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WO2024217484A1 - Composés, compositions et procédés associés - Google Patents

Composés, compositions et procédés associés Download PDF

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Publication number
WO2024217484A1
WO2024217484A1 PCT/CN2024/088496 CN2024088496W WO2024217484A1 WO 2024217484 A1 WO2024217484 A1 WO 2024217484A1 CN 2024088496 W CN2024088496 W CN 2024088496W WO 2024217484 A1 WO2024217484 A1 WO 2024217484A1
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WIPO (PCT)
Prior art keywords
ring
compound
optionally substituted
disease
heteroatoms
Prior art date
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PCT/CN2024/088496
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English (en)
Inventor
Ruichao Richard SHEN
Xiaoguang Lei
Xiaoming Wang
Yulong Li
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Hepaitech Beijing Biopharma Technology Co Ltd
Original Assignee
Hepaitech Beijing Biopharma Technology Co Ltd
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Priority to CN202480026786.6A priority Critical patent/CN121127453A/zh
Publication of WO2024217484A1 publication Critical patent/WO2024217484A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure provides compounds and compositions, among other things, useful for modulating MRGPRX4 activities.
  • provided compounds and compositions are useful for preventing or treating MRGPRX4-associated conditions, disorders or diseases, e.g., pruritus.
  • the present disclosure provides technologies for preparing provided compounds and compositions.
  • MRGPRX4 Mas-related G-protein coupled receptor X4
  • MRGPRX4 has a number of biological functions and can be associated with various conditions, disorders or diseases.
  • patients with liver condition, disorder or disease such as primary biliary cholangitis (PBC) , primary sclerosing cholangitis (PSC) , or progressive familial intrahepatic cholestasis (PFIC)
  • PBC primary biliary cholangitis
  • PSC primary sclerosing cholangitis
  • PFIC progressive familial intrahepatic cholestasis
  • MRGPRX4 and its agonism by bile acid and derivatives thereof have been reported to be likely associated with pruritus occurred in these diseases (e.g., Meixiong et al. MRGPRX4 is a G protein-coupled receptor activated by bile acids that may contribute to cholestatic pruritus, PNAS, 2019, 116 (21) , 10525-10530; Yu et al. MRGPRX4 is bile acid receptor for human cholestatic itch, eLife, 2019, 8, e48431) .
  • MRGPRX4 has been reported to express in at least human dorsal root ganglion (hDRG) neurons and to co-expresses with itch receptor HRH1. It has been reported that bile acids or MRGPRX4 specific agonists in the skin can activate MRGPRX4 in itch-related primary fibers, elicits Ca 2+ responses, and induce itch in human subjects.
  • hDRG dorsal root ganglion
  • Small compounds that can allegedly act as MRGPRX4 modulators have been disclosed in, e.g., WO 2020/198537, US 2021/0032213, WO 2021/211839, US 2021/0340106, WO 2022/061008, etc.
  • the present disclosure provides various compounds, e.g., compounds having the structure of formula I or salts thereof, and compositions and methods thereof.
  • provided compounds are useful as MRGPRX4 modulators.
  • provided technologies e.g., compounds, compositions, methods, etc.
  • a condition, disorder or disease is a MRGPRX4-associated condition, disorder or disease.
  • a condition, disorder or disease is or comprises itch.
  • a condition, disorder or disease is or comprises pruritus.
  • a condition, disorder or disease is associated with administration of another therapeutic agent, e.g., a FXR agonist, a bile acid or an analog or derivative thereof, etc.
  • the present disclosure provides a compound, wherein the compound has the structure of formula I
  • R 1 is an isostere of -C (O) OH, or -C (O) OR 11 , -C (O) N (R 12 ) SO 2 R 13 , -C (O) NR 14 R 15 , or
  • R 2 is optionally substituted C 1-6 alkyl
  • each of R 3 , R 4 and R 5 is independently R’, -OR’, halogen, -CN, -NO 2 , or -N (R’) 2 ;
  • each of R 11 , R 12 , R 13 , R 14 and R 15 is independently R’;
  • L is optionally substituted - (CH 2 ) m -;
  • n 1 or 2;
  • Ring A is an optionally substituted ring selected from a 6-10 membered aryl ring and a 5-10 membered heteroaryl ring having 1-6 heteroatoms, or Ring A is wherein each R a is independently -R’, -OR’, halogen, -CN, -NO 2 , or -N (R’) 2 and n is 1-5;
  • each R’ is independently R, -OR, -C (O) R, -C (O) OR, or -S (O) 2 R;
  • each R is independently hydrogen or an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C 1 -C 6 aliphatic, and 5-10 membered heteroaryl having 1-6 heteroatoms-C 1 -C 6 aliphatic; or
  • R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted 3-10 membered ring having, in addition to the atom, 0-4 heteroatoms; or
  • two R groups on two atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3-10 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms.
  • the present disclosure provides a pharmaceutical composition of a provided compounds. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a provided compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition delivering a provided compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present disclosure provides a method for preventing a condition, disorder or disease, comprising administering or delivering to a subject susceptible thereto an effective amount a provided compound.
  • the present disclosure provides a method for treating a condition, disorder or disease, comprising administering or delivering to a subject suffering therefrom an effective amount a provided compound.
  • a condition, disorder or disease is a MRGPRX4-associated condition, disorder or disease.
  • a condition, disorder or disease is associated with MRGPRX4 activation.
  • a condition, disorder or disease is associated with MRGPRX4 activation by an agent.
  • a condition, disorder or disease is associated with MRGPRX4 interaction with an agent.
  • a condition, disorder or disease is associated with administration of an agent.
  • a condition, disorder or disease is associated with delivery of an agent.
  • an agent is a therapeutic agent.
  • an agent can bind to MRGPRX4.
  • an agent can activate MRGPRX4.
  • an agent is a FXR agonist.
  • an agent is a bile acid or an analog or derivative thereof.
  • a condition, disorder or disease is pruritus.
  • the present disclosure provides a method for preventing a condition, disorder or disease, comprising administering or delivering to a subject susceptible thereto an effective amount a provided compound and another agent.
  • the present disclosure provides a method for treating a condition, disorder or disease, comprising administering or delivering to a subject suffering therefrom an effective amount a provided compound and another agent.
  • a condition, disorder or disease is associated with Farnesoid X receptor (FXR) , and an another agent is a FXR agonist.
  • a condition, disorder or disease is associated with TGR5, and an another agent is a TGR5 agonist.
  • an another agent can activate MRGPRX4.
  • an another agent is a FXR agonist. In some embodiments, an another agent is a bile acid or an analog or derivative thereof. In some embodiments, a condition, disorder or disease is a liver condition, disorder or disease. For example, in some embodiments, a condition, disorder or disease is nonalcoholic steatohepatitis (NASH) .
  • NASH nonalcoholic steatohepatitis
  • the present disclosure provides technologies, e.g., methods, reagents, etc., for preparing a compound of Formula (I) or a pharmaceutical acceptable salt thereof.
  • the term “a” or “an” may be understood to mean “at least one” ;
  • the term “or” may be understood to mean “and/or” ;
  • the terms “comprising” , “comprise” , “including” (whether used with “not limited to” or not) , and “include” (whether used with “not limited to” or not) may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps;
  • the term “another” may be understood to mean at least an additional/second one or more;
  • the terms “about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art; and (vi) where ranges are provided, endpoints are included.
  • isomers of compounds are included.
  • compounds may be provided, administered, or delivered in various forms, e.g., salts (e.g., pharmaceutically acceptable salts) , solvates, hydrates, esters, prodrugs, tautomers, etc.
  • Aliphatic 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 (but not aromatic) , or a substituted or unsubstituted monocyclic, bicyclic, or polycyclic hydrocarbon ring that is completely saturated or that contains one or more units of unsaturation (but not aromatic) , or combinations thereof.
  • aliphatic groups contain 1-50 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-20 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms.
  • aliphatic groups contain 1-9 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-7 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1, 2, 3, or 4 aliphatic carbon atoms.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl.
  • alkenyl refers to an aliphatic group, as defined herein, having one or more double bonds.
  • Alkyl As used herein, the term “alkyl” is given its ordinary meaning in the art and may include saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In some embodiments, alkyl has 1-100 carbon atoms. In certain embodiments, a straight chain or branched chain alkyl has about 1-20 carbon atoms in its backbone (e.g., C 1 -C 20 for straight chain, C 2 -C 20 for branched chain) , and alternatively, about 1-10.
  • cycloalkyl rings have from about 3-10 carbon atoms in their ring structure where such rings are monocyclic, bicyclic, or polycyclic, and alternatively about 5, 6 or 7 carbons in the ring structure.
  • an alkyl group may be a lower alkyl group, wherein a lower alkyl group comprises 1-4 carbon atoms (e.g., C 1 -C 4 for straight chain lower alkyls) .
  • Alkynyl refers to an aliphatic group, as defined herein, having one or more triple bonds.
  • animal refers to any member of the animal kingdom. In some embodiments, “animal” refers to humans, at any stage of development. In some embodiments, “animal” refers to non-human animals, at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate and/or a pig) . In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish and/or worms. In some embodiments, an animal may be a transgenic animal, a genetically-engineered animal and/or a clone.
  • Aryl refers to monocyclic, bicyclic or polycyclic ring systems having a total of five to thirty ring members, wherein at least one ring in the system is aromatic.
  • an aryl group is a monocyclic, bicyclic or polycyclic ring system having a total of five 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.
  • each monocyclic ring unit is aromatic.
  • an aryl group is a biaryl group.
  • aryl may be used interchangeably with the term “aryl ring. ”
  • aryl refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, binaphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • Characteristic portion refers to a portion of a substance whose presence (or absence) correlates with presence (or absence) of a particular feature, attribute, or activity of the substance.
  • a characteristic portion of a substance is a portion that is found in the substance and in related substances that share the particular feature, attribute or activity, but not in those that do not share the particular feature, attribute or activity.
  • a characteristic portion shares at least one functional characteristic with the intact substance.
  • a “characteristic portion” of a protein or polypeptide is one that contains a continuous stretch of amino acids, or a collection of amino acids, in some embodiments, a collection of continuous stretches of amino acids, that together are characteristic of a protein or polypeptide. In some embodiments, each such continuous stretch generally contains at least 2, 5, 10, 15, 20, 50, or more amino acids.
  • a characteristic portion of a substance e.g., of a protein, antibody, etc.
  • a characteristic portion may be biologically active.
  • Comparable is used herein to describe two (or more) sets of conditions or circumstances that are sufficiently similar to one another to permit comparison of results obtained or phenomena observed.
  • comparable sets of conditions or circumstances are characterized by a plurality of substantially identical features and one or a small number of varied features.
  • sets of conditions are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under the different sets of conditions or circumstances are caused by or indicative of the variation in those features that are varied.
  • Cycloaliphatic The term “cycloaliphatic, ” “carbocycle, ” “carbocyclyl, ” “carbocyclic radical, ” and “carbocyclic ring, ” are used interchangeably, and as used herein, refer to saturated or partially unsaturated, but non-aromatic, cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having, unless otherwise specified, from 3 to 30 ring members.
  • Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl.
  • a cycloaliphatic group has 3–6 carbons.
  • a cycloaliphatic group is saturated and is cycloalkyl.
  • cycloaliphatic may also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl or tetrahydronaphthyl.
  • a cycloaliphatic group is bicyclic.
  • a cycloaliphatic group is tricyclic.
  • a cycloaliphatic group is polycyclic.
  • cycloaliphatic refers to C 3 -C 6 monocyclic hydrocarbon, or C 8 -C 10 bicyclic or polycyclic hydrocarbon, that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule, or a C 9 -C 16 polycyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Heteroaliphatic The term “heteroaliphatic” , as used herein, is given its ordinary meaning in the art and refers to aliphatic groups as described herein in which one or more carbon atoms are independently replaced with one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, and the like) . In some embodiments, one or more units selected from C, CH, CH 2 , and CH 3 are independently replaced by one or more heteroatoms (including oxidized and/or substituted forms thereof) . In some embodiments, a heteroaliphatic group is heteroalkyl. In some embodiments, a heteroaliphatic group is heteroalkenyl.
  • Heteroalkyl The term “heteroalkyl” , as used herein, is given its ordinary meaning in the art and refers to alkyl groups as described herein in which one or more carbon atoms are independently replaced with one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, and the like) .
  • heteroalkyl groups include, but are not limited to, alkoxy, poly (ethylene glycol) -, alkyl-substituted amino, tetrahydrofuranyl, piperidinyl, morpholinyl, etc.
  • Heteroaryl and “heteroar–” , as used herein, used alone or as part of a larger moiety, e.g., “heteroaralkyl, ” or “heteroaralkoxy, ” refer to monocyclic, bicyclic or polycyclic ring systems having a total of five to thirty ring members, wherein at least one ring in the system is aromatic and at least one aromatic ring atom is a heteroatom.
  • a heteroaryl group is a group having 5 to 10 ring atoms (i.e., monocyclic, bicyclic or polycyclic) , in some embodiments 5, 6, 9, or 10 ring atoms.
  • each monocyclic ring unit is aromatic.
  • a heteroaryl group has 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • a heteroaryl is a heterobiaryl group, such as bipyridyl and the like.
  • heteroaryl and heteroheteroar– also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido [2, 3–b] –1, 4–oxazin–3 (4H) –one.
  • heteroaryl group may be monocyclic, bicyclic or polycyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring, ” “heteroaryl group, ” or “heteroaromatic, ” any of which terms include rings that are optionally substituted.
  • heterooaralkyl refers to an alkyl group substituted by a heteroaryl group, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • Heteroatom means an atom that is not carbon or hydrogen.
  • a heteroatom is boron, oxygen, sulfur, nitrogen, phosphorus, or silicon (including oxidized forms of nitrogen, sulfur, phosphorus, or silicon; charged forms of nitrogen (e.g., quaternized forms, forms as in iminium groups, etc. ) , phosphorus, sulfur, oxygen; etc. ) .
  • a heteroatom is silicon, phosphorus, oxygen, sulfur or nitrogen.
  • a heteroatom is silicon, oxygen, sulfur or nitrogen.
  • a heteroatom is oxygen, sulfur or nitrogen.
  • Heterocycle As used herein, the terms “heterocycle, ” “heterocyclyl, ” “heterocyclic radical, ” and “heterocyclic ring” , as used herein, are used interchangeably and refer to a monocyclic, bicyclic or polycyclic ring moiety (e.g., 3-30 membered) that is saturated or partially unsaturated and has one or more heteroatom ring atoms.
  • a heterocyclyl group is a stable 5–to 7–membered monocyclic or 7–to 10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes substituted nitrogen.
  • the nitrogen may be N (as in 3, 4–dihydro–2H–pyrrolyl) , NH (as in pyrrolidinyl) , or + NR (as in N–substituted pyrrolidinyl) .
  • 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 optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle ” “heterocyclyl, ” “heterocyclyl ring, ” “heterocyclic group, ” “heterocyclic moiety, ” and “heterocyclic radical, ” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclyl group may be monocyclic, bicyclic or polycyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • a leaving group or a LG is an atom or group of atoms that detaches from the main or residual part of a substrate during a reaction or elementary step of a reaction.
  • LG is a halogen.
  • LG is -Cl.
  • LG is -OH.
  • compounds of the disclosure may contain optionally substituted and/or substituted moieties.
  • 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.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • an optionally substituted group is unsubstituted.
  • C 1–20 e.g., C 1-9 , C 1-6 , C 1-5 , C 1-4 , etc.
  • heteroaliphatic having 1–5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus
  • –CH 2 - C 6-14 (e.g., C 6-10 , C 6 , etc. ) aryl)
  • –O (CH 2 ) 0–1 C 6-14 (e.g., C 6-10 , C 6 , etc. ) aryl)
  • -CH 2 - (5-14 e.g., 5-10, 5-6, 5, 6, 9, 10, 14, etc.
  • a 3–20 e.g., 3-10, 3-9, 3-7, 3-6, 5-10, 5-6, etc.
  • membered heteroaryl ring a 3–20 (e.g., 3-10, 3-9, 3-7, 3-6, 5-10, 5-6, etc. ) membered, monocyclic, bicyclic, or polycyclic, saturated, partially unsaturated or aryl ring having 0–5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom (s) , form a 3–20 (e.g., 3-10, 3-9, 3-7, 3-6, 5-10, 5-6, etc. ) membered, monocyclic, bicyclic, or polycyclic, saturated, partially unsaturated or aryl ring having 0–5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, which may be substituted as defined below.
  • Suitable monovalent substituents on R ⁇ are independently halogen, — (CH 2 ) 0–2 R ⁇ , – (haloR ⁇ ) , – (CH 2 ) 0–2 OH, – (CH 2 ) 0–2 OR ⁇ , – (CH 2 ) 0–2 CH (OR ⁇ ) 2 ; –O (haloR ⁇ ) , –CN, –N 3 , – (CH 2 ) 0–2 C (O) R ⁇ , – (CH 2 ) 0–2 C (O) OH, – (CH 2 ) 0–2 C (O) OR ⁇ , – (CH 2 ) 0–2 SR ⁇ , – (CH 2 ) 0–2 SH, – (CH 2 ) 0–2 NH 2 , – (CHCH 2 )
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O (CR * 2 ) 2–3 O–, wherein each independent occurrence of R * is selected from hydrogen, C 1–6 aliphatic which may be substituted as defined below, or an unsubstituted 3–6 (e.g., 4-6, 5-6, etc. ) –membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, –R ⁇ , - (haloR ⁇ ) , –OH, –OR ⁇ , –O (haloR ⁇ ) , –CN, –C (O) OH, –C (O) OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or –NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O (CH 2 ) 0–1 Ph, or a 3–6 (e.g., 4-6, 5-6, etc. ) –membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • halogen e.g., 4-6
  • suitable substituents on a substitutable nitrogen include or wherein each is independently hydrogen, C 1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 3–6 (e.g., 4-6, 5-6, etc. ) –membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences of taken together with their intervening atom (s) form an unsubstituted 3–12 (e.g., 3-10, 3-7, 3-6, 5-10, 5-7, 5-6, etc. ) –membered saturated, partially unsaturated, or aryl mono–or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • each is independently hydrogen, C 1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an
  • Suitable substituents on the aliphatic group of are independently halogen, –R ⁇ , - (haloR ⁇ ) , –OH, –OR ⁇ , –O (haloR ⁇ ) , –CN, –C (O) OH, –C (O) OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or –NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O (CH 2 ) 0–1 Ph, or a 3–6 (e.g., 4-6, 5-6, etc. ) –membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • halogen e.g., 4-6,
  • Partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • 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.
  • composition refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers.
  • an active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population.
  • compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions) , tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.
  • oral administration for example, drenches (aqueous or non-aqueous solutions
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ring
  • compositions that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well 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) .
  • pharmaceutically acceptable salt include, but are not limited to, nontoxic acid addition salts, which 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, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • nontoxic acid addition salts which 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, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • pharmaceutically acceptable salts include, but are not limited to, 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
  • a provided compound comprises one or more acidic groups
  • a pharmaceutically acceptable salt is an alkali, alkaline earth metal, or ammonium (e.g., an ammonium salt of N (R) 3 , wherein each R is independently defined and described in the present disclosure) salt.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • a pharmaceutically acceptable salt is a sodium salt.
  • a pharmaceutically acceptable salt is a potassium salt.
  • a pharmaceutically acceptable salt is a calcium salt.
  • pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • a provided compound comprises two or more acid groups.
  • a pharmaceutically acceptable salt, or generally a salt, of such a compound comprises two or more cations, which can be the same or different.
  • all ionizable hydrogen e.g., in an aqueous solution with a pKa no more than about 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2; in some embodiments, no more than about 7; in some embodiments, no more than about 6; in some embodiments, no more than about 5; in some embodiments, no more than about 4; in some embodiments, no more than about 3 in the acidic groups are replaced with cations.
  • Protecting group The term “protecting group, ” as used herein, is well known in the art and includes those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3 rd edition, John Wiley &Sons, 1999, the entirety of which is incorporated herein by reference. Also included are those protecting groups specially adapted for nucleoside and nucleotide chemistry described in Current Protocols in Nucleic Acid Chemistry, edited by Serge L. Beaucage et al. 06/2012, the entirety of Chapter 2 is incorporated herein by reference.
  • Suitable amino–protecting groups include methyl carbamate, ethyl carbamante, 9–fluorenylmethyl carbamate (Fmoc) , 9– (2–sulfo) fluorenylmethyl carbamate, 9– (2, 7–dibromo) fluoroenylmethyl carbamate, 2, 7–di–t–butyl— [9– (10, 10–dioxo–10, 10, 10, 10–tetrahydrothioxanthyl) ] methyl carbamate (DBD–Tmoc) , 4–methoxyphenacyl carbamate (Phenoc) , 2, 2, 2–trichloroethyl carbamate (Troc) , 2–trimethylsilylethyl carbamate (Teoc) , 2–phenylethyl carbamate (hZ) , 1– (1–adamantyl) –1–methylethyl carbamate (Adpoc) , 1, 1
  • Suitably protected carboxylic acids further include, but are not limited to, silyl–, alkyl–, alkenyl–, aryl–, and arylalkyl–protected carboxylic acids.
  • suitable silyl groups include trimethylsilyl, triethylsilyl, t–butyldimethylsilyl, t–butyldiphenylsilyl, triisopropylsilyl, and the like.
  • suitable alkyl groups include methyl, benzyl, p–methoxybenzyl, 3, 4–dimethoxybenzyl, trityl, t–butyl, tetrahydropyran–2–yl.
  • suitable alkenyl groups include allyl.
  • suitable aryl groups include optionally substituted phenyl, biphenyl, or naphthyl.
  • suitable arylalkyl groups include optionally substituted benzyl (e.g., p–methoxybenzyl (MPM) , 3, 4–dimethoxybenzyl, O–nitrobenzyl, p–nitrobenzyl, p–halobenzyl, 2, 6–dichlorobenzyl, p–cyanobenzyl) , and 2–and 4–picolyl.
  • MPM p–methoxybenzyl
  • Suitable hydroxyl protecting groups include methyl, methoxylmethyl (MOM) , methylthiomethyl (MTM) , t–butylthiomethyl, (phenyldimethylsilyl) methoxymethyl (SMOM) , benzyloxymethyl (BOM) , p–methoxybenzyloxymethyl (PMBM) , (4–methoxyphenoxy) methyl (p–AOM) , guaiacolmethyl (GUM) , t–butoxymethyl, 4–pentenyloxymethyl (POM) , siloxymethyl, 2–methoxyethoxymethyl (MEM) , 2, 2, 2–trichloroethoxymethyl, bis (2–chloroethoxy) methyl, 2– (trimethylsilyl) ethoxymethyl (SEMOR) , tetrahydropyranyl (THP) , 3–bromotetrahydropyranyl, tetrahydrothiopyranyl, 1–me
  • the protecting groups include methylene acetal, ethylidene acetal, 1–t–butylethylidene ketal, 1–phenylethylidene ketal, (4–methoxyphenyl) ethylidene acetal, 2, 2, 2–trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p–methoxybenzylidene acetal, 2, 4–dimethoxybenzylidene ketal, 3, 4–dimethoxybenzylidene acetal, 2–nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ortho ester, 1–methoxyethy
  • a hydroxyl protecting group is acetyl, t-butyl, tbutoxymethyl, methoxymethyl, tetrahydropyranyl, 1 -ethoxyethyl, 1 - (2-chloroethoxy) ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2, 4-dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2, 6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl) , 4, 4'-dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloro
  • each of the hydroxyl protecting groups is, independently selected from acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl and 4, 4'-dimethoxytrityl.
  • the hydroxyl protecting group is selected from the group consisting of trityl, monomethoxytrityl and 4, 4'-dimethoxytrityl group.
  • a protecting group is attached to a sulfur atom of an phosphorothioate group.
  • a protecting group is attached to an oxygen atom of an internucleotide phosphorothioate linkage.
  • a protecting group is attached to an oxygen atom of the internucleotide phosphate linkage.
  • a protecting group is 2-cyanoethyl (CE or Cne) , 2-trimethylsilylethyl, 2-nitroethyl, 2-sulfonylethyl, methyl, benzyl, o-nitrobenzyl, 2- (p-nitrophenyl) ethyl (NPE or Npe) , 2-phenylethyl, 3- (N-tert-butylcarboxamido) -1-propyl, 4-oxopentyl, 4-methylthio-l-butyl, 2-cyano-1, 1-dimethylethyl, 4-N-methylaminobutyl, 3- (2-pyridyl) -1-propyl, 2- [N-methyl-N- (2-pyridyl) ] aminoethyl, 2- (N-formyl, N-methyl) aminoethyl,
  • subject refers to any organism to which a compound or composition is administered in accordance with the present disclosure e.g., for experimental, diagnostic, prophylactic and/or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms; etc. ) and plants. In some embodiments, a subject is a human. In some embodiments, a subject may be suffering from and/or susceptible to a disease, disorder and/or condition.
  • the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
  • One of ordinary skill in the biological and/or chemical arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result.
  • the term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and/or chemical phenomena.
  • an individual who is “susceptible to” a disease, disorder and/or condition is one who has a higher risk of developing the disease, disorder and/or condition than does a member of the general public.
  • an individual who is susceptible to a disease, disorder and/or condition is predisposed to have that disease, disorder and/or condition.
  • an individual who is susceptible to a disease, disorder and/or condition may not have been diagnosed with the disease, disorder and/or condition.
  • an individual who is susceptible to a disease, disorder and/or condition may exhibit symptoms of the disease, disorder and/or condition.
  • an individual who is susceptible to a disease, disorder and/or condition may not exhibit symptoms of the disease, disorder and/or condition.
  • an individual who is susceptible to a disease, disorder, and/or condition will develop the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will not develop the disease, disorder, and/or condition.
  • therapeutic agent in general refers to any agent that elicits a desired effect (e.g., a desired biological, clinical, or pharmacological effect) when administered to a subject.
  • a desired effect e.g., a desired biological, clinical, or pharmacological effect
  • an agent is considered to be a therapeutic agent if it demonstrates a statistically significant effect across an appropriate population.
  • an appropriate population is a population of subjects suffering from and/or susceptible to a disease, disorder or condition.
  • an appropriate population is a population of model organisms.
  • an appropriate population may be defined by one or more criterion such as age group, gender, genetic background, preexisting clinical conditions, prior exposure to therapy.
  • a therapeutic agent is a substance that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms or features of a disease, disorder, and/or condition in a subject when administered to the subject in an effective amount.
  • a “therapeutic agent” is an agent that has been or is required to be approved by a government agency before it can be marketed for administration to humans.
  • a “therapeutic agent” is an agent for which a medical prescription is required for administration to humans.
  • a therapeutic agent is a provided compound.
  • therapeutically effective amount means an amount of a substance (e.g., a therapeutic agent, composition, and/or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen.
  • a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, diagnose, prevent, and/or delay the onset of the disease, disorder, and/or condition.
  • the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc.
  • the effective amount of compound in a formulation to treat a disease, disorder, and/or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or features of the disease, disorder, and/or condition.
  • a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.
  • Treat As used herein, the term “treat, ” “treatment, ” or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and/or condition, for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.
  • Unsaturated means that a moiety has one or more units of unsaturation.
  • a provided compound has the structure of formula I:
  • each variable is independently as described herein.
  • R 1 is -C (O) OR 11 , -C (O) N (R 12 ) SO 2 R 13 , -C (O) NR 14 R 15 , or wherein each variable is independently as described herein.
  • R 1 is -C (O) OH. In some embodiments, R 1 is -C (O) OR 11 , wherein each variable is independently as described herein. In some embodiments, R 1 is -C (O) N (R 12 ) SO 2 R 13 , wherein each variable is independently as described herein. In some embodiments, R 1 is -C (O) NR 14 R 15 , wherein each variable is independently as described herein. In some embodiments, R 1 is
  • R 1 is -C (O) OR 11 .
  • R 11 is R as described herein.
  • R 11 is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C 1 -C 6 aliphatic, and 5-10 membered heteroaryl having 1-6 heteroatoms-C 1 -C 6 aliphatic.
  • R 11 is C 1-6 aliphatic.
  • R 11 is C 1-6 alkyl.
  • R 11 is methyl.
  • R 11 is ethyl.
  • R 1 is -C (O) N (R 12 ) SO 2 R 13 wherein each of R 12 and R 13 is independently as described herein. In some embodiments, R 1 is -C (O) NHSO 2 R 13 wherein R 13 is as described herein.
  • R 12 is R’ described herein. In some embodiments, R 12 is R as described herein. In some embodiments, R 12 is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C 1 -C 6 aliphatic, and 5-10 membered heteroaryl having 1-6 heteroatoms-C 1 -C 6 aliphatic. In some embodiments, R 12 is H. In some embodiments, R 12 is optionally substituted C 1-6 aliphatic. In some embodiments, R 12 is C 1-6 alkyl. In some embodiments, R 12 is methyl. In some embodiments, R 12 is ethyl.
  • R 13 is R’ described herein. In some embodiments, R 13 is R as described herein. In some embodiments, R 13 is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C 1 -C 6 aliphatic, and 5-10 membered heteroaryl having 1-6 heteroatoms-C 1 -C 6 aliphatic. In some embodiments, R 13 is H. In some embodiments, R 13 is optionally substituted C 1-6 aliphatic. In some embodiments, R 13 is C 1-6 alkyl. In some embodiments, R 13 is methyl. In some embodiments, R 13 is ethyl.
  • each of R 12 and R 13 is independently R’a s described herein. In some embodiments, each of R 12 and R 13 is independently R as described herein.
  • R 1 is -C (O) NR 14 R 15 wherein each of R 14 and R 15 is independently as described herein. In some embodiments, R 1 is -C (O) NHR 15 wherein R 15 is as described herein.
  • R 14 is R’ described herein. In some embodiments, R 14 is R as described herein. In some embodiments, R 14 is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C 1 -C 6 aliphatic, and 5-10 membered heteroaryl having 1-6 heteroatoms-C 1 -C 6 aliphatic. In some embodiments, R 14 is H. In some embodiments, R 14 is optionally substituted C 1-6 aliphatic. In some embodiments, R 14 is C 1-6 alkyl. In some embodiments, R 14 is methyl. In some embodiments, R 14 is ethyl.
  • R 15 is R’ described herein. In some embodiments, R 15 is R as described herein. In some embodiments, R 15 is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C 1 -C 6 aliphatic, and 5-10 membered heteroaryl having 1-6 heteroatoms-C 1 -C 6 aliphatic. In some embodiments, R 15 is H. In some embodiments, R 15 is optionally substituted C 1-6 aliphatic. In some embodiments, R 15 is C 1-6 alkyl. In some embodiments, R 15 is methyl. In some embodiments, R 15 is ethyl.
  • each of R 14 and R 15 is independently R’a s described herein. In some embodiments, each of R 14 and R 15 is independently R as described herein.
  • R 1 is -C (O) NR 14 R 15 , wherein each of R 14 and R 15 is independently H or an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C 1 -C 6 aliphatic, and 5-10 membered heteroaryl having 1-6 heteroatoms- C 1 -C 6 aliphatic.
  • R 1 is -C (O) NR 14 R 15 , wherein each of R 14 and R 15 is independently H or optionally substituted C 1 -C 6 alkyl. In some embodiments, R 1 is -C (O) NR 14 R 15 , wherein each of R 14 and R 15 is independently H. In some embodiments, R 1 is -C (O) NR 14 R 15 , wherein R 14 is H and R 15 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 1 is -C (O) NR 14 R 15 , wherein R 14 is H and R 15 is methyl.
  • R 1 is R 1 is -C (O) NR 14 R 15 , wherein each of R 14 and R 15 is independently C 1 -C 6 alkyl. In some embodiments, R 1 is R 1 is -C (O) NR 14 R 15 , wherein each of R 14 and R 15 is methyl.
  • R 1 is an isostere of -C (O) OH.
  • a compound is a carboxylic acid isostere of a carboxylic acid compound, e.g., where R 1 is -C (O) OH.
  • a carboxylic acid isostere is one described in WO 2020/198537, US 2021/0032213, WO 2021/211839, or WO 2022/061008, the carboxylic acid isosteres of each of which are independently incorporated herein by reference.
  • a carboxylic acid isostere is described in Ballatore et al., ChemMedChem. 2013 Mar; 8(3) : 385–395, the carboxylic acid isosteres of which are incorporated herein by reference.
  • -X 1 X 2 -is -X 1 X 2 -wherein each variable is independently as described herein.
  • R 2 is optionally substituted C 1-6 alkyl. In some embodiments, R 2 is C 1-6 alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is propyl.
  • -X 1 X 2 - is optionally substituted -CH 2 -CH 2 -. In some embodiments, -X 1 X 2 -is -CH 2 -CH 2 -.
  • R 3 is R’, -OR’, halogen, -CN, -NO 2 , or -N (R’) 2 , wherein each variable is independently as described herein.
  • R 3 is halogen.
  • R 3 is F.
  • R 3 is Cl.
  • R 3 is Br.
  • R 3 is I.
  • R 3 is -CN.
  • R 3 is -NO 2 .
  • R 3 is –OR’ wherein R’ is as described herein.
  • R 3 is -N (R’) 2 wherein R’ is as described herein.
  • R 3 is R’ described herein. In some embodiments, R 3 is R as described herein. In some embodiments, R 3 is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C 1 -C 6 aliphatic, and 5-10 membered heteroaryl having 1-6 heteroatoms-C 1 -C 6 aliphatic. In some embodiments, R 3 is H. In some embodiments, R 3 is optionally substituted C 1-6 aliphatic. In some embodiments, R 3 is C 1-6 alkyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl.
  • R 3 is optionally substituted 6-10 membered aryl. In some embodiments, R 3 is optionally substituted phenyl. In some embodiments, R 3 is phenyl.
  • R 3 is optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms.
  • each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • R 3 is optionally substituted C 3 -C 8 cycloalkyl. In some embodiments, R 3 is optionally substituted In some embodiments, R 3 is optionally substituted In some embodiments, R 3 is optionally substituted In some embodiments, R 3 is optionally substituted In some embodiments, R 3 is optionally substituted In some embodiments, R 3 is optionally substituted In some embodiments, R 3 is In some embodiments, R 3 is X 4
  • R 4 is R’, -OR’, halogen, -CN, -NO 2 , or -N (R’) 2 , wherein each variable is independently as described herein.
  • R 4 is halogen.
  • R 4 is F.
  • R 4 is Cl.
  • R 4 is Br.
  • R 4 is I.
  • R 4 is -CN.
  • R 4 is –OR’ wherein R’ is as described herein.
  • R 4 is -NO 2 .
  • R 4 is -N (R’) 2 wherein R’ is as described herein.
  • R 4 is R’ described herein. In some embodiments, R 4 is R as described herein. In some embodiments, R 4 is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C 1 -C 6 aliphatic, and 5-10 membered heteroaryl having 1-6 heteroatoms-C 1 -C 6 aliphatic. In some embodiments, R 4 is H. In some embodiments, R 4 is optionally substituted C 1-6 aliphatic. In some embodiments, R 4 is C 1-6 alkyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl.
  • R 4 is optionally substituted 6-10 membered aryl. In some embodiments, R 4 is optionally substituted phenyl. In some embodiments, R 4 is phenyl.
  • R 4 is optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms.
  • each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • R 4 is optionally substituted C 3 -C 8 cycloalkyl. In some embodiments, R 4 is optionally substituted In some embodiments, R 4 is optionally substituted In some embodiments, R 4 is optionally substituted In some embodiments, R 4 is optionally substituted In some embodiments, R 4 is optionally substituted In some embodiments, R 4 is optionally substituted In some embodiments, R 4 is optionally substituted In some embodiments, R 4 is In some embodiments, R 4 is In some embodiments, R 4 is In some embodiments, R 4 is, R 4 is In some embodiments, R 4 is,
  • R 5 is R’, -OR’, halogen, -CN, -NO 2 , or -N (R’) 2 , wherein each variable is independently as described herein.
  • R 5 is halogen.
  • R 5 is F.
  • R 5 is Cl.
  • R 5 is Br.
  • R 5 is I.
  • R 5 is -CN.
  • R 5 is -NO 2 .
  • R 5 is –OR’ wherein R’ is as described herein.
  • R 5 is -N (R’) 2 wherein R’ is as described herein.
  • R 5 is R’ described herein. In some embodiments, R 5 is R as described herein. In some embodiments, R 5 is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C 1 -C 6 aliphatic, and 5-10 membered heteroaryl having 1-6 heteroatoms-C 1 -C 6 aliphatic. In some embodiments, R 5 is H. In some embodiments, R 5 is optionally substituted C 1-6 aliphatic. In some embodiments, R 5 is C 1-6 alkyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl.
  • R 5 is optionally substituted 6-10 membered aryl. In some embodiments, R 5 is optionally substituted phenyl. In some embodiments, R 5 is phenyl.
  • R 5 is optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms.
  • each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • R 5 is optionally substituted C 3 -C 8 cycloalkyl. In some embodiments, R 5 is optionally substituted In some embodiments, R 5 is optionally substituted In some embodiments, R 5 is optionally substituted In some embodiments, R 5 is optionally substituted In some embodiments, R 5 is optionally substituted In some embodiments, R 5 is optionally substituted In some embodiments, R 5 is In some embodiments, R 5 is In some embodiments, R 5 is, R 5 is optionally substituted C 3 -C 8 cycloalkyl. In some embodiments, R 5 is optionally substituted In some embodiments, R 5 is optionally substituted In some embodiments, R 5 is optionally substituted In some embodiments, R 5 is optionally substituted In some embodiments, R 5 is optionally substituted In some embodiments, R 5 is In some embodiments, R 5 is In some embodiments, R 5 is optionally substituted C 3 -C 8 cycloalkyl. In some embodiments, R 5 is optionally substituted In some embodiments
  • L is optionally substituted - (CH 2 ) m -wherein m is 1 or 2. In some embodiments, L is optionally substituted -CH 2 -. In some embodiments, L is –CH (CH 3 ) -. In some embodiments, L is optionally substituted - (CH 2 ) 2 -. In some embodiments, L is –CH (CH 3 ) -. In some embodiments, L is -CH 2 -. In some embodiments, L is - (CH 2 ) 2 -.
  • each substitutable hydrogen is independently and optionally substituted by R’, -OR’, halogen, -CN, -NO 2 , or -N (R’) 2 , wherein R’ is -H, C 1-4 alkyl or C 1-4 haloalkyl.
  • Ring A is an optionally substituted ring selected from a 6-10 membered aryl ring and a 5-10 membered heteroaryl ring having 1-6 heteroatoms. In some embodiments, Ring A is optionally substituted 6-10 membered aryl ring. In some embodiments, Ring A is optionally substituted phenyl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is optionally substituted In some embodiments, Ring A is optionally substituted In some embodiments, Ring A is In some embodiments, Ring A is, Ring A is, Ring A is an optionally substituted ring selected from a 6-10 membered aryl ring and a 5-10 membered heteroaryl ring having 1-6 heteroatoms. In some embodiments, Ring A is optionally substituted 6-10 membered aryl ring. In some embodiments, Ring A is optionally substituted phenyl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is optionally substituted In some embodiment
  • Ring A is wherein each R a is independently -R’, -OR’, halogen, -CN, -NO 2 , or -N (R’) 2 , each R’ is independently as described herein and n is 1, 2, 3, 4, or 5.
  • Ring A is wherein each of R a1 , R a2 , R a3 , R a4 , and R a5 is independently R a as described herein.
  • R a is R a1 as described herein.
  • R a is R a2 as described herein.
  • R a is R a3 as described herein.
  • R a is R a4 as described herein.
  • R a is R a5 as described herein.
  • R a1 is H. In some embodiments, R a1 is halogen. In some embodiments, R a1 is F. In some embodiments, R a1 is Cl. In some embodiments, R a1 is Br. In some embodiments, R a1 is I. In some embodiments, R a1 is –CN. In some embodiments, R a1 is -NO 2 . In some embodiments, R a1 is -OR’ wherein R’ is as described herein. In some embodiments, R a1 is -OH. In some embodiments, R a1 is -OMe. In some embodiments, R a1 is –OCF 3 . In some embodiments, R a1 is -N (R’) 2 wherein each R’ is independently as described herein.
  • R a1 is R’. In some embodiments, R a1 is R. In some embodiments, R a1 is optionally substituted group selected from C 1 -C 6 aliphatic. In some embodiments, R a1 is C 1 -C 6 aliphatic optionally substituted by halogen. In some embodiments, R a1 is C 1 -C 6 alkyl group optionally substituted by halogen. In some embodiments, R a1 is methyl group optionally substituted by halogen. In some embodiments, R a1 is –CF 3 .
  • R a2 is H. In some embodiments, R a2 is halogen. In some embodiments, R a2 is F. In some embodiments, R a2 is Cl. In some embodiments, R a2 is Br. In some embodiments, R a2 is I. In some embodiments, R a2 is –CN. In some embodiments, R a2 is -NO 2 . In some embodiments, R a2 is -OR’ wherein R’ is as described herein. In some embodiments, R a2 is -OH. In some embodiments, R a2 is -OMe. In some embodiments, R a2 is –OCF 3 . In some embodiments, R a2 is -N (R’) 2 wherein each R’ is independently as described herein.
  • R a2 is R’. In some embodiments, R a2 is R. In some embodiments, R a2 is optionally substituted group selected from C 1 -C 6 aliphatic. In some embodiments, R a2 is C 1 -C 6 aliphatic optionally substituted by halogen. In some embodiments, R a2 is C 1 -C 6 alkyl group optionally substituted by halogen. In some embodiments, R a2 is methyl group optionally substituted by halogen. In some embodiments, R a2 is –CF 3 .
  • R a3 is H. In some embodiments, R a3 is halogen. In some embodiments, R a3 is F. In some embodiments, R a3 is Cl. In some embodiments, R a3 is Br. In some embodiments, R a3 is I. In some embodiments, R a3 is –CN. In some embodiments, R a3 is -NO 2 . In some embodiments, R a3 is -OR’ wherein R’ is as described herein. In some embodiments, R a3 is -OH. In some embodiments, R a3 is -OMe. In some embodiments, R a3 is –OCF 3 . In some embodiments, R a3 is -N (R’) 2 wherein each R’ is independently as described herein.
  • R a3 is R’. In some embodiments, R a3 is R. In some embodiments, R a3 is optionally substituted group selected from C 1 -C 6 aliphatic. In some embodiments, R a3 is C 1 -C 6 aliphatic optionally substituted by halogen. In some embodiments, R a3 is C 1 -C 6 alkyl group optionally substituted by halogen. In some embodiments, R a3 is methyl group optionally substituted by halogen. In some embodiments, R a3 is –CF 3 .
  • R a4 is H. In some embodiments, R a4 is halogen. In some embodiments, R a4 is F. In some embodiments, R a4 is Cl. In some embodiments, R a4 is Br. In some embodiments, R a4 is I. In some embodiments, R a4 is –CN. In some embodiments, R a4 is -NO 2 . In some embodiments, R a4 is -OR’ wherein R’ is as described herein. In some embodiments, R a4 is -OH. In some embodiments, R a4 is -OMe. In some embodiments, R a4 is –OCF 3 . In some embodiments, R a4 is -N (R’) 2 wherein each R’ is independently as described herein.
  • R a4 is R’. In some embodiments, R a4 is R. In some embodiments, R a4 is optionally substituted group selected from C 1 -C 6 aliphatic. In some embodiments, R a4 is C 1 -C 6 aliphatic optionally substituted by halogen. In some embodiments, R a4 is C 1 -C 6 alkyl group optionally substituted by halogen. In some embodiments, R a4 is methyl group optionally substituted by halogen. In some embodiments, R a4 is –CF 3 .
  • R a5 is H. In some embodiments, R a5 is halogen. In some embodiments, R a5 is F. In some embodiments, R a5 is Cl. In some embodiments, R a5 is Br. In some embodiments, R a5 is I. In some embodiments, R a5 is –CN. In some embodiments, R a5 is -NO 2 . In some embodiments, R a5 is -OR’ wherein R’ is as described herein. In some embodiments, R a5 is -OH. In some embodiments, R a5 is -OMe. In some embodiments, R a5 is –OCF 3 . In some embodiments, R a5 is -N (R’) 2 wherein each R’ is independently as described herein.
  • R a5 is R’. In some embodiments, R a5 is R. In some embodiments, R a5 is optionally substituted group selected from C 1 -C 6 aliphatic. In some embodiments, R a5 is C 1 -C 6 aliphatic optionally substituted by halogen. In some embodiments, R a5 is C 1 -C 6 alkyl group optionally substituted by halogen. In some embodiments, R a5 is methyl group optionally substituted by halogen. In some embodiments, R a5 is –CF 3 .
  • Ring A is wherein R a is -R’, -OR’, halogen, -CN, -NO 2 , or -N (R’) 2 and each R’ is independently as described herein.
  • Ring A is Ring A is wherein R a is -R’, -OR’, halogen, -CN, -NO 2 , or -N (R’) 2 and each R’ is independently as described herein.
  • Ring A is wherein R a is -R’, -OR’, halogen, -CN, -NO 2 , or -N (R’) 2 and each R’ is independently as described herein.
  • Ring A is wherein R a is -R’, -OR’, halogen, -CN, -NO 2 , or -N (R’) 2 and each R’ is independently as described herein.
  • Ring A is wherein R a is -R’, -OR’, halogen, -CN, -NO 2 , or -N (R’) 2 and each R’ is independently as described herein.
  • Ring A is wherein R a is -R’, -OR’, halogen, -CN, -NO 2 , or -N (R’) 2 and each R’ is independently as described herein.
  • Ring A is and R a is -R’, -OR’, halogen, -CN, -NO 2 , or -N (R’) 2 and each R’is independently as described herein and n is 1 or 2. In some embodiments, Ring A is and R a is halogen and n is 1 or 2.
  • Ring A is and R a is -R’, -OR’, halogen, -CN, -NO 2 , or -N (R’) 2 and each R’ is independently as described herein.
  • Ring A is and R a is halogen.
  • Ring A is and R a is halogen.
  • Ring A is and R a is halogen.
  • Ring A is and R a is halogen.
  • Ring A is and each R a is independently -R’, -OR’, halogen, -CN, -NO 2 , or -N (R’) 2 and each R’ is independently as described herein. In some embodiments, Ring A is and each R a is independently halogen. In some embodiments, Ring A is and each R a is independently halogen.
  • R a is H. In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, R a is Cl. In some embodiments, R a is Br. In some embodiments, R a is I. In some embodiments, R a is –CN. In some embodiments, R a is -NO 2 . In some embodiments, R a is -OR’ wherein R’ is as described herein. In some embodiments, R a is -OH. In some embodiments, R a is -OMe. In some embodiments, R a is –OCF 3 . In some embodiments, R a is -N (R’) 2 wherein each R’ is independently as described herein.
  • R a is R’. In some embodiments, R a is R. In some embodiments, R a is optionally substituted group selected from C 1 -C 6 aliphatic. In some embodiments, R a is C 1 -C 6 aliphatic optionally substituted by halogen. In some embodiments, R a is C 1 -C 6 alkyl group optionally substituted by halogen. In some embodiments, R a is methyl group optionally substituted by halogen. In some embodiments, R a is –CF 3 .
  • Ring A is selected from:
  • Ring A is an optionally substituted 5-10 membered heteroaryl ring having 1-6 heteroatoms. In some embodiments, Ring A is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms. In some embodiments, Ring A is a 6 membered heteroaryl ring having 1-2 heteroatoms. In some embodiments, Ring A is a 6 membered heteroaryl ring having 1-2 heteroatoms independently selected from O, N, and S. In some embodiments, Ring A is a 6 membered heteroaryl ring having a heteroatom selected from O, N, and S. In some embodiments, Ring A is a 6 membered heteroaryl ring having a nitrogen atom.
  • Ring A is a 6 membered heteroaryl ring having 2 heteroatoms independently selected from O, N, and S. In some embodiments, Ring A is a 6 membered heteroaryl ring having 2 heteroatoms each of which is N. In some embodiments, Ring A is a 6 membered heteroaryl ring having 3 heteroatoms. In some embodiments, Ring A is a 6 membered heteroaryl ring having 3 heteroatoms independently selected from O, N, and S. In some embodiments, Ring A is a 6 membered heteroaryl ring having 3 heteroatoms wherein one is N. In some embodiments, Ring A is a 5 membered heteroaryl ring having 1-2 heteroatoms.
  • Ring A is a 5 membered heteroaryl ring having 1-2 heteroatoms independently selected from O, N, and S. In some embodiments, Ring A is a 5 membered heteroaryl ring having an oxygen atom. In some embodiments, Ring A is a 5 membered heteroaryl ring having a nitrogen atom. In some embodiments, Ring A is a 5 membered heteroaryl ring having a sulfur atom. In some embodiments, Ring A is a 5 membered heteroaryl ring having 2 heteroatoms independently selected from O, N, and S. In some embodiments, Ring A is a 5 membered heteroaryl ring having 2 heteroatoms one of which is N.
  • Ring A is a 5 membered heteroaryl ring having 2 heteroatoms independently selected from N and S. In some embodiments, Ring A’ is a 5 membered heteroaryl ring having 2 heteroatoms independently selected from N and O. In some embodiments, Ring A is a 5 membered heteroaryl ring having 2 heteroatoms independently selected from O and S. In some embodiments, Ring A is a 5 membered heteroaryl ring having 3 heteroatoms. In some embodiments, Ring A is a 5 membered heteroaryl ring having 3 heteroatoms independently selected from O, N, and S. In some embodiments, a ring has a single heteroatom.
  • a ring has two or more heteroatoms at least one of which is nitrogen. In some embodiments, each is nitrogen. In some embodiments, all heteroatoms are the same. In some embodiments, at least one heteroatom is different from the other heteroatom (s) .
  • Ring A is an optionally substituted 9 membered heteroaryl ring having 1-4 heteroatoms. In some embodiments, Ring A is an optionally substituted 9-membered heteroaryl ring having 4 heteroatoms independently selected from O, N, and S. In some embodiments, Ring A is an optionally substituted 9-membered heteroaryl ring having 3 heteroatoms independently selected from O, N, and S. In some embodiments, Ring A is an optionally substituted 9-membered heteroaryl ring having 3 heteroatoms one of which is N. In some embodiments, Ring A is an optionally substituted 9-membered heteroaryl ring having 3 heteroatoms independently selected from O and N.
  • Ring A is an optionally substituted 9-membered heteroaryl ring having 3 heteroatoms independently selected from O and S. In some embodiments, Ring A is an optionally substituted 9-membered heteroaryl ring having 3 heteroatoms independently selected from N and S. In some embodiments, Ring A is an optionally substituted 9-membered heteroaryl ring having 2 heteroatoms independently selected from O, N, and S. In some embodiments, Ring A is an optionally substituted 9-membered heteroaryl ring having 2 heteroatoms one of which is N. In some embodiments, Ring A is an optionally substituted 9-membered heteroaryl ring having 2 heteroatoms independently selected from O and N.
  • Ring A is an optionally substituted 9-membered heteroaryl ring having 2 heteroatoms independently selected from O and S. In some embodiments, Ring A is an optionally substituted 9-membered heteroaryl ring having 2 heteroatoms independently selected from N and S. In some embodiments, Ring A is an optionally substituted 9-membered heteroaryl ring having 2 heteroatoms both of which are N. In some embodiments, Ring A is an optionally substituted 9-membered heteroaryl ring having 1 heteroatom selected from O, N, and S. In some embodiments, Ring A is an optionally substituted 9-membered heteroaryl ring having a nitrogen atom.
  • Ring A is an optionally substituted 9-membered heteroaryl ring having an oxygen atom. In some embodiments, Ring A is an optionally substituted 9-membered heteroaryl ring having an sulfur atom. In some embodiments, a ring has a single heteroatom. In some embodiments, a ring has two or more heteroatoms at least one of which is nitrogen. In some embodiments, each is nitrogen. In some embodiments, all heteroatoms are the same. In some embodiments, at least one heteroatom is different from the other heteroatom (s) .
  • Ring A is an optionally substituted 10 membered heteroaryl ring having 1-4 heteroatoms. In some embodiments, Ring A is an optionally substituted 10-membered heteroaryl ring having 4 heteroatoms independently selected from O, N, and S. In some embodiments, Ring A is an optionally substituted 10-membered heteroaryl ring having 3 heteroatoms independently selected from O, N, and S. In some embodiments, Ring A is an optionally substituted 10-membered heteroaryl ring having 3 heteroatoms all of which are N. In some embodiments, Ring A is an optionally substituted 10-membered heteroaryl ring having 2 heteroatoms independently selected from O, N, and S.
  • Ring A is an optionally substituted 10-membered heteroaryl ring having 2 heteroatoms one of which is N. In some embodiments, Ring A is an optionally substituted 10-membered heteroaryl ring having 2 heteroatoms independently selected from O and N. In some embodiments, Ring A is an optionally substituted 10-membered heteroaryl ring having 2 heteroatoms independently selected from O and S. In some embodiments, Ring A is an optionally substituted 10-membered heteroaryl ring having 2 heteroatoms independently selected from N and S. In some embodiments, Ring A is an optionally substituted 10-membered heteroaryl ring having 2 heteroatoms both of which are N.
  • Ring A is an optionally substituted 10-membered heteroaryl ring having 1 heteroatom selected from O, N, and S. In some embodiments, Ring A is an optionally substituted 10-membered heteroaryl ring having a nitrogen atom. In some embodiments, Ring A is an optionally substituted 10-membered heteroaryl ring having an oxygen atom. In some embodiments, Ring A is an optionally substituted 10-membered heteroaryl ring having a sulfur atom. In some embodiments, a ring has a single heteroatom. In some embodiments, a ring has two or more heteroatoms at least one of which is nitrogen. In some embodiments, each is nitrogen. In some embodiments, all heteroatoms are the same. In some embodiments, at least one heteroatom is different from the other heteroatom (s) .
  • R’a is hydrogen
  • R’ is R as described herein. In some embodiments, R’ is -OR wherein R is as described herein. In some embodiments, R’ is -C (O) R wherein R is as described herein. In some embodiments, R’ is -C (O) OR wherein R is as described herein. In some embodiments, R’ is -S (O) 2 R wherein R is as described herein. R
  • R can be any variable as described herein.
  • Various embodiments for R are extensively described herein, including in various sections for other variables that can be R (e.g., R 1 , R 2 , R’, etc. ) .
  • R is -H. In some embodiments, R is not -H.
  • each R is independently hydrogen or an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C 1 -C 6 aliphatic, and 5-10 membered heteroaryl having 1-6 heteroatoms-C 1 -C 6 aliphatic.
  • R is optionally substituted C 1-6 aliphatic. In some embodiments, R is optionally substituted C 1-6 alkyl. In some embodiments, R is optionally substituted methyl. In some embodiments, R is optionally substituted ethyl. In some embodiments, R is optionally substituted n-propyl. In some embodiments, R is optionally substituted isopropyl. In some embodiments, R is n-butyl. In some embodiments, R is t-butyl. In some embodiments, R is pentyl. In some embodiments, R is hexyl.
  • R is optionally substituted C 1-6 heteroaliphatic having 1-3 (e.g., 1, 2, or 3) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, R is optionally substituted C 1-6 heteroaliphatic having 1-3 (e.g., 1, 2, or 3) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a heteroatom is nitrogen. In some embodiments, a heteroatom is oxygen. In some embodiments, a heteroatom is sulfur.
  • R is optionally substituted C 3-10 (e.g., C 4-10 , C 3-9 , C 3-7 , or 3, 4, 5, 6, 7, 8, 9, or 10-membered) cycloaliphatic.
  • a cycloaliphatic group is a cycloalkyl group.
  • a cycloaliphatic group is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, each monocyclic unit is independently a 3-10 (e.g., C 4-10 , C 3-9 , C 3-7 , or 3, 4, 5, 6, 7, 8, 9, or 10, etc. ) membered cycloaliphatic ring.
  • a cycloaliphatic group is saturated. In some embodiments, it is partially unsaturated.
  • R is optionally substituted cyclopropyl. In some embodiments, R is optionally substituted cyclobutyl. In some embodiments, R is optionally substituted cyclopentyl. In some embodiments, R is optionally substituted cyclohexyl. In some embodiments, R is optionally substituted cycloheptyl. In some embodiments, R is cyclopropyl. In some embodiments, R is cyclobutyl. In some embodiments, R is cyclopentyl. In some embodiments, R is cyclohexyl. In some embodiments, R is cycloheptyl.
  • R is optionally substituted 3-10 (e.g., 3-9, 3-6, 3-5, or 3, 4, 5, 6, 7, 8, 9, or 10, etc. ) membered heterocyclyl having 1-4 (e.g., 1, 2, 3, or 4, etc. ) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.
  • R is optionally substituted 3-10 (e.g., 3-9, 3-6, 3-5, or 3, 4, 5, 6, 7, 8, 9, or 10, etc. ) membered heterocyclyl having 1-4 (e.g., 1, 2, 3, or 4, etc. ) heteroatoms independently selected from oxygen, nitrogen and sulfur.
  • a heterocyclyl group is monocyclic. In some embodiments, it is bicyclic.
  • each monocyclic unit is independently a 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10, etc. ) membered heterocyclyl ring having 1-4 (e.g., 1, 2, 3, or 4 etc. ) heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • a heterocyclyl group is saturated. In some embodiments, it is partially unsaturated.
  • a heterocyclyl ring has one heteroatom. In some embodiments, a heterocyclyl ring has two or more heteroatoms. In some embodiments, a heterocyclyl ring has three or more heteroatoms. In some embodiments, a heterocyclyl ring has four or more heteroatoms.
  • a heteroatom is nitrogen. In some embodiments, a heteroatom is oxygen. In some embodiments, a heteroatom is sulfur.
  • R is optionally substituted C 6-10 (e.g., C 6 , C 10 , etc. ) aryl.
  • an aryl ring is monocyclic.
  • an aryl ring is bicyclic.
  • an aryl ring is polycyclic.
  • each monocyclic unit is independently a 6-membered aromatic ring.
  • R is optionally substituted phenyl.
  • R is phenyl.
  • R is optionally substituted 10-membered aryl.
  • R is optionally substituted naphthyl. In some embodiments, R is naphthyl.
  • R is optionally substituted 5-10 (e.g., 5-9, or 5, 6, 7, 8, 9, or 10 etc. ) membered heteroaryl having 1-6 (e.g., 1-6, 1-5, 1-4, or 1, 2, 3, 4, 5, or 6 etc. ) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.
  • R is 5-10 (e.g., 5-9, or 5, 6, 9, 10 etc. ) membered heteroaryl having 1-4 (e.g., 1, 2, 3, or 4, etc. ) heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • a heteroaryl ring is monocyclic.
  • a heteroaryl ring is bicyclic.
  • a heteroaryl ring is polycyclic.
  • each monocyclic unit is independently a 5-or 6-membered aromatic ring having 0-4 heteroatoms, e.g., independently selected from nitrogen, oxygen and sulfur, wherein at least one monocyclic unit contains 1-4 heteroatoms.
  • R is optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • R is optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • R is optionally substituted 8-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • R is optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a heteroaryl ring has one heteroatom. In some embodiments, a heteroaryl ring has two or more heteroatoms. In some embodiments, a heteroaryl ring has three or more heteroatoms. In some embodiments, a heteroaryl ring has four or more heteroatoms. In some embodiments, a heteroatom is nitrogen. In some embodiments, a heteroatom is oxygen. In some embodiments, a heteroatom is sulfur.
  • R is optionally substituted C 6-10 (e.g., C 6 , C 10 , etc. ) aryl-C 1-6 aliphatic, wherein the aryl and aliphatic are independently as described herein. In some embodiments, R is optionally substituted C 6-10 aryl-C 1- 6 alkyl.
  • R is optionally substituted 5-10 (e.g., 5-9, or 5, 6, 7, 8, 9, or 10 etc. ) membered heteroaryl having 1-6 (e.g., 1, 2, 3, 4, 5, or 6) heteroatoms-C 1-6 aliphatic wherein the heteroaryl and aliphatic are independently as described herein.
  • R is optionally substituted 5-10 membered heteroaryl having 1-5 heteroatoms-C 1-6 aliphatic.
  • R is optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms-C 1-6 aliphatic.
  • R is optionally substituted 5-10 membered heteroaryl having 1-6 (e.g., 1, 2, 3, 4, 5, or 6) heteroatoms-C 1-6 alkyl wherein the heteroaryl and alkyl are independently as described herein. In some embodiments, R is optionally substituted 5-10 membered heteroaryl having 1-5 heteroatoms-C 1-6 alkyl. In some embodiments, R is optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms-C 1-6 alkyl. Various suitable heteroaryl and aliphatic groups are as described herein.
  • two R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10, etc. ) membered ring having, in addition to the atom, 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms.
  • two R groups on two atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10, etc. ) membered ring having, in addition to the intervening atoms, 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms
  • two R groups, or two groups that are or can be R can be taken together with their intervening atom (s) to form an optionally substituted ring as described herein.
  • a formed ring is substituted (in addition to groups attached to the intervening atom (s) ) .
  • a formed ring is unsubstituted.
  • a formed ring is 3-membered.
  • a formed ring is 4-membered.
  • a formed ring is 5-membered.
  • a formed ring is 6-membered.
  • a formed ring is 7-membered. In some embodiments, a formed ring is 8-membered. In some embodiments, a formed ring is 9-membered. In some embodiments, a formed ring is 10-membered. In some embodiments, a formed ring is saturated. In some embodiments, a formed ring is partially unsaturated. In some embodiments, a formed ring is aromatic. In some embodiments, a formed ring is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, each monocyclic unit is independently a 3-10 (e.g., 3-8, 3-6, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10, etc.
  • each monocyclic unit is independently a 3-10 (e.g., 3-8, 3-6, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10, etc.
  • each monocyclic unit is independently a 3-10 (e.g., 3-10, 3-8, 3-6, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10, etc. ) membered ring which is independently saturated, partially unsaturated or aromatic and has 0-4 (e.g., 0, 1, 2, 3, or 4, etc. ) heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • each monocyclic ring unit is independently 3-7 membered.
  • each monocyclic ring unit is independently 3-6 membered.
  • each monocyclic ring unit is independently 5-7 membered. In some embodiments, each monocyclic unit is independently saturated or partially unsaturated. In some embodiments, at least one monocyclic unit is saturated. In some embodiments, at least one monocyclic unit is partially unsaturated. In some embodiments, at least one monocyclic unit is aromatic. In some embodiments, a formed ring has, in addition to the intervening atom (s) , 0-4 (e.g., 0, 1, 2, 3, or 4, etc. ) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, there are no additional heteroatoms. In some embodiments, there is one additional heteroatom. In some embodiments, there are 2 additional heteroatoms.
  • an additional heteroatom is nitrogen. In some embodiments, an additional heteroatom is oxygen. In some embodiments, an additional heteroatom is sulfur.
  • the present disclosure provides a compound of Formula (II) , or a salt thereof, wherein each of X 1 , X 2 , X 3 , X 4 , R 5 , L, and Ring A is independently as described herein.
  • the present disclosure provides a compound of Formula (III) , or a salt thereof, wherein each of X 1 , X 2 , X 3 , X 4 , R 5 , L, and Ring A is independently as described herein.
  • the present disclosure provides a compound of Formula (IV) , or a salt thereof, wherein each of R 3 , R 4 , R 5 , L, and Ring A is independently as described herein.
  • the present disclosure provides a compound of Formula (V) , or a salt thereof, wherein each of R 3 , R 4 , R 5 , L, and Ring A is independently as described herein.
  • a provided compound is a compound selected from Compounds 1-55 or a salt thereof in the Exemplification.
  • each heteroatom is independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, each heteroatom is independently selected from oxygen, nitrogen and sulfur.
  • one or more isotopes may be utilized or enriched in compounds of the present disclosure at one or more locations.
  • deuterium is utilized or enriched at one or more positions.
  • an enrichment is about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, or 99%more than a natural abundance as applicable.
  • a level of an isotope at a position is about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, or 99%of all compound molecules.
  • the present disclosure provides stereochemically pure, e.g., enantiomerically pure, compounds with purities as described herein.
  • a compound is stereochemically pure.
  • a compound is enantiomerically pure.
  • a provided composition is enriched for one enantiomer over the other, or with respect to a chiral center, for one configuration over the other.
  • the percentage of an enantiomer, or one configuration with respect to a chiral center is about or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5%.
  • it is about or at least about 60%. In some embodiments, it is about or at least about 65%. In some embodiments, it is about or at least about 70%. In some embodiments, it is about or at least about 75%. In some embodiments, it is about or at least about 80%. In some embodiments, it is about or at least about 85%. In some embodiments, it is about or at least about 90%. In some embodiments, it is about or at least about 95%. In some embodiments, it is about or at least about 96%. In some embodiments, it is about or at least about 97%. In some embodiments, it is about or at least about 98%. In some embodiments, it is about or at least about 99%. In some embodiments, it is about or at least about 99.5%. In some embodiments, the (S) enantiomer or configuration is enriched. In some embodiments, the (R) enantiomer or configuration is enriched.
  • the present disclosure provides various technologies, e.g., reagents, intermediates, conditions, etc. for preparing compounds and compositions as described herein. Those skilled in the art appreciate that many technologies are available and can be utilized in accordance with the present disclosure.
  • a reaction is performed in a single solvent, e.g., DCM, THF, Et2O, EtOH, toluene, etc.
  • a reaction is performed in a mixture of two or more solvents.
  • a solvent is polar.
  • a solvent is non-polar.
  • a solvent is protic.
  • a solvent is non-protic.
  • a solvent is polar but is not protic. Suitable solvents for various reactions are available to those skilled in the art and can be utilized in accordance with the present disclosure.
  • a reaction is conducted under an inert atmosphere, e.g., N 2 , Ar, etc. In some embodiments, a reaction is conducted with exposure to air. In some embodiments, a reaction is conducted under anhydrous conditions, e.g., with reagents, solvents, vessels, etc., properly dried. In some embodiments, a reaction is conducted in the presence of significant of water (e.g., about or more than about 0.1, 0.5, or 1 equivalent) .
  • significant of water e.g., about or more than about 0.1, 0.5, or 1 equivalent
  • reactions are performed, or are performed for periods of time, at temperatures that are higher or lower than or about a standard ambient temperature (25 °C) .
  • a reaction temperature is lower than a standard ambient temperature.
  • a temperature is about or no more than about -78, -60, -50, -40, -30, -20, -10, 0 or 10 °C.
  • a temperature is about or no more than about 10 °C.
  • a temperature is about or no more than about 15 °C.
  • a temperature is about or no more than about 20 °C.
  • a reaction temperature is about a standard ambient temperature.
  • a reaction temperature is higher than a standard ambient temperature. In some embodiments, a reaction temperature is about or at least about 35, 40, 50, 60, 70, 80, 90, 100, or 100 °C. In some embodiments, a reaction comprises refluxing in a boiling solvent system, e.g., in ether, toluene, etc. In some embodiments, temperature changes during a reaction process, e.g., increasing from a lower temperature to a higher temperature, decreasing from a higher temperature to a lower temperature, or both.
  • a product is selectively produced over another potential product.
  • a product is produced with chemoselectivity, stereoselectivity and/or regioselectivity.
  • a selectivity is presented as a ratio, e.g., of one product over another. In some embodiments, a ratio is about or at least about 1.5: 1, 2: 1, 2.5: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11: 1, 12: 1, 13: 1, 14: 1, 15: 1, 16: 1, 17: 1, 18: 1, 19: 1, 20: 1, 25: 1, 30: 1, 40: 1, 50: 1, 60: 1, 70: 1, 80: 1, 90: 1, 100: 1, 200: 1, 500: 1 or more.
  • Reactions may be performed for a variety of time lengths. In some embodiments, reactions complete instantly. In some embodiments, reaction times varies from minutes to hours to days, e.g., 5, 10, 15, 20, 30, 45 minutes, or 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 18, 20 or 22 hours, or one or two days or longer. Those skilled in the art can use various technologies to determine when to terminate reactions, e.g., based on consumption of starting materials, products formation, by-products formation, etc.
  • the present disclosure provides compounds of high purity.
  • purity of a compound is or greater than about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.7%, or 99.9%.
  • purity of a compound is or greater than about 80%.
  • purity of a compound is or greater than about 85%.
  • purity of a compound is or greater than about 90%.
  • purity of a compound is or greater than about 95%.
  • purity of a compound is or greater than about 96%.
  • purity of a compound is or greater than about 97%.
  • purity of a compound is or greater than about 98%. In some embodiments, purity of a compound is or greater than about 99%. In some embodiments, purity of a compound is or greater than about 99.5%. In some embodiments, purity of a compound is or greater than about 99.7%. In some embodiments, purity of a compound is or greater than about 99.9%.
  • stereochemical purity of a compound is or greater than about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.7%, or 99.9%.
  • stereochemical purity of a compound is or greater than about 80%.
  • stereochemical purity of a compound is or greater than about 85%.
  • stereochemical purity of a compound is or greater than about 90%.
  • stereochemical purity of a compound is or greater than about 95%.
  • stereochemical purity of a compound is or greater than about 96%.
  • stereochemical purity of a compound is or greater than about 97%. In some embodiments, stereochemical purity of a compound is or greater than about 98%. In some embodiments, stereochemical purity of a compound is or greater than about 99%. In some embodiments, stereochemical purity of a compound is or greater than about 99.5%. In some embodiments, stereochemical purity of a compound is or greater than about 99.7%. In some embodiments, stereochemical purity of a compound is or greater than about 99.9%.
  • the present disclosure provides compounds of high enantiomeric purity.
  • enantiomeric purity of a compound is or greater than about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.7%, or 99.9%.
  • enantiomeric purity of a compound is or greater than about 80%.
  • enantiomeric purity of a compound is or greater than about 85%.
  • enantiomeric purity of a compound is or greater than about 90%.
  • enantiomeric purity of a compound is or greater than about 95%.
  • enantiomeric purity of a compound is or greater than about 96%. In some embodiments, enantiomeric purity of a compound is or greater than about 97%. In some embodiments, enantiomeric purity of a compound is or greater than about 98%. In some embodiments, enantiomeric purity of a compound is or greater than about 99%. In some embodiments, enantiomeric purity of a compound is or greater than about 99.5%. In some embodiments, enantiomeric purity of a compound is or greater than about 99.7%. In some embodiments, enantiomeric purity of a compound is or greater than about 99.9%.
  • Stereochemically pure, e.g., enantiomerically pure, compounds and compositions can be prepared utilizing various technologies in accordance with the present disclosure. For example, in some embodiments, they can be prepared through separation including chiral separation; in some embodiments, they can be prepared through stereoselective synthesis.
  • the present disclosure provides a method, comprising:
  • each variable is independently as described herein.
  • the present disclosure provides a method, comprising:
  • each variable is independently as described herein.
  • a method for preparing provided compounds is illustrated in Scheme 1 as an example, wherein each variable is independently as described herein.
  • a leaving group is a halogen.
  • LG is Cl. In some embodiments, LG is Br. In some embodiments, LG is I. In some embodiments, LG is -OS (O) 2 R wherein R is as described herein and is not H. In some embodiments, R is optionally substituted C 1-6 aliphatic. In some embodiments, R is optionally substituted phenyl.
  • R is optionally substituted C 1-6 aliphatic. In some embodiments, R is optionally substituted phenyl.
  • Many suitable conditions may be utilized in accordance with the present disclosure. For example, in some embodiments, a condition is an alkylation condition. In some embodiments, a reaction is performed in the presence of a base. In some embodiments, a base is Cs 2 CO 3 . Hydrolysis of ester compound of formula B3 or a salt thereof under basic conditions such as LiOH, NaOH, or KOH affords compound of formula II or a salt thereof.
  • the present disclosure provides a method, comprising:
  • each variable is independently as described herein.
  • the present disclosure provides a method, comprising:
  • each variable is independently as described herein.
  • a method for preparing provided compounds is illustrated in Scheme 2 as an example, wherein each variable is independently as described herein.
  • a leaving group is a halogen.
  • LG is Cl. In some embodiments, LG is Br. In some embodiments, LG is I. In some embodiments, LG is -OS (O) 2 R wherein R is as described herein and is not H. In some embodiments, R is optionally substituted C 1-6 aliphatic. In some embodiments, R is optionally substituted phenyl.
  • R is optionally substituted C 1-6 aliphatic. In some embodiments, R is optionally substituted phenyl.
  • Many suitable conditions may be utilized in accordance with the present disclosure. For example, in some embodiments, a condition is an alkylation condition. In some embodiments, a reaction is performed in the presence of a base. In some embodiments, a base is Cs 2 CO 3 . Treatment of cyano compound of formula C3 or a salt thereof under tetrazole formation conditions such as TMSN 3 /Bu 2 SnO affords compound of formula III or a salt thereof.
  • the present disclosure provides a method, comprising:
  • each variable is independently as described herein.
  • the present disclosure provides a method, comprising:
  • each variable is independently as described herein.
  • a leaving group is a halogen.
  • LG is Cl.
  • LG is Br.
  • LG is I.
  • LG is -OS (O) 2 R wherein R is as described herein and is not H.
  • R is optionally substituted C 1-6 aliphatic.
  • R is optionally substituted phenyl.
  • Many suitable conditions may be utilized in accordance with the present disclosure.
  • a condition is an alkylation condition.
  • a reaction is performed in the presence of a base.
  • a base is Cs 2 CO 3 .
  • Treatment of compound of formula D2 or a salt thereof with cyanides such as CuCN or Zn (CN) 2 to replace Hal with CN affords compound of formula C3 or a salt thereof.
  • the present disclosure provides a method for modulating MRGPRX4 activity by contacting MRGPRX4 with an effective amount of a compound or a pharmaceutical composition as described herein.
  • the present disclosure provides a method for modulating MRGPRX4 activity in a system comprising MRGPRX4, comprising administering or delivering to the system an effective amount of a compound or a pharmaceutical composition as described herein.
  • a system is or comprises a cell.
  • a system is or comprises a tissue.
  • a system is or comprises an organ.
  • a system is or comprises an organism.
  • a system is a subject.
  • a system is an animal.
  • a system is a human.
  • a system expresses MRGPRX4.
  • a method reduces MRGPRX4 activity level compared absence of a provided compound. In some embodiments, a reduction is about or at least about 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%.
  • the present disclosure provides a method for preventing a condition, disorder or disease, comprising administering to a subject susceptible thereto an effective amount of a provided compound or composition. In certain embodiments, the present disclosure provides a method for treating a condition, disorder or disease, comprising administering to a subject suffering therefrom an effective amount of a provided compound or composition. In certain embodiments, the present disclosure provides a method for preventing a condition, disorder or disease, comprising delivering to a subject susceptible thereto an effective amount of a provided compound or composition. In certain embodiments, the present disclosure provides a method for treating a condition, disorder or disease, comprising delivering to a subject suffering therefrom an effective amount of a provided compound or composition. In some embodiments, a compound is administered or delivered as a pharmaceutically acceptable salt form. In some embodiments, a composition is a pharmaceutical composition. In some embodiments, to deliver a provided compound, a prodrug thereof may be administered.
  • a compound is utilized in a racemic form.
  • a composition is a stereorandom mixture of multiple stereoisomers.
  • a composition is a stereorandom mixture of two enantiomers.
  • a compound is utilized in a stereochemically pure form as described herein.
  • a compound is utilized in an enantiomerically pure form.
  • a composition is enriched for one or more stereoisomers over the others as described herein.
  • a composition is enriched for an enantiomer as described herein.
  • a composition is stereochemically pure.
  • a composition is enantiomerically pure.
  • a condition, disorder or disease is or comprises itch. In some embodiments, a condition, disorder or disease is itch. In some embodiments, a condition, disorder or disease is a MRGPRX4-associated condition, disorder or disease. In some embodiments, a condition, disorder or disease is associated with MRGPRX4 activation.
  • a condition, disorder or disease is chronic itch, cholestatic pruritus, contact dermatitis, allergic blepharitis, anemia, atopic dermatitis, bullous pemphigoid, candidiasis, chicken pox, cholestasis, end-stage renal failure, hemodialysis, contact dermatitis, dermatitis herpetiformis, diabetes, drug allergy, dry skin, dyshidrotic dermatitis, ectopic eczema, eczema, erythrasma, folliculitis, fungal skin infection, hemorrhoids, herpes, HIV infection, Hodgkin's disease, hyperthyroidism, iron deficiency anemia, kidney disease, leukemia, liver disease, lymphoma, malignancy, multiple myeloma, neurodermatitis, onchocerciasis, Paget's disease, pediculosis, polycythemia rubra vera,
  • a condition, disorder or disease is MRGPRX4-associated pruritus. In some embodiments, a condition, disorder or disease is MRGPRX4-associated acute or chronic pruritus associated a liver condition, disorder or disease.
  • an MRGPRX4-associated pruritus is acute or chronic pruritus associated with a hepatobiliary condition, disorder or disease.
  • a hepatobiliary condition, disorder or disease is intrahepatic cholestasis of pregnancy (ICP) , estrogen-, progesterone-or testosterone-induced cholestasis, toxin-or other drug induced hepatocellular cholestasis, benign recurrent intrahepatic cholestasis (BRIC) , progressive familial intrahepatic cholestasis (PFIC) , chronic viral hepatitis C, chronic hepatitis B, alcoholic or nonalcoholic fatty liver disease (NAFLD) , nonalcoholic steatohepatitis (NASH) , primary biliary cholangitis (PBC) , primary sclerosing cholangitis (PSC) , secondary sclerosing cholangitis (SSC
  • a condition, disorder or disease is a liver condition, disorder or disease.
  • a liver condition, disorder or disease is NASH.
  • a liver condition, disorder or disease is NAFLD.
  • a liver condition, disorder or disease is ICP.
  • a liver condition, disorder or disease is PBC.
  • a liver condition, disorder or disease is PFIC.
  • a liver condition, disorder or disease is PSC.
  • a liver condition, disorder or disease is BRIC.
  • a liver condition, disorder or disease is chronic hepatitis B.
  • a condition, disorder or disease is nonalcoholic steatohepatitis (NASH) .
  • NASH nonalcoholic steatohepatitis
  • a condition, disorder or disease is bile acid synthesis condition, disorder or disease.
  • a bile acid synthesis condition, disorder or disease is due to single enzyme defects (SEDs) .
  • a condition, disorder or disease is a peroxisomal condition, disorder or disease, e.g., a Zellweger spectrum disorder.
  • a condition, disorder or disease is a liver condition, disorder or disease, steatorrhea or complications from decreased fat-soluble vitamin absorption.
  • a condition, disorder or disease is cardiovascular disease, atherosclerosis, arteriosclerosis, hypercholesteremia, hyperlipidemia, chronic liver disease, gastrointestinal disease, renal disease, metabolic disease, cancer (i.e., colorectal cancer) , or neurological indications such as stroke.
  • a condition, disorder or disease is primary biliary cirrhosis (PBC) , cerebrotendinous xanthomatosis (CTX) , primary sclerosing cholangitis (PSC) , drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC) , bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD) , nonalcoholic steatohepatitis (NASH) , liver transplant associated graft versus host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra-or extrahepatic malignancy, Sjogren's syndrome, Sarcoidosis, Wilson's disease, Gaucher’s disease, hemochromato
  • a gastrointestinal disease is inflammatory bowel disease (IBD) (including Crohn’s disease and ulcerative colitis) , irritable bowel syndrome (IBS) , bacterial overgrowth, malabsorption, postradiation colitis, or microscopic colitis.
  • the renal disease is diabetic nephropathy, focal segmental glomerulosclerosis (FSGS) , hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, or poly cystic kidney disease.
  • a cardiovascular disease is atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesterolemia, or hypertriglyceridemia.
  • a metabolic disease is insulin resistance, Type I and Type II diabetes, or obesity.
  • a condition, disorder or disease is an inflammatory condition, disorder or disease, e.g., allergy, osteoarthritis, appendicitis, bronchial asthma, pancreatitis, allergic rash, psoriasis, etc.
  • a condition, disorder or disease is an autoimmune condition, disorder or disease.
  • a condition, disorder or disease is rheumatoid arthritis, multiple sclerosis, and type I diabetes.
  • a condition, disorder or disease is a gastrointestinal disease, e.g., inflammatory bowel disease (Crohn's disease, ulcerative colitis) , short bowel syndrome (post-radiation colitis) , microscopic colitis, irritable bowel syndrome (malabsorption) , and bacterial overgrowth.
  • a condition, disorder or disease is cancer.
  • a cancer is colorectal cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, gastric cancer, pancreatic cancer, prostate cancer, or insulanoma.
  • a condition, disorder or disease is FXR-mediated.
  • a condition, disorder or disease is TGR5-mediated. In some embodiments, subjects susceptible thereto and/or suffering therefrom benefit from increased levels of FXR and/or TGR5 activity. In some embodiments, a condition, disorder or disease is a chronic kidney disease. In some embodiments, a condition, disorder or disease is uremic pruritus.
  • a condition, disorder or disease is associated with administration or delivery of an agent that can activate MRGPRX4.
  • Many technologies for assessing MRGPRX4 activation e.g., in vivo, in vitro, etc. can be utilized to assess if an agent can activate MRGPRX4.
  • Certain useful technologies are described in, e.g., Meixiong et al. MRGPRX4 is a G protein-coupled receptor activated by bile acids or analogs or derivatives thereof that may contribute to cholestatic pruritus, PNAS, 2019, 116 (21) , 10525-10530; Yu et al. MRGPRX4 is bile acid receptor for human cholestatic itch, eLife, 2019, 8, e48431.
  • a condition, disorder or disease is associated with administration or delivery of an agent that can activate MRGPRX4 but can also provide another activity or can be utilized as a therapeutic agent for treating a condition, disorder or disease.
  • the present disclosure provides methods for preventing or treating a condition, disorder or disease associated with administration of an agent, comprising administering or delivering to a subject an effective amount of a provided compound or composition.
  • the present disclosure provides methods for preventing a condition, disorder or disease associated with administration of an agent, comprising administering to a subject an effective amount of a provided compound or composition.
  • the present disclosure provides methods for preventing a condition, disorder or disease associated with administration of an agent, comprising delivering to a subject an effective amount of a provided compound or composition. In some embodiments, the present disclosure provides methods for treating a condition, disorder or disease associated with administration of an agent, comprising administering to a subject an effective amount of a provided compound or composition. In some embodiments, the present disclosure provides methods for treating a condition, disorder or disease associated with administration of an agent, comprising delivering to a subject an effective amount of a provided compound or composition. In some embodiments, an agent can activate MRGPRX4. In some embodiments, an agent is a bile acid or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • an agent is a bile acid analog or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • an agent is a bile acid derivative or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • an agent is a bile acid conjugate, e.g., a taurine conjugate, or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • a bile acid is cholic acid.
  • a bile acid is ursodeoxycholic acid (UDCA) .
  • a bile acid is ursocholic acid.
  • a bile acid is chenodeoxycholic acid. In some embodiments, a bile acid or an analog or derivative thereof is obeticholic acid. In some embodiments, a bile acid or an analog or derivative thereof is taurursodiol or a salt (e.g., a pharmaceutically acceptable salt) thereof; in some embodiments, it is taurursodiol; in some embodiments, it is sodium taurursodiol.
  • an agent is a FXR agonist. In some embodiments, an agent is a TGR5 agonist. In some embodiments, an agent is a therapeutic agent.
  • an agent is an approved therapeutic agent, e.g., by the U.S. Food and Drug Administration (e.g., cholic acid, obeticholic acid, taurursodiol, ursodeoxycholic acid, etc. ) , either individually or in combination with another therapeutic agent.
  • an agent is obeticholic acid and it is utilized in combination with ursodeoxycholic acid.
  • an agent is taurursodiol and it is utilized with sodium phenylbutyrate.
  • a condition, disorder or disease associated with administration of agent is or comprises itch.
  • provided methods can increase patient adherence of the agent.
  • provided methods can increase single doses, total doses, dose frequency, and/or length of dosage regimen of an agent.
  • provided compounds can reduce severity of a side effect, e.g., itch.
  • a provided compound is administered or delivered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, or about 1, 2, 3, 4, or 5 weeks, or about 1, 2, 3, 4, or 5 months before administration of an agent.
  • a provided compound is administered or delivered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, or about 1, 2, 3, 4, or 5 weeks, or about 1, 2, 3, 4, or 5 months after administration of an agent.
  • a provided compound is administered or delivered together with administration of an agent.
  • a compound as described herein can be used together with another therapeutic agent as a combination therapy to prevent or treat a condition, disorder or disease.
  • a condition, disorder or disease is associated with MRGPRX4 activation.
  • a therapeutic agent administered or delivered to a subject can activate MRGPRX4.
  • a provided compound can reduce a condition, disorder or disease associated with MRGPRX4 activation.
  • a condition, disorder or disease is or comprises concurring MRGPRX4 related pruritus.
  • a therapeutic agent is a Farnesoid X receptor (FXR) agonist, such as obeticholic acid (OCA) , cilofexor (GS-9674) , tropifexor (LJN452) , EDP-305, EDP-297, nidufexor, TERN-101 (LY2562175) , MET-409, BAR704, BAR502, EYP-001, RDX-023, AGN-242266, HPG-1860, AGN-242256, IOT-022, M-480, INV-33, etc.
  • FXR Farnesoid X receptor
  • a therapeutic agent is an ileal bile acid transport (IBAT) inhibitor, such as odevixibat, maralixibat, etc.
  • IBAT ileal bile acid transport
  • a therapeutic agent is ursocholic acid.
  • a therapeutic agent is ursodeoxycholic acid (UDCA) .
  • a therapeutic agent is a thyroid hormone receptor ⁇ (THR- ⁇ ) agonist, such as resmetirom (MGL-3196) , GC-24, MGL-3745, VK-2809, KB141 [3,5-dichloro-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid] , MB07811 (2R, 4S) -4- (3-chlorophenyl) -2- ( (3, 5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenoxy) methyl] -2-oxido- [l, 3, 2] -dioxaphosphonane) , etc.
  • TTR- ⁇ thyroid hormone receptor ⁇
  • a therapeutic agent is a peroxisome proliferator-activated receptors (PPAR) agonist, such as elafibranor, lanifibranor, saroglitazar, pioglitazone, rosiglitazone etc.
  • PPAR peroxisome proliferator-activated receptors
  • a therapeutic agent is a glucagon-like peptide 1 (GLP-1) agonist, such as semaglutide, exenatide, dulaglutide, liraglutide, lixisenatide, danuglipron (PF-06882961) PF-07081532 etc.
  • GLP-1 glucagon-like peptide 1
  • a therapeutic agent is a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist such as tirzepatide.
  • a therapeutic agent is an acetyl CoA- carboxylase (ACC) inhibitor such as firsocostat, PF-05221304, WZ66, etc.
  • ACC acetyl CoA- carboxylase
  • a therapeutic agent is a diacylglycerol O-acyltransferase 2 (DGAT2) inhibitor such as PF-06865571.
  • the other therapeutic agent is a ketohexokinase (KHK) inhibitor such as PF-06835919.
  • a therapeutic agent is an approved agent (e.g., by U.S.
  • an agent is obeticholic acid approved for treatment of adult patients with primary biliary cholangitis (PBC) without cirrhosis or with compensated cirrhosis who do not have evidence of portal hypertension, either in combination with ursodeoxycholic acid (UDCA) with an inadequate response to UDCA or as monotherapy in patients unable to tolerate UDCA.
  • PBC primary biliary cholangitis
  • UDCA ursodeoxycholic acid
  • an agent is cholic acid approved for treatment of bile acid synthesis disorders due to single enzyme defects (SEDs) or adjunctive treatment of peroxisomal disorders (PDs) including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat-soluble vitamin absorption.
  • an agent is taurursodiol, in combination with sodium phenylbutyrate (Relyvrio) approved for the treatment of amyotrophic lateral sclerosis (ALS) .
  • a provided compound is administered or delivered concurrently with another therapeutic agent. In some embodiments, a provided compound is administered or delivered in a single composition with another therapeutic agent. In some embodiments, a provided compound is administered or delivered concurrently with another therapeutic agent but in different compositions. In some embodiments, a provided compound is administered or delivered prior to another therapeutic agent (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, or about 1, 2, 3, 4, or 5 weeks, or about 1, 2, 3, 4, or 5 months prior to another therapeutic agent) .
  • another therapeutic agent e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, or about 1, 2, 3, 4, or 5 weeks, or about 1, 2, 3, 4, or 5 months prior to another therapeutic agent.
  • a provided compound is administered or delivered after another therapeutic agent (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, or about 1, 2, 3, 4, or 5 weeks, or about 1, 2, 3, 4, or 5 months after another therapeutic agent) .
  • another therapeutic agent e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, or about 1, 2, 3, 4, or 5 weeks, or about 1, 2, 3, 4, or 5 months after another therapeutic agent.
  • a provided compound is administered or delivered when a subject is under the therapeutic effect of another therapeutic agent.
  • MRGPRX4 is a G protein-coupled receptor activated by bile acids that may contribute to cholestatic pruritus, PNAS, 2019, 116 (21) , 10525-10530; Yu et al. MRGPRX4 is bile acid receptor for human cholestatic itch, eLife, 2019, 8, e48431.
  • a bile acid or an analog or derivative thereof is reported in WO 2016086169, US 10519191, WO 2016130809, US 10246483, WO 2017147174, WO 2017147159, WO 2017147137, US 10364267, US 10323061, US 10323060, WO 2017189663, WO 2017189652, WO 2017189651, US 10080743, US 10080742, US 10080741, WO 2017201155, WO 2017201152, WO 2017201150, US 10144729, US 10138228, WO 2018067704, US 10450306, WO 2018081285, US 10597391, WO 2018102418, US 10584145, WO 2018152171, US 10472386, WO 2018187804, US 10676500, WO 2019118571, US 10689391, WO 2020231917, WO 2016073767, US 10266560, WO 2016086134, US 10208081, WO 2016086218
  • a FXR agonist is reported in WO 2016086169, US 10519191, WO 2016130809, US 10246483, WO 2017147174, WO 2017147159, WO 2017147137, US 10364267, US 10323061, US 10323060, WO 2017189663, WO 2017189652, WO 2017189651, US 10080743, US 10080742, US 10080741, WO 2017201155, WO 2017201152, WO 2017201150, US 10144729, US 10138228, WO 2018067704, US 10450306, WO 2018081285, US 10597391, WO 2018102418, US 10584145, WO 2018152171, US 10472386, WO 2018187804, US 10676500, WO 2019118571, US 10689391, WO 2020231917, WO 2016073767, US 10266560, WO 2016086134, US 10208081, WO 2016086218, US 106967
  • a condition, disorder or disease is primary biliary cholangitis (PBC) without cirrhosis or with compensated cirrhosis who do not have evidence of portal hypertension.
  • PBC primary biliary cholangitis
  • another therapeutic agent is obeticholic acid.
  • UDCA ursodeoxycholic acid
  • a condition, disorder or disease is a bile acid synthesis disorder. In some embodiments, a condition, disorder or disease is a bile acid synthesis disorder due to single enzyme defects (SEDs) . In some embodiments, a condition, disorder or disease is peroxisomal disorders (PDs) . In some embodiments, a condition, disorder or disease is peroxisomal disorders (PDs) including Zellweger spectrum disorders. In some embodiments, a subject exhibits manifestations of liver disease, steatorrhea or complications. In some embodiments, another therapeutic agent is cholic acid.
  • a condition, disorder or disease is a neurodegenerative condition, disorder or disease.
  • a condition, disorder or disease is ALS.
  • another therapeutic agent is taurursodiol in combination with sodium phenylbutyrate (Relyvrio) .
  • a subject is an adult patient. In some embodiments, a subject is a pediatric patient.
  • the present disclosure provides a pharmaceutical composition that comprise a provided compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition that can deliver a provided compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a route and/or mode of administration can vary depending upon desired results.
  • dosage regimens can be adjusted to provide a desired response, e.g., a therapeutic response.
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intrathecal, intravaginal, transdermal, rectal, by inhalation, or topical, particularly to the ears, nose, eyes, or skin.
  • a mode of administration is left to discretion of a practitioner.
  • compositions can be incorporated into and administered as pharmaceutical compositions. Such pharmaceutical compositions are useful for, among other things, administration and delivery to a subject in vivo or ex vivo.
  • pharmaceutical compositions also contain a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier is a pharmaceutical agent that does not itself induce an immune response harmful to the individual receiving a composition, and which may be administered without undue toxicity.
  • Pharmaceutically acceptable carriers include, but are not limited to, liquids such as water, saline, glycerol, sugars and ethanol. Additionally, auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, may be present in such vehicles.
  • salts can be formed with many acids, including but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, benzenesulfonic, etc.
  • salts can be formed with bases.
  • salts are alkali, alkaline earth metal, or ammonium salts, e.g., sodium, calcium, diethanolamine, ethanolamine, trialkylamine salts, etc.
  • salts are more soluble in aqueous or other protonic solvents than corresponding, free acid or base forms.
  • a pharmaceutical composition may be a lyophilized powder.
  • a pharmaceutical composition comprises a provided compound, e.g., a compound of formula I or a pharmaceutically acceptable salt thereof dissolved in a pharmaceutically acceptable buffer.
  • a buffer is a saline buffer.
  • a buffer has a pH around 7.4.
  • compositions can include solvents (aqueous or non-aqueous) , solutions (aqueous or non-aqueous) , emulsions (e.g., oil-in-water or water-in-oil) , suspensions, syrups, elixirs, dispersion and suspension media, coatings, isotonic and absorption promoting or delaying agents, compatible with pharmaceutical administration or in vivo contact or delivery.
  • Aqueous and non-aqueous solvents, solutions and suspensions may include suspending agents and thickening agents.
  • pharmaceutical compositions or formulations are tablets (coated or uncoated) , capsules (hard or soft) , microbeads, powder, granules and/or crystals.
  • Supplementary active compounds e.g., preservatives, antibacterial, antiviral and antifungal agents
  • compositions can be formulated to be compatible with a particular route of administration or delivery as set forth herein or known to one of skill in the art.
  • compositions are suitable for parenteral administration.
  • such compositions comprise aqueous and non-aqueous solutions, suspensions or emulsions of active compounds, which preparations are typically sterile and can be isotonic with blood of intended recipients.
  • Non-limiting illustrative examples include water, buffered saline, Hanks's olution, Ringer's solution, dextrose, fructose, ethanol, animal, vegetable or synthetic oils.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • suspensions of active compounds may be prepared as appropriate oil injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • a suspension may also contain suitable stabilizers or agents which increase solubility to allow for the preparation of highly concentrated solutions.
  • Co-solvents and adjuvants may be added to compositions and formulations.
  • co-solvents contain hydroxyl groups or other polar groups, for example, alcohols, such as isopropyl alcohol; glycols, such as propylene glycol, polyethyleneglycol, polypropylene glycol, glycol ether; glycerol; polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
  • Adjuvants include, for example, surfactants such as, soya lecithin and oleic acid; sorbitan esters such as sorbitan trioleate; and polyvinylpyrrolidone.
  • compositions After pharmaceutical compositions have been prepared, they may be placed in an appropriate container and labeled for treatment.
  • labeling can include amount, frequency, and method of administration.
  • compositions and delivery systems appropriate for compositions, methods and uses of the present disclosure are known in the art (see, e.g., Remington: The Science and Practice of Pharmacy. 21st Edition. Philadelphia, PA. Lippincott Williams &Wilkins, 2005) and can be utilized in accordance with the present disclosure.
  • the present disclosure provides methods for delivering provided compounds and compositions into cells, animals or subjects.
  • such methods include contacting a subject (e.g., a cell or tissue of a subject) with, or administering or delivering to a subject (e.g., a subject such as a mammal or human) a provided compound, e.g., a compound of formula I or a salt thereof, or a composition thereof.
  • a compound or composition described herein can be administered in a sufficient or effective amount to a subject (or a cell, tissue or organ thereof) in need thereof.
  • Doses can vary and may depend upon the type, onset, progression, severity, frequency, duration, or probability of a condition, disorder or disease to which treatment is directed, a clinical endpoint desired, previous or simultaneous treatments, general health, age, gender, race or immunological competency of a subject and other factors that will be appreciated by a skilled artisan.
  • Dose amount, number, frequency or duration may be proportionally increased or reduced, as indicated by efficacy, any adverse side effects, complications or other risk factors of a treatment or therapy and the status of a subject.
  • a dose to achieve a therapeutic effect will vary based on several factors including route of administration, amount to achieve a therapeutic effect, specific condition, disorder or disease treated, any host immune response to administered compound or composition, stability of administered compound or composition, etc.
  • An effective amount or a sufficient amount can be provided in a single administration, may require multiple administrations, and, can be, administered alone or in combination with another composition (e.g., comprising or delivering another therapeutic agent) .
  • another composition e.g., comprising or delivering another therapeutic agent
  • an amount may be proportionally increased as indicated by the need of a subject, type, status and severity of a condition, disorder or disease treated and/or side effects (if any) of treatment.
  • Amounts considered effective also include amounts that result in a reduction of the use of another treatment, therapeutic regimen or protocol.
  • compositions comprise or deliver active ingredients, e.g., compounds of formula I or pharmaceutically acceptable salts thereof, in effective amounts to achieve intended purposes e.g., therapeutic purposes.
  • active ingredients e.g., compounds of formula I or pharmaceutically acceptable salts thereof
  • Various technologies may be utilized to determine therapeutically effective amounts in accordance with the present disclosure.
  • Therapeutic doses can depend on, among other factors, ages and general conditions of subjects, severity of conditions, disorders or diseases, etc.
  • therapeutically effective amounts in humans may fall in a relatively broad range that may be determined by medical practitioners based on responses of individual patients.
  • methods and uses of the present disclosure include delivery and administration systemically, regionally or locally, or by any route, for example, by injection or infusion or orally.
  • delivery of a pharmaceutical composition in vivo may generally be accomplished via injection using a conventional syringe, although other delivery methods such as convection-enhanced delivery can also be used
  • compounds and compositions may be delivered subcutaneously, epidermally, intradermally, intrathecally, intraorbitally, intramucosally, intraperitoneally, intravenously, intra-pleurally, intraarterially, orally, intrahepatically, via the portal vein, or intramuscularly.
  • modes of administration include oral and pulmonary administration, suppositories, and transdermal applications. Clinicians specializing in treating patients may determine optimal routes for administration of compounds and compositions as described herein.
  • Step 1 To a solution of 5-fluoro-1H-indole-4-carboxylic acid (250 mg, 1.40 mmol) dissolved in MeOH (5 mL) was added H 2 SO 4 (100 uL) dropwise. The resulting solution was stirred at 80 °C for 2 h. After complete conversion, the reaction mixture was cooled to room temperature, quenched with water, and extracted with EA for three times. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. Purification of the residue via column chromatography afforded 1-1 (264 mg, 62%yield) as colorless oil. MS (m/z) : 194.03 (M+1) .
  • Step 2 Compound 1-1 (100 mg, 0.518 mmol) , 4- (bromomethyl) -2-chloro-1- (trifluoromethyl) benzene (169 mg, 0.622 mmol) and Cs 2 CO 3 (506 mg, 1.554 mmol) were added to DMF (3 mL) and the resulting mixture was heated at 80 °C for 2 h. After complete conversion, the reaction mixture was cooled to room temperature, quenched with water, and extracted with EA for three times. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. Purification of the residue via column chromatography afforded compound 1-2 (50.8 mg, 26%yield) as yellow solid. MS (m/z) : 386.2 (M+1) .
  • Step 3 Compound 1-2 (50.8 mg, 0.132 mmol) and LiOH ⁇ H 2 O (31.7 mg, 1.319 mmol) were dissolved in THF/MeOH/H 2 O (1: 1: 1, 2 mL) under Ar. The mixture was stirred at room temperature for 2 h. After complete conversion, the solution was adjusted to pH 6 with aq. HCl and concentrated. The residue was purified by reversed phase high-performance liquid chromatography to afford Compound 1 (9 mg, 18.4%yield) as white solid. LC-MS, ES (m/z) : 372.08 (M+1) .
  • Step 1 Compound 38-1 was prepared in a similar way as described for compound 1-2. To a stirred solution of compound 38-1 (100 mg, 0.22 mmol) in toluene/H 2 O (10: 1, 5.5 mL) at rt was added K 3 PO 4 (166 mg, 0.78 mmol) , cyclopropylboronic acid (23.1 mg, 0.268 mmol) and Pd (OAc) 2 (2.8 mg, 0.011mmol) under N 2 . The reaction mixture was stirred at 120 °C overnight. The mixture was extracted with EA and H 2 O. The organic layer was dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 38-2 (46 mg, yield 51.3%) . LC-MS, ES + (m/z) : 407.09 (M+1) .
  • Step 2 To a stirred solution of compound 38-2 (46 mg, 0.113mmol) in THF/H 2 O (1: 1, 2 mL) at rt was added NaOH (23 mg, 0.565 mmol) . The resulting solution was stirred at 70 °C overnight. The mixture was acidified to pH 2 with 1 M aq. HCl and extracted with EA and H 2 O. The organic layer was dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give Compound 38 (18 mg, yield 40.4%) as a white solid. LC-MS, ES + (m/z) : 394.09 (M+1) .
  • Step 1 To a stirred solution of 4-bromo-7-chloro-1H-indole (220 mg, 1.0 mmol) in DMF (5 mL) at rt was added Cs 2 CO 3 (650 mg, 2.0 mmol, 2.0 eq) , and 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene (270 mg, 1.0 mmol) .
  • the reaction mixture was stirred at 80°C for 3 h. The mixture was extracted with EA and H 2 O. The organic layer was dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • the crude product was purified by silica gel chromatography to give 40-1 (290 mg, yield 68.6%) .
  • Step 2 To a stirred solution of 40-1 (170 mg, 0.40 mmol) in NMP (3 mL) at rt was added CuCN (54 mg, 0.61 mmol) . The reaction mixture was stirred at 200°C for 3 h. The mixture was extracted with EA and H 2 O. The organic layer was dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 40-2 (22 mg, yield 14.9%) . LC-MS, ES + (m/z) : 369.06 (M+1) .
  • Step 3 To a stirred solution of 40-2 (22 mg, 0.06 mmol) in MeOH/H 2 O (1: 1, 2 mL) at rt was added KOH (33 mg, 0.60 mmol) . The resulted solution was stirred at 90 °C overnight. The mixture was acidified with HCl (1N, aq) to pH 2, and extracted with EA and H 2 O. The organic layer was dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give Compound 40 (5 mg, yield 21.5%) as a white solid. LC-MS, ES + (m/z) : 388.05 (M+1) .
  • Step 1 1H-indole-4-carbonitrile (100 mg, 0.703 mmol) , 1- (bromomethyl) -4- (trifluoromethyl) benzene (202 mg, 0844 mmol) and Cs 2 CO 3 (688 mg, 2.11 mmol) were added to DMF (3 mL) and the resulting mixture was stirred at 80 °C for 2 h. After complete conversion, the reaction mixture was cooled to room temperature, quenched with water, and extracted with EA for three times. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Step 2 Compound 41-1 (45 mg, 0.15 mmol) and TMSN 3 (34.5 mg, 0.3 mmol) were dissolved in toluene (1 mL) . Dibutyltin oxide (3.7 mg, 0.015 mmol) was added. The mixture was stirred at 105 °C for 15 h and cooled to room temperature. The reaction mixture was quenched with MeOH, and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford compound 41 (15 mg, 29%yield) as white solid. LC -MS, ES (m/z) : 343.92 (M+1) .
  • Step 1 4-bromo-6-chloro-1H-indole (400 mg, 1.735 mmol) , 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene (480 mg, 1.758 mmol) and Cs 2 CO 3 (1696 mg, 5.205 mmol) were added to DMF (8 mL) and the resulting mixture was stirred at 80 °C for 2 h. After complete conversion, the reaction mixture was cooled to room temperature, quenched with water, and extracted with EA for three times. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Step 2 To a solution of compound 49-1 (100 mg, 0.236 mmol) dissolved in NMP (1 mL) was added CuCN (25 mg, 0.284 mmol) and the mixture was stirred at 180°C for 3 h. The reaction was cooled to room temperature, quenched with water, and extracted with EA three times. The organic fractions were combined, washed with NaCl, and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford 49-2 (59mg, 67%yield) .
  • Step 3 Compound 49-2 (46 mg, 0.124 mmol) and TMSN 3 (29 mg, 0.249 mmol) were dissolved in toluene (1 mL) . Dibutyltin oxide (3mg, 0.0124mmol) was added. The mixture was heated at 110°C for 15 h and cooled to room temperature. The reaction mixture was quenched with MeOH, and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford Compound 49 (12 mg, 23%yield) as white solid. LC -MS, ES (m/z) : 412.01 (M+1) .
  • Example 10 Provided technologies can reduce MRGPRX4 activation.
  • provided technologies can reduce MRGPRX4 activation.
  • Various technologies can be utilized in accordance with the present disclosure to access activities of provided compounds. An example is described below.
  • HEK293T cells stably expressing human MRGPRX4 were cultured in DMEM medium supplements with 10%FBS, 100 U/mL penicillin-streptomycin, 20 mM HEPES and 1 ⁇ g/mL puromycin at 37 °C with 5% (v/v) CO 2 .
  • DMEM medium supplements with 10%FBS, 100 U/mL penicillin-streptomycin, 20 mM HEPES and 1 ⁇ g/mL puromycin at 37 °C with 5% (v/v) CO 2 One day before test, the cells were detached using TrypLETM Express and counted using cell counter.
  • IC 50 values were calculated by fitting %inhibition against log of compound concentrations (top conc. 30 ⁇ M, ten 3-fold serial dilutions) with Hill equation using XLfit. MRGPRX4 antagonist activities of certain compounds tested in this assay were listed in Table 1 as examples. Those skilled in the art appreciate that IC 50 of various compounds can be assessed in accordance with the present disclosure. In some embodiments, inhibition of various compounds was assessed at certain concentrations, e.g., about 0.5 ⁇ M, about 2 ⁇ M, etc; certain data were presented in the Table below as examples.

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Abstract

Entre autres, la présente invention concerne des composés, par exemple, de formule I ou des sels de ceux-ci. Dans certains modes de réalisation, la présente invention concerne des procédés de modulation de l'activité de MRGPRX4. Dans certains modes de réalisation, la présente invention concerne des procédés de prévention ou de traitement d'états, de troubles ou de maladies, par exemple, des états, des troubles ou des maladies associés à MRGPRX4.
PCT/CN2024/088496 2023-04-19 2024-04-18 Composés, compositions et procédés associés Pending WO2024217484A1 (fr)

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