclic carbocyclic ring, wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a 6-membered bicyclic carbocyclic ring, wherein Cy1is substituted with 0- 3 instances of R5. In some embodiments, a Cy1is a 7-membered bicyclic carbocyclic ring, wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a 8-membered bicyclic carbocyclic ring, wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a 9-membered bicyclic carbocyclic ring, wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a 10-membered bicyclic carbocyclic ring, wherein Cy1is substituted with 0-3 instances of R5.

[0111] In some embodiments of any Formulae described herein, a Cy1is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a 4-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., an azetidine), wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a 5-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., a pyrrolidine or a tetrahydrofuran), wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a 6-membered heterocyclicring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., a piperidine, piperazine, tetrahydropyran, morpholine, or dioxane), wherein Cy1is substituted with 0-3 instances of R5. In some embodiments, a Cy1is a 7-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with 0-3 instances of R5.

[0112] In some embodiments of any Formulae described herein, each R5is independently selected from oxo, halogen, -CN, -OR, -N(R)2, -N(R)Cy2, -C(O)R, -C(O)Cy2, -C(O)N(R)2, - C(O)OR, -C(O)OCy2, -(CH2)xN(R)C(O)R, -N(R)C(O)(CH2)xCy2, -(CH2)xN(R)C(O)OR, - N(R)C(O)OCy2, -SO2R, -Cy2, and optionally substituted C1-6alkyl. In some embodiments, each R5is independently selected from oxo, halogen, -CN, -OR, -N(R)2, -N(R)Cy2, -C(O)R, -C(O)Cy2, -C(O)N(R)2, -C(O)OR, -C(O)OCy2, -(CH2)xN(R)C(O)R, -N(R)C(O)(CH2)xCy2, - (CH2)xN(R)C(O)OR, -N(R)C(O)OCy2, -SO2R, -Cy2, and C1-6aliphatic optionally substituted with one or more R8. In some embodiments, each R5is independently selected from halogen, -CN, - OR, -N(R)2, -N(R)Cy2, -C(O)R, -C(O)Cy2, -C(O)N(R)2, -C(O)OR, -C(O)OCy2, - (CH2)xN(R)C(O)R, -N(R)C(O)(CH2)xCy2, -(CH2)xN(R)C(O)OR, -N(R)C(O)OCy2, -SO2R, -Cy2, and optionally substituted C1-6aliphatic. In some embodiments, an R5is oxo. In some embodiments, an R5is halogen (e.g., fluoro). In some embodiments, an R5is –CN. In some embodiments, an R5is –OR (e.g., -OCH3or -OCH(CH3)2). In some embodiments, an R5is -N(R)2. In some embodiments, an R5is -N(R)Cy2(e.g., -N(H)Cy2). In some embodiments, an R5is -C(O)R (e.g., -C(O)CH2CH3, -C(O)CH2CH2Cl, -C(O)CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)C≡CH, or –C(O)C≡CCH3). In some embodiments, an R5is -C(O)Cy2. In some embodiments, an R5is - C(O)N(R)2. In some embodiments, an R5is -C(O)OR (e.g., -C(O)OC(CH3)3). In some embodiments, an R5is -C(O)OCy2. In some embodiments, an R5is -(CH2)xN(R)C(O)R (e.g., - N(H)C(O)CH=CH2or -CH2N(H)C(O)CH=CH2). In some embodiments, an R5is - N(R)C(O)(CH2)xCy2(e.g., -N(H)C(O)Cy2or -N(H)C(O)CH2Cy2). In some embodiments, an R5is -(CH2)xN(R)C(O)OR (e.g., -N(H)C(O)OC(CH3)3 or - CH2N(H)C(O)OC(CH3)3). In some embodiments, an R5is -N(R)C(O)OCy2(e.g., -N(H)C(O)OCy2). In some embodiments, an R5is -SO2R (e.g., -SO2CH=CH2). In some embodiments, an R5is -Cy2. In some embodiments, an R5is optionally substituted C1-6aliphatic. In some embodiments, an R5is C1-6aliphatic optionally substituted with one or more R8. In some embodiments, an R5is optionally substituted C1-6alkyl. In some embodiments, an R5is C1-6alkyl optionally substituted with one or more R8. In someembodiments, an R5is C1-6alkyl optionally substituted with one or more halogen, -OH, or –NH2. In some embodiments, an R5is selected from –CH3, -CF3, -CH2OH, -CH2NH2, -CH2CF3, - CH(CH3)2, and –C(CH3)3.

[0113] In some embodiments of any Formulae described herein, each Cy1substituted with 0- 3 instances of R5is independently selected from:

[0114] In some embodiments of any Formulae described herein, each Cy2is 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 Cy2is substituted with 0-3 instances of R6. In some embodiments, each Cy2is independently selected from phenyl and 3- to 7-membered carbocyclic ring, wherein Cy2is substituted with 0-3 instances of R6. In some embodiments, each Cy2is 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 Cy2is substituted with 0-3 instances of R6. Insome embodiments, a Cy is phenyl, wherein Cy is substituted with 0-3 instances of R6. In some embodiments, a Cy2is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy2is substituted with 0-3 instances of R6. In some embodiments, a Cy2is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy2is substituted with 0-3 instances of R6. In some embodiments, a Cy2is a 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a pyridine), wherein Cy2is substituted with 0-3 instances of R6. In some embodiments, a Cy2is a 3- to 7-membered carbocyclic ring (e.g., a C3-7 cycloalkyl ring), wherein Cy2is substituted with 0-3 instances of R6. In some embodiments, a Cy2is a 5- to 6-membered carbocyclic ring (e.g., a C5-6cycloalkyl ring, such as a cyclohexane), wherein Cy2is substituted with 0-3 instances of R6. In some embodiments, a Cy2is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy2is substituted with 0-3 instances of R6. In some embodiments, a Cy2is a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy2is substituted with 0-3 instances of R6. In some embodiments, a Cy2is a 5-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., a pyrrolidine), wherein Cy2is substituted with 0-3 instances of R6. In some embodiments, a Cy2is 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 Cy2is substituted with 0-3 instances of R6.

[0115] In some embodiments of any Formulae described herein, each Cy2substituted with 0- 3 instances of R6is selected from:

[0116] In some embodiments of any Formulae described herein, each R6is independently selected from oxo, halogen, -CN, -(CH2)xOR, -(CH2)xN(R)2, -(CH2)xC(O)R, -(CH2)xC(O)OR, - (CH2)xC(O)N(R)2, -(CH2)xN(R)C(O)R, and optionally substituted C1-6alkyl. In someembodiments, each R6is independently selected from oxo, halogen, -CN, -(CH2)xOR, - (CH2)xN(R)2, -(CH2)xC(O)R, -(CH2)xC(O)OR, -(CH2)xC(O)N(R)2, -(CH2)xN(R)C(O)R, and C1-6aliphatic. In some embodiments, each R6is independently selected from oxo, halogen, -CN, - (CH2)xOR, -(CH2)xN(R)2, -(CH2)xC(O)R, -(CH2)xC(O)OR, -(CH2)xC(O)N(R)2, - (CH2)xN(R)C(O)R, and C1-6alkyl. In some embodiments, each R6is independently selected from halogen, -CN, -(CH2)xOR, -(CH2)xN(R)2, -(CH2)xC(O)R, -(CH2)xC(O)OR, -(CH2)xC(O)N(R)2, - (CH2)xN(R)C(O)R, and optionally substituted C1-6aliphatic. In some embodiments, an R6is oxo. In some embodiments, an R6is halogen. In some embodiments, an R6is –CN. In some embodiments, an R6is -(CH2)xOR (e.g., -OH). In some embodiments, an R6is -(CH2)xN(R)2(e.g., -CH2NH2). In some embodiments, an R6is -(CH2)xC(O)R (e.g., -C(O)CH=CH2). In some embodiments, an R6is -(CH2)xC(O)OR (e.g., -C(O)OH or -C(O)OC(CH3)3). In some embodiments, an R6is -(CH2)xC(O)N(R)2(e.g., -C(O)NH2or –C(O)N(CH3)2). In some embodiments, an R6is -(CH2)xN(R)C(O)OR (e.g., -CH2N(H)C(O)OC(CH3)3). In some embodiments, an R6is optionally substituted C1-6aliphatic. In some embodiments, an R6is optionally substituted C1-6alkyl. In some embodiments, an R6is C1-6aliphatic. In some embodiments, an R6is C1-6alkyl. In some embodiments, an R6is selected from –CH3, =CH2, - CH(CH3)2, or –C(CH3)3.

[0117] In some embodiments of any 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, and IB4-c, each Cy3is independently selected from phenyl and 3- to 7-membered carbocyclic ring, wherein Cy3is substituted with 0-3 instances of R6. In some embodiments, each Cy3is 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 Cy3is substituted with 0-3 instances of R6. In some embodiments, each Cy3is independently selected from phenyl and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy3is substituted with 0-3 instances of R6. In some embodiments, each Cy3is 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 Cy3is substituted with 0-3 instances of R6. In some embodiments, a Cy3is phenyl, wherein Cy3is substituted with 0-3 instances of R6. In some embodiments, a Cy3is 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy3is substituted with 0-3 instances of R6. In some embodiments, a Cy3is a 5- membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a triazole or tetrazole), wherein Cy3is substituted with 0-3 instances of R6. In some embodiments, a Cy3is a 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a pyridine, pyridone, or pyrimidine), wherein Cy3is substituted with 0-3 instances of R6. In some embodiments, a Cy3is a 3- to 7-membered carbocyclic ring (e.g., a C3-7 cycloalkyl ring), wherein Cy3is substituted with 0-3 instances of R6. In some embodiments, a Cy3is a 4- to 6-membered carbocyclic ring (e.g., a C4-6 cycloalkyl ring, such as a cyclobutane), wherein Cy3is substituted with 0-3 instances of R6. In some embodiments, a Cy3is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy3is substituted with 0-3 instances of R6. In some embodiments, a Cy3is a 4-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., an oxetane), wherein Cy3is substituted with 0-3 instances of R6. In some embodiments, a Cy3is a 5-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., a pyrrolidine), wherein Cy3is substituted with 0-3 instances of R6. In some embodiments, a Cy3is 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 Cy3is substituted with 0- 3 instances of R6. In some embodiments, a Cy3is a 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy3is substituted with 0-3 instances of R6. In some embodiments, each Cy3substituted with 0-3 instances of R6is independently selected from:, and.

[0118] In some embodiments of any of Formulae I, IB, IB1, IB2, IB3, IB4-a, IB4-b, and IB4- c, R4and R4’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)-. In some embodiments, R4and R4’are connected with a C8-12hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O- or –N(R)-. In some embodiments, R4and R4’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, R4and R4’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, R4and R4’are connected with an optionally substituted C9-11hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O-. In some embodiments, R4and R4’are connected with –O(CH2)8O-.

[0119] In some embodiments of Formula I, q is 0. In some embodiments, q is 1. It will be appreciated that q has the same value for both R4and R4’, such that either both R4and R4’are present or both R4and R4’are absent.

[0120] In some embodiments of any of Formulae II, IIA, IIA1, IIA2, IIA3, IIB, IIB1, IIB2, IIB3, and IID, J is a covalent bond. In some embodiments, J is a bivalent straight or branched C1-4 hydrocarbon chain. In some embodiments, J is a bivalent straight or branched C1-2 hydrocarbon chain. In some embodiments, when J is a covalent bond, X is not –OR or –N(R)2.

[0121] In some embodiments of any of Formulae II, IIA, IIA1, IIA2, IIA3, IIB, IIB1, IIB2, IIB3, IIC, and IID, X is –OR or –N(R)2. In some embodiments, 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. In some embodiments, 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 C1-6alkyl and / or one or more R8. In some embodiments, 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 C1-6alkyl. In some embodiments, X is –OR (e.g., -OH or –OCH3). In some embodiments, X is –N(R)2(e.g., -N(CH3)2). In some embodiments, X is -C(O)N(R)2(e.g., -C(O)N(CH3)2). In some embodiments, 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 C1-6alkyl). In some embodiments, X is optionally substituted 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, 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.

[0122] In some embodiments of any of Formulae II, IIA, IIA1, IIA2, IIA3, IIB, IIB1, IIB2, IIB3, IIC, and IID, a moietyis selected from:, , , and.

[0123] In some embodiments of any Formulae described herein, each R8is independently selected from halogen, -OR9, and -N(R9)2. In some embodiments, each R8is independentlyselected from -C(O)OR9, -C(O)N(R9)2, and -N(R9)C(O)R9. In some embodiments, an R8is halogen (e.g., fluoro). In some embodiments, an R8is -OR9(e.g., -OH or –O(C1-6alkyl)). In some embodiments, an R8is -N(R9)2(e.g., -NH2, -NH(C1-6alkyl), or –N(C1-6alkyl)2). In some embodiments, an R8is -C(O)OR9(e.g., -C(O)OH or -C(O)O(C1-6alkyl)). In some embodiments, an R8is -C(O)N(R9)2(e.g., -C(O)NH2, -C(O)NH(C1-6alkyl), or -C(O)N(C1-6alkyl)2). In some embodiments, an R8is -N(R9)C(O)R9(e.g., -N(H)C(O)(C1-6alkyl) or -N(C1-6alkyl)C(O)(C1-6alkyl)).

[0124] In some embodiments of any Formulae described herein, each R9is independently selected from hydrogen or C1-6alkyl. In some embodiments, an R9is hydrogen. In some embodiments, an R9is C1-6aliphatic (e.g., C1-6alkyl).

[0125] Also provided herein are embodiments wherein any embodiment described herein may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive. As used herein, 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 CH2is mutually exclusive with an embodiment wherein the same group is NH.

[0126] In some embodiments, 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. In some embodiments, 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.

[0127] In some embodiments, 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. Berge, et al. describes pharmaceutically acceptable 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 asion exchange. Other pharmaceutically acceptable 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, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. 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.

[0128] It will be appreciated that compounds described herein may be provided and / or utilized in any available form (e.g., a salt form) and that all such forms are contemplated by the present disclosure. The present disclosure also contemplates forms such as esters, tautomers, prodrugs, zwitterionic forms, and stereoisomers of the compounds provided herein.

[0129] It will be appreciated that throughout the present disclosure, unless otherwise indicated, 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

[0130] The present disclosure also provides compositions comprising a compound provided herein with one or more other components. In some embodiments, 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)

[0131] In some embodiments, 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, 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) and further comprises a pharmaceutically acceptable carrier. Pharmaceutical 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. In some embodiments, 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.

[0132] In some embodiments, provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein 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. In some embodiments, 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.

[0133] Provided compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of any disease or disorder described herein. Uses

[0134] 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). In some embodiments, 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). In some embodiments, provided compounds and compositions are useful as medicaments. In some embodiments, provided compounds and compositions are useful in research as, for example, analytical tools and / or control compounds in biological assays.

[0135] In some embodiments, 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 PI3Kα protein. In some embodiments, 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 PI3Kα protein in a subject, comprising administering a provided compound or composition. In some embodiments, 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 PI3Kα protein in a biological sample, comprising administering a provided compound or composition. In some embodiments, 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 PI3Kα protein with a provided compound or composition. In some such embodiments, a small GTPase is capable of binding a RAS-binding domain (RBD) of a PI3Kα protein. In some embodiments, a small GTPase is selected from Rac1, CDC42, and RAS proteins. In some embodiments, a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1. In some embodiments, a RAS protein is a wild-type RAS protein. In some embodiments, a RAS protein is a mutant RAS protein. In some embodiments, 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). In some embodiments, 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. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, 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. In some embodiments, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, a PI3Kα protein is a wild-type PI3Kα protein. In some embodiments, a PI3Kα protein is a mutant PI3Kα protein. In some embodiments, a PI3Kα 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. In some embodiments, a PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

[0136] In some embodiments, the present disclosure provides methods comprising administering a provided compound or composition to a subject in need thereof. In some such embodiments, 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 PI3Kα protein. In some embodiments, 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 PI3Kα protein. In some embodiments, a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) is capable of binding a RAS- binding domain (RBD) of a PI3Kα protein. In some embodiments, a small GTPase is selected from Rac1, CDC42, and RAS proteins. In some embodiments, a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1. In some embodiments, 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. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, 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. Insome embodiments, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, a RAS protein is a wild-type RAS protein. In some embodiments, a PI3Kα protein is a wild-type PI3Kα protein. In some embodiments, a PI3Kα protein is a mutant PI3Kα protein. In some embodiments, a PI3Kα 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. In some embodiments, a PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a subject has a cancer or other indication described herein. In some embodiments, a subject has previously undergone a treatment regimen for a cancer. In some embodiments, a subject has previously entered remission from a cancer.

[0137] In some embodiments, 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.

[0138] In some embodiments, the present disclosure provides methods of treating a cancer, comprising administering to a subject a provided compound or composition. In some embodiments, a cancer is associated with and / or characterized by aberrant activation of PI3Kα. In some embodiments, a cancer is characterized by a mutation in a RAS protein (e.g., HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1). In some embodiments, a cancer is characterized by a mutation in a KRAS protein. In some embodiments, 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. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, a cancer is characterized by a mutation in an NRAS protein. In some embodiments, 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. In some embodiments, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, a cancer is characterized by a mutation in an HRAS protein. In some embodiments, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K,Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, a cancer is characterized by a mutation in a PI3Kα protein. In some embodiments, a PI3Kα 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. In some embodiments, a PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

[0139] As used herein, “cancer” (and also, “malignancy”, “neoplasm”, “tumor”, and “carcinoma”), refer 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. In some embodiments, a tumor may be or comprise cells that are precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and / or non-metastatic. In some embodiments, a cancer may be characterized by a solid tumor. In some embodiments, a cancer may be characterized by a hematologic tumor. Numerous different types of cancers are known.

[0140] In some embodiments, 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 Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML), and lymphomas including lymphocytic, granulocytic and monocytic lymphomas. 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, lymphomas, lymphangiosarcoma, lymphangioendotheliosarcoma, medullary thyroid carcinoma, medulloblastoma, meningioma mesothelioma, myelomas, myxosarcoma neuroblastoma, neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma, epithelial ovarian cancer, papillary carcinoma, papillary adenocarcinomas, paraganglioma, parathyroid tumors, pheochromocytoma, pinealoma, plasmacytomas, retinoblastoma, rhabdomyosarcoma, sebaceous gland carcinoma, seminoma, skin cancers, melanoma, small cell lung carcinoma, non-small cell lung carcinoma, squamous cell carcinoma, sweat gland carcinoma, synovioma, thyroid cancer, uveal melanoma, and Wilm’s tumor. In some embodiments, 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.

[0141] In some embodiments, a cancer is characterized by one or more mutations. In some such embodiments, 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. In some embodiments, a cancer is characterized by a mutation in a RAS protein (e.g., KRAS, HRAS, or NRAS). In some embodiments, a cancer is characterized by a mutation in a KRAS protein. In some embodiments, 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. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, a cancer is characterized by a mutation in an NRAS protein. In some embodiments, 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. In some embodiments, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, a cancer is characterized by a mutation in an HRAS protein. In some embodiments, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, a cancer is characterized by a mutation in a PI3Kα protein. In some embodiments, the PI3Kα 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. In some embodiments, a PI3Kαprotein comprises a E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, 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). In some embodiments, a cancer is characterized by a mutation in or a deletion of a PTEN protein. In some embodiments, a cancer has demonstrable sensitivity to Avastin. For example, a cancer may be non-small cell lung cancer (NSCLC) or colorectal cancer. In some embodiments, a cancer is ER positive (e.g., having estrogen receptors). In some embodiments, a cancer is PR positive (e.g., having progesterone receptors).

[0142] In some embodiments, the present disclosure provides methods of treating a metabolic syndrome, comprising administering to a subject a provided compound or composition. In some embodiments, a metabolic syndrome is selected from hyperinsulinemia and type 2 diabetes.

[0143] In some embodiments, 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. In some embodiments, a RASopathy is selected from the group consisting of capillary malformation-arteriovenous malformation syndrome and Legius syndrome. In some embodiments, a RASopathy is neurofibromatosis type 1 (NF1).

[0144] In some embodiments, the present disclosure provides methods of treating a vascular disorder, comprising administering to a subject a provided compound or composition. In some embodiments, 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)).

[0145] In some embodiments, the present disclosure provides methods of treating pulmonary hypertension, such as pulmonary arterial hypertension, comprising administering to a subject a provided compound or composition.

[0146] In some embodiments, 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.

[0147] In some embodiments, the present disclosure provides compounds or compositions for use in the manufacture of a medicament. In some embodiments, 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 PI3Kα protein. In some embodiments, a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) is capable of binding a RAS- binding domain (RBD) of a PI3Kα protein. In some embodiments, a small GTPase is selected from Rac1, CDC42, and RAS proteins. In some embodiments, a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1. In some embodiments, a RAS protein is a wild-type RAS protein. In some embodiments, a RAS protein is a mutant RAS protein. In some embodiments, 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). In some embodiments, 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. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, 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. In some embodiments, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, a PI3Kα protein is a wild-type PI3Kα protein. In some embodiments, a PI3Kα protein is a mutant PI3Kα protein. In some embodiments, a PI3Kα 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. In some embodiments, a PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, 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. In some embodiments, 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 PI3Kα protein. In some embodiments, a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) is capable of binding a RAS-binding domain (RBD) of a PI3Kα protein. In some embodiments, a small GTPase is selected from Rac1, CDC42, and RAS proteins. In some embodiments, a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1. In some embodiments, a RAS protein is a wild-type RAS protein. In some embodiments, a RAS protein is a mutant RAS protein. In some embodiments, 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). In some embodiments, 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. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, 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. In some embodiments, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, a PI3Kα protein is a wild-type PI3Kα protein. In some embodiments, a PI3Kα protein is a mutant PI3Kα protein. In some embodiments, a PI3Kα 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. In some embodiments, a PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, provided compounds or compositions are useful for treating a disease, disorder, or condition described herein. In some embodiments, provided compounds or compositions are useful for treating a cancer or other indication as described herein.

[0149] In some embodiments, a provided compound or composition is administered as part of a combination therapy. As used herein, 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). In some embodiments, the two or more regimens may be administered simultaneously. In some embodiments, 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. In some embodiments, “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. For clarity, 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.

[0150] In some embodiments, 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). Exemplary 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 HIF2α 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).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). 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). Additional examples of 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; titanocene dichloride; tretinoin; anabolic steroids such as fluoxymesterone(HALOTESTIN); estrogens such as estradiol, diethylstilbestrol (DES), and dienestrol; progestins such as medroxyprogesterone acetate (MPA) and megestrol; and testosterone. EXAMPLES

[0151] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

[0152] Selected abbreviations used in the preceding sections and the Examples are summarized in the following table:Materials & Methods

[0153] Preparative thin layer chromatography (PTLC) separations described herein were typically performed on 20 x 20 cm plates (500-µm thick silica gel).

[0154] Chromatographic purifications were typically performed using Biotage Isolera. One automated system running Biotage Isolera One 2.0.6 software (Biotage LLC, Charlotte, NC). Flow rates were the default values specified for the column in use. Reverse phase chromatography was performed using elution gradients of water and acetonitrile on KP-C18-HS Flash+ columns (Biotage LLC) of various sizes. Typical loading was between 1:50 and 1:1000 crude sample: RP SiO2by weight. 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: SiO2by weight. Alternatively, silica gel chromatography was performed on a Biotage Horizon flash chromatography system.

[0155] 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 (δ) are reported in parts per million (ppm) with splitting patterns abbreviated to: s (singlet), br. s (broad singlet), d (doublet), dd (double doublet), t (triplet), and m (multiplet). The coupling constant (J) is given in Hz. Typical deuterated solvents were utilized as indicated in the individual examples.

[0156] 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. using a poroshell 120 EC-C1850 mm x 3.0 mm x 2.7 μm capillary column; Flow Rate: 0.7 mL / min. Mass spectra (MS) were measured by electrospray ion- mass spectroscopy (ESI). All temperatures are in degrees Celsius (°C) unless otherwise noted.

[0158] (2) LCMS spectra were taken on an Agilent Technologies 1290-6420 Triple Quadrupole spectrometer: The mobile phase for the LC was acetonitrile (A) with 0.05% formic acid, and water (B) with 0.05% formic acid, and the eluent gradient was from 5-95% A in 5.0 min, using a ZORBAX SB-C1850 mm x 2.1 mm x 1.8 μm capillary column; Flow Rate: 0.3 mL / min. Mass spectra (MS) were measured by electrospray ion-mass spectroscopy (ESI).

[0159] (3) LC-MS analysis was performed using an Agilent 6120b single quadrupole mass spectrometer with an Agilent 1260 infinity II chromatography separations module and Agilent 1260 infinity II photodiode array detector controlled by Agilent Chemstation software. The HPLC column used was an Agilent ZORBAX Eclipse XDB-C184.6 mm x 150 mm x 3.5 μm RapidResol column with a mobile phase of water (0.1 % formic acid) / MeCN (0.1% formic acid) and a gradient of 5-95% MeCN over 10 minutes at a flow rate of 1 mL / min. Accurate mass data was obtained using a Thermo Fisher extractive plus EMR orbitrap LCMS system. Exact mass values were calculated by ChemCalc.

[0160] (4) LCMS spectra were taken on an alliance Waters 2695 coupled to a dual absorbance detector waters 2487 and a waters micro mass ZQ-2000 single quadrupole spectrometer. Themobile phase for the LC was acetonitrile (A) and water (B) with 0.01% formic acid, and the eluent gradient was from 5-100% A in 10.0 minute using a Kromasil 100-5-C18150 mm x 4.6 mm x 5 µm column. Mass spectra (MS) were measured by electrospray ion-mass spectroscopy (ESI).

[0161] (5) 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 μm); Flow Rate: 0.5 mL / min. Mass spectra (MS) were measured by Electrospray Ion-Mass spectroscopy (ESI).

[0162] Typically, analytical HPLC spectrometry conditions were as follows:

[0163] LC1: Agilent Technologies 1260 Infinity coupled, Column: poroshell 120 EC-C18150 mm x 4.6 mm x 4 μm; 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.

[0164] LC2: Shimadzu 2010 CHT, Column Waters X-select CSH C18 (150 x 4.6) mm x 3.5 µm, 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.

[0165] 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 μm; 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.

[0167] 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 µm OBDTM19 x 250 mm column with a mobile phase of water / MeCN or water (0.1% TFA) / MeCN (0.1% TFA).

[0168] Condition 3: Shimadzu Preparative HPLC System; Column: Phenomenex Luna C18, 21.1 mm × 250 mm, 10 μm; 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. Synthesis of Provided Compounds

[0170] The compounds provided herein, including in various forms such as salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc., may be prepared according to various methods including those set forth in the following examples. Synthetic Example 1: Synthesis 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 (Compound 51)

[0171] Step A: Preparation of benzyl 2-(benzyloxy)-4-fluorobenzoate: 4-fluoro-2- hydroxybenzoic acid (25.0 g, 392 mmol) was dissolved in acetone (500 mL). Solid K2CO3 (54.2 g, 392 mmol) was added, and the mixture was stirred at room temperature for 30 minutes before benzyl bromide (60.3 g, 41.9 mL, 352 mmol) was added via syringe. The mixture was warmed to 50 °C overnight and then cooled to room temperature, filtered through Celite® and concentrated in vacuo to give an orange oil. The oil was dissolved in DCM (300 mL) then washed with 0.5 M aqueous NaOH (100 mL), water (100 mL) and brine (100 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo to give an orange oil. The crude product was purifiedby chromatography on silica gel (330 g cartridge, 0-20% EtOAc / isohexane) to afford benzyl 2- (benzyloxy)-4-fluorobenzoate (50.4 g, 93% yield) as a white solid.1H NMR (500 MHz, DMSO- d6) δ 7.82 (dd, J = 8.7, 7.0 Hz, 1H), 7.48 – 7.42 (m, 2H), 7.42 – 7.29 (m, 8H), 7.19 (dd, J = 11.6, 2.4 Hz, 1H), 6.92 – 6.85 (m, 1H), 5.28 (s, 2H), 5.22 (s, 2H). LCMS ESI (+) m / z 359.4 (M+Na).

[0172] 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. The precipitate formed was isolated by filtration, washed with water (3 x 200 mL) and hexane (3 x 100 mL) and dried to give 2-(benzyloxy)-4- fluorobenzoic acid (36.0 g, 97% yield) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 12.69 (s, 1H), 7.75 (dd, J = 8.6, 7.1 Hz, 1H), 7.52 – 7.47 (m, 2H), 7.43 – 7.36 (m, 2H), 7.35 – 7.30 (m, 1H), 7.11 (dd, J = 11.6, 2.4 Hz, 1H), 6.84 (td, J = 8.4, 2.4 Hz, 1H), 5.22 (s, 2H). LCMS ESI (+) m / z 268.8 (M+Na).

[0173] 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). After 1 h, additional triethylamine (16.8 g, 23.0 mL, 166 mmol) and solid N,O- dimethylhydroxylamine hydrochloride (15.4 g, 158 mmol) were added. The mixture was allowed to reach room temperature and stirred for 2 h. The mixture was washed with 1 M aqueous HCl (3 x 200 mL), water (200 mL) and brine (200 mL) and then dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (330 g cartridge, 0-50% DCM / EtOAc) to afford 2-(benzyloxy)-4-fluoro-N-methoxy-N-methylbenzamide (42.0 g, 91% yield) as a solid.1H NMR (500 MHz, DMSO-d6) δ 7.45 – 7.36 (m, 4H), 7.36 – 7.28 (m, 2H), 7.13 – 7.02 (m, 1H), 6.83 (td, J = 8.4, 2.3 Hz, 1H), 5.17 (s, 2H), 3.47 (s, 3H), 3.17 (s, 3H). LCMS ESI (+) m / z 289.8 (M+H).

[0174] 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 30minutes. The mixture was allowed to reach rt and stirred overnight. The mixture was quenched with water (30 mL) and then partitioned between 3 M aq. HCl (300 mL) and EtOAc (300 mL). The aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried (MgSO4), filtered and concentrated in vacuo to give 2-(2-(benzyloxy)-4-fluorobenzoyl)thiophene-3- carboxylic acid (55.8 g, 79% yield) as an oil which was used without further purification. LCMS ESI (+) m / z 356.8 (M+H).

[0175] 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). After drying overnight at 50 °C in vacuo, 7-(2-(benzyloxy)-4-fluorophenyl)thieno[2,3-d]pyridazin-4(5H)-one (19.4 g, 50% yield) was isolated as a white solid.1H NMR (500 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.05 (d, J = 5.2 Hz, 1H), 7.65 (d, J = 5.2 Hz, 1H), 7.50 (dd, J = 8.4, 6.7 Hz, 1H), 7.29 – 7.21 (m, 4H), 7.21 – 7.16 (m, 2H), 6.96 (td, J = 8.4, 2.4 Hz, 1H), 5.18 (s, 2H). LCMS ESI (+) m / z 352.8 (M+H).

[0176] 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. After reaching rt, the resulting precipitate was isolated by filtration and then dried under a stream of air for 0.5 h giving 7-(2-(benzyloxy)-4-fluorophenyl)-4- chlorothieno[2,3-d]pyridazine (9.71 g, 100% yield) as a solid.1H NMR (500 MHz, DMSO-d6) δ 8.45 (d, J = 5.4 Hz, 1H), 7.74 (d, J = 5.4 Hz, 1H), 7.61 (dd, J = 8.5, 6.8 Hz, 1H), 7.30 (dd, J = 11.4, 2.4 Hz, 1H), 7.27 – 7.20 (m, 3H), 7.19 – 7.14 (m, 2H), 7.03 (td, J = 8.4, 2.4 Hz, 1H), 5.21 (s, 2H). LCMS ESI (+) m / z 371.8 / 373.8 (M+H).

[0177] 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. The precipitate formed was isolated by filtration and washed with water (3 x 200 mL) then with hexane (3 x 100 mL). After drying in vacuo at 50 °C for 2 h, 2-(4-chlorothieno[2,3-d]pyridazin-7-yl)-5-fluorophenol (6.82 g, 86% yield) was isolated as an off white solid.NMR (500 MHz, DMSO- d6) δ 11.00 (s, 1H), 8.48 (d, J = 5.3 Hz, 1H), 7.76 (d, J = 5.4 Hz, 1H), 7.64 – 7.56 (m, 1H), 6.91 – 6.82 (m, 2H). LCMS ESI (+) m / z 281.1 / 283.1 (M+H).

[0178] 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. The reaction mixture was cooled to rt then poured into water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-80% EtOAc / isohexane) to afford tert-butyl (2-(2-(2-(4-chlorothieno[2,3-d]pyridazin- 7-yl)-5-fluorophenoxy)ethoxy)ethyl)carbamate (4.73 g, 94% yield) as a tan oil.1H NMR (500 MHz, DMSO-d6) δ 8.47 (d, J = 5.3 Hz, 1H), 7.74 (d, J = 5.4 Hz, 1H), 7.62 – 7.55 (m, 1H), 7.29 – 7.22 (m, 1H), 7.05 – 6.97 (m, 1H), 6.68 – 6.60 (m, 1H), 4.20 (t, J = 4.7 Hz, 2H), 3.55 – 3.47 (m, 2H), 3.19 – 3.09 (m, 2H), 2.91 – 2.83 (m, 2H), 1.34 (s, 9H). LCMS ESI (+) m / z 468.8 (M+H).

[0179] 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 µmol), tert-butyl (2-(2-(2-(4-chlorothieno[2,3- d]pyridazin-7-yl)-5-fluorophenoxy)ethoxy)ethyl)carbamate (100 mg, 203 µmol), and K2CO3(112 mg, 812 µmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) DCM complex (19.9 mg, 24.4 µmol). The resulting reaction mixture was degassed with N2for 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.1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 5.4 Hz, 1H), 8.07 (d, J = 7.7 Hz, 2H), 7.97 – 7.90 (m, 2H), 7.79 (d, J = 5.4 Hz, 1H), 7.63 (dd, J = 8.5, 6.8 Hz, 1H), 7.26(dd, J = 11.4, 2.4 Hz, 1H), 7.03 (td, J = 8.4, 2.4 Hz, 1H), 6.64 (t, J = 5.6 Hz, 1H), 4.26 – 4.18 (m, 2H), 3.58 – 3.52 (m, 2H), 3.51 – 3.43 (m, 2H), 3.15 (t, J = 6.1 Hz, 2H), 3.08 (t, J = 6.5 Hz, 2H), 2.89 – 2.80 (m, 2H), 1.32 (s, 9H). LCMS ESI (+) m / z 579.4 (M+H). Synthetic Example 2: Synthesis of 7-[2-(2-methoxyethoxy)phenyl]-4-(1-methylsulfonyl-4- piperidyl)thieno[2,3-d]pyridazine (Compound 17)

[0180] Step A: Preparation of tert-butyl 4-[7-[2-(2-methoxyethoxy)phenyl]thieno[2,3- d]pyridazin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate: To a solution of 4-chloro-7-[2-(2- methoxyethoxy)phenyl]thieno[2,3-d]pyridazine (300 mg, 0.935 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine-1-carboxylate (376 mg, 1.22 mmol), anhydrous sodium carbonate (198 mg, 1.87 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (68 mg, 0.094 mmol) under Ar. The mixture was stirred at 100 °C for 1 hour. The mixture was concentrated and purified by Prep-TLC (Petroleum ether:EtOAc = 1:1) to give tert-butyl 4-[7-[2-(2- methoxyethoxy)phenyl]thieno[2,3-d]pyridazin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (400 mg, 91% yield). LCMS ESI (+) m / z 468.2 (M+H).

[0181] 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 H2. The mixture was stirred at 100 °C for 1 hour. The mixture was filtered and washed with EtOAc. The filtrate was concentrated to dryness to give crude tert-butyl 4-[7-[2-(2-methoxyethoxy)phenyl]thieno[2,3-d]pyridazin-4- yl]piperidine-1-carboxylate (275 mg, 55% yield) which was used in the next step without further purifications.

[0182] 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. The mixture was concentrated and diluted with EtOAc (20 mL) and saturated NaHCO3aqueous solution (20 mL). The organic phase was separated, washed with saturated brine solution, dried over anhydrous Na2SO4and concentrated to dryness to give 7-[2-(2-methoxyethoxy)phenyl]-4-(4- piperidyl)thieno[2,3-d]pyridazine (165 mg, 95% yield). LCMS ESI (+) m / z 370.2 (M+H).

[0183] 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. The mixture was diluted with DCM (10 mL) and washed with water (10 mL). The organic phase was separated and dried ( Na2SO4) before concentrated to dryness. The residue was purified by Prep-HPLC to give 7-[2-(2-methoxyethoxy)phenyl]-4-(1-methylsulfonyl-4- piperidyl)thieno[2,3-d]pyridazine (5.1 mg, 17% yield) as a white solid.1H NMR (400 MHz, CD3OD) δ 8.18 (d, J = 5.4 Hz, 1H), 7.86 (d, J = 5.4 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.16 (t, J = 7.4 Hz, 1H), 4.16 (t, J = 4.6 Hz, 2H), 3.94 (d, J = 11.8 Hz, 2H), 3.74-3.56 (m, 1H), 3.50 (t, J = 4.4 Hz, 2H), 3.12-3.07 (m, 1H), 3.06 (s, 3H), 3.05- 2.98 (m, 1H), 2.92 (s, 3H), 2.33-2.11 (m, 4H). LCMS ESI (+) m / z 448.1 (M+H). Synthetic Example 3: Synthesis of 4,13-dioxa-2(7,4)-thieno[2,3-d]pyridazina-1(1,2),3(1,3)- dibenzenacyclotridecaphane (Compound 24)

[0184] Step A: Preparation of 2-[4-(3-hydroxyphenyl)thieno[2,3-d]pyridazin-7-ylphenol: To a solution of 2-(4-chlorothieno[2,3-d]pyridazin-7-yl)phenol (115 mg, 0.438 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL) were added (3-hydroxyphenyl)boronic acid (78 mg, 0.57 mmol), sodium carbonate anhydrous (92 mg, 0.88 mmol) and [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (32 mg, 0.044 mmol) under Ar. The mixturewas stirred at 100 C for 2 hours. The mixture was concentrated and purified by Prep-TLC (DCM:MeOH=20:1) to give 2-[4-(3-hydroxyphenyl)thieno [2,3-d]pyridazin-7-yl]phenol (118 mg, 84% yield).

[0185] 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. The mixture was stirred at 60 °C for 60 hours. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-TLC (PE:EtOAc=2:1) to give 4,13- dioxa-2(7,4)-thieno[2,3-d]pyridazina-1(1,2),3(1,3)-dibenzenacyclotridecaphane (6.5 mg, 49% yield).1H NMR (400 MHz, CD3OD) δ 8.49 (d, J = 5.4 Hz, 1H), 7.99 (d, J = 5.2 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H),7.71-7.61 (m, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.37 (s, 1H), 7.31-7.18 (m, 2H), 7.13 (d, J = 7.6 Hz, 1H), 4.26 (t, J = 7.6 Hz, 2H), 4.18-4.02 (m, 1H), 4.01-3.88 (m, 2H), 2.00 (s, 1H), 1.84-1.69 (m, 2H), 1.65 (d, J = 6.8 Hz, 1H), 1.51-1.42 (m, 2H), 1.39-1.35 (m, 2H), 1.23 (t, J = 7.2 Hz, 1H), 1.19-1.13 (m, 2H). LCMS ESI (+) m / z 431.2 (M+H). Synthetic Example 4: Synthesis of 7-[2-(2-methoxyethoxy)phenyl]-N-phenyl-thieno[2,3- d]pyridazine-4-carboxamide (Compound 26)

[0186] A suspension of 4-chloro-7-[2-(2-methoxyethoxy)phenyl]thieno[2,3-d]pyridazine (100 mg, 0.312 mmol), aniline (0.0430 mL, 0.468 mmol), Pd(OAc)2(3.5 mg, 0.016 mmol), XantPhos (9.0 mg, 0.016 mmol) and Na2CO3(99 mg, 0.94 mmol) in toluene (6 mL) was stirred at 80 °C for 16 h under CO. The reaction was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with saturated brine solution, filtered and dried (MgSO4) before concentrated to dryness. The crude was purified by Prep-HPLC to give 7-[2-(2- methoxyethoxy)phenyl]-N-phenyl-thieno[2,3-d]pyridazine-4-carboxamide (27 mg, 21% yield) as a trifluoroacetic acid salt.1H NMR (400 MHz, CD3OD) δ 8.55 (d, J = 5.2 Hz, 1H), 8.42 (d, J = 5.2Hz, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.71 - 7.60 (m, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.29 - 7.20 (m, 2H), 4.21 (t, J = 4.8 Hz, 2H), 3.52 (t, J = 4.8 Hz, 2H), 3.09 (s, 3H). LCMS ESI (+) m / z 406.2 (M+H). Synthetic Example 5: Synthesis of tert-butyl 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 (Compound

[0187] To a solution of tert-butyl N-[2-[2-[2-(4-chlorothieno[2,3-d]pyridazin-7-yl)-5-fluoro- phenoxy]ethoxy]ethyl]carbamate (30 mg, 0.064 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL) were added 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (20 mg, 0.077 mmol), sodium carbonate (14 mg, 0.13 mmol) and [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (4.7 mg, 0.0064 mmol) under Ar. The mixture was stirred at 95 °C for 2 h. The mixture was concentrated and the residue was purified by Prep-HPLC to give tert- butyl 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 (6.1 mg, 17% yield) as white solid.1H NMR (400 MHz, CD3OD) δ 8.23 (d, J = 5.4 Hz, 1H), 7.84-7.76 (m, 2H), 7.74 (d, J = 5.4 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 7.4 Hz, 1H), 7.15-7.08 (m, 1H), 6.98-6.91 (m, 1H), 4.57 (s, 4H), 4.36 (s, 2H), 4.21 (t, J = 4.4 Hz, 2H), 3.61 (t, J = 4.2 Hz, 2H), 3.45 (t, J = 5.6 Hz, 1H), 3.26-3.14 (m, 4H), 3.00- 2.89 (m, 2H), 1.37 (s, 9H). LCMS ESI (+) m / z 565.2 (M+H). Synthetic Example 6: Synthesis 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 (Compound 104)

[0188] 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. A solution of DIAD (432 mg, 416 µL, 2.14 mmol) in THF (1 mL) was added dropwise, and the reaction was stirred at room temperature for 1 hr. The reaction was diluted with EtOAc (100 mL) and sequentially washed with water (2 x 50 mL) and brine (1 x 50 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-60% EtOAc / isohexane) to afford 4-chloro-7-(4-fluoro-2-((tetrahydro-2H-pyran-4- yl)methoxy)phenyl)thieno[2,3-d]pyridazine (350 mg, 86% yield) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 8.52 – 8.42 (m, 1H), 7.76 (d, J = 5.4 Hz, 1H), 7.62 – 7.51 (m, 1H), 7.28 – 7.20 (m, 1H), 7.04 – 6.95 (m, 1H), 3.92 (d, J = 6.4 Hz, 2H), 3.73 – 3.61 (m, 2H), 3.16 – 3.07 (m, 2H), 1.28 – 0.95 (m, 5H). LCMS ESI (+) m / z = 379.8 / 381.8 (M+H).

[0189] 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 µmol), PdCl2(dppf)-CH2Cl2adduct (80 mg, 98 µmol) and potassium acetate (77.7 mg, 792 µmol) were added to a round bottom flask and the flask was evacuated and back-filled with N2(x 3).7-Bromo-1,4-dihydroisoquinolin-3(2H)-one (179 mg, 792 µmol) was added, followed by dry 1,4-dioxane (8 mL). The reaction was degassed for 10 mins with an N2balloon. 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 µmol), PdCl2(dppf)-CH2Cl2adduct (80 mg, 98 µmol) and a solution of potassium carbonate (109 mg, 792 µmol) in water (0.5 ml). The resulting reaction mixture was degassed with N2for 10 mins and thenheated 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.1H NMR (500 MHz, DMSO-d6) δ 8.35 (d, J = 5.4 Hz, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.86 – 7.78 (m, 2H), 7.63 – 7.56 (m, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.24 (dd, J = 11.5, 2.5 Hz, 1H), 7.01 (td, J = 8.3, 2.4 Hz, 1H), 4.51 (s, 2H), 3.94 (d, J = 6.5 Hz, 2H), 3.72 – 3.64 (m, 2H), 3.59 (s, 2H), 3.12 (t, J = 11.1 Hz, 2H), 1.84 – 1.73 (m, 1H), 1.34 – 1.25 (m, 2H), 1.11 – 1.00 (m, 2H). LCMS ESI (+) m / z 490.4 (M+H). Synthetic Example 7: Synthesis of tert-butyl (2-(2-(2-(4-(4-((2H-tetrazol-5- yl)methyl)phenyl)thieno[2,3-d]pyridazin-7-yl)-5-fluorophenoxy)ethoxy)ethyl)carbamate (Compound 128)

[0190] TMS-N3 (50.4 mg, 58.1 µL, 437 µmol) was added into a suspension of tert-butyl (2- (2-(2-(4-(4-(cyanomethyl)phenyl)thieno[2,3-d]pyridazin-7-yl)-5- fluorophenoxy)ethoxy)ethyl)carbamate (prepared as described in Synthetic Example 5, substituting 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile for 6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline, 160 mg, 292 µmol) and copper(II) oxide (0.362 mg, 4.55 µmol) in DMF (3 mL) and MeOH (0.3 mL). 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. The crude product was purified by chromatography on silica gel(12 g cartridge, 0-10% MeOH / DCM) to afford tert-butyl (2-(2-(2-(4-(4-((2H-tetrazol-5- yl)methyl)phenyl)thieno[2,3-d]pyridazin-7-yl)-5-fluoro phenoxy)ethoxy)ethyl)carbamate (10 mg, 5.7% yield) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 8.34 (d, J = 5.4 Hz, 1H), 7.94 (d, J = 7.9 Hz, 2H), 7.73 (d, J = 5.4 Hz, 1H), 7.62 (dd, J = 8.5, 6.8 Hz, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.30 – 7.23 (m, 1H), 7.05 – 6.98 (m, 1H), 6.68 – 6.59 (m, 1H), 4.41 (s, 2H), 4.21 (t, J = 4.8 Hz, 2H), 3.56 – 3.50 (m, 2H), 3.15 (t, J = 6.1 Hz, 2H), 2.89 – 2.80 (m, 2H), 1.32 (s, 9H). LCMS ESI (+) m / z 592.6 (M+H). Synthetic Example 8: Synthesis of 6-(4-(2-(2-methoxyethoxy)phenyl)-6,7-dihydro-5H- cyclopenta[d]pyridazin-1-yl)-3,4-dihydroisoquinolin-1(2H)-one (Compound 133)

[0191] Step A: Preparation of 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine: To a solution of 3,6-dichloro-1,2,4,5-tetrazine (1.0 g, 6.7 mmol) in DCM (40 mL) at 0 °C was added 1- (cyclopent-1-en-1-yl) pyrrolidine (0.80 g, 5.8 mmol) dropwise with stirring over 10 min. Citric acid (10% in water) (12 mL) was added followed by water (12 mL) and the reaction mixture was warmed to rt and stirred for an additional 10 min. The resulting solution was extracted with DCM (2 x 10 mL) and the organic fractions were pooled, washed with brine (10 mL), dried (Na2SO4), filtered, and the solvent was removed in-vacuo. The residue was purified by MPLC on silica (Biotage Sfär HC 5 g; 0-50% EtOAc / hexanes) to give 1,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyridazine (600 mg, 48% yield) as a pink solid. LCMS ESI (+) m / z 189 (M+H).

[0192] 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 Cs2CO3(340 mg, 1.00 mmol). Dioxane (4 mL) was added followed by Pd(dppf)2Cl2(38 mg, 0.050 mmol). Thevial was heated under microwave irradiation to 100 C under Ar for 2 h. The crude reaction mixture was filtered through a plug of Celite® then purified by C18 reverse phase preparative HPLC (0- 100% MeCN / water) to give 6-(4-chloro-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-3,4- dihydroisoquinolin-1(2H)-one (100 mg, 66% yield) as a pink oil. LCMS ESI (+) m / z 300 (M+H).

[0193] 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 Cs2CO3(194 mg, 0.600 mmol). Dioxane (4 mL) was added followed by Pd(dppf)2Cl2(21 mg, 0.030 mmol). The vial was capped and heated under microwave irradiation to 100 °C under Ar for 2 h. The crude reaction mixture was filtered through a plug of Celite® then the solvent was removed in-vacuo. The residue was purified by C18 reverse phase preparative HPLC (0-100% MeCN / water) to give 6-(4-(2-(2-methoxyethoxy)phenyl)-6,7-dihydro-5H- cyclopenta[d]pyridazin-1-yl)-3,4-dihydroisoquinolin-1(2H)-one (29 mg, 20% yield).1H NMR (700 MHz, CD3OD) δ 8.11 (d, J = 8.0 Hz, 1H), 7.86 -7.83 (m, 1H), 7.82 (dd, J = 1.7, 0.8 Hz, 1H), 7.52 -7.48 (m, 1H), 7.45 ( dd, J = 7.5, 1.7 Hz, 1H), 7.18 ( dd, J = 8.5, 1.0 Hz, 1H), 7.14 (d, J = 1.0 Hz, 1H), 4.19-4.16 (m, 2H), 3.65-3.61 (m, 2H), 3.57 (dd, J = 7.1, 6.3 Hz, 2H), 3.28 (s, 3H), 3.24 (t, J = 7.4 Hz, 2H), 3.11 (t, J = 6.7 Hz, 2H), 3.02 (s, 2H), 2.14 (m, 2H); LCMS ESI (+) m / z 416.2 (M+H). Synthetic Example 9: Synthesis 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 (Compound 146)

[0194] 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 µmol), copper(I) iodide (814 µg, 4.27 µmol) 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 µmol) and the mixture was stirred at room temperature for 30 min. A solution of ethyl pent-4-ynoate (75.5 mg, 598 µmol) in triethylamine (1.45 g, 2.00 mL, 14.3 mmol) was added and the resulting mixture was stirred at 80 °C for 5 h. The 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.1H NMR (500 MHz, DMSO-d6) δ 8.38 (d, J = 5.4 Hz, 1H), 7.67 (d, J = 5.4 Hz, 1H), 7.59 – 7.54 (m, 1H), 7.26 – 7.20 (m, 1H), 7.04 – 6.96 (m, 1H), 6.68 – 6.60 (m, 1H), 4.19 (t, J = 4.8 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H), 3.51 (t, J = 4.8 Hz, 2H), 3.15 (t, J = 6.0 Hz, 2H), 2.93 – 2.85 (m, 4H), 2.76 (t, J = 7.0 Hz, 2H), 1.34 (s, 9H), 1.22 (t, J = 7.1 Hz, 3H). LCMS ESI (+) m / z 558.8 (M+H).

[0195] 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 astirring solution of ethyl 5-(7-(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. The reaction mixture was concentrated in vacuo to give lithium 5-(7-(2-(2-(2-((tert- butoxycarbonyl)amino)ethoxy)ethoxy)-4-fluorophenyl)thieno[2,3-d]pyridazin-4-yl)pent-4- ynoate (56 mg, 98% yield) as an off-white solid. The product was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6) δ 8.32 (d, J = 5.3 Hz, 1H), 7.74 (d, J = 5.3 Hz, 1H), 7.59 – 7.54 (m, 1H), 7.22 (dd, J = 11.4, 2.4 Hz, 1H), 7.02 – 6.97 (m, 1H), 6.69 – 6.63 (m, 1H), 4.18 (t, J = 4.8 Hz, 2H), 3.51 (t, J = 4.8 Hz, 2H), 3.16 (t, J = 6.1 Hz, 2H), 2.88 (d, J = 6.0 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H), 2.21 (t, J = 7.5 Hz, 2H), 1.34 (s, 9H). LCMS ESI (+) m / z 530.8 (M+H).

[0196] 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 µL, 0.62 mmol). 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. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-10% MeOH / DCM) to afford tert-butyl (2-(2-(2-(4-(5-(dimethylamino)-5-oxopent-1-yn-1- yl)thieno[2,3-d]pyridazin-7-yl)-5-fluorophenoxy)ethoxyethyl)carbamate (28 mg, 49% yield) as a solid.1H NMR (500 MHz, Chloroform-d) δ 7.85 (d, J = 5.4 Hz, 1H), 7.68 (d, J = 5.4 Hz, 1H), 7.66 – 7.53 (m, 1H), 6.90 – 6.76 (m, 2H), 4.82 (s, 1H), 4.13 (t, J = 4.9 Hz, 2H), 3.59 (t, J = 4.8 Hz, 2H), 3.30 (t, J = 5.2 Hz, 2H), 3.14 (d, J = 5.4 Hz, 2H), 3.07 (s, 3H), 3.03 – 2.91 (m, 5H), 2.79 (t, J = 7.5 Hz, 2H), 1.42 (s, 9H). LCMS ESI (+) m / z 557.4 (M+H). Synthetic Example 10: Synthesis 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 (Compound 160)

[0197] Step A: Preparation of 4-chloro-N,2-dimethoxy-N-methyl-benzamide: To a solution of 4-chloro-2-methoxy-benzoic acid (10.0 g, 53.6 mmol), N,N-diisopropylethylamine (28.0 mL, 161 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (22.4 g, 59.0 mmol) in DMF (100 mL) was added N,O-dimethylhydroxylamine hydrochloride (5.49 g, 56.3 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was poured into water (100 mL) and extracted with EtOAc (100 mL). The organic phase was washed with saturated brine solution (100 mLx2), dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel column (Petroleum ether:EtOAc = 1:1) to give 4-chloro-N,2-dimethoxy- N-methyl-benzamide (12.0 g, 98% yield). LCMS ESI (+) m / z 230.1 (M+H).

[0198] 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. 1 N HCl solution was added to adjust the pH to 3, and the mixture was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with saturated brine solution, dried (Na2SO4) and concentrated. The residue was purified by reserve-phase column chromatography to give 2-(4- chloro-2-methoxy-benzoyl)thiophene-3-carboxylic acid (13.0 g, 84% yield). LCMS ESI (+) m / z 297.0 (M+H).

[0199] 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. The solid was filtered, washed with water and dried in vacuo to give crude 7-(4-chloro-2-methoxy-phenyl)-5H- thieno[2,3-d]pyridazin-4-one (10.0 g, 78% yield) which was used in the next step without further purification. LCMS ESI (+) m / z 293.0 (M+H).

[0200] 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 NaHCO3solution was added to adjust the pH to 8. The mixture was extracted with DCM, dried (Na2SO4), filtered and concentrated to dryness to give 4-chloro-7-(4- chloro-2-methoxy-phenyl)thieno[2,3-d]pyridazine (8.00 g, 94% yield). LCMS ESI (+) m / z 313.0 (M+H).

[0201] 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). The combined organic layers were dried (Na2SO4) and concentrated to dryness to give crude 5-chloro-2-(4-chlorothieno[2,3-d]pyridazin-7-yl)phenol (3.80 g, 99% yield) which was used in the next step without further purification. LCMS ESI (+) m / z 299.0 (M+H).

[0202] 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), Cs2CO3(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. The mixture was cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4and concentrated. The residue was purified by Prep-TLC (25% EtOAc in petroleum ether) to give 4-[[5-chloro-2-(4-chloro-7H-cyclopenta[d]pyridazin-1-yl)phenoxy]methyl]-1-methyl-piperidin-2-one (105 mg, 77% yield). LCMS ESI (+) m / z 422.1 (M+H).

[0203] 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), Na2CO3(55 mg, 0.52 mmol) and Pd(dppf)Cl2(19 mg, 0.026 mmol) under Ar. After stirring for 3 h at 90 °C, the mixture was concentrated and purified by Prep-TLC (40% EtOAc in Petroleum ether) to give 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, 55% yield).

[0204] 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). The mixture was stirred at 25 °C for 1 h. After concentration to dryness under vacuum, the mixture was purified by Prep-HPLC to give 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 as a trifluoroacetic acid salt (29 mg, 40% yield).1H NMR (400 MHz, CD3OD) δ 8.42 (d, J = 5.6 Hz, 1H), 7.95 - 7.81 (m, 3H), 7.62 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.27 (d, J = 6.8 Hz, 1H), 4.53 (s, 2H), 4.15 - 3.91 (m, 2H), 3.64 - 3.55 (m, 2H), 3.25 - 3.11 (m, 2H), 2.81 (s, 3H), 2.12 - 2.05 (m, 2H), 1.96 - 1.80 (m, 1H), 1.79 - 1.70 (m, 1H), 1.51 - 1.31 (m, 1H). LCMS ESI (+) m / z 519.1 (M+H). Synthetic Example 11: Synthesis of tert-butyl 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 (Compound 176)

[0205] 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 NH4Cl (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 Na2SO4and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether to give 3- bromo-4-(diethoxymethyl)thiophene (140 g, 87% yield). LCMS ESI (+) m / z 219.0 / 221.0 (M+H).

[0206] 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. The resulting mixture was stirred at -78 °C for 30 min, and then warmed to room temperature and stirred for an additional 3 h. The reaction was quenched with H2O (500 mL) and extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (300 mL x 1), filtered and concentrated. The residue was purified by silica gel column (eluting with petroleum ether) to give crude [3-bromo-4-(diethoxymethyl)-5- trimethylsilyl-2-thienyl]-trimethyl-silane (185 g, 92% yield).

[0207] 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. A solution of N-fluorobenzenesulfonimide (50.8 g, 161 mmol) in THF (200 mL) was added at -78 °C under Ar. The mixture was stirred for 2 h and quenched with H2O (200 mL). The mixture was extracted with EtOAc (200 mL x 3) and washed with brine (200 mL x 2). The organic solvent was removed under vacuum and the residue was purified by silica gel column (100% petroleum ether) to give [3-(diethoxymethyl)-4-fluoro-5-trimethylsilyl-2-thienyl]-trimethyl-silane (40.0 g, 68% yield).

[0208] 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). The organic phase was washed with brine (100 mL) and concentrated. The residue was purified by column chromatography (100% petroleum ether) to give 3-(diethoxymethyl)-4-fluoro-thiophene (520 mg, 25% yield) as an oil.

[0209] 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. Sodium phosphate monobasic (920 mg, 7.67 mmol) and sodium chlorite (450 mg, 4.98 mmol) were added, and the resulting mixture was stirred at 30 °C for 0.5 h. The mixture was diluted with water (20 mL) and the product was extracted with EtOAc (20 mL x 2). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by reserve-phase column chromatography to give 4-fluorothiophene-3-carboxylic acid (180 mg, 48% yield) as a white solid. LCMS ESI (-) m / z 144.9 (M-H).

[0210] 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. The mixture was stirred at -70 C for 10 min, then allowed to warm to rt. The mixture was diluted with NH4Cl aqueous solution (20 mL), and the product was extracted with EtOAc (20 mL x 2). The combined organic layers were dried over Na2SO4and concentrated. The residue was purified by reserve-phase column chromatography to give 4-fluoro-2-(4-fluoro- 2-methoxy-benzoyl)thiophene-3-carboxylic acid (230 mg, 63% yield) which was used in the next step directly. LCMS ESI (+) m / z 299.0 (M+H).

[0211] 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. The mixture was concentrated and purified by column chromatography (EtOAc / PE:1 / 2) to give crude 3-fluoro-7-(4-fluoro-2-methoxy- phenyl)-5H-thieno[2,3-d]pyridazin-4-one (230 mg) which was used in the next step directly. LCMS ESI (+) m / z 295.1 (M+H).

[0212] 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 NaHCO3aqueous solution was added to adjust the pH to 7-8. The mixture was extracted with EtOAc, dried over anhydrous Na2SO4and concentrated. The residue was purified by Prep- TLC (EtOAc / petroleum ether:1 / 5) to give 4-chloro-3-fluoro-7-(4-fluoro-2-methoxy- phenyl)thieno[2,3-d]pyridazine (136 mg, 56% yield) as a light-yellow solid. LCMS ESI (+) m / z 313.1 (M+H).

[0213] 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. The mixture was poured into cold NaHCO3aqueous solution (20 mL) and stirred at rt for 15 min. The product was extracted with EtOAc (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness to give 2-(4-chloro-3-fluoro- thieno[2,3-d]pyridazin-7-yl)-5-fluoro-phenol (126 mg, 97% yield). LCMS ESI (+) m / z 299.0 (M+H).

[0214] 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. The mixture was stirred at rt for 16 h. The mixture was poured into water and the product was extracted with EtOAc, dried over anhydrous Na2SO4and concentrated. The residue was purified by Prep-TLC (EtOAc / petroleum ether:1 / 4) to give tert-butyl N-[2-[2-[2-(4-chloro-3-fluoro-thieno[2,3- d]pyridazin-7-yl)-5-fluoro-phenoxy]ethoxy]ethyl]carbamate (108 mg, 53% yield). LCMS ESI (+) m / z 486.1 (M+H).

[0215] Step L: Preparation of tert-butyl 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 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) were added sodium carbonate (11 mg, 0.10 mmol) and 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (2.0 mg, 0.0027 mmol). The mixture was stirred at 100 °C for 4 h under Ar. The mixture was concentrated and purified by Prep-HPLC to give tert-butyl 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 (8.2 mg, 68% yield) as a trifluoroacetic acid salt.1H NMR (400 MHz, CD3OD) δ 7.83 (s, 1H), 7.78-7.67 (m, 2H), 7.60 (t, J = 7.0 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.13 (d, J =10.6 Hz, 1H), 6.97 (t, J = 8.1 Hz, 1H), 4.45 (s, 2H), 4.28-4.15 (m, 2H), 3.69-3.60 (m, 2H), 3.54 (t, J =6.2 Hz, 2H), 3.31-3.20 (m, 4H), 3.05-2.92 (m, 2H), 1.39 (s, 9H); LCMS ESI (+) m / z 583.3 (M+H). Synthetic Example 12: Synthesis of tert-butyl N-[2-[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 (Compound 180)

[0216] 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. The mixture was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7 / 1) to give 5-bromo-1,4- dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine (1.06 g, 59% yield). LCMS ESI (+) m / z 267.0 / 269.0 (M+H).

[0217] 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. The residue was suspended in 30 mL of EtOAc and filtered through a pad of Celite®. The filter cake was rinsed with 50 mL of EtOAc. The filtrate was washed with saturated brine solution (30 mL). The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (20%-55% EtOAc in hexane) to afford 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazin-5-ol (307 mg, 38% yield). LCMS ESI (+) m / z 205.0 (M+H).

[0218] 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 (1290mg, 3.02 mmol), Pd(dppf)Cl2(55.3 mg, 0.0755 mmol) and Na2CO3(400 mg, 3.78 mmol) in 1,4- dioxane (10 mL) and water (0.5 mL) was stirred at 95 °C for 4 h. The 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 Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (30%-50% EtOAc in petroleum ether) to afford tert-butyl N-[2-[2-[2-(4-chloro-7-hydroxy-6,7-dihydro-5H- cyclopenta[d]pyridazin-1-yl)-5-fluoro-phenoxy]ethoxy]ethyl]carbamate (62 mg, 8.8% yield) and 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 (110 mg, 16% yield). LCMS ESI (+) m / z 468.1 (M+H).

[0219] 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. The reaction mixture was stirred at 0 °C for 15 minutes. The reaction was diluted with DCM (10 mL) and quenched by saturated NaHCO3aqueous solution. The mixture was extracted with DCM (10 mL x 2). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by Prep-TLC (petroleum ether / EtOAc=2 / 1) to give 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 (15 mg, 50% yield).

[0220] Step E: Preparation of tert-butyl N-[2-[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-(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)Cl2(3.4 mg, 0.0048 mmol) and Na2CO3(8.5 mg, 0.080 mmol) in 1,4- dioxane (2 mL) and water (0.2 mL) was stirred at 95 °C for 2 h. After the completion of the reaction, the mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with saturated brine solution (10 mL), dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by Prep-HPLC to afford tert-butyl N-[2-[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 (2.3 mg, 13% yield) as a trifluoroacetic acid salt.1H NMR (400 MHz, CD3OD) δ 7.93 – 7.85 (m, 2H), 7.57 – 7.50 (m, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.07 – 7.00 (m, 1H), 6.96 – 6.87 (m, 1H), 6.29 – 6.11 (m, 1H), 4.49 (s, 2H), 4.30 – 4.14 (m, 2H), 3.78- 3.65 (m, 2H), 3.59 (t, J = 6.3 Hz, 1H), 3.50 – 3.38 (m, 2H), 3.18 – 3.07 (m, 2H), 2.96 – 2.83 (m, 1H), 2.51 – 2.33 (m, 2H), 1.41 (s, 9H); LCMS ESI (+) m / z 567.3 (M+H). Synthetic Example 13: Synthesis of Isomer 1 of tert-butyl N-[2-[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 (Compound 191)

[0221] Step A: Preparation of 3-(2-((benzyloxy)carbonyl)-1,2,3,4-tetrahydroisoquinoline-6- carbonyl)thiophene-2-carboxylic acid: To a solution of benzyl 6-[methoxy(methyl)carbamoyl]- 3,4-dihydro-1H-isoquinoline-2-carboxylate (5.10 g, 14.4 mmol) in THF (40 mL) with an inert atmosphere of nitrogen was added n-BuLi (2.5 M in hexanes, 13.0 mL, 31.7 mmol) at -78 °C. The resulting solution was stirred at -78 °C for 30 min, then thiophene-2-carboxylic acid (2.03 g, 15.8 mmol) was added. The reaction was stirred at -78 °C for 3 h. The mixture was concentrated and diluted with 50 mL of EtOAc, which was washed with saturated brine solution (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford crude 3-(2-((benzyloxy)carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonyl)thiophene-2-carboxylic acid (6.8 g), which was used in next step without further purification. LCMS ESI (+) m / z 436.2 (M+H).

[0222] 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. The mixture was cooled to rt, concentrated and filtered. The filter-cake was dried in vacuo to give benzyl 6-(7-oxo-6H- thieno[2,3-d]pyridazin-4-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (2.50 g, 42% yield for two steps). LCMS ESI (+) m / z 418.1 (M+H).

[0223] 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. After cooling to rt, the reaction mixture was poured into ice-water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with sodium bicarbonate aqueous solution (100 mL) and saturated brine solution (100 mL), dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica (50% ethyl acetate / petroleum ether) to afford benzyl 6-(7- chlorothieno[2,3-d]pyridazin-4-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (2.10 g, 77% yield).1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 5.1 Hz, 1H), 7.85 (d, J = 4.9 Hz, 1H), 7.79 – 7.69 (m, 2H), 7.52 – 7.26 (m, 6H), 5.16 (s, 2H), 4.83 – 4.64 (m, 2H), 3.01 – 2.90 (m, 2H), 1.99 (s, 2H), 1.25 – 1.09 (m, 2H); LCMS ESI (+) m / z 436.1 (M+H).

[0224] 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)Cl2(39 mg, 0.055 mmol) and Na2CO3(97 mg, 0.92 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was stirred at 95 °C for 8 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by Prep-TLC (petroleum ether / EtOAc=3 / 1) to afford benzyl 6-[7-(4-phenylcyclohexen- 1-yl)thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (76 mg, 37% yield).

[0225] 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). The mixture was stirred at 25 °C for 48 h under 1 atm of H2 gas. The reaction mixture was filtered through a Celite® plug and washed with ethyl acetate (20 mL). The filtrate was concentrated and purified by Prep-HPLC to afford two isomers in which the stereochemistry was arbitrarily assigned. Isomer 1: trans-benzyl 6-[7-(4-phenylcyclohexyl)thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2- carboxylate (40 mg, 52% yield). Isomer 2: cis-benzyl 6-[7-(4-phenylcyclohexyl)thieno[2,3- d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (10 mg, 13% yield). LCMS ESI (+) m / z 560.2 (M+H).

[0226] 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). The resulting mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure and purified by Prep-HPLC to afford Isomer 1 of 7-(4-phenylcyclohexyl)-4- (1,2,3,4-tetrahydroisoquinolin-6-yl)thieno[2,3-d]pyridazine (6.6 mg, 35% yield) as a trifluoroacetic acid salt.1H NMR (400 MHz, CD3OD) δ 8.36 (d, J = 5.4 Hz, 1H), 7.90 – 7.75 (m, 3H), 7.53 (d, J = 8.5 Hz, 1H), 7.41 – 7.23 (m, 4H), 7.15 (t, J = 7.2 Hz, 1H), 4.52 (s, 2H), 3.82 – 3.69 (m, 1H), 3.60 (t, J = 6.3 Hz, 2H), 2.96 – 2.86 (m, 1H), 2.50 – 2.25 (m, 4H), 2.22 – 2.08 (m, 2H), 1.98 – 1.85 (m, 2H). LCMS ESI (+) m / z 426.2 (M+H). Synthetic Example 14: Synthesis of Isomer 2 of tert-butyl N-[2-[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 (Compound 200)

[0227] To a solution of Isomer 2 of benzyl 6-[7-(4-phenylcyclohexyl)thieno[2,3-d]pyridazin- 4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (10 mg, 0.018 mmol) in 1,4-dioxane (1 mL) was added LiOH (0.5 M, 0.93 mL, 0.047 mmol). The reaction mixture was stirred at 80 °C for 48 hrs. The mixture was concentrated and purified by Prep-HPLC to afford Isomer 2 of 7-(4- phenylcyclohexyl)-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)thieno[2,3-d]pyridazine (4.0 mg, 53% yield) as a trifluoroacetic acid salt.1H NMR (400 MHz, CD3OD) δ 8.50 (d, J = 5.4 Hz, 1H), 7.91 (d, J = 5.4 Hz, 1H), 7.89 – 7.81 (m, 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.39 – 7.15 (m, 5H), 4.53 (s, 2H), 3.61 (t, J = 6.2 Hz, 2H), 3.48 (t, J = 11.9 Hz, 1H), 2.77 (t, J = 12.0 Hz, 1H), 2.41 – 2.08 (m, 6H), 1.93 – 1.72 (m, 2H); LCMS ESI (+) m / z 426.2 (M+H). Synthetic Example 15: Synthesis of 7-(1-phenyl-4-piperidyl)-4-(1,2,3,4-tetrahydroisoquinolin-6- yl)thieno[2,3-d]pyridazine (Compound 199)

[0228] Step A: Preparation of benzyl 6-(7-(1-phenyl-1,2,3,6-tetrahydropyridin-4- yl)thieno[2,3-d]pyridazin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate: A solution of benzyl 6-(7-chlorothieno[2,3-d]pyridazin-4-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (100 mg, 0.229 mmol), 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine(79 mg, 0.28 mmol), 1,1-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (17 mg, 0.0229 mmol) and sodium acetate (38 mg, 0.46 mmol) in 1,4-dioxane / H2O (3 mL, 10 / 1) was stirred at 80 °C for 6 hours. The mixture was concentrated and purified by Prep- TLC (EtOAc / petroleum ether: 1 / 5) to give benzyl 6-(7-(1-phenyl-1,2,3,6-tetrahydropyridin-4- yl)thieno[2,3-d]pyridazin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (95 mg, 74% yield).

[0229] 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). The mixture was stirred at 25 °C under H2atmosphere for 6 h. The mixture was filtered through a pad of Celite® and washed with THF (10 mL). The filtrate was concentrated to dryness to give crude benzyl 6-[7-(1-phenyl-4-piperidyl)thieno[2,3-d]pyridazin-4-yl]-3,4- dihydro-1H-isoquinoline-2-carboxylate (24 mg, 96% yield). LCMS ESI (+) m / z 561.2 (M+H).

[0230] 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 / CH3COOH (1.0 mL) was stirred at 25 °C for 0.5 hour. The mixture was diluted with water (5 mL). Aqueous ammonia was added to adjust the pH to 9, and the mixture was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with saturated brine solution (10 mL), dried (MgSO4) and filtered before concentration to dryness. The crude was then purified by Prep-HPLC to give 7-(1-phenyl-4-piperidyl)-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)thieno[2,3- d]pyridazine (5.4 mg, 25% yield) as a trifluoroacetic acid salt.1H NMR (400 MHz, CD3OD) δ 8.39 (d, J = 5.6 Hz, 1H), 7.90 - 7.76 (m, 3H), 7.7- 7.42 (m, 6H), 4.53 (s, 2H), 4.02 - 3.74 (m, 5H), 3.70 - 3.51 (m, 2H), 2.78 - 2.61 (m, 2H), 2.60 - 2.45 (m, 2H); LCMS ESI (+) m / z 427.2 (M+H). Synthetic Example 16: Synthesis of (2,2,2-trifluoro-1,1-dimethyl-ethyl) 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 (Compound 220)

[0231] 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). The organic fractions were pooled, washed with brine (5 mL), dried (Na2SO4), filtered, and the solvent was removed in vacuo to give (2,2,2-trifluoro-1,1- dimethyl-ethyl)imidazole-1-carboxylate (350 mg, 99% yield) as a colorless oil, which was used in the next reaction without further purification. LCMS ESI (+) m / z 223 (M+H).

[0232] 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. The solvent was removed in vacuo to give (2,2,2-trifluoro-1,1-dimethyl-ethyl)3- methylimidazol-3-ium-1-carboxylate iodide (318 mg, 65% yield) as a viscous oil, which was used in the next reaction without further purification. LCMS ESI (+) m / z 238 (M+H).

[0233] 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 Et3N (0.250 mL, 1.74 mmol) in chloroform (1 mL). The reaction was stirred at rt for 3 h then heated to 60 °C for an additional 3 h. The solvent was removed in vacuo and the residue was purified by MPLC on silica (Biotage Sfär HC 5g; 0-100% EtOAc / hexanes) togive 2-[2-[(2,2,2-trifluoro-1,1-dimethyl-ethoxy)carbonylamino]ethoxy]ethyl 4- methylbenzenesulfonate (200 mg, 56% yield) as a viscous oil. LCMS ESI (+) m / z 414 (M+H).

[0234] 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 Cs2CO3(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 (Na2SO4), filtered and concentrated. The residue was purified by MPLC on silica (Biotage Sfär HC 5 g; 0-100% EtOAc / hexanes) to give 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 (29 mg, 31% yield). LCMS ESI (+) m / z 522 (M+H).

[0235] Step E: Preparation of (2,2,2-trifluoro-1,1-dimethyl-ethyl) 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: A Biotage microwave vial was charged with (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 (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 mmol), Na2CO3(20 mg, 0.19 mmol), and Pd(dppf)2Cl2DCM complex (5.6 mg, 0.0077 mmol). Dioxane (700 µL) and water (250 µL) were added and the vial was sealed and degassed for 15 min. The reaction mixture was heated to 120 °C for 4 h under Ar. The crude reaction mixture was filtered through Celite® and the solvent was removed in vacuo. The residue was purified MPLC on silica (Biotage Sfär HC 5g; 0-15% MeOH / DCM) and then repurified by preparative TLC on silica (10% MeOH / DCM) to give (2,2,2-trifluoro-1,1-dimethyl-ethyl) 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 (2.6 mg, 5% yield).1H NMR (700 MHz, CD3OD) δ 8.21 (d, J = 5.4 Hz, 1H), 7.75 (d, J = 5.4 Hz, 1H), 7.73 -7.68 (m, 2H), 7.60 (dd, J = 8.4, 6.5 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.11 (dd, J = 11.1, 2.3Hz, 1H), 6.95 (td, J = 8.3, 2.4 Hz, 1H), 4.24-4.20 (m, 2H), 4.10 (s, 2H), 3.62 (dd, J = 5.5, 3.6 Hz, 2H), 3.23 (t, J = 5.7 Hz, 2H), 3.18 (t, J = 6.0 Hz, 2H), 2.99 (dt, J = 11.9, 5.8 Hz, 4H), 1.61 (s, 6H); LCMS ESI (+) m / z 519 (M-100).Synthetic Example 17: Synthesis 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 (Compound 225)

[0236] Step A: Preparation of (4-nitrophenyl) [1-(trifluoromethyl)cyclopropyl]methyl carbonate: A solution of [1-(trifluoromethyl)cyclopropyl]methanol (50 mg, 0.36 mmol), (4- nitrophenyl)carbonochloridate (65 mg, 0.32 mmol) and triethylamine (0.15 mL, 1.1 mmol) in DCM (5 mL) was stirred for 2 h at rt. The mixture was poured into water and extracted with DCM. The organic phase was dried over Na2SO4, filtered and concentrated to dryness to give crude (4- nitrophenyl) [1-(trifluoromethyl)cyclopropyl]methyl carbonate (100 mg, 92% yield), which was used in the next step without further purification. LCMS ESI (+) m / z 306.1 (M+H).

[0237] 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- (trifluoromethyl)cyclopropyl]methyl carbonate (53 mg, 0.17 mmol). The mixture was stirred at rt for 16 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether / EtOAc = 2 / 1) to give 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 (60 mg, 71% yield). LCMS ESI (+) m / z 731.2 (M+H).

[0238] 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). The mixture was stirred at rt for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by Prep-HPLC to give [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 (32 mg, 92% yield) as a trifluoroacetic acid salt.NMR (400 MHz, CD3OD) δ 8.46 (dd, J = 14.7, 4.8 Hz, 1H), 7.88 (dd, J = 13.4, 6.2 Hz, 3H), 7.68 (dd, J = 8.3, 6.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = 10.9, 2.2 Hz, 1H), 7.00 (td, J = 8.4, 2.3 Hz, 1H), 4.53 (s, 2H), 4.32 – 4.20 (m, 2H), 4.12 (s, 2H), 3.71 – 3.52 (m, 4H), 3.33 – 3.21 (m, 4H), 3.04 (t, J = 5.5 Hz, 2H), 1.02 – 0.96 (m, 2H), 0.88 – 0.82 (m, 2H); LCMS ESI (+) m / z 631.2 (M+H). Synthetic Example 18: Synthesis 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 (Compound 228)

[0239] Step A: Preparation of tert-butyl 6-[7-(4-fluoro-2-methoxy-phenyl)thieno[2,3- d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: A mixture of 4-chloro-7-(4-fluoro- 2-methoxy-phenyl)thieno[2,3-d]pyridazine (2.50 g, 8.48 mmol), tert-butyl 6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (3.96 g, 11.0 mmol), 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (621 mg, 0.848mmol) and sodium carbonate (2.70 g, 25.4 mmol) in 1,4-dioxane (60 mL) / water (6 mL) was stirred at 85 °C under N2 for 12 hours. The mixture was concentrated, diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc=1 / 1) to give 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, 74% yield). LCMS ESI (+) m / z 492.2 (M+H).

[0240] 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. The mixture was stirred at 20 °C for 12 h. The solution was poured into ice-water and NaHCO3aqueous solution was added to adjust the pH to 7. Potassium carbonate (1.68 g, 12.2 mmol) was then added, followed by di-tert-butyl dicarbonate (1.38 g, 6.30 mmol) in ethanol (10 mL) dropwise at 0 °C. The mixture was stirred at 20 °C for 2 hours.1N HCl was added to adjust the pH to 6 and the product was extracted with DCM (30 mL x 2). The combined organic layers were dried (Na2SO4) and concentrated. The residue was washed with petroleum ether and dried in vacuo to give tert-butyl 6-[7-(4-fluoro-2-hydroxy-phenyl)thieno[2,3-d]pyridazin-4-yl]- 3,4-dihydro-1H-isoquinoline-2-carboxylate (2.30 g, 76% yield). LCMS ESI (+) m / z 476.2 (M+H).

[0241] 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, 1.57 mmol) at 0 °C. The mixture was stirred at 15 °C for 14 h. The mixture was diluted with saturated brine solution (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic fractions were dried (Na2SO4) and concentrated. The residue was purified by Prep-TLC (petroleum ether / EtOAc = 4 / 1) to give 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 (384 mg, 98% yield). LCMS ESI (+) m / z 622.2 (M+H).

[0242] 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.H2O (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 (Na2SO4) and filtered before concentrating to dryness. The crude was then purified by column chromatography on silica gel eluting with 25% EtOAc in petroleum ether to give 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 (102 mg, 97% yield). LCMS ESI (+) m / z 594.3 (M+H).

[0243] 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. The mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc (20 mL) and washed with saturated brine solution (20 mL x 2). The organic phase was separated, dried (Na2SO4) and concentrated. The residue was purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 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, 67% yield). LCMS ESI (+) m / z 661.3 (M+H).

[0244] 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. The mixture was stirred for 2 h. After concentration, the residue was purified by Prep-HPLC to give 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 (11 mg, 44% yield).1H NMR (400 MHz, CD3OD) δ 8.25 (d, J = 4.0 Hz,1H), 7.93 (m, 3H), 7.73 (dd, J = 8, 12 Hz, 1H), 7.55 (d, J = 12 Hz, 1H), 7.20 (dd, J = 6.0, 6.0 Hz, 1H), 7.02 (m, 1H), 4.54 (s, 2H), 4.30 – 4.19 (m, 2H), 3.69–3.56 (m, 4H), 3.51 (t, J = 6.4 Hz, 2H), 3.46–3.33 (m, 6H), 2.44 (t, J = 6.3 Hz, 2H), 1.65–1.32 (m, 6H); LCMS ESI (+) m / z 561.2 (M+H). Synthetic Example 19: Synthesis 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 (Compound 323)

[0245] Step A: Preparation of tert-butyl 6-(7-(2-(2-(2-((((1-(((9H-fluoren-9- yl)methoxy)carbonyl)pyrrolidin-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 9H-fluoren-9-ylmethyl 3-(4-nitrophenoxy)carbonyloxypyrrolidine-1-carboxylate (300 mg, 0.632 mmol) in DCM (8 mL) were added triethylamine (0.260 mL, 1.90 mmol) and 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 (200 mg, 0.354 mmol). The reaction mixture was stirred at 20 °C for 12 hours. The mixture was poured into water (20 mL) and extracted with DCM (20 mL x 2). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether:1 / 2) to afford tert-butyl 6-(7-(2-(2-(2-((((1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidin-3- yl)oxy)carbonyl)amino)ethoxy)ethoxy)-4-fluorophenyl)thieno[2,3-d]pyridazin-4-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (140 mg, 25% yield).

[0246] 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. The reaction was concentrated and purified by column chromatography (DCM / MeOH: 15 / 1) to give 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 (50 mg, 66% yield). LCMS ESI (+) m / z 678.3 (M+H).

[0247] Step C: Preparation of tert-butyl 6-(7-(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 mmol) and prop-2-enoyl prop-2-enoate (9.3 mg, 0.074 mmol). The reaction mixture was stirred at 20 °C for 1.5 hours. The mixture was poured into water (20 mL) and extracted with DCM (20 mL x 2). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by Prep-TLC (EtOAc / petroleum ether: 1 / 2) to afford tert-butyl 6-(7-(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 (30 mg, 56% yield). LCMS ESI (+) m / z 732.0 (M+H).

[0248] 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 (0.60 mL, 7.8 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure and purified by Prep-HPLC to afford 1-acryloyl pyrrolidin-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 (18 mg, 68% yield) as a bis trifluoroacetic acid salt.1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.82 – 7.72 (m, 3H), 7.69 – 7.64 (m, 1H), 7.36 – 7.32 (m, 1H),6.96 – 6.83 (m, 2H), 6.37 – 6.25 (m, 2H), 5.76 – 5.72 (m, 1H), 5.19 – 5.11 (m, 1H), 4.48 (s, 2H), 4.24 – 4.24 (m, 2H), 3.70 – 3.35 (m, 8H), 3.31- 3.10 (s, 5H), 2.95 – 2.88 (m, 2H), 2.10 – 1.97 (m, 2H), 1.95 – 1.87 (m, 1H). LCMS ESI (+) m / z 632.2 (M+H). Synthetic Example 20: Synthesis 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 (Compound 324)

[0249] Step A: Preparation of tert-butyl (3S,4R)-3-[2-(4-chlorothieno[2,3-d]pyridazin-7-yl)- 5-fluoro-phenoxy]-4-methoxy-pyrrolidine-1-carboxylate: A solution of tert-butyl (3R,4R)-3- hydroxy-4-methoxy-pyrrolidine-1-carboxylate (80 mg, 0.37 mmol) in anhydrous THF (1 mL) was cooled to 0 °C. Triphenylphosphine (101 mg, 0.390 mmol), 2-(4-chlorothieno[2,3-d]pyridazin-7- yl)-5-fluoro-phenol (109 mg, 0.390 mmol), and DIAD (73 µL, 0.39 mmol) were added and the resulting solution was warmed to rt and stirred for an additional 12 h. Water (1 mL) was added, and the product was extracted with EtOAc (2 x 20 mL). The organic phases were pooled, washed with brine (5 mL), dried (Na2SO4), filtered, and the solvent was removed in vacuo. The residue was purified by MPLC on silica (Biotage Sfär HC 10 g; 0-50% EtOAc / hexanes) to give tert-butyl (3S,4R)-3-[2-(4-chlorothieno[2,3-d]pyridazin-7-yl)-5-fluoro-phenoxy]-4-methoxy-pyrrolidine-1- carboxylate (123 mg, 70% yield) as a viscous liquid. LCMS ESI (+) m / z 481.1 (M+H).

[0250] 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), Cs2CO3(136 mg, 0.42 mmol), and Pd(dppf)Cl2DCM complex (8.5 mg, 0.010 mmol). Dioxane (0.7 mL) and water (0.25 mL) were added and the vial was capped, degassed, and heatedto 120 C under microwave irradiation under Ar for 4 h. The reaction mixture was passed through a pad of Celite®, and the solvent was removed in-vacuo. The residue was purified by MPLC on silica (Biotage Sfär HC 5 g; 0-15% MeOH / DCM) to give 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 (24 mg, 40% yield) as an off-white semi solid.1H NMR (700 MHz, DMSO-d6) δ 10.04 (d, J = 22.7 Hz, 1H), 8.43 (d, J = 5.4 Hz, 1H), 7.81 (dd, J = 33.7, 6.6 Hz, 3H), 7.71 – 7.66 (m, 3H), 7.29 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 11.4 Hz, 2H), 3.99 (s, 3H), 3.04 (t, J = 5.8 Hz, 3H), 2.86 (t, J = 5.9 Hz, 3H), 2.55 (s, 1H), 1.30 – 1.09 (m, 20H). LCMS ESI (+) m / z 578.2 (M+H). Synthetic Example 21: Synthesis of 5,5-difluoro-1,4-bis(2-(2-methoxyethoxy)phenyl)-6,7- dihydro-5H-cyclopenta[d]pyridazine (Compound 328)

[0251] Step A: Preparation of 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazin-5-one: To a solution of 5-hydroxy-1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine (390 mg, 1.90 mmol) in DCM (20 mL) was added Dess-Martin periodinane (1.00 g, 2.20 mmol). The reaction was stirred at rt for 18 h then saturated aqueous Na2S2O3(12 mL) and saturated aqueous NaHCO3(12 mL) were added. The reaction was stirred at rt for 10 min then poured into water (10 mL). The product was extracted with DCM (2 x 10 mL). The organic fractions were pooled, washed with brine (15 mL), dried (Na2SO4), filtered, and the solvent was removed in-vacuo. The residue was purified by MPLC on silica (Biotage Sfär HC 5g; 0-50% EtOAc / hexanes) to give 1,4-dichloro- 6,7-dihydro-5H-cyclopenta[d]pyridazin-5-one (239 mg, 63% yield). LCMS ESI (+) m / z 203 (M+H).

[0252] 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. The reactionmixture was quenched with saturated aqueous NaHCO3(5 mL) and the product was extracted with DCM (2 x 5 mL). The organic phases were pooled, washed with brine (5 mL), dried (Na2SO4), and the solvent was removed in-vacuo. The residue was MPLC on silica (Biotage Sfär HC 5g; 0- 50% EtOAc / hexanes) to give 4-chloro-5,5-difluoro-1-[2-(2-methoxyethoxy)phenyl]-6,7- dihydrocyclopenta[d]pyridazine (150 mg, 23% yield).

[0253] 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 Cs2CO3(86 mg, 0.26 mmol). Dioxane (1.3 mL) and water (150 µL) were added followed by Pd(dppf)Cl2DCM complex (11 mg, 0.013 mmol). The vial was heated under microwave irradiation to 100 °C under Ar for 2 h. The crude product was filtered through a pad of Celite® then purified by C18 reverse phase preparative HPLC (0-100% MeCN / water) to give 5,5- difluoro-1,4-bis(2-(2-methoxyethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyridazine (19 mg, 21% yield) as a solid.1H NMR (700 MHz, CD3OD) δ 7.62 – 7.53 (m, 3H), 7.44 (dd, J = 7.5, 1.7 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.20 (td, J = 7.5, 1.0 Hz, 1H), 7.16 (td, J = 7.4, 1.0 Hz, 1H), 4.25 – 4.21 (m, 2H), 4.20 – 4.16 (m, 2H), 3.67 – 3.63 (m, 2H), 3.63 – 3.60 (m, 2H), 3.32 (s, 3H), 3.27 (s, 2H), 3.23 (s, 3H), 2.66 (s, 1H), 2.65 – 2.61 (m, 1H); LCMS ESI (+) m / z 457 (M+H). Synthetic Example 22: Synthesis of tert-butyl N-[2-[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 (Compound 330)

[0254] Step A: Preparation of tert-butyl N-[2-[2-[2-(4-chloro-5,5-difluoro-6,7- dihydrocyclopenta[d]pyridazin-1-yl)-5-fluoro-phenoxy]ethoxy]ethyl]carbamate: A Biotage microwave vial was charged with 1,4-dichloro-5,5-difluoro-6,7-dihydrocyclopenta[d]pyridazine (63 mg, 0.28 mmol), tert-butyl N-[2-[2-[5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]ethoxy]ethyl]carbamate (131 mg, 0.310 mmol), and Cs2CO3(227 mg, 0.700 mmol).Dioxane (3.2 mL) and water (0.4 mL) were added followed by Pd(dppf)2Cl2DCM complex (23 mg, 0.028 mmol) and the vial was sealed and degassed for 15 min with Ar. The reaction mixture was heated under microwave irradiation at 100 °C for 2 h. The reaction was filtered through a plug of Celite® then purified by MPLC on silica (Biotage Sfär HC 5g; 0-100% EtOAc / hexanes) to give 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, 65% yield) as an oil. LCMS ESI (+) m / z 488 (M+H).

[0255] Step B: Preparation of tert-butyl N-[2-[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), and Cs2CO3(119 mg, 0.37 mmol). Dioxane (2 mL) and water (250 µL) were added followed by Pd(dppf)2Cl2(15 mg, 0.018 mmol). The reaction mixture was capped and degassed for 15 min with Ar. The reaction was heated under microwave irradiation at 100 °C for 2 h. The 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-[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.1H NMR (700 MHz, DMSO-d6) δ 7.64 (d, J = 6.3 Hz, 2H), 7.58 (dd, J = 8.4, 6.8 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 11.4, 2.4 Hz, 1H), 7.00 (td, J = 8.3, 2.4 Hz, 1H), 6.77 (t, J = 5.8 Hz, 1H), 4.23 – 4.19 (m, 2H), 4.03 (s, 2H), 3.66 – 3.62 (m, 2H), 3.34 (t, J = 6.1 Hz, 2H), 3.09 (t, J = 5.9 Hz, 3H), 3.03 (q, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 2H), 2.66 – 2.57 (m, 2H), 2.54 (s, 1H), 1.35 (s, 9H); LCMS ESI (+) m / z 585 (M+H). Synthetic Example 23: Synthesis 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 (Compound 353)

[0256] 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 diisopropyl azodicarboxylate (0.083 mL, 0.43 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was diluted with EtOAc (10 mL) and washed with saturated brine solution (10 mL). The organic phase was dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether:EtOAc = 1:1) to give 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 (160 mg, 108% yield). LCMS ESI (+) m / z 695.2 (M+H).

[0257] 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 hours. The mixturewas cooled to rt. The solid was filtered off, and the filtrate was concentrated to dryness to give crude 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 (700 mg) which was used in the next step directly. LCMS ESI (+) m / z 565.3 (M+H).

[0258] Step C: Preparation of tert-butyl 6-[7-[2-[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 3Å molecular sieve (100 mg) in DCM (3 mL) was stirred at 20 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated to dryness to give crude tert-butyl 6-[7-[2-[2-[2-[(E)-benzylideneamino]ethoxy]ethoxy]-4-fluoro- phenyl]thieno[2,3-d]pyridazin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (22 mg, 95% yield) which was used in the next step directly.

[0259] 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-[(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 mg, 0.059 mmol) at 0 °C. The mixture was stirred at 0 °C for 20 min, then (trifluoromethyl)trimethylsilane (0.016 mL, 0.099 mmol) was added and the mixture was stirred at rt for 16 h. The reaction was concentrated to dryness. The residue was taken up in EtOAc (20 ml) and washed with saturated brine solution (20 mL). The organic phase was separated and dried (MgSO4) before concentrating to dryness. The crude was then purified by Prep-TLC (Petroleum ether:EtOAc = 1 / 1) to give 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, 19% yield).

[0260] 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, 9.1mmol) at 20 C. The mixture was stirred at 20 C for 2 h. The mixture was concentrated and purified by Prep-HPLC to give 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 (6.4 mg, 82% yield) as a bis trifluoroacetic acid salt.1H NMR (400 MHz, CD3OD) δ 8.42 (d, J = 5.2 Hz, 1H), 7.96 - 7.80 (m, 3H), 7.69 (t, J = 7.2 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.53 -7.32 (m, 5H), 7.18 (d, J = 10.4 Hz, 1H), 7.00 (t, J = 8.4 Hz, 1H), 5.05 (q, t = 7.6 Hz, 1H), 4.54 (s, 2H), 4.34 - 4.22 (m, 2H), 3.81 - 3.50 (m, 6H), 3.05 - 2.91 (m, 2H). LCMS ESI (+) m / z 623.1 (M+H). Synthetic Example 24: Synthesis 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 (Compound 387)

[0261] Step A: Preparation of benzyl 6-[methoxy(methyl)carbamoyl]-3,4-dihydro-1H- isoquinoline-2-carboxylate: A mixture of benzyl 6-bromo-3,4-dihydro-1H-isoquinoline-2- carboxylate (6.00 g, 17.3 mmol), N,O-dimethylhydroxylamine hydrochloride (2.54 g, 26.0 mmol), Pd(OAc)2(0.194 g, 0.865 mmol), X-Phos (0.825 g, 1.73 mmol) and Na2CO3(0.917 g, 86.5 mmol) in toluene (100 mL) was stirred at 100 °C for 12 h under CO (1 atm). The mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated brine solution, dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (petroleumether / ethyl acetate = 1 / 1) to afford benzyl 6-[methoxy(methyl)carbamoyl]-3,4-dihydro-1H- isoquinoline-2-carboxylate (5.10 g, 83% yield).1H NMR (400 MHz, CDCl3) δ 7.56 - 7.28 (m, 7H), 7.20 – 7.03 (m, 1H), 5.19 (s, 2H), 4.68 (s, 2H), 3.80 – 3.65 (m, 2H), 3.56 (s, 1H), 3.35 (s, 1H), 2.95 - 2.81 (m, 2H).

[0262] 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. The mixture was stirred at -78 °C for 30 min, followed by dropwise addition of a solution of benzyl 6- [methoxy(methyl)carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.37 g, 3.87 mmol) in THF at -78 °C. The resulting mixture was stirred at 1 h at room temperature.1 N HCl aqueous solution was added to the mixture to adjust the pH to 2-3 and the product was extracted with EtOAc (60 mL x 3). The combined organic layers were washed with saturated brine solution (40 mL), dried (Na2SO4) and concentrated to dryness to give crude 2-(2-((benzyloxy)carbonyl)-1,2,3,4- tetrahydroisoquinoline-6-carbonyl)-4-methylthiophene-3-carboxylic acid (1.8 g). LCMS ESI (+) m / z 436.1 (M+H).

[0263] 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. After cooling to the room temperature, the solid was collected by filtration and dried to give benzyl 6-(3-methyl-4-oxo-5H-thieno[2,3-d]pyridazin-7-yl)-3,4-dihydro-1H- isoquinoline-2-carboxylate (600 mg, 61% yield). LCMS ESI (+) m / z 432.1 (M+H).

[0264] 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. POCl3was removed under vacuum and the residue was dissolved in DCM. After adjusting the pH to 7-8 with saturated aqueous NaHCO3, the mixture was extracted with DCM (30 mL x 3). The combined organic layers were washed with saturated brine solution (30 mL x 1), dried over anhydrous Na2SO4, filtered and concentrated to dryness to give crude benzyl 6-(4-chloro-3-methyl-thieno[2,3-d]pyridazin-7-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (610 mg, 89% yield) which was used in the next step without further purification. LCMS ESI (+) m / z 450.1 (M+H).

[0265] 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-(tert-butoxycarbonylamino)ethoxy]ethoxy]-4-fluoro-phenyl]boronic acid (57 mg, 0.17 mmol), Na2CO3(35 mg, 0.33 mmol) and Pd(dppf)Cl2(8.1 mg, 0.011 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was stirred at 90 °C for 4 h. After cooling to room temperature, the mixture was concentrated and purified by Prep-HPLC to give 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, 69% yield) as a yellow solid. LCMS ESI (+) m / z 713.3 (M+H).

[0266] 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). The mixture was stirred at 80 °C for 72 h. After cooling to room temperature, the mixture was diluted with saturated brine solution (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic fractions were dried over Na2SO4and concentrated. The residue was purified by Prep- HPLC to give 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 (14 mg, 30% yield) as a yellow solid. NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 8.05 - 7.97 (m, 2H), 7.60 - 7.51 (m, 2H), 7.13 (dd, J = 10.8, 2.0 Hz, 1H), 7.04 - 6.93 (m ,1H), 4.53 (s, 2H), 4.22 - 4.05 (m, 2H), 3.66 - 3.52 (m, 4H), 3.21 -3.10 (m, 2H), 2.93 (t, J = 5.6 Hz, 2H), 1.39 (s, 9H); LCMS ESI (+) m / z 579.1 (M+H). Synthetic Example 25: Synthesis 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 (Compound 393)

[0267] 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. The mixture was stirred for 30 min at -78 °C followed by the addition of a solution of benzyl 6- [methoxy(methyl)carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (1334 mg, 3.76 mmol) in THF at -78 °C. The mixture was stirred at room temperature for 1 h.1 N HCl was added to the mixture to adjust the pH to 4-5. The mixture was extracted with EtOAc (60 mL x 3) and washed with brine (40 mL x 2). The organic solvent was removed under vacuum to give the crude product (1.7 g) which was used directly for the next step. LCMS ESI (+) m / z 487.2 (M+H).

[0268] 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). The mixture was stirred at 140 °C for 5 h. After cooling to room temperature, the mixture was poured into water and extracted with DCM (20 mL x 2). The combined organic layers were dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography eluting with 3%MeOH in DCM to give benzyl 6-(3-fluoro-4-oxo-5H-thieno[2,3-d]pyridazin-7-yl)-3,4-dihydro- 1H-isoquinoline-2-carboxylate (410 mg, 56% yield). LCMS ESI (+) m / z 436.0 (M+H).

[0269] 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. POCl3was removed under vacuum and the residue was dissolved in DCM. After the pH was adjusted to 7-8 with saturated aqueous NaHCO3, the mixture was extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL x 1), dried over anhydrous Na2SO4and concentrated. The residue was purified by Prep-TLC (DCM / MeOH =30 / 1) to give benzyl 6-(4- chloro-3-fluoro-thieno[2,3-d]pyridazin-7-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (200 mg, 42% yield). LCMS ESI (+) m / z 454.1 (M+H).

[0270] 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), Na2CO3(26 mg, 0.24 mmol) and Pd(dppf)Cl2(5.9 mg, 0.0080 mmol) in 1,4- dioxane (2 mL) and water (0.5 mL) was stirred at 90 °C for 4 h. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic fractions were washed with brine (30 mL x 2), dried over Na2SO4and concentrated. The residue was purified by Prep-TLC (DCM / MeOH=30 / 1) to give 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, 64% yield). LCMS ESI (+) m / z 717.1 (M+H).

[0271] 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.H2O (87 mg, 2.1 mmol) in 1,4-dioxane (1.5 mL) and water (1 mL) was stirred at 80 °C for 72 h. After cooling to room temperature, the mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were dried over Na2SO4andconcentrated. The residue was purified by Prep-HPLC to give 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 (7.7 mg, 25% yield) as a bis trifluoroacetic acid salt.1H NMR (400 MHz, CD3OD) δ 8.05 - 7.97 (m, 2H), 7.85 (s, 1H), 7.60 (dd, J = 8.4, 6.8 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.04 (dd, J = 10.8, 2.0 Hz, 1H), 7.00 - 6.89 (m ,1H), 4.53 (s, 2H), 4.16 (t, J = 4.4 Hz, 2H), 3.66 - 3.52 (m, 4H), 3.21 (t, J = 5.6 Hz, 2H), 2.97 (t, J = 5.6 Hz, 2H), 1.39 (s, 9H); LCMS ESI (+) m / z 583.3 (M+H). Synthetic Example 26: Synthesis 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 (Compound 413)

[0272] Step A: Preparation 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: 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 (70 mg, 0.14 mmol), N,N-dimethyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)tetralin-2-amine (52 mg, 0.17 mmol), 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (11 mg, 0.014 mmol) and sodium carbonate (31 mg, 0.29 mmol) in 1,4-dioxane (1.2 mL) and water (0.3 mL) was stirred at 95 °C for 4 h under N2atmosphere. The mixture was concentrated and purified by Prep-TLC (MeOH / DCM = 1 / 20) to give 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 (70 mg, 78% yield). LCMS ESI (+) m / z 625.3 (M+H).

[0273] 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). The mixture was stirred at rt for 1 h. The mixture was concentrated and diluted with EtOAc (10 mL). The solution was washed with NaHCO3aqueous solution and saturated brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to dryness to give 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, 92% yield) which was used in the next step without further purification.

[0274] 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 mmol) in DCM (3 mL) was stirred for 3 h at rt. The mixture was diluted with water (30 mL) and extracted with DCM (40 mL x 3). The combined organic layers were washed with saturated brine solution, dried (Na2SO4) and filtered before concentrating to dryness. The residue was purified by Prep-HPLC to give (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 (17 mg, 49% yield) as a trifluoroacetic acid salt.1H NMR (400 MHz, CD3OD) δ 7.90 (s, 1H), 7.62 (d, J = 6.7 Hz, 3H), 7.42 (d, J = 7.5 Hz, 1H), 7.14 (d, J = 10.9 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 6.62 – 6.45 (m, 1H), 6.29 – 6.18 (m, 1H), 5.75 – 5.68 (m, 1H), 5.14 (d, J = 17.2 Hz, 1H), 4.25 – 4.20 (m, 2H), 3.84 – 3.70 (m, 2H), 3.69 – 3.53 (m, 4H), 3.50 – 3.01 (m, 16H), 2.41 (d, J = 9.9 Hz, 1H), 2.21 – 1.93 (m, 3H); LCMS ESI (+) m / z 692.3 (M+H).Synthetic Example 27: Synthesis 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 (Compound 416)

[0275] Step A: Preparation 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: To a suspension of tert-butyl 6-(3-fluoro-7-(4-fluoro-2-methoxyphenyl)thieno[2,3-d]pyridazin-4-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (610 mg, 1.20 mmol) in DCM (3 mL) was added boron tribromide (0.340 mL, 3.59 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was poured into water. Sodium bicarbonate was added to adjust the pH to 8. Di-tert-butyl dicarbonate (0.330 mL, 1.44 mmol) in MeOH (5 mL) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction was quenched by the addition of ammonia hydroxide (0.5 mL) and stirred for 5 min. Aqueous HCl solution was added to adjust the pH to 6 and the mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with saturated brine solution, dried over anhydrous Na2SO4and concentrated. The residue was purified by column chromatography on silica gel (EtOAc / petroleum ether: 1 / 3) to give 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, 62% yield). LCMS ESI (+) m / z 496.2 (M+H).

[0276] 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 mmol) in THF (4 mL) was added DIAD (0.66 mL, 3.73 mmol) at 0 °C. The mixture was stirred at 25 °C for 3 h. The mixture was poured into water (10 mL) and the product was extracted with EtOAc (10 mL x 2). The combined organic fractions were washed with saturated brine solution, dried over anhydrous Na2SO4and concentrated. The residue was purified by column chromatography (EtOAc / petroleum ether: 1 / 2) to give 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, 56% yield). LCMS ESI (+) m / z 713.3 (M+H).

[0277] 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). The mixture was stirred at 70 °C for 4 h. The mixture was filtered and washed with EtOAc. The filtrate was washed with saturated brine solution, dried over anhydrous Na2SO4and concentrated to dryness to give crude 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 (200 mg, 82% yield). LCMS ESI (+) m / z 583.3 (M+H).

[0278] 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 (105 mg, 0.343 mmol) in DCM (3 mL) was added TEA (0.096 mL, 0.69 mmol). The mixture was stirred at rt for 1 h. The mixture was poured into water. The product was extracted with DCM, dried over anhydrous Na2SO4and concentrated. The residue was purified by Prep-TLC (EtOAc / petroleum ether:1 / 1) to give 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, 27% yield). LCMS ESI (+) m / z 750.3 (M+H).

[0279] 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, 0.047 mmol) in DCM (2 mL) was added TFA (0.01 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated and purified by Prep-HPLC to give [(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 (9.2 mg, 29% yield) as a white solid. LCMS ESI (+) m / z 650.2 (M+H).

[0280] 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). The mixture was stirred at 25 °C for 1 h under Ar, Sodium cyanoborohydride (3.5 mg, 0.055 mmol) was added at 25 °C. The mixture was stirred at 25 °C for an additional 1 h. The mixture was poured into water and extracted with EtOAc. The organics were dried over anhydrous Na2SO4and concentrated. The residue was purified by Prep- HPLC to give (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 (5.2 mg, 42% yield) as a trifluoroacetic acid salt.1H NMR (400 MHz, CD3OD) δ 7.89 (s, 1H), 7.78 (s, 2H), 7.68 – 7.59 (m, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.16 (dd, J = 11.1, 1.9 Hz, 1H), 7.00 (td, J = 8.1, 1.7 Hz, 1H), 6.64 – 6.48 (m, 1H), 6.30 – 6.23 (m, 1H), 5.80 – 5.70 (m, 1H), 5.20 – 5.11 (m, 1H), 4.24 (s, 2H), 3.89 – 3.52 (m, 8H), 3.31 – 3.24 (m, 2H), 3.16 (s, 3H), 3.07 – 3.02 (m, 2H), 1.36 – 1.30 (m, 1H); LCMS ESI (+) m / z 664.2 (M+H). Synthetic Example 28: Synthesis 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 (Compound 437)

[0281] Step A: Preparation 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: 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 (50 mg, 0.089 mmol) in anhydrous DCM (1 mL) was added (4- nitrophenyl)[1-prop-2-enoyl-3-(trifluoromethyl)pyrrolidin-3-yl]carbonate (100 mg, 0.27 mmol). The reaction was stirred at rt for 30 min and then Et3N (50 µL, 0.36 mmol) in anhydrous DCM (1 mL) was added dropwise with stirring at 0 °C. The reaction mixture was warmed to rt and stirred for an additional 12 h. The crude product was purified by C18 reverse phase preparative HPLC (0- 100% MeCN / water) to give 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 (59 mg, 83% yield) as a white semi- solid. LCMS ESI (+) m / z 800.2 (M+H).

[0282] 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 µL, 0.52 mmol) at 0 °C. The reaction was warmed to rt and stirred for 1 hour. The solvent was removed in vacuo and the residue was purified by C18 reverse phase HPLC (0-100% MeCN / water) to give [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 (4.4 mg, 50% yield) as an off-white solid.1H NMR (500 MHz, CD3OD) δ 8.27 (d, J = 5.4 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.76 (dd, J = 5.4, 2.7 Hz, 1H), 7.63 (ddd, J = 8.1, 6.5, 1.4 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.14 (dd, J = 10.9, 2.4 Hz, 1H), 6.98 (td, J = 8.3, 2.4 Hz, 1H), 6.57 (ddd, J = 28.5, 16.8, 10.4 Hz, 1H), 6.29 (ddd, J = 16.8, 12.9, 1.9 Hz,1H), 5.77 (ddd, J = 14.4, 10.4, 1.9 Hz, 1H), 4.54 (s, 2H), 4.23 (ddd, J = 5.2, 4.0, 2.2 Hz, 2H), 4.03 (s, 1H), 3.97 – 3.77 (m, 1H), 3.66 – 3.60 (m, 4H), 3.51 – 3.43 (m, 1H), 3.36 – 3.29 (m, 4H), 3.22 (q, J = 5.7 Hz, 2H), 2.99 (dt, J = 11.4, 5.5 Hz, 2H), 2.84 (d, J = 0.9 Hz, 2H), 2.68 (s, 2H), 2.61 – 2.52 (m, 1H), 2.38 (dd, J = 8.7, 7.5 Hz, 1H), 2.13 – 1.99 (m, 1H); LCMS ESI (+) m / z 700.2 (M+H). Synthetic Example 29: Synthesis 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 (Compound 443)

[0283] Step A: Preparation of 1-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]prop-2-en-1- one: To a solution of 3-(trifluoromethyl)pyrrolidin-3-ol (200 mg, 1.29 mmol) in anhydrous DCM (2 mL) was added K2CO3(547 mg, 5.16 mmol) at 0 °C. Prop-2-enoyl chloride (104 µL, 1.29 mmol) in DCM (0.5 mL) was added and the reaction was stirred at rt for 2 h. The reaction was quenched with saturated aqueous NaHCO3solution (5 mL) and the crude mixture was extracted in DCM (2 x 10 mL). The organic fractions were pooled, dried (Na2SO4) and the solvent was removed in vacuo to give 1-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]prop-2-en-1-one (310 mg, 115%) as a pale-yellow viscous liquid, which was used without further purification. LCMS ESI (+) m / z 210.1 (M+H).

[0284] 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 Et3N (130 µl, 0.930 mmol). The reaction mixture was stirred at rt for 2 h and thenpurified by MPLC on silica gel (Biotage Sfär HC 10 g; 20-80% EtOAc / hexanes) to give (4- nitrophenyl) [1-prop-2-enoyl-3-(trifluoromethyl)pyrrolidin-3-yl] carbonate (92 mg, 79% yield) as off-white semi-solid. LCMS ESI (+) m / z 375.0 (M+H).

[0285] 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, 0.27 mmol). The reaction mixture was stirred at rt for 30 min and then Et3N (49 µL, 0.35 mmol) in anhydrous DCM (0.5 mL) was added dropwise with stirring at 0 °C. The reaction mixture warmed to rt and stirred for 12 h. The crude product was purified by C18 reverse phase preparative HPLC (0-100% MeCN / water) to give [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 (4.8 mg, 8% yield) as a trifluoroacetic acid salt.1H NMR (500 MHz, CD3OD) δ 8.46 (t, J = 5.9 Hz, 1H), 8.01 – 7.80 (m, 3H), 7.71 (ddd, J = 8.5, 6.4, 4.5 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.19 (dd, J = 10.9, 2.4 Hz, 1H), 7.14 – 6.83 (m, 1H), 6.57 (ddd, J = 31.9, 16.8, 10.5 Hz, 1H), 6.29 (ddd, J = 16.6, 14.7, 1.9 Hz, 1H), 5.78 (ddd, J = 17.7, 10.5, 1.9 Hz, 1H), 4.35 – 4.21 (m, 3H), 4.02 (s, 1H), 3.97 – 3.76 (m, 1H), 3.73 – 3.62 (m, 2H), 3.49 – 3.36 (m, 2H), 3.26 (q, J = 5.5 Hz, 2H), 3.16 (s, 3H), 3.07 – 2.95 (m, 2H), 2.68 (s, 1H), 2.66 – 2.50 (m, 1H), 2.50 – 2.31 (m, 1H); LCMS ESI (+) m / z 714.2 (M+H). Synthetic Example 30: Synthesis 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 (Compound 452)

[0286] 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. The mixture was stirred at 0 °C for 1 h. The mixture was diluted with H2O (50 mL), and then HCl aqueous solution was added to adjust the pH to 6. The mixture was extracted with EtOAc (50 mLx2). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated. The crude was purified by reserve-phase column chromatography to give 2-(1,2-dimethylbenzimidazole-5-carbonyl)-4-fluoro-thiophene-3-carboxylic acid (215 mg, 18% yield). LCMS ESI (+) m / z 319.1 (M+H).

[0287] 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. The reaction mixture was concentrated to dryness to give crude 7-(1,2-dimethylbenzimidazol-5-yl)-3-fluoro-5H- thieno[2,3-d]pyridazin-4-one (165 mg, 90% yield). LCMS ESI (+) m / z 315.1 (M+H).

[0288] 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 POCl3(2 mL) was stirred at 90 °C for 2hours. The mixture was concentrated under reduced pressure. The crude was diluted with EtOAc (30 mL) and washed with saturated NaHCO3aqueous solution (30 mL) followed by brine (30 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-TLC (DCM / MeOH=15 / 1) to give 4-chloro-7-(1,2-dimethylbenzimidazol-5-yl)- 3-fluoro-thieno[2,3-d]pyridazine (20 mg, 13% yield). LCMS ESI (+) m / z 333.1 (M+H).

[0289] 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), Na2CO3(9.6 mg, 0.090 mmol) and Pd(dppf)Cl2(3.2 mg, 0.0045 mmol) in the 1,4-dioxane (1 mL) and water (0.1 mL) was stirred at 100 °C for 2 h under Ar. After the completion of the reaction, the reaction mixture was concentrated and purified by Prep-TLC (DCM / MeOH = 20 / 1) to afford 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 (10 mg, 37% yield).

[0290] 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). The mixture was stirred at 30 °C for 2 h. The mixture was diluted with saturated brine solution (10 mL) and extracted with EtOAc (10 mL). The organics were then separated and dried before concentration to dryness. The crude was purified by Prep-HPLC to afford (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 (0.81 mg, 12% yield).1H NMR (400 MHz, CD3OD) δ 8.30 (s, 1H), 8.01 (dd, J = 8.4, 1.4 Hz, 1H), 7.80 – 7.70 (m, 2H), 7.59 (dd, J = 8.3, 6.6 Hz, 1H), 6.96 (dd, J = 11.1, 2.3 Hz, 1H), 6.90 (td, J = 8.4, 2.3 Hz, 1H), 4.03 – 3.92 (m, 3H), 3.90 (s, 3H), 2.68 (s, 3H), 2.25 – 1.83 (m, 3H), 1.57 – 1.35 (m, 2H); LCMS ESI (+) m / z 493.2 (M+H).

[0291] Table 1 includes selected compounds of the present disclosure. Table 1. Selected compounds of the present disclosure.Biological Assays Biological Example 1: Binding affinity of compounds to PI3Kα using isothermal titration calorimetry (ITC) assay

[0292] The binding affinities of the full-length and RAS-binding domain (RBD) of PI3Kα 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 MgCl2, and 1 mM TCEP. Before titration, all proteins were centrifuged at 14,000 × g for 5 minutes to remove any debris and air bubbles. 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 μL administered at 150-second intervals. Typically, an ITC experiment consisted of 30-50 μM of protein in the cell and 300-500 μM 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).

[0293] Binding affinities of selected compounds measured using this assay are provided in Table 2. For KDvalues shown in Table 2, “A” means KD< 5 µM; “B” means KD≥ 5 µM and ≤ 25 µM; and “C” means KD> 25 µM.Table 2. KD of selected compounds of the present disclosure to full-length PI3Kα as measured by ITCBiological Example 2: Binding affinity of compounds to PI3Kα using surface plasmon resonance (SPR) assay

[0294] 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 µL / min using 20 mM HEPES pH 7.4, 150 mM NaCl as the running buffer. Next, neutravidin was diluted to 20 µg / 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 PI3Kα was captured on all flow cells in 20 mM HEPES pH 7.4, 150 mM NaCl, 5 mM MgCl2, 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 PI3Kα surface at 30 µL / min and 25 °C. The KDfor 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. For KDvalues shown in Table 3, “A” means KD< 5 µM; “B” means KD≥ 5 µM and ≤ 25 µM; and “C” means KD> 25 µM. Table 3. KD of selected compounds of the present disclosure to full-length PI3Kα as measured by SPRBiological Example 3: Disrupting KRAS PI3Kα interaction by SPR inhibition assay

[0296] 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 µL / min using 20 mM HEPES pH 7.4, 150 mM NaCl as the running buffer. Next, neutravidin was diluted to 20 µg / 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 PI3Kα was captured on all flow cells in 20 mM HEPES pH 7.4, 150 mM NaCl, 5 mM MgCl2, 1 mM TCEP, 0.05% tween 20, 5% DMSO buffer. KRAS-Q25A at 20 µM was mixed with 8 concentrations of compound (50 nM – 100 µM) and injected over the full-length PI3Kα at 30 µL / min and 25oC. Steady-state levels of KRAS binding were recorded and fit with a 4-parameter inhibition model to determine the IC50values.

[0297] IC50values of selected compounds measured using this assay are provided in Table 4. For IC50values shown in Table 4, “A” means IC50< 5 µM; “B” means IC50≥ 5 µM and ≤ 25 µM; and “C” means IC50> 25 µM.Table 4. SPR inhibition IC50of selected compounds of the present disclosureBiological Example 4: Covalent modification assay using MALDI-TOF MS

[0298] 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 µM protein target, and 1:7.5 protein to compound ratio.

[0299] Reaction: 3.33 µM of PIK3CA (157-299) protein (produced by Protein Expression Laboratory, FNLCR / Leidos Biomed) in 20 mM HEPES buffer containing 150 mM NaCl, 2 mM MgCl2, pH 7.3 was prepared freshly before assay. Twelve-µL aliquots of protein were dispensed onto low volume 384-well plate, then 470 nL DMSO and 30 nL of tested compounds from 10 mM DMSO stocks were added to appropriate wells using ECHO 555 acoustic liquid handler (Labcyte Inc.). For each reaction / assay, three blanks were prepared by mixing 12 µL of protein solution with 500 nL DMSO. The wells content was carefully mixed by aspiration, and then the plate was sealed by an adhesive cover, centrifuged at 931 g for 1 minute, and kept in the dark at room temperature until 15 min, 30 min, 2 h, or 4 h collections.

[0300] Target pretreatment: Before each assay, MALDI target (Bruker MPT 384 ground steel BC) was pre-treated by pipetting on each spot 0.75 µL of saturated sinapinic acid in acetonitrile (ACN). This step significantly improves the uniformity of sample crystallization across the plate resulting in enhanced sensitivity.

[0301] Sample preparation: At collection time point, 2 µL of reaction mixtures were pipetted out into 20 µL MALDI matrix solution (saturated solution of sinapinic acid in 1:1 ACN: watersolution containing 0.15% trifluoroacetic acid (TFA)) deposited on 384 well polypropylene plate. The resulting solution was mixed by aspiration, centrifuged at 931 g for 1 minute, then 1.5 µL aliquots were dispensed on a pre-treated MALDI target using Beckman Coulter Biomek FXP96 / 384-Span-8 Laboratory Automation Workstation. Finally, the MALDI target was dried under a mild vacuum to produce spots with a fine crystalline structure.

[0302] Measurements: MALDI-TOF measurements were performed on Bruker Daltonics rapifleX Tissuetyper TOF-TOF mass spectrometer using linear mode and mass ranging from 16.0 to 19.6 kDa. 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 µm 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.

[0303] 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.

[0304] Calculation of percent modification: 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.

[0305] Percent of modification (%mod) of selected compounds measured using this assay is provided in Table 5. Data reported in Table 5 are from the 4 h reaction time point. “A” meanspercent of modification of PIK3CA protein ≥ 75%; B means 50% ≤ percent of modification < 75%; “C” means 25% ≤ percent of modification < 50%; and “D” means percent of modification < 25%. Table 5. Covalent modification using MALDI-TOF MS of selected compoundsBiological Example 5: Cell-based pAKT HTRF assay in Tet-on KRAS G12D HeLa cells

[0306] To determine the effectiveness of compounds in disrupting PIK3CA / KRAS signaling in cells, a pAKT HTRF assay (Perkin-Elmer) in Tet-on KRAS G12D HeLa cells was implemented.

[0307] On Day 1, cells were seeded into 96-well plates at 2 x 104 cells / well in complete growth media (DMEM, 10% Tet-Screened FBS) supplemented with 200 ng / mL doxycycline.

[0308] 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 compoundswere run in a 9-point concentration curve starting at 75 μM, with a 3-fold dilution between concentrations. As the potency increased, the highest dose was decreased to 25 μM while keeping a 3-fold serial dilution.20 μL was transferred onto the cell plates (final volume in wells was 100 μL). 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 µL 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 μL 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 μL 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. Plates were centrifuged again (524 g for 1 min) and analyzed on the EnVision plate reader using the following settings: Excitation 320 nM, Bandwidth 75 nM; Emission 615 nM, Bandwidth 85 nM, Gain 100%, Flashes 100, Lag 60 µs.

[0309] IC50values of selected compounds measured using this assay are provided in Table 6. For pAKT inhibition IC50values shown in Table 6, “A” means IC50< 5 µM; “B” means IC50≥ 5 µM and ≤ 25 µM; and “C” means IC50> 25 µM. Table 6. pAKT inhibition IC50of selected compounds in Tet-on KRAS G12D HeLa cellsBiological 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 μM, with a3-fold dilution between concentrations.20 μL was transferred onto the cell plates (final volume in wells was 100 μL). Plates were harvested after 4 h incubation by aspirating media and adding kit- supplied 1x supplemented lysis buffer to all wells (75 µL 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 μL 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 μL 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 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. Plates were centrifuged again (524 g for 1 min) and analyzed on the EnVision plate reader using the following settings: Excitation 320 nM, Bandwidth 75 nM; Emission 615 nM, Bandwidth 85 nM, Gain 100%, Flashes 100, Lag 60 µs.

[0311] IC50values of selected compounds measured using this assay are provided in Table 7. For pAKT inhibition IC50values shown in Table 7, “A” means IC50< 0.1 mM; “B” means IC50≥ 0.1 µM and < 1 µM; “C” means IC50≥ 1 µM and ≤ 3 µM; and “D” means IC50> 3 µM. Table 7. pAKT inhibition IC50of selected compounds in BT474 cellsBiological 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 μM, with a half-log dilutionbetween concentrations.20 μL was transferred onto the cell plates (the final volume in wells was 100 μL). Plates were harvested after 4hr incubation by aspirating media and adding kit-supplied 1x supplemented lysis buffer to all wells (50 µl 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 μL 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 μL 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. Therefore, readings can be made between 4 and 24 h of incubation. Plates were centrifuged again (524 g for 1 min) and analyzed on the EnVision plate reader using the following settings: Excitation 320 nM, Bandwidth 75 nM; Emission 615 nM, Bandwidth 85 nM, Gain 100%, Flashes 100, Lag 60 µs.

[0313] For pAKT inhibition IC50values shown in Table 8, “A” means IC50< 0.1 µM; “B” means IC50≥ 0.1 µM and < 1 µM; “C” means IC50≥ 1 µM. Table 8. pAKT inhibition IC50of selected compounds in SKUT-1 cells

[0314] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

CLAIMS 1. A compound of Formula I:or a salt (e.g., a pharmaceutically acceptable salt) 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 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, 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; each R1is independently selected from halogen and –L-R7; each L is independently a covalent bond or a bivalent straight or branched C1-12hydrocarbon 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)-, -SO2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, - OC(O)-, -OC(O)N(R)-, -N(R)C(O)O-, -SO2N(R)-, and –N(R)SO2-;each R7is independently selected from hydrogen, optionally substituted C1-6aliphatic, and – Cy1; each R2is independently selected from halogen, -OR, and optionally substituted C1-6aliphatic; each R3is independently selected from oxo, halogen, -(CH2)xCN, -(CH2)xOR, -OCH2CH2OR, -(CH2)xN(R)2, -(CH2)xC(O)N(R)2, -(CH2)xC(O)N(R)(OH), -(CH2)xC(O)N(R)(CN), - (CH2)xC(O)N(R)SO2R, -(CH2)xC(O)OR, -(CH2)xN(R)C(O)R, -(CH2)xSO2R, - (CH2)xSO2N(R)2, -(CH2)xCy3, -(CH2)xC(O)Cy3, -(CH2)xC(O)N(R)Cy3, -C(O)O(CH2)xCy3, and optionally substituted C1-6aliphatic; R4and R4’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)-; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0 or 1; each x is independently 0, 1, 2, or 3; each R is independently selected from hydrogen and optionally substituted C1-6aliphatic; each Cy1is independently selected from phenyl, 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, 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 10-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with 0-3 instances of R5; each R5is independently selected from oxo, halogen, -CN, -OR, -N(R)2, -N(R)Cy2, -C(O)R, - C(O)Cy2, -C(O)N(R)2, -C(O)OR, -C(O)OCy2, -(CH2)xN(R)C(O)R, -N(R)C(O)(CH2)xCy2, -(CH2)xN(R)C(O)OR, -N(R)C(O)OCy2, -SO2R, -Cy2, and optionally substituted C1-6aliphatic; each Cy2is 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 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 0-3 instances of R6; each R6is independently selected from oxo, halogen, -CN, -(CH2)xOR, -(CH2)xN(R)2, - (CH2)xC(O)R, -(CH2)xC(O)OR, -(CH2)xC(O)N(R)2, -(CH2)xN(R)C(O)OR, and optionally substituted C1-6aliphatic; and each Cy3is 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 Cy3is substituted with 0-3 instances of R6.

2. The compound of claim 1, wherein the compound is of Formula IA:or a salt (e.g., a pharmaceutically acceptable salt) thereof.

3. The compound of claim 1, wherein the compound is of Formula IB:or a salt (e.g., a pharmaceutically acceptable salt) thereof.

4. The compound of any one of claims 1-3, wherein 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.

5. The compound of claim 4, wherein Ring B is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

6. The compound of claim 4, wherein Ring B is a 5-membered carbocyclic ring.

7. The compound of any one of claims 1-3, wherein Ring B is selected from:

8. The compound of claim 1 or 2, wherein the compound is of Formula IA4-a, IA4-b, or IA4-c:or a salt (e.g., a pharmaceutically acceptable salt) thereof.

9. The compound of claim 8, wherein the compound is of Formula IA4-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

10. The compound of claim 8, wherein the compound is of Formula IA4-b, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

11. The compound of claim 8, wherein the compound is of Formula IA4-c, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

12. The compound of any one of claims 1-11, wherein each R2is independently selected from halogen, -OR, and C1-6alkyl.

13. The compound of any one of claims 1-12, wherein n is 0.

14. The compound of any one of claims 1-12, wherein n is 1.

15. The compound of any one of claims 1-12, wherein n is 2.

16. The compound of any one of claims 1-15, wherein 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.

17. The compound of claim 16, wherein Ring A is phenyl.

18. The compound of any one of claims 1-17, wherein at least one R1is –L-R7.

19. The compound of claim 18, wherein one R1is –L-R7, and any other R1groups are halogen.

20. The compound of any one of claims 1-19, wherein a moietyis.

21. The compound of claim 20, wherein a moiety, ,, 22. The compound of any one of claims 1-21, wherein each L is independently a covalent bond.

23. The compound of any one of claims 1-21, wherein each L is independently a bivalent straight or branched C1-12 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)-, -SO2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -OC(O)N(R)-, -N(R)C(O)O-, - SO2N(R)-, and –N(R)SO2-.

24. The compound of claim 23, wherein each L is independently a bivalent straight or branched C1-12hydrocarbon 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-, -SO2N(R)-, and –N(R)SO2-.

25. The compound of any one of claims 1-21, wherein each L is independently selected from: -(CH2)x-, -O(CH2)x-, -OCH(CH3)-, –O(CH2)2O(CH2)x-, –O(CH2)2O-, -O(CH2)2O(CH2)2O-, -O(CH2)2O(CH2)2OC(O)N(R)-, –O(CH2)2O(CH2)2N(R)SO2-, – O(CH2)2O(CH2)2N(R)-, –O(CH2)2O(CH2)2N(R)CH(CF3)-, – O(CH2)2O(CH2)xN(R)C(O)(CH2)x-, –O(CH2)2O(CH2)2N(R)C(O)O(CH2)x-, – O(CH2)2O(CH2)2N(R)C(O)O(CH2)2N(R)C(O)-, – O(CH2)2O(CH2)2N(R)C(O)OCH(CH3)CH2N(R)C(O)-, – O(CH2)2O(CH2)2N(R)C(O)N(R)-, –O(CH2)2O(CH2)xC(O)N(R)-, –O(CH2)2O(CH2)xC(O)- , -N(R)(CH2)2O-, -N(R)(CH2)x-, -N(R)C(O)(CH2)x-, -N(R)(CH2)2O(CH2)2N(R)-, - N(R)(CH2)2O(CH2)2N(R)C(O)O-, and -N(R)C(O)CH2O(CH2)2N(R)C(O)O-.

26. The compound of claim 25, wherein each L is independently selected from: -O(CH2)x-, – O(CH2)2O(CH2)xN(R)C(O)(CH2)x-, and –O(CH2)2O(CH2)2N(R)C(O)O(CH2)x-.

27. The compound of any one of claims 1-26, wherein each R7is independently optionally substituted C1-6aliphatic or -Cy1.

28. The compound of any one of claims 1-26, wherein each R7is independently hydrogen.

29. The compound of any one of claims 1-26, wherein each R7is independently optionally substituted C1-6aliphatic.

30. The compound of any one of claims 1-26, wherein each R7is independently –Cy1.

31. The compound of any one of claims 1-30, wherein m is 2 or 3.

32. The compound of any one of claims 1-31, wherein a moietyis selected from:

33. The compound of any one of claims 1-32, wherein 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.

34. The compound of any one of claims 1-32, wherein 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.

35. The compound of any one of claims 1-32, wherein 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.

36. The compound of claim 35, wherein Ring C is phenyl.

37. The compound of claim 35, wherein Ring C is.

38. The compound of any one of claims 1-37, wherein each R3is independently selected from oxo, halogen, -(CH2)xOR, -(CH2)xC(O)N(R)2, and optionally substituted C1-6aliphatic.

39. The compound of any one of claims 1-38, wherein p is 1 or 2.

40. The compound of any one of claims 1-39, wherein a moietyis selected from:

41. The compound of any one of claims 1-40, wherein each Cy1is 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 Cy1is substituted with 0-3 instances of R5.

42. The compound of any one of claims 1-40, wherein each Cy1is 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 Cy1is substituted with 0-3 instances of R5.

43. The compound of any one of claims 1-42, wherein each Cy2is 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 Cy2is substituted with 0-3 instances of R6.

44. The compound of any one of claims 1-43, wherein each Cy3is independently selected from phenyl and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy3is substituted with 0-3 instances of R6.

45. The compound of any one of claims 1-43, wherein each Cy3is 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 Cy3is substituted with 0-3 instances of R6.

46. The compound of claim 1 or 3, wherein R4and R4’are connected with an optionally substituted C9-11hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O- or –N(R)-.

47. The compound of claim 46, wherein R4and R4’are connected with –O(CH2)8O-.

48. The compound of any one of claims 1-47, wherein each R is hydrogen or C1-6alkyl optionally substituted with one or more halogen.

49. A compound of Formula II:or a salt (e.g., a pharmaceutically acceptable salt) 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; 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 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; each R1is independently halogen and –L-R7; each L is independently a covalent bond or a bivalent straight or branched C1-12 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 agroup selected from –N(R)-, -O-, -S-, -C(O)-, -SO2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, - OC(O)-, -OC(O)N(R)-, -N(R)C(O)O-, -SO2N(R)-, and –N(R)SO2-; each R7is independently selected from hydrogen, optionally substituted C1-6aliphatic, and – Cy1; each R2is independently selected from halogen, -OR, and optionally substituted C1-6aliphatic; m is 0, 1, 2, or 3; n is 0, 1, or 2; each x is independently 0, 1, 2, or 3; each R is independently selected from hydrogen and optionally substituted C1-6aliphatic; each Cy1is independently selected from phenyl, 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, 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 10-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy1is substituted with 0-3 instances of R5; each R5is independently selected from oxo, halogen, -CN, -OR, -N(R)2, -N(R)Cy2, -C(O)R, - C(O)Cy2, -C(O)N(R)2, -C(O)OR, -C(O)OCy2, -(CH2)xN(R)C(O)R, -N(R)C(O)(CH2)xCy2, -(CH2)xN(R)C(O)OR, -N(R)C(O)OCy2, -SO2R, -Cy2, and optionally substituted C1-6aliphatic; each Cy2is 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 Cy2is substituted with 0-3 instances of R6; and each R6is independently selected from oxo, halogen, -CN, -(CH2)xOR, -(CH2)xN(R)2, - (CH2)xC(O)R, -(CH2)xC(O)OR, -(CH2)xC(O)N(R)2, -(CH2)xN(R)C(O)OR, and optionally substituted C1-6aliphatic.

50. The compound of claim 49, wherein the compound is of Formula IIC:or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein: X is -C(O)N(R)2or 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.

51. The compound of claim 49, wherein the compound is of Formula IID:or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein: J is a bivalent straight or branched C1-4hydrocarbon chain; and X is –OR or -N(R)2.

52. The compound of claim 49 or 50, wherein X is -C(O)N(R)2or a group selected from a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a 4- to 7-membered heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein any ring is optionally substituted with C1-6alkyl.

53. The compound of any one of claims 49-52, wherein a moietyis selected from:

54. The compound of any one of claims 49-53, wherein 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.

55. The compound of claim 54, wherein Ring B is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

56. The compound of claim 54, wherein Ring B is a 5-membered carbocyclic ring.

57. The compound of any one of claims 49-53, wherein Ring B is selected from:

58. The compound of any one of claims 49-57, wherein each R2is independently selected from halogen, -OR, and C1-6alkyl.

59. The compound of any one of claims 49-58, wherein n is 0.

60. The compound of any one of claims 49-58, wherein n is 1.

61. The compound of any one of claims 49-58, wherein n is 2.

62. The compound of any one of claims 49-61, wherein 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.

63. The compound of claim 62, wherein Ring A is phenyl.

64. The compound of any one of claims 49-63, wherein at least one R1is –L-R7.

65. The compound of claim 64, wherein one R is –L-R7, and any other R groups are halogen.

66. The compound of any one of claims 49-65, wherein a moietyis67. The compound of claim 66, wherein a a moiety isor68. The compound of any one of claims 49-67, wherein each L is independently a covalent bond.

69. The compound of any one of claims 49-67, wherein each L is independently a bivalent straight or branched C1-12 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)-, -SO2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -OC(O)N(R)-, -N(R)C(O)O-, - SO2N(R)-, and –N(R)SO2-.

70. The compound of claim 69, wherein each L is independently a bivalent straight or branched C1-12hydrocarbon 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-, -SO2N(R)-, and –N(R)SO2-.

71. The compound of any one of claims 49-67, wherein each L is independently selected from: -(CH2)x-, -O(CH2)x-, -OCH(CH3)-, –O(CH2)2O(CH2)x-, –O(CH2)2O-, - O(CH2)2O(CH2)2O-, -O(CH2)2O(CH2)2OC(O)N(R)-, –O(CH2)2O(CH2)2N(R)SO2-, – O(CH2)2O(CH2)2N(R)-, –O(CH2)2O(CH2)2N(R)CH(CF3)-, –O(CH2)2O(CH2)xN(R)C(O)(CH2)x-, –O(CH2)2O(CH2)2N(R)C(O)O(CH2)x-, – O(CH2)2O(CH2)2N(R)C(O)O(CH2)2N(R)C(O)-, – O(CH2)2O(CH2)2N(R)C(O)OCH(CH3)CH2N(R)C(O)-, – O(CH2)2O(CH2)2N(R)C(O)N(R)-, –O(CH2)2O(CH2)xC(O)N(R)-, –O(CH2)2O(CH2)xC(O)- , -N(R)(CH2)2O-, -N(R)(CH2)x-, -N(R)C(O)(CH2)x-, -N(R)(CH2)2O(CH2)2N(R)-, - N(R)(CH2)2O(CH2)2N(R)C(O)O-, and -N(R)C(O)CH2O(CH2)2N(R)C(O)O-.

72. The compound of claim 71, wherein each L is independently selected from: -O(CH2)x-, – O(CH2)2O(CH2)xN(R)C(O)(CH2)x-, and –O(CH2)2O(CH2)2N(R)C(O)O(CH2)x-.

73. The compound of any one of claims 49-72, wherein each R7is independently optionally substituted C1-6aliphatic or -Cy1.

74. The compound of any one of claims 49-72, wherein each R7is independently hydrogen.

75. The compound of any one of claims 49-72, wherein each R7is independently optionally substituted C1-6aliphatic.

76. The compound of any one of claims 49-72, wherein each R7is independently –Cy1.

77. The compound of any one of claims 49-76, wherein m is 2 or 3.

78. The compound of any one of claims 49-77, wherein each Cy1is 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 Cy1is substituted with 0-3 instances of R5.

79. The compound of any one of claims 49-77, wherein each Cy1is 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 Cy1is substituted with 0-3 instances of R5.

80. The compound of any one of claims 49-79, wherein each Cy2is 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 Cy2is substituted with 0-3 instances of R6.

81. The compound of any one of claims 49-80, wherein each R is hydrogen or C1-6alkyl optionally substituted with one or more halogen.

82. A compound selected from Table 1, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

83. A pharmaceutical composition comprising a compound according to any one of claims 1- 82, or a salt (e.g., pharmaceutically acceptable salt) thereof, and a pharmaceutically acceptable carrier or excipient.

84. A method comprising administering a therapeutically effective amount of a compound according to any one of claims 1-82 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

85. The method of claim 84, wherein the subject has a disease, disorder, or condition ameliorated by disruption, inhibition, and / or prevention of an interaction between a small GTPase and a PI3Kα protein.

86. The method of claim 85, wherein the small GTPase is Rac1, CDC42, or a RAS protein.

87. The method of claim 86, wherein the small GTPase is a RAS protein.

88. The method of claim 87, wherein the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1.

89. The method of any one of claims 84-88, wherein the subject has a cancer.

90. A method of treating a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-82 or a pharmaceutically acceptable salt thereof.

91. The method of claim 89 or 90, wherein the cancer is associated with and / or characterized by aberrant activation of PI3Kα and / or a mutation in PI3Kα.

92. The method of claim 91, wherein the PI3Kα 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.

93. The method of claim 92, wherein the PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

94. The method of any one of claims 89-93, wherein the cancer is characterized by a mutation in a RAS protein.

95. The method of claim 94, wherein the RAS protein comprises a mutation in codon 12, 13, or 61.

96. The method of claim 94 or 95, wherein the RAS protein is KRAS.

97. The method of claim 96, wherein the 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.

98. The method of claim 97, wherein the KRAS protein comprises a G12C or G12D mutation.

99. The method according to claim 94 or 95, wherein the RAS protein is HRAS.

100. The method according to claim 99, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.

101. The method according to claim 94 or 95, wherein the RAS protein is NRAS.

102. The method according to claim 101, wherein the 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.

103. The method according to any one of claims 89-102, wherein the cancer is selected from pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; bowel 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 Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML),) and lymphomas including lymphocytic, granulocytic and monocytic lymphomas.

104. The method according to claim 103, wherein the 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.

105. The method according to any one of claims 89-102, wherein the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family, Met, FGFR, Alk, PDGF, EGFR, or ROS kinases).

106. The method according to any one of claims 89-105, wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein.

107. The method according to any one of claims 84-106, wherein the subject has previously undergone a treatment regimen for cancer.

108. The method according to any one of claims 84-107, wherein the subject has previously entered remission from cancer.

109. A method of treating a metabolic disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-82 or a pharmaceutically acceptable salt thereof.

110. The method according to claim 109, wherein the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes.

111. A method of treating a RASopathy, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-82 or a pharmaceutically acceptable salt thereof.

112. The method according to claim 111, wherein the RASopathy is selected from neurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformation syndrome, and Legius syndrome.

113. A method of treating a vascular disorder or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-82 or a pharmaceutically acceptable salt thereof.

114. The method according to claim 113, wherein the vascular disorder or condition 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)).

115. A method of disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Kα protein in a subject, comprising administering to the subject a compound according to any one of claims 1-82 or a pharmaceutically acceptable salt thereof.

116. A method of disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Kα protein, comprising contacting a cell containing the small GTPase and the PI3Kα protein with a compound according to any one of claims 1-82 or a pharmaceutically acceptable salt thereof.

117. A method comprising contacting a cell containing a small GTPase and a PI3Kα protein with a compound according to any one of claims 1-82 or a pharmaceutically acceptable salt thereof.

118. The method of claim 116 or 117, wherein the cell is included in a subject.

119. The method of any one of claims 115-118, wherein the small GTPase is selected from Rac1, CDC42, and a RAS protein.

120. The method of claim 119, wherein the small GTPase is a RAS protein.

121. The method of claim 120, wherein the RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1.

122. The method of claim 121, wherein the RAS protein is KRAS.

123. The method of claim 122, wherein the 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.

124. The method of claim 123, wherein the KRAS protein comprises a G12C or G12D mutation.

125. The method according to claim 121, wherein the RAS protein is HRAS.

126. The method according to claim 125, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.

127. The method according to claim 121, wherein the RAS protein is NRAS.

128. The method according to claim 127, wherein the 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.

129. A compound according to any one of claims 1-82 or a pharmaceutically acceptable salt thereof for use as a medicament.

130. Use of a compound according to any one of claims 1-82 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament.

131. The compound or use according to claim 129 or 130, wherein the medicament is for treating a cancer.

132. The compound or use according to claim 131, wherein the cancer is associated with and / or characterized by aberrant activation of PI3Kα and / or a mutation in PI3Kα.

133. The compound or use according to claim 132, wherein the PI3Kα 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.

134. The compound or use according to claim 133, wherein the PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

135. The compound or use according to any one of claims 131-134, wherein the cancer is characterized by a mutation in a RAS protein.

136. The compound or use according to claim 135, wherein the RAS protein comprises a mutation in codon 12, 13, or 61.

137. The compound or use according to claim 135 or 136, wherein the RAS protein is KRAS.

138. The compound or use according to claim 137, wherein the 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.

139. The compound or use according to claim 138, wherein the KRAS protein comprises a G12C or G12D mutation.

140. The compound or use according to claim 135 or 136, wherein the RAS protein is HRAS.

141. The compound according to claim 140, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.

142. The compound or use according to claim 135 or 136, wherein the RAS protein is NRAS.

143. The compound or use according to claim 142, wherein the 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.

144. The compound or use according to any one of claims 131-143, wherein the cancer is selected from pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; bowel 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 Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML),) and lymphomas including lymphocytic, granulocytic and monocytic lymphomas.

145. The compound or use according to claim 144, wherein the 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.

146. The compound or use according to any one of claims 131-145, wherein the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family, Met, FGFR, Alk, PDGF, EGFR, or ROS kinases).

147. The compound or use according to any one of claims 131-145, wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein.

148. The compound or use according to claim 129 or 130, wherein the medicament is for treating a metabolic disorder, a RASopathy, or a vascular disorder.

149. The compound or use according to claim 148, wherein: (i) the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes; (ii) the RASopathy is selected from neurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformationsyndrome, and Legius syndrome; and / or (iii) the vascular disorder or condition 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); or fibro-adipose vascular anomaly (FAVA)).

150. A compound according to any one of claim 1-82 or a pharmaceutically acceptable salt thereof for use in treating a disease, disorder, or condition.

151. The compound for use according to claim 150 for use in treating a cancer.

152. The compound for use according to claim 151, wherein the cancer is associated with and / or characterized by aberrant activation of PI3Kα and / or a mutation in PI3Kα.

153. The compound for use according to claim 152, wherein the PI3Kα 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.

154. The compound for use according to claim 153, wherein the PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

155. The compound for use according to any one of claims 151-154, wherein the cancer is characterized by a mutation in a RAS protein.

156. The compound for use according to claim 155, wherein the RAS protein comprises a mutation in codon 12, 13, or 61.

157. The compound for use according to claim 155 or 156, wherein the RAS protein is KRAS.

158. The compound for use according to claim 157, wherein the 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.

159. The compound for use according to claim 158, wherein the KRAS protein comprises a G12C or G12D mutation.

160. The compound for use according to claim 155 or 156, wherein the RAS protein is HRAS.

161. The compound for use according to claim 160, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.

162. The compound for use according to claim 155 or 156, wherein the RAS protein is NRAS.

163. The compound for use according to claim 162, wherein the 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.

164. The compound for use according to any one of claims 151-163, wherein the cancer is selected from pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; bowel 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 Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML),) and lymphomas including lymphocytic, granulocytic and monocytic lymphomas.

165. The compound for use according to claim 164, wherein the 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.

166. The compound for use according to any one of claims 151-165, wherein the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family, Met, FGFR, Alk, PDGF, EGFR, or ROS kinases).

167. The compound for use according to any one of claims 151-166, wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein.

168. The compound for use according to claim 150 for use in treating a metabolic disorder, a RASopathy, or a vascular disorder.

169. The compound for use according to claim 168, wherein: (i) the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes; (ii) the RASopathy is selected fromneurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformation syndrome, and Legius syndrome; and / or (iii) the vascular disorder or condition 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)).

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