WO2022111473A1 - Composés utilisés en tant qu'antagonistes de mrgprx2 - Google Patents
Composés utilisés en tant qu'antagonistes de mrgprx2 Download PDFInfo
- Publication number
- WO2022111473A1 WO2022111473A1 PCT/CN2021/132441 CN2021132441W WO2022111473A1 WO 2022111473 A1 WO2022111473 A1 WO 2022111473A1 CN 2021132441 W CN2021132441 W CN 2021132441W WO 2022111473 A1 WO2022111473 A1 WO 2022111473A1
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- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- compound
- pharmaceutically acceptable
- stereoisomer
- acceptable salt
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 347
- 239000005557 antagonist Substances 0.000 title abstract description 7
- 101001029072 Homo sapiens Mas-related G-protein coupled receptor member X2 Proteins 0.000 claims abstract description 10
- 102100037125 Mas-related G-protein coupled receptor member X2 Human genes 0.000 claims abstract 4
- 150000003839 salts Chemical class 0.000 claims description 118
- 125000005843 halogen group Chemical group 0.000 claims description 108
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 97
- 238000000034 method Methods 0.000 claims description 71
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 68
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 66
- 125000000623 heterocyclic group Chemical group 0.000 claims description 59
- 229910052757 nitrogen Inorganic materials 0.000 claims description 40
- 239000003814 drug Substances 0.000 claims description 39
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- 125000005842 heteroatom Chemical group 0.000 claims description 34
- 229910052731 fluorine Inorganic materials 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 25
- 210000003630 histaminocyte Anatomy 0.000 claims description 24
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 24
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 229940079593 drug Drugs 0.000 claims description 23
- 208000003251 Pruritus Diseases 0.000 claims description 21
- 230000001404 mediated effect Effects 0.000 claims description 21
- 229910052801 chlorine Inorganic materials 0.000 claims description 20
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 20
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 19
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 208000003455 anaphylaxis Diseases 0.000 claims description 15
- 206010002198 Anaphylactic reaction Diseases 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 230000036783 anaphylactic response Effects 0.000 claims description 13
- 230000020411 cell activation Effects 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 229940124597 therapeutic agent Drugs 0.000 claims description 12
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 11
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 10
- 102000004328 Cytochrome P-450 CYP3A Human genes 0.000 claims description 10
- 108010081668 Cytochrome P-450 CYP3A Proteins 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 8
- 241001303601 Rosacea Species 0.000 claims description 7
- 230000004913 activation Effects 0.000 claims description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 230000008406 drug-drug interaction Effects 0.000 claims description 7
- 208000027866 inflammatory disease Diseases 0.000 claims description 7
- 201000004700 rosacea Diseases 0.000 claims description 7
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 claims description 6
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 6
- 239000000739 antihistaminic agent Substances 0.000 claims description 6
- 208000006673 asthma Diseases 0.000 claims description 6
- 201000008937 atopic dermatitis Diseases 0.000 claims description 6
- 208000030949 chronic idiopathic urticaria Diseases 0.000 claims description 6
- 206010072757 chronic spontaneous urticaria Diseases 0.000 claims description 6
- 208000024376 chronic urticaria Diseases 0.000 claims description 6
- 102000048835 human MRGPRX2 Human genes 0.000 claims description 6
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims description 5
- 206010065390 Inflammatory pain Diseases 0.000 claims description 5
- 208000007920 Neurogenic Inflammation Diseases 0.000 claims description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 235000013305 food Nutrition 0.000 claims description 5
- 239000003158 myorelaxant agent Substances 0.000 claims description 5
- 125000003566 oxetanyl group Chemical group 0.000 claims description 5
- 201000001245 periodontitis Diseases 0.000 claims description 5
- 229950000688 phenothiazine Drugs 0.000 claims description 5
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical group C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims description 4
- 230000001387 anti-histamine Effects 0.000 claims description 4
- 230000000561 anti-psychotic effect Effects 0.000 claims description 4
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 4
- 239000003306 quinoline derived antiinfective agent Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 121
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 228
- 238000001819 mass spectrum Methods 0.000 description 102
- 238000005160 1H NMR spectroscopy Methods 0.000 description 86
- -1 therapeutic agents Chemical class 0.000 description 80
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- 239000000243 solution Substances 0.000 description 43
- 239000007787 solid Substances 0.000 description 39
- 239000000460 chlorine Substances 0.000 description 31
- 239000000651 prodrug Substances 0.000 description 29
- 229940002612 prodrug Drugs 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 125000004432 carbon atom Chemical group C* 0.000 description 27
- 235000019439 ethyl acetate Nutrition 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- 210000004027 cell Anatomy 0.000 description 25
- 239000012044 organic layer Substances 0.000 description 21
- 239000012071 phase Substances 0.000 description 21
- 238000005516 engineering process Methods 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 16
- 239000000741 silica gel Substances 0.000 description 16
- 229910002027 silica gel Inorganic materials 0.000 description 16
- 230000005764 inhibitory process Effects 0.000 description 15
- 238000000746 purification Methods 0.000 description 14
- 238000003556 assay Methods 0.000 description 13
- 125000001072 heteroaryl group Chemical group 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- 230000002829 reductive effect Effects 0.000 description 13
- 125000004122 cyclic group Chemical group 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 241000282414 Homo sapiens Species 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 11
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 9
- KWRNTYYGWQUJGH-UHFFFAOYSA-N CCC(C)C(N=C1N2C(C=CC=C3)=C3N1)=C(CC)C2=O Chemical compound CCC(C)C(N=C1N2C(C=CC=C3)=C3N1)=C(CC)C2=O KWRNTYYGWQUJGH-UHFFFAOYSA-N 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- BYGQBDHUGHBGMD-UHFFFAOYSA-N 2-methylbutanal Chemical compound CCC(C)C=O BYGQBDHUGHBGMD-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 239000000556 agonist Substances 0.000 description 8
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- 230000008569 process Effects 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- JWYUFVNJZUSCSM-UHFFFAOYSA-N 2-aminobenzimidazole Chemical class C1=CC=C2NC(N)=NC2=C1 JWYUFVNJZUSCSM-UHFFFAOYSA-N 0.000 description 7
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
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- 238000004440 column chromatography Methods 0.000 description 7
- 125000001188 haloalkyl group Chemical group 0.000 description 7
- 239000001301 oxygen Chemical group 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
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- UNNGUFMVYQJGTD-UHFFFAOYSA-N 2-Ethylbutanal Chemical compound CCC(CC)C=O UNNGUFMVYQJGTD-UHFFFAOYSA-N 0.000 description 6
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
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- CIPBJUSDKQTOED-UHFFFAOYSA-N ethyl 2-ethyl-4-methyl-3-oxohexanoate Chemical compound CCOC(=O)C(CC)C(=O)C(C)CC CIPBJUSDKQTOED-UHFFFAOYSA-N 0.000 description 5
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 5
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- BKYHTWFRZPRHNM-UHFFFAOYSA-N acetyloxymethyl 2-[n-[2-(acetyloxymethoxy)-2-oxoethyl]-4-[3-(acetyloxymethoxy)-6-oxoxanthen-9-yl]-2-[2-[2-[bis[2-(acetyloxymethoxy)-2-oxoethyl]amino]phenoxy]ethoxy]anilino]acetate Chemical compound CC(=O)OCOC(=O)CN(CC(=O)OCOC(C)=O)C1=CC=CC=C1OCCOC1=CC(C2=C3C=CC(=O)C=C3OC3=CC(OCOC(C)=O)=CC=C32)=CC=C1N(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O BKYHTWFRZPRHNM-UHFFFAOYSA-N 0.000 description 3
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- 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
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Definitions
- the present disclosure relates generally to compounds that bind to human Mas-Related G Protein-Coupled Receptor-X2 (MRGPRX2) and act as antagonists and are useful in treating human MRGPRX2-associated conditions.
- Compositions containing the compounds of the present disclosure are also provided.
- Mast cells are tissue-resident, long-lived innate immune cells, which are predominately located in the skin and the respiratory tract. Mast cells can also be found in close proximity to peripheral nerve endings where, upon activation, they release a broad range of pro-inflammatory cytokines and chemokines. Mast cells play key roles in allergy, anaphylaxis/anaphylactoid reactions. The immediate response upon mast cell activation to an appropriate stimulus is degranulation; a process characterized by the extrusion of cytoplasmic granule contents into the extracellular space by the process of exocytosis. Acute effects result from the rapid release of inflammatory mediators from activated MCs and underlie diseases like rhinoconjunctivitis, asthma, urticaria, food allergy, and anaphylaxis.
- histamine is the best-characterized endogenous agent evoking the development of itch. Itch, or pruritus, is the unpleasant sensation that leads to a desire to scratch. It is a common and distressing symptom in a variety of conditions and diseases.
- the standard treatment for itch is the administration of antihistamines.
- not all forms of itch are responsive to antihistamines and there is no universally effective anti-pruritic drug.
- the receptor MRGPRX2 is a member of a family of 5 human, 31 mouse, and 2 rat coding sequences that is related to the Mas1 oncogene. MRGPRX2 has been shown to have a limited expression profile, both peripheral and within the central nervous system, with highest levels in dorsal root ganglia and mast cells. (Robas, N.; et al.; J. Biol. Chem. 278, 44400, (2003) ) .
- MRGPRX2 is activated by basic secretagogues –molecules known to activate mast cells through a non-IgE mechanism. MRGPRX2 responds to various ligands to elicit pseudo-allergic or anaphylactic reactions. (McNeil, B.D.; et al.; Nature 519, 237, (2015) ) . MRGPRX2 mediated mast cell degranulation has been shown for a multitude of drugs, including the muscle relaxant Mivacurium (Che, D.; et al.; Cellular Immunol. 332, 121, (2016) ) , fluoroquinolone antibiotics (Liu, R.; et al.; Int. Immunopharmacol.
- MRGPRX2 is most likely the principal receptor involved in anaphylaxis in patients who do not suffer from type-I allergy. (Babina, M.; et al.; Itch 5: e32, (2020) ) . MRGPRX2 may also contribute to the development of asthma (Manorak, W.; et al., Resp. Res. 19, 1, (2016) ) and has been implicated in the pathology of other chronic inflammatory diseases such as rosacea (Muto, Y.; et al.; J. Invest. Dermatol. 134, 2728, (2014) ) , and urticaria (Fujisawa, D.; et al.; J Allergy Clin Immunol. 134, 622, (2014) ) .
- Increased MRGPRX2 expression on mast cells and their inappropriate activation may contribute to periodontitis, neurogenic inflammation, and inflammatory pain.
- Antagonists of human MRGPRX2 may be of benefit in the treatment of itch, inflammation, and drug reactions. There is an urgent need for therapeutic agents for itch that do not target the histamine pathway. There is also an urgent need for reducing the severity of pseudo-allergic or anaphylactic drug reactions.
- R 1 , R 2 , R 3 , R 4 , and n are as described herein.
- R 1 , R 2 , R 3 , and n are as described herein.
- composition comprising a compound of formula (I’) , or an isotopically enriched form, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
- composition comprising a compound of formula (I) , or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
- provided herein is a method of treating a condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of the compound of formula (I’) , or an isotopically enriched form, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein the condition is mediated by IgE-independent mast cell activation.
- a method of treating a condition in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the compound of formula (I) , or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the condition is mediated by IgE-independent mast cell activation.
- the mast cell activation is mediated by activation of MRGPRX2.
- the MRGPRX2 is human MRGPRX2 and the individual is a human.
- the condition is itch, an inflammatory disorder (e.g., asthma, irritable bowel syndrome, periodontitis, neurogenic inflammation, inflammatory pain, chronic idiopathic urticaria, atopic dermatitis, or rosacea) or a drug or food anaphylaxis (e.g., drug anaphylaxis caused by a muscle relaxant, a fluoroquinolone antibiotic, a phenothiazine antipsychotic, or an opioid) .
- the condition is itch.
- the itch is associated with an inflammatory disorder such as chronic idiopathic urticaria, atopic dermatitis, or rosacea. In some embodiments, the itch is not mediated by histamine.
- the compound is administered topically or orally. In some embodiments, the compound is administered topically. In some embodiments, the compound is administered orally. In some embodiments, the method further comprises administering to the individual an additional therapeutic agent, wherein the additional therapeutic agent is an anti-histamine.
- FIG. 1 shows dose normalized plasma concentration of the compound from Example S02 following a single oral administration of prodrugs S83, S84 and S88 to SD rats.
- Described herein are compounds, including therapeutic agents, that are antagonists of MRGPRX2. These compounds can be used in the treatment of certain pathological conditions as described herein.
- references to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X” .
- Alkyl refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 10 carbon atoms (i.e., C 1-10 alkyl or C 1 -C 10 alkyl) , 1 to 8 carbon atoms (i.e., C 1-8 alkyl or C 1 -C 8 alkyl) , 1 to 6 carbon atoms (i.e., C 1-6 alkyl or C 1 -C 6 alkyl) , or 1 to 4 carbon atoms (i.e., C 1-4 alkyl or C 1 -C 4 alkyl) .
- alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl.
- alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e.
- - (CH 2 ) 3 CH 3 ) sec-butyl (i.e., -CH (CH 3 ) CH 2 CH 3 ) , isobutyl (i.e., -CH 2 CH (CH 3 ) 2 ) and tert-butyl (i.e., -C (CH 3 ) 3 ) ; and “propyl” includes n-propyl (i.e., - (CH 2 ) 2 CH 3 ) and isopropyl (i.e., -CH (CH 3 ) 2 ) .
- Alkoxy refers to the group “-O-alkyl” .
- alkoxy groups include, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1, 2-dimethylbutoxy.
- Alkenyl refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl or C 2 -C 20 alkenyl) , 2 to 8 carbon atoms (i.e., C 2-8 alkenyl or C 2 -C 8 alkenyl) , 2 to 6 carbon atoms (i.e., C 2-6 alkenyl or C 2 -C 6 alkenyl) or 2 to 4 carbon atoms (i.e., C 2-4 alkenyl or C 2 -C 4 alkenyl) .
- alkenyl groups include, without limitation, ethenyl, propenyl, and butadienyl (e.g., 1, 2-butadienyl and 1, 3-butadienyl) .
- Alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkynyl or C 2 -C 20 alkynyl) , 2 to 8 carbon atoms (i.e., C 2-8 alkynyl or C 2 -C 8 alkynyl) , 2 to 6 carbon atoms (i.e., C 2-6 alkynyl or C 2 -C 6 alkynyl) or 2 to 4 carbon atoms (i.e., C 2-4 alkynyl or C 2 -C 4 alkynyl) .
- alkynyl also includes those groups having one triple bond and one double bond.
- Cycloalkyl refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro ring systems.
- the term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp 3 carbon atom (i.e., at least one non-aromatic ring) .
- cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl or C 3 -C 20 cycloalkyl) , 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl or C 3 -C 12 cycloalkyl) , 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl or C 3 -C 10 cycloalkyl) , 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl or C 3 -C 8 cycloalkyl) , or 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl or or C 3 -C 6 cycloalkyl) .
- Monocyclic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- cycloalkyl is intended to encompass any non-aromatic cyclic alkyl which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule.
- cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom.
- Halo or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85.
- Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine.
- a haloalkyl is an alkyl group that is substituted with one or more halogens, which may be same of different. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc.
- Aryl refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems.
- aryl has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl or C 6 -C 20 aryl) , 6 to 12 carbon ring atoms (i.e., C 6-12 aryl or C 6 -C 12 aryl) , or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl or C 6 -C 10 aryl) .
- aryl groups include, without limitation, phenyl, naphthyl, fluorenyl and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl.
- Heteroaryl refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur.
- heteroaryl includes 1 to 20 ring carbon atoms (i.e., C 1-20 or C 1 -C 20 heteroaryl) , 3 to 12 ring carbon atoms (i.e., C 3-12 or C 3 -C 12 heteroaryl) , or 3 to 8 carbon ring atoms (i.e., C 3-8 or C 3 -C 8 heteroaryl) and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur.
- heteroaryl includes 5-12 membered ring systems, 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings) . Heteroaryl does not encompass or overlap with aryl as defined above.
- heteroaryl groups include, but are not limited to, pyridyl, pyrimidyl, thiophenyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, thiophenyl, pyrrolyl, pyrazolyl, 1, 3, 4-oxadiazolyl, imidazolyl, isothiazolyl, triazolyl, 1, 3, 4-thiadiazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, pyrazolopyridinyl, indazolyl, benzothiazolyl, benzooxazolyl, and benzoimidazolyl and the like.
- Heterocyclyl refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur.
- heterocyclyl includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond) , bridged-heterocyclyl groups, fused-heterocyclyl groups and spiro-heterocyclyl groups.
- Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom) .
- the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule.
- heterocyclyl has 2 to 20 ring carbon atoms (i.e., C 2-20 or C 2 -C 20 heterocyclyl) , 2 to 12 ring carbon atoms (i.e., C 2-12 or C 2 -C 12 heterocyclyl) , 2 to 10 ring carbon atoms (i.
- heterocyclyl includes 3-12 membered ring systems, 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur.
- heterocyclyl also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom.
- heterocyclyl groups include, but are not limited to, tetrahydropyranyl, dihydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxetanyl, and the like.
- “Substituted” as used herein means one or more (e.g., 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5, or 3-4) hydrogen atoms of the group are replaced with the substituents listed for that group, which may be the same or different.
- “Optionally substituted” means that a group may be unsubstituted or substituted by one or more (e.g., 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5, or 3-4) substituents listed for that group, wherein the substituents may be the same or different.
- an individual intends a mammal, including but not limited to a primate, human, bovine, horse, feline, canine, or rodent. In one variation, the individual is a human.
- treatment is an approach for obtaining beneficial or desired results including clinical results.
- beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the condition, diminishing the extent of the condition, stabilizing the condition (e.g., preventing or delaying the worsening of the condition) , preventing or delaying the spread of the condition, delaying the occurrence or recurrence of the condition, delay or slowing the progression of the condition, ameliorating the condition, providing a remission (whether partial or total) of the condition, decreasing the dose of one or more other medications required to treat the condition, enhancing effect of another medication, delaying the progression of the condition, increasing the quality of life, and/or prolonging survival.
- the methods of the present disclosure contemplate any one or more of these aspects of treatment.
- an effective amount intends such amount of a compound described herein which should be effective in a given therapeutic form.
- an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint.
- An effective amount may be considered in the context of administering one or more therapeutic agents (e.g., a compound, or pharmaceutically acceptable salt thereof) , and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
- Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
- a “therapeutically effective amount” refers to an amount of a compound or salt thereof sufficient to produce a desired therapeutic outcome.
- unit dosage form refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- Unit dosage forms may contain a single or a combination therapy.
- pharmaceutically acceptable or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
- Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
- “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual.
- Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
- a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
- coordinates with an organic base e.
- Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like.
- Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
- Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the present disclosure in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.
- excipient means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the present disclosure as an active ingredient.
- a drug or pharmaceutical such as a tablet containing a compound of the present disclosure as an active ingredient.
- Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent.
- prodrug refers to a compound which provides an active compound following administration to the individual in which it is used, by a chemical and/or biological process in vivo (e.g., by hydrolysis and/or an enzymatic conversion) .
- the prodrug itself may be active, or it may be relatively inactive, then transformed into a more active compound.
- This disclosure embraces prodrugs of the compounds described herein.
- R 1 is C 1 -C 6 alkyl, C 4 -C 12 cycloalkyl, or 3-12 membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 4 -C 12 cycloalkyl, and 3-12 membered heterocyclyl are each independently optionally substituted by halo, -OH, or C 1 -C 6 alkoxy;
- R 2 is hydrogen, -CN, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl are each independently optionally substituted by halo, -OH, or C 1 -C 6 alkoxy;
- each R 3 is independently halo, C 1 -C 6 alkyl, -CN, or -OH;
- n is an integer from 0-4;
- R 4 is hydrogen
- R 5a is C 1 -C 8 alkyl, C 2 -C 20 alkenyl, - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , or C 6 -C 10 aryl;
- R 5b is C 1 -C 6 alkyl or - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) ;
- R 5c is C 1 -C 6 alkyl, - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , or - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) ;
- R 5d is C 1 -C 6 alkyl, - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , or - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) ;
- R 5e is C 1 -C 6 alkyl
- R 5f is C 1 -C 6 alkyl, - (C 1 -C 6 alkylene) -OH, - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , or - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) ;
- R 5g and R 5h are independently C 1 -C 6 alkyl, - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , or -O- (C 1 -C 6 alkyl) ,
- R 5g and R 5h are taken together with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, and wherein the 4-to 10-membered heterocyclyl is optionally substituted by 1-5 groups independently selected from the group consisting of C 1 -C 6 alkyl, - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , or -O- (C 1 -C 6 alkyl) ; and R 5i and R 5j are independently C 1 -C 6 alkyl or - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) ,
- R 5i and R 5j are taken together with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, and wherein the 4-to 10-membered heterocyclyl is optionally substituted by 1-5 groups independently selected from the group consisting of C 1 -C 6 alkyl, - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , or -O- (C 1 -C 6 alkyl) .
- R 1 is methyl, ethyl, propyl, isobutyl, or tert-butyl, each of which is independently optionally substituted by halo, -OH, or C 1 -C 6 alkoxy
- R 2 is not H, methyl, ethyl, propyl, butyl, or pentyl, each of which is independently optionally substituted by halo, -OH, or C 1 -C 6 alkoxy.
- R 1 is C 1 -C 6 alkyl, C 4 -C 12 cycloalkyl, or 3-12 membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 4 -C 12 cycloalkyl, and 3-12 membered heterocyclyl are each independently optionally substituted by halo, -OH, or C 1 -C 6 alkoxy;
- R 2 is hydrogen, -CN, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl are each independently optionally substituted by halo, -OH, or C 1 -C 6 alkoxy;
- each R 3 is independently halo, C 1 -C 6 alkyl, -CN, or -OH;
- n is an integer from 0-4.
- R 1 is methyl, ethyl, propyl, isobutyl, or tert-butyl, each of which is optionally substituted by halo, -OH, or C 1 -C 6 alkoxy
- R 2 is not H, methyl, ethyl, propyl, butyl, or pentyl, each of which is independently optionally substituted by halo, -OH, or C 1 -C 6 alkoxy.
- R 1 when R 1 is methyl optionally substituted by halo, then R 2 is not H, methyl, ethyl, propyl, butyl, or pentyl, each of which is independently optionally substituted by halo, -OH, or C 1 -C 6 alkoxy;
- R 1 when R 1 is ethyl optionally substituted by halo, then R 2 is not H, methyl, ethyl, or propyl, each of which is independently optionally substituted by halo, -OH, or C 1 -C 6 alkoxy; and/or
- R 1 is propyl optionally substituted by halo
- R 2 is not H, methyl, ethyl, or propyl, each of which is independently optionally substituted by halo, -OH, or C 1 -C 6 alkoxy.
- (a) applies. In some embodiments, (b) applies. In some embodiments, (c) applies. In some embodiments, (a) and (b) apply. In some embodiments, (a) and (c) apply. In some embodiments, (b) and (c) apply. In some embodiments, (a) , (b) , and (c) apply.
- R 1 when R 1 is methyl, ethyl, or propyl, each of which is independently optionally substituted by halo, -OH, or C 1 -C 6 alkoxy, then R 2 is not H, methyl, ethyl, propyl, butyl, or pentyl, each of which is independently optionally substituted by halo, -OH, or C 1 -C 6 alkoxy; and
- (a) applies. In some embodiments, (b) applies. In some embodiments, (a) and (b) apply.
- R 1 when R 1 is methyl optionally substituted by halo or C 1 -C 6 alkoxy, then R 2 is not H, methyl, ethyl, propyl, butyl, or pentyl, each of which is independently optionally substituted by halo, -OH, or C 1 -C 6 alkoxy;
- R 1 when R 1 is ethyl optionally substituted by halo, then R 2 is not H, methyl, ethyl, or propyl, each of which is independently optionally substituted by halo, -OH, or C 1 -C 6 alkoxy;
- R 1 is propyl optionally substituted by halo or –OH
- R 2 is not H, methyl, ethyl, or propyl, each of which is independently optionally substituted by halo, -OH, or C 1 -C 6 alkoxy;
- R 1 when R 1 is tert-butyl, then R 2 is not H or ethyl.
- (a) applies. In some embodiments, (b) applies. In some embodiments, (c) applies. In some embodiments, (d) applies. In some embodiments, (e) applies. In some embodiments, (a) and (b) apply. In some embodiments, (a) and (c) apply. In some embodiments, (a) and (d) apply. In some embodiments, (a) and (e) apply. In some embodiments, (b) and (c) apply. In some embodiments, (b) and (d) apply. In some embodiments, (b) and (e) apply. In some embodiments, (c) and (d) apply. In some embodiments, (c) and (e) apply. In some embodiments, (d) and (e) apply.
- (a) , (b) , and (c) apply. In some embodiments, (a) , (b) , and (d) apply. In some embodiments, (a) , (b) , and (e) apply. In some embodiments, (a) , (c) , and (d) apply. In some embodiments, (a) , (c) , and (e) apply. In some embodiments, (a) , (d) , and (e) apply. In some embodiments, (b) , (c) , and (d) apply. In some embodiments, (b) , (c) , and (e) apply. In some embodiments, (b) , (d) , and (e) apply. In some embodiments, (b) , (d) , and (e) apply.
- (c) , (d) , and (e) apply. In some embodiments, (a) , (b) , (c) , and (d) apply. In some embodiments, (a) , (b) , (c) , and (e) apply. In some embodiments, (a) , (c) , (d) , and (e) apply. In some embodiments, (b) , (c) , (d) , and (e) apply. In some embodiments, (a) , (b) , (c) , (d) , and (e) apply.
- the compound of formula (I’) is of formula (II’) ,
- R 1a is methyl or ethyl, each of which is substituted by 0-3 halo;
- R 1b is hydrogen or halo
- R 1c is C 2 -C 4 alkyl or C 2 -C 4 haloalkyl.
- the compound of formula (I) is of formula (II) ,
- R 1a is methyl or ethyl, each of which is substituted by 0-3 halo;
- R 1b is hydrogen or halo
- R 1c is C 2 -C 4 alkyl or C 2 -C 4 haloalkyl.
- the compound of formula (II’) is of formula (II’-a) ,
- the compound of formula (II) is of formula (II-a) ,
- the compound of formula (II’) is of formula (II’-b) ,
- the compound of formula (II) is of formula (II-b) ,
- the compound of formula (I’) is of formula (I’-a) ,
- the compound of formula (I’) is of formula (I’-b) ,
- the compound of formula (I’) is a compound of formula (II’-c) ,
- R 2 is C 1 -C 6 alkyl. In some embodiments, R 2 is -CH 3 . In some embodiments, R 2 is -CD 3 . In some embodiments, R 2 is -CH 2 CH 3 . In some embodiments, R 2 is C 1 -C 6 haloalkyl. In some embodiments, R 2 is -CH 2 F, -CF 3 , -CH 2 CH 2 F, -CH 2 CH 2 CH 2 F, or -CH 2 CF 3 . In some embodiments, R 2 is -CF 3 or -CH 2 CF 3 .
- n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 1 and R 3 is halo (e.g., fluoro) . In some embodiments, n is 2 and both R 3 are halo (e.g., fluoro) . In some embodiments, R 4 is H.
- the compound of formula (I) is a compound of formula (II-c) ,
- R 2 is C 1 -C 6 alkyl. In some embodiments, R 2 is -CH 3 . In some embodiments, R 2 is -CD 3 . In some embodiments, R 2 is -CH 2 CH 3 . In some embodiments, R 2 is C 1 -C 6 haloalkyl. In some embodiments, R 2 is -CH 2 F, -CF 3 , -CH 2 CH 2 F, -CH 2 CH 2 CH 2 F, or -CH 2 CF 3 . In some embodiments, R 2 is -CF 3 or -CH 2 CF 3 .
- n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 1 and R 3 is halo (e.g., fluoro) . In some embodiments, n is 2 and both R 3 are halo (e.g., fluoro) .
- the compound of formula (I’) is a compound of formula (II’-d) ,
- R 1 is C 1 -C 6 alkyl. In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is C 1 -C 6 haloalkyl. In some embodiments, R 1 is In some embodiments, R 2 is C 1 -C 6 alkyl. In some embodiments, R 2 is -CH 3 . In some embodiments, R 2 is -CD 3 . In some embodiments, R 2 is -CH 2 CH 3 . In some embodiments, R 2 is C 1 -C 6 haloalkyl.
- R 2 is -CH 2 F, -CF 3 , -CH 2 CH 2 F, -CH 2 CH 2 CH 2 F, or -CH 2 CF 3 . In some embodiments, R 2 is -CF 3 or -CH 2 CF 3 . In some embodiments, R 4 is H.
- the compound of formula (I) is a compound of formula (II-d) ,
- R 1 is C 1 -C 6 alkyl. In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is C 1 -C 6 haloalkyl. In some embodiments, R 1 is In some embodiments, R 2 is C 1 -C 6 alkyl. In some embodiments, R 2 is -CH 3 . In some embodiments, R 2 is -CD 3 . In some embodiments, R 2 is -CH 2 CH 3 . In some embodiments, R 2 is C 1 -C 6 haloalkyl.
- R 2 is -CH 2 F, -CF 3 , -CH 2 CH 2 F, -CH 2 CH 2 CH 2 F, or -CH 2 CF 3 . In some embodiments, R 2 is -CF 3 or -CH 2 CF 3 .
- the compound of formula (I’) is a compound of formula (II’-e) ,
- the compound of formula (I’) is a compound of (II’-f) ,
- R 1 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of the compound of formula (I) , R 1 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments, R 1 is C 1 -C 6 alkyl. In some embodiments, R 1 is C 1 -C 4 alkyl.
- R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In some embodiments, R 1 is n-butyl, sec-butyl, isobutyl, or tert-butyl. In some embodiments, R 1 is sec-butyl. In some embodiments, R 1 is
- R 1 is C 1 -C 6 haloalkyl. In some embodiments of the compound of formula (I) , R 1 is C 1 -C 6 haloalkyl. In some embodiments, R 1 is C 1 -C 6 haloalkyl containing 1-7 halogen atoms. In some embodiments, R 1 is C 1 -C 4 haloalkyl. In some embodiments, R 1 is C 1 -C 4 haloalkyl containing 1-5 halogen atoms.
- R 1 is C 1 -C 4 haloalkyl containing 1-3 halogen atoms. In some embodiments, R 1 is C 4 haloalkyl containing 1-3 halogen atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of F, Cl, and Br. In some embodiments, the halogen atoms are independently selected from the group consisting of F and Cl. In some embodiments, the halogen atoms are all F. In some embodiments, the halogen atoms are all Cl. In some embodiments, the halogen atoms are a combination of F and Cl.
- R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is C 4 -C 12 cycloalkyl optionally substituted by halo, -OH, or C 1 -C 6 alkoxy. In some embodiments, R 1 is C 4 -C 12 cycloalkyl. In some embodiments, R 1 is cyclobutyl. In some embodiments, R 1 is 3-12 membered heterocyclyl optionally substituted by halo, -OH, or C 1 -C 6 alkoxy. In some embodiments, R 1 is 3-12 membered heterocyclyl. In some embodiments, R 1 is oxetanyl. In some embodiments, R 1 is cyclobutyl, or
- R 1 is wherein: R 1a is methyl or ethyl, each of which is substituted by 0-3 halo; R 1b is hydrogen or halo; and R 1c is C 2 -C 4 alkyl or C 2 -C 4 haloalkyl. In some embodiments of the compound of formula (I) , R 1 is wherein:
- R 1a is methyl or ethyl, each of which is substituted by 0-3 halo; R 1b is hydrogen or halo; and R 1c is C 2 -C 4 alkyl or C 2 -C 4 haloalkyl. In some embodiments, R 1 is In some embodiments, R 1 is
- n is an integer from 0-4. In some embodiments of the compound of formula (I) , (II) , (II-a) , or (II-b) , n is an integer from 0-4. In some embodiments of the compound of formula (I) , (II) , (II-a) , or (II-b) , n is an integer from 0-4. In some embodiments, n is 0-3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 1-4. In some embodiments, n is 2-4. In some embodiments, n is 1-3.
- each R 3 is independently halo, C 1 -C 6 alkyl, -CN, or -OH. In some embodiments of the compound of formula (I) , (II) , (II-a) , or (II-b) , each R 3 is independently halo, C 1 -C 6 alkyl, -CN, or -OH.
- each R 3 is independently halo. In some embodiments, each R 3 is independently F, Cl, Br, or I. In some embodiments, each R 3 is independently F or Cl. In some embodiments, R 3 is F. In some embodiments, R 3 is Cl. In some embodiments, R 3 is Br. In some embodiments, R 3 is I. In some embodiments, each R 3 is independently C 1 -C 6 alkyl. In some embodiments, each R 3 is independently C 1 -C 4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In some embodiments, R 3 is -CH 3 . In some embodiments, R 3 is -CN. In some embodiments, R 3 is -OH.
- R 2 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- R 2 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- R 2 is hydrogen. In some embodiments of the compound of formula (I) , (II’) , (II’-a) , or (II-b) , R 2 is hydrogen.
- R 2 is C 1 -C 6 alkyl. In some embodiments of the compound of formula (I) , (II) , (II-a) , or (II-b) , R 2 is C 1 -C 6 alkyl. In some embodiments, R 2 is C 1 -C 4 alkyl.
- R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In some embodiments, R 2 is methyl, ethyl, n-propyl, isopropyl, or sec-butyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is n-propyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is sec-butyl.
- R 2 is C 1 -C 6 haloalkyl. In some embodiments of the compound of formula (I) , (II) , (II-a) , or (II-b) , R 2 is C 1 -C 6 haloalkyl.
- R 2 is C 1 -C 6 haloalkyl containing 1-7 halogen atoms. In some embodiments, R 2 is C 1 -C 4 haloalkyl. In some embodiments, R 2 is C 1 -C 4 haloalkyl containing 1-5 halogen atoms. In some embodiments, R 2 is C 1 -C 4 haloalkyl containing 1-3 halogen atoms. In some embodiments, R 2 is C 1 haloalkyl. In some embodiments, R 2 is C 1 haloalkyl containing 1-3 halogen atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of F, Cl, and Br.
- the halogen atoms are independently selected from the group consisting of F and Cl. In some embodiments, the halogen atoms are all F. In some embodiments, the halogen atoms are all Cl. In some embodiments, the halogen atoms are a combination of F and Cl. In some embodiments, R 2 is –CH 2 F, -CHF 2 , -CF 3 , -CH 2 Cl, -CHCl 2 , -CCl 3 , -CHFCl, -CClF 2 , or –CCl 2 F. In some embodiments, R 2 is –CH 2 F.
- R 2 is –CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CHFCH 3 , -CF 2 CH 3 , -CH 2 CH 2 Cl, -CH 2 CHCl 2 , -CH 2 CCl 3 , -CHClCH 3 , or –CCl 2 CH 3 .
- R 2 is –CH 2 CF 3 .
- R 2 is –CH 2 F, -CF 3 , -CH 2 CH 2 F, -CH 2 CH 2 CH 2 F, or –CH 2 CF 3 .
- R 1 is –CH 3
- R 2 is C 5 -C 6 alkyl or C 1 -C 6 haloalkyl.
- R 1 is –CH 3
- R 2 is C 5 -C 6 alkyl or C 1 -C 6 haloalkyl.
- R 1 is –CH 3
- R 2 is C 5 -C 6 alkyl or C 1 -C 6 haloalkyl.
- R 1 is –CH 3
- R 2 is C 5 -C 6 alkyl.
- R 1 is –CH 3
- R 2 is pentyl.
- R 1 is –CH 3 , and R 2 is hexyl. In some embodiments, R 1 is –CH 3 , and R 2 is C 1 -C 6 haloalkyl. In some embodiments, R 1 is –CH 3 , and R 2 is C 1 -C 6 haloalkyl containing 1-7 halogen atoms. In some embodiments, R 1 is –CH 3 , and R 2 is C 1 -C 4 haloalkyl. In some embodiments, R 1 is –CH 3 , and R 2 is C 1 -C 4 haloalkyl containing 1-5 halogen atoms.
- R 1 is –CH 3
- R 2 is C 1 -C 4 haloalkyl containing 1-3 halogen atoms.
- R 1 is –CH 3
- R 2 is C 1 haloalkyl.
- R 1 is –CH 3
- R 2 is C 1 haloalkyl containing 1-3 halogen atoms.
- the halogen atoms are independently selected from the group consisting of F, Cl, and Br.
- the halogen atoms are independently selected from the group consisting of F and Cl.
- the halogen atoms are all F.
- the halogen atoms are all Cl.
- the halogen atoms are a combination of F and Cl.
- R 1 is –CH 3
- R 2 is –CH 2 F, -CHF 2 , -CF 3 , -CH 2 Cl, -CHCl 2 , -CCl 3 , -CHFCl, -CClF 2 , or –CCl 2 F.
- R 1a is methyl or ethyl, each of which is substituted by 0-3 halo. In some embodiments of the compound of formula (II) , (II-a) , or (II-b) , R 1a is methyl substituted by 0-3 halo. In some embodiments of the compound of formula (II) , (II-a) , or (II-b) , R 1a is ethyl substituted by 0-3 halo. In some embodiments, R 1a is –CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , or CF 3 . In some embodiments, R 1a is –CH 3 . In some embodiments, R 1a is -CH 2 CH 3 . In some embodiments, R 1a is –CH 2 F. In some embodiments, R 1a is –CF 3 . In some embodiments, R 1a is –CD 3 .
- R 1b is H or halo. In some embodiments of the compound of formula (II) , (II-a) , or (II-b) , R 1b is H or halo. In some embodiments, R 1b is H. In some embodiments, R 1b is F, Cl, Br, or I. In some embodiments, R 1b is F or Cl. In some embodiments, R 1b is F. In some embodiments, R 1b is Cl. In some embodiments, R 1b is Br. In some embodiments, R 1b is I.
- R 1c is C 2 -C 4 alkyl or C 2 -C 4 haloalkyl. In some embodiments of the compound of formula (II) , (II-a) , or (II-b) , R 1c is C 2 -C 4 alkyl or C 2 -C 4 haloalkyl. In some embodiments, R 1c is C 2 -C 4 alkyl. In some embodiments, R 1c is ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In some embodiments, R 1c is ethyl.
- R 1c is C 2 -C 4 haloalkyl. In some embodiments, R 1c is C 2 -C 4 haloalkyl containing 1-5 halogen atoms. In some embodiments, R 1c is C 2 -C 4 haloalkyl containing 1-3 halogen atoms. In some embodiments, R 1c is C 2 -C 3 haloalkyl. In some embodiments, R 1c is C 2 -C 3 haloalkyl containing 1-3 halogen atoms. In some embodiments, R 1c is C 2 haloalkyl. In some embodiments, R 1c is C 2 haloalkyl containing 1-3 halogen atoms.
- the halogen atoms are independently selected from the group consisting of F, Cl, and Br. In some embodiments, the halogen atoms are independently selected from the group consisting of F and Cl. In some embodiments, the halogen atoms are all F. In some embodiments, the halogen atoms are all Cl. In some embodiments, the halogen atoms are a combination of F and Cl.
- R 1c is –CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CHFCH 3 , -CF 2 CH 3 , -CH 2 CH 2 Cl, -CH 2 CHCl 2 , -CH 2 CCl 3 , -CHClCH 3 , or –CCl 2 CH 3 .
- R 1c is –CH 2 CH 2 F or –CH 2 CF 3 .
- R 1c is –CH 2 CH 2 F.
- R 1c is –CH 2 CF 3 .
- R 1a is –CH 3 , –CH 2 CH 3 , -CH 2 F, or –CF 3 ;
- R 1b is H or F;
- R 1c is —CH 2 CH 3 , -CH 2 CH 2 F, or –CH 2 CF 3 .
- R 1a is –CH 3 , –CH 2 CH 3 , -CH 2 F, or –CF 3 ;
- R 1b is H or F;
- R 1c is –CH 2 CH 3 , -CH 2 CH 2 F, or –CH 2 CF 3 .
- R 1a is –CH 3 ; R 1b is H or F; and R 1c is —CH 2 CH 3 , -CH 2 CH 2 F, or –CH 2 CF 3 .
- R 1a is –CH 2 CH 3 ; R 1b is H or F; and R 1c is –CH 2 CH 3 , -CH 2 CH 2 F, or –CH 2 CF 3 .
- R 1a is –CH 3 or –CH 2 CH 3 ; R 1b is H or F; and R 1c is –CH 2 CH 3 , -CH 2 CH 2 F, or –CH 2 CF 3 .
- R 1a is –CH 2 F; R 1b is H or F; and R 1c is —CH 2 CH 3 , -CH 2 CH 2 F, or –CH 2 CF 3 .
- R 1a is –CF 3 ;
- R 1b is H or F;
- R 1c is –CH 2 CH 3 , -CH 2 CH 2 F, or –CH 2 CF 3 .
- R 1a is –CH 3 , –CH 2 CH 3 , -CH 2 F, or –CF 3 ;
- R 1b is H; and R 1c is –CH 2 CH 3 , -CH 2 CH 2 F, or –CH 2 CF 3 .
- R 1a is –CH 3 , –CH 2 CH 3 , -CH 2 F, or –CF 3 ;
- R 1b is F;
- R 1c is —CH 2 CH 3 , -CH 2 CH 2 F, or –CH 2 CF 3 .
- R 1c is –CH 2 CH 3 ;
- R 1a is –CH 3 , –CH 2 CH 3 , -CH 2 F, or –CF 3 ;
- R 1b is H or F.
- R 1c is –CH 2 CH 2 F;
- R 1a is –CH 3 , –CH 2 CH 3 , -CH 2 F, or –CF 3 ;
- R 1b is H or F.
- R 1c is –CH 2 CF 3 ;
- R 1a is –CH 3 , –CH 2 CH 3 , -CH 2 F, or –CF 3 ; and
- R 1b is H or F.
- R 1 is sec-butyl and R 2 is ethyl.
- R 4 is hydrogen
- R 4 is hydrogen.
- R 4 is wherein R 5a is C 1 -C 8 alkyl, C 2 -C 20 alkenyl, - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , or C 6 -C 10 aryl. In some embodiments, R 5a is C 1 -C 8 alkyl.
- R 5a is methyl, ethyl, n-propyl, isopropyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments, R 5a is methyl, isopropyl, n-pentyl, or n-heptyl. In some embodiments, R 5a is C 2 -C 20 alkenyl. In some embodiments, R 5a is C 15 -C 20 alkenyl. In some embodiments, R 5a is C 17 alkenyl.
- R 5a is -(C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) . In some embodiments, R 5a is - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) . In some embodiments, R 5a is - (C 1 -C 2 alkylene) -O- (C 1 -C 2 alkylene) -O- (C 1 -C 2 alkyl) .
- R 5a is -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 3 . In some embodiments, R 5a is C 6 -C 10 aryl. In some embodiments, R 5a is phenyl.
- R 4 is wherein R 5b is C 1 -C 6 alkyl or - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) . In some embodiments, R 5b is C 1 -C 6 alkyl. In some embodiments, R 5b is C 1 -C 4 alkyl.
- R 5b is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In some embodiments, R 5b is isopropyl or tert-butyl. In some embodiments, R 5b is - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) . In some embodiments, R 5b is - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) .
- R 5b is -CH 2 -O-CH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 -O-CH (CH 3 ) 2 .
- R 5b is -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 -O-CH (CH 3 ) 2 .
- R 5b is -CH 2 CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 CH 2 -O-CH (CH 3 ) 2 . In some embodiments, R 5b is -CH 2 CH 2 -O-CH 3 .
- R 4 is wherein R 5c is C 1 -C 6 alkyl, - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , or - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) . In some embodiments, R 5c is C 1 -C 6 alkyl.
- R 5c is C 1 -C 4 alkyl. In some embodiments, R 5c is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In some embodiments, R 5c is ethyl, isopropyl, isobutyl, or tert-butyl. In some embodiments, R 5c is - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) . In some embodiments, R 5c is - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) .
- R 5c is -CH 2 -O-CH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 -O-CH (CH 3 ) 2 .
- R 5c is -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 -O-CH (CH 3 ) 2 .
- R 5c is -CH 2 CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 CH 2 -O-CH (CH 3 ) 2 .
- R 5c is -CH 2 CH 2 -O-CH 3 or -CH 2 CH 2 CH 2 -O-CH 3 .
- R 5c is - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) .
- R 5c is - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) .
- R 5c is -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 -O-CH 2 CH 2 -O-CH (CH 3 ) 2 .
- R 5c is -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 3 .
- R 4 is wherein R 5d is C 1 -C 6 alkyl, - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , or - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) . In some embodiments, R 5d is C 1 -C 6 alkyl.
- R 5d is C 1 -C 4 alkyl. In some embodiments, R 5d is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In some embodiments, R 5d is methyl, isopropyl, or tert-butyl. In some embodiments, R 5d is - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) . In some embodiments, R 5d is - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) .
- R 5d is -CH 2 -O-CH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 -O-CH (CH 3 ) 2 .
- R 5d is -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 -O-CH (CH 3 ) 2 .
- R 5d is -CH 2 CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 CH 2 -O-CH (CH 3 ) 2 .
- R 5d is -CH 2 CH 2 -O-CH 3 .
- R 5d is - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) .
- R 5d is - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) .
- R 5d is -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 -O-CH 2 CH 2 -O-CH (CH 3 ) 2 .
- R 5d is -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 3 .
- R 4 is wherein R 5e is C 1 -C 6 alkyl and R 5f is C 1 -C 6 alkyl, - (C 1 -C 6 alkylene) -OH, - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , or - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) .
- R 5e is C 1 -C 6 alkyl. In some embodiments, R 5e is C 1 -C 3 alkyl. In some embodiments, R 5e is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 5e is methyl. In some embodiments, R 5f is C 1 -C 6 alkyl. In some embodiments, R 5f is C 1 -C 3 alkyl. In some embodiments, R 5f is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 5f is ethyl.
- R 5f is - (C 1 -C 6 alkylene) -OH. In some embodiments, R 5f is - (C 1 -C 3 alkylene) -OH. In some embodiments, R 5f is -CH 2 -OH, -CH 2 CH 2 -OH, or -CH 2 CH 2 CH 2 -OH. In some embodiments, R 5f is -CH 2 CH 2 -OH. In some embodiments, R 5f is - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) . In some embodiments, R 5f is -(C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) .
- R 5f is -CH 2 -O-CH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 -O-CH (CH 3 ) 2 .
- R 5f is -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 -O-CH (CH 3 ) 2 .
- R 5f is -CH 2 CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 CH 2 -O-CH (CH 3 ) 2 .
- R 5f is -CH 2 CH 2 -O-CH 3 .
- R 5f is - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) .
- R 5f is - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) .
- R 5f is -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 2 -O- CH 2 CH 3 , -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 -O-CH 2 CH 2 -O-CH (CH 3 ) 2 .
- R 5f is -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 3 .
- R 5e is methyl and R 5f is ethyl, -CH 2 CH 2 -OH, -CH 2 CH 2 -O-CH 3 , or -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 3 .
- R 5e is methyl and R 5f is ethyl.
- R 5e is methyl and R 5f is -CH 2 CH 2 -OH.
- R 5e is methyl and R 5f is -CH 2 CH 2 -O-CH 3 .
- R 5e is methyl and R 5f is -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 3 .
- R 4 is wherein R 5g and R 5h are independently C 1 -C 6 alkyl, - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , or -O- (C 1 -C 6 alkyl) , or R 5g and R 5h are taken together with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, and wherein the 4-to
- R 4 is wherein R 5g and R 5h are independently C 1 -C 6 alkyl, - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , or -O- (C 1 -C 6 alkyl) .
- R 5g and R 5h are independently C 1 -C 3 alkyl, - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) , - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) , or -O- (C 1 -C 3 alkyl) .
- the R 5g groups as specified below can be combined with any R 5h groups as specified below.
- R 5g is -CH 3 and R 5h is -OCH 3 .
- R 5g and R 5h are both -CH 3 .
- R 5g is C 1 -C 6 alkyl, - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , -(C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , or -O- (C 1 -C 6 alkyl) .
- R 5g is C 1 -C 6 alkyl.
- R 5g is C 1 -C 3 alkyl.
- R 5g is methyl, ethyl, n-propyl, or isopropyl.
- R 5g is methyl or ethyl. In some embodiments, R 5g is - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) . In some embodiments, R 5g is - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) .
- R 5g is -CH 2 -O-CH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 -O-CH 2 CH 2 CH 3 , -CH 2 -O-CH (CH 3 ) 2 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 2 CH 2 CH 3 , -CH 2 CH 2 -O-CH (CH 3 ) 2 , -CH 2 CH 2 CH 2 -O- CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 CH 2 -O-CH (CH 3 ) 2 .
- R 5g is -CH 2 CH 2 -O-CH 3 . In some embodiments, R 5g is - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) . In some embodiments, R 5g is - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) .
- R 5g is -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 -O-CH 2 CH 2 -O-CH (CH 3 ) 2 .
- R 5g is -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 3 .
- R 5g is -O- (C 1 -C 6 alkyl) .
- R 5g is -O- (C 1 -C 3 alkyl) .
- R 5g is -OCH 3 .
- R 5h is C 1 -C 6 alkyl, - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , or -O- (C 1 -C 6 alkyl) .
- R 5h is C 1 -C 6 alkyl.
- R 5h is C 1 -C 3 alkyl.
- R 5h is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 5h is methyl or ethyl. In some embodiments, R 5h is - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) . In some embodiments, R 5h is - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) .
- R 5h is -CH 2 -O-CH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 -O-CH 2 CH 2 CH 3 , -CH 2 -O-CH (CH 3 ) 2 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 2 CH 2 CH 3 , -CH 2 CH 2 -O-CH (CH 3 ) 2 , -CH 2 CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 CH 2 -O-CH (CH 3 ) 2 .
- R 5h is -CH 2 CH 2 -O-CH 3 . In some embodiments, R 5h is - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) . In some embodiments, R 5h is - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) .
- R 5h is -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 -O-CH 2 CH 2 -O-CH (CH 3 ) 2 .
- R 5h is -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 3 .
- R 5h is -O- (C 1 -C 6 alkyl) .
- R 5h is -O- (C 1 -C 3 alkyl) .
- R 5h is -OCH 3 .
- R 5g is C 1 -C 6 alkyl and R 5h is C 1 -C 6 alkyl, - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , or -O- (C 1 -C 6 alkyl) .
- R 5g is C 1 -C 3 alkyl and R 5h is C 1 -C 3 alkyl, - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) , - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) , or -O- (C 1 -C 3 alkyl) .
- R 5g is C 1 -C 3 alkyl (for example, methyl or ethyl) and R 5h is methyl, ethyl, -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 2 -O-CH 3 , or -OCH 3 .
- R 5g and R 5h are independently - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) .
- R 5g and R 5h are independently - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) .
- R 5g and R 5h are both -CH 2 CH 2 -O-CH 3 .
- R 4 is wherein R 5g and R 5h are taken together with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, and wherein the 4-to 10-membered heterocyclyl is optionally substituted by 1-5 groups independently selected from the group consisting of C 1 -C 6 alkyl, - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , or -O- (C 1 -C 6 alkyl) .
- R 5g and R 5h are taken together with the nitrogen atom to which they are attached to form a 4-to 6-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, and wherein the 4-to 6-membered heterocyclyl is optionally substituted by 1-2 groups independently selected from the group consisting of C 1 -C 3 alkyl, - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) , or -O- (C 1 -C 3 alkyl) .
- the 4-to 6-membered heterocyclyl is unsubstituted.
- the 4-to 6-membered heterocyclyl is optionally substituted by 1-2 groups independently selected from the group consisting of methyl, -CH 2 -O-CH 3 , or -OCH 3 .
- the 4-to 6-membered heterocyclyl contains 1 nitrogen atom.
- the 4-to 6-membered heterocyclyl contains 2 nitrogen atoms.
- the 4-to 6-membered heterocyclyl contains 1 nitrogen atom and 1 oxygen atom.
- the 4-to 6-membered heterocyclyl contains 1 nitrogen atom and 1 sulfur atom.
- the 4-to 6-membered heterocyclyl is pyrrolidinyl, piperazinyl, or morpholinyl.
- R 4 is wherein R 5i and R 5j are independently C 1 -C 6 alkyl or - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , or R 5i and R 5j are taken together with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, and wherein the 4-to 10-membered heterocyclyl is optionally substituted by 1-5 groups independently selected from the group consisting of C 1 -C 6 alkyl, - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl)
- R 4 is wherein R 5i and R 5j are independently C 1 -C 6 alkyl or - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) . In some embodiments, R 5i and R 5j are independently C 1 -C 3 alkyl or - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) .
- R 5i groups as specified below can be combined with any R 5j groups as specified below.
- R 5i is -CH 3 and R 5j is -CH 2 CH 2 OCH 3 .
- R 5i and R 5j are both -CH 3 .
- R 5i is C 1 -C 6 alkyl or - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) .
- R 5i is C 1 -C 6 alkyl.
- R 5i is C 1 -C 3 alkyl.
- R 5i is methyl, ethyl, n-propyl, or isopropyl.
- R 5i is methyl. In some embodiments, R 5i is - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) . In some embodiments, R 5i is - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) .
- R 5i is -CH 2 -O-CH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 -O-CH 2 CH 2 CH 3 , -CH 2 -O-CH (CH 3 ) 2 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 2 CH 2 CH 3 , -CH 2 CH 2 -O-CH (CH 3 ) 2 , -CH 2 CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 3 , or -CH 2 CH 2 CH 2 -O-CH (CH 3 ) 2 .
- R 5i is -CH 2 CH 2 -O-CH 3 .
- R 5j is C 1 -C 6 alkyl or - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) .
- R 5j is C 1 -C 6 alkyl.
- R 5j is C 1 -C 3 alkyl.
- R 5j is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 5j is methyl.
- R 5j is - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) . In some embodiments, R 5j is - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) .
- R 5j is -CH 2 -O-CH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 -O-CH 2 CH 2 CH 3 , -CH 2 -O-CH (CH 3 ) 2 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 2 CH 2 CH 3 , -CH 2 CH 2 -O-CH (CH 3 ) 2 , -CH 2 CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 3 , or -CH 2 CH 2 CH 2 -O-CH (CH 3 ) 2 .
- R 5j is -CH 2 CH 2 -O-CH 3 .
- R 5i is C 1 -C 6 alkyl and R 5j is C 1 -C 6 alkyl.
- R 5i is C 1 -C 3 alkyl and R 5j is C 1 -C 3 alkyl.
- both R 5i and R 5j are -CH 3 .
- R 5i is C 1 -C 6 alkyl and R 5j is - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) .
- R 5i is C 1 -C 3 alkyl and R 5j is - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) .
- R 5i is -CH 3 and R 5j is -CH 2 CH 2 -O-CH 3 .
- R 5i is - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) and R 5j is - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) .
- R 5i is - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) and R 5j is - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) .
- both R 5i and R 5j are -CH 2 CH 2 -O-CH 3 .
- R 5i is C 1 -C 3 alkyl and R 5j is C 1 -C 3 alkyl or - (C 1 - C 3 alkylene) -O- (C 1 -C 3 alkyl) .
- R 5i is methyl and R 5j is methyl or -CH 2 CH 2 -O-CH 3 .
- R 5i is - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) and R 5j is C 1 -C 3 alkyl or - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) .
- R 5i is -CH 2 CH 2 -O-CH 3 and R 5j is methyl or -CH 2 CH 2 -O-CH 3 .
- R 4 is wherein R 5i and R 5j are taken together with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, and wherein the 4-to 10-membered heterocyclyl is optionally substituted by 1-5 groups independently selected from the group consisting of C 1 -C 6 alkyl, - (C 1 -C 6 alkylene) -O- (C 1 -C 6 alkyl) , or -O- (C 1 -C 6 alkyl) .
- R 5i and R 5j are taken together with the nitrogen atom to which they are attached to form a 4-to 6-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, and wherein the 4-to 6-membered heterocyclyl is optionally substituted by 1-2 groups independently selected from the group consisting of C 1 -C 3 alkyl, - (C 1 -C 3 alkylene) -O- (C 1 -C 3 alkyl) , or -O- (C 1 -C 3 alkyl) .
- the 4-to 6-membered heterocyclyl is unsubstituted.
- the 4-to 6-membered heterocyclyl contains 1 nitrogen atom. In some embodiments, the 4-to 6-membered heterocyclyl contains 2 nitrogen atoms. In some embodiments, the 4-to 6-membered heterocyclyl contains 1 nitrogen atom and 1 oxygen atom. In some embodiments, the 4-to 6-membered heterocyclyl contains 1 nitrogen atom and 1 sulfur atom. In some embodiments, the 4-to 6-membered heterocyclyl is morpholinyl.
- R 4 is
- R 4 is In some embodiments of the compound of formula (I’) , (II’) , (II’-a) , (II’-b) , (I’-a) , (I’-b) , (II’-c) , or (II’-d) , R 4 is In some embodiments, the compound of formula (I’) , (II’) , (II’-a) , (II’-b) , (I’-a) , (I’-b) , (II’-c) , or (II’-d) is a prodrug and R 4 is In some embodiments, the prodrug is an ester derivative and R 4 is In some embodiments, the prodrug is an alkyloxycarbonyl derivative and R 4 is In some embodiments, the prodrug is a carbamate derivative and R 4 is In some embodiments, the prodrug is an acyloxymethyl derivative and R 4 is In some embodiments, the prod
- R 4 is
- every description, variation, embodiment or aspect provided herein with respect to R 2 of formula (I’) may be combined with every description, variation, embodiment or aspect of R 1 , R 1a , R 1b , R 1c , R 3 , R 4 , R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , R 5h , R 5i , R 5j , and/or n the same as if each and every combination were specifically and individually listed.
- tautomeric forms may be present for any of the compounds described herein, each and every tautomeric form is intended even though only one or some of the tautomeric forms may be explicitly depicted.
- the tautomeric forms specifically depicted may or may not be the predominant forms in solution or when used according to the methods described herein.
- the compound detailed herein is selected from the group consisting of:
- salts of compounds disclosed herein such as pharmaceutically acceptable salts.
- the present disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of the compounds described.
- a particular stereochemical form such as a specific enantiomeric form or diastereomeric form
- any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of that same compound are herein described.
- tautomeric forms may be present for any of the compounds described herein, each and every tautomeric form is intended even though only one or some of the tautomeric forms may be explicitly depicted.
- the tautomeric forms specifically depicted may or may not be the predominant forms in solution or when used according to the methods described herein.
- the disclosure also intends isotopically-labeled and/or isotopically-enriched forms of compounds described herein.
- the compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. These forms of compounds may also be referred to as an “isotopically enriched analog. ”
- the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (I’) or variations thereof described herein, where a fraction of one or more atoms are replaced by an isotope of the same element.
- the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (I) or variations thereof described herein, where a fraction of one or more atoms are replaced by an isotope of the same element.
- isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C 13 N, 15 O, 17 O, 32 P, 35 S, 18 F, 36 Cl.
- Certain isotope labeled compounds e.g. 3 H and 14 C are useful in compound or substrate tissue distribution studies.
- isotopically-labeled compounds described herein can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples substituting appropriate isotopically-labeled reagents in place of the corresponding non-labeled reagent.
- the disclosure also includes any or all metabolites of any of the compounds described.
- the metabolites may include any chemical species generated by a biotransformation of any of the compounds described, such as intermediates and products of metabolism of the compound, such as would be generated in vivo following administration to a human.
- Solvates of a compound provided herein or a salt thereof are also contemplated. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
- compositions comprising a compound as detailed herein are provided, such as compositions of substantially pure compounds.
- a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
- substantially pure intends a composition that contains no more than 35%impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof.
- a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25%, 20%, 15%, 10%, or 5%impurity.
- a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3%, 2%, 1%or 0.5%impurity.
- One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art.
- a pharmacologically acceptable carrier which are known in the art.
- the carrier may be in various forms.
- the manufacture of a medicament is for use in any of the methods disclosed herein.
- compositions of any of the compounds detailed herein are embraced by this disclosure.
- the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein, or an isotopically enriched form, stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier or excipient.
- the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid.
- Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
- disclosed herein is a pharmaceutical composition comprising a prodrug.
- compositions comprising a compound in purified forms are detailed herein.
- Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds.
- a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
- the compounds herein are synthetic compounds prepared for administration to an individual.
- compositions are provided containing a compound in substantially pure form.
- the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier.
- methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
- a compound detailed herein, or an isotopically enriched form, stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt of any of the foregoing, may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal) , parenteral (e.g., intramuscular, subcutaneous or intravenous) , topical or transdermal delivery form.
- oral, mucosal e.g., nasal, sublingual, vaginal, buccal or rectal
- parenteral e.g., intramuscular, subcutaneous or intravenous
- topical or transdermal delivery form e.g., topical or transdermal delivery form.
- a compound disclosed herein may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules) , cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices) , pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers) , gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions) , solutions and elixirs.
- a compound detailed herein is formulated for oral or topical use.
- a compound detailed herein is formulated for oral use.
- a compound detailed herein is formulated for topical use.
- a compound detailed herein, or an isotopically enriched form, stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt of any of the foregoing can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a salt thereof, as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above.
- a pharmaceutically acceptable carrier such as those mentioned above.
- the carrier may be in various forms.
- pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
- Formulations comprising the compound may also contain other substances which have valuable therapeutic properties.
- Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20 th ed. (2000) , which is incorporated herein by reference.
- a compound detailed herein, or an isotopically enriched form, stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt of any of the foregoing may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions.
- examples of carriers, which may be used for the preparation of such compositions are lactose, corn starch or its derivatives, talc, stearate or its salts, etc.
- Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid polyols, and so on.
- pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
- any of the compounds described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein or a salt thereof can be formulated as a 10 mg tablet.
- the prodrugs described herein will, upon oral administration, deliver the parent molecule providing a curve of concentration of the parent molecule in plasma over time, the curve having an area under the curve (AUC) at least the same or larger than would be obtained by administering an equivalent dose of the parent drug molecule.
- the prodrug optimizes the physicochemical and pharmacological properties of the parent drug molecule to improve its solubility and/or pharmacokinetic features, and enables the delivery of the active molecule at efficacious levels.
- the prodrug promote solubility, permeability and/or oral absorption.
- the prodrug leads to enhanced skin permeation for transdermal delivery (David D. N’Da, Molecules, 19, 20780-20807, 2014) .
- Prodrugs of the phenolic hydroxyl group have been described in the literature (e.g. Férriz JM, et al.; Current Pharmaceutical Design, 2010, 16, 2033-2052) .
- Compounds and compositions detailed herein such as a pharmaceutical composition containing a compound of any formula provided herein, or an isotopically enriched form, stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein.
- the compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays.
- provided herein is a method of treating a condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of the compound of formula (I’) or any related formula, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the condition is mediated by IgE-independent mast cell activation.
- a method of treating a condition in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the compound of formula (I) or any related formula, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the condition is mediated by IgE-independent mast cell activation.
- a compound or a composition disclosed herein for the preparation of a medicament for treating a condition mediated by IgE-independent mast cell activation.
- the mast cell activation is mediated by activation of MRGPRX2.
- the MRGPRX2 is human MRGPRX2 and the individual is a human.
- the condition is itch, an inflammatory disorder (e.g., asthma, irritable bowel syndrome, periodontitis, neurogenic inflammation, inflammatory pain, chronic idiopathic urticaria, atopic dermatitis, or rosacea) , or a drug or food anaphylaxis (e.g., drug anaphylaxis caused by a muscle relaxant, a fluoroquinolone antibiotic, a phenothiazine antipsychotic, or an opioid) .
- the condition is an inflammatory disorder.
- the condition is itch.
- the itch is associated with an inflammatory disorder such as chronic idiopathic urticaria, atopic dermatitis, or rosacea. In some embodiments, the itch is not mediated by histamine.
- the condition is a drug or food anaphylaxis. In some embodiments, the condition is a drug anaphylaxis. In some embodiments, the compound is administered topically or orally. In some embodiments, the method further comprises administering to the individual an additional therapeutic agent, wherein the additional therapeutic agent is an anti-histamine.
- a compound or a composition disclosed herein can be used to inhibit activity of MRGPRX2 in a cell or in an individual or patient in need thereof by administering an inhibiting amount of the compound or the composition to the cell, individual, or patient.
- a method of reversing or stopping the progression of MRGPRX2-mediated condition in an individual comprising administering to the individual a therapeutically effective amount of a compound or a composition disclosed herein.
- a compound disclosed herein does not inhibit Cytochrome P450 (CYP) such as CYP3A4.
- CYP Cytochrome P450
- a compound disclosed herein has an IC 50 for CYP3A4 of at least 10 ⁇ M, at least 15 ⁇ M, at least 20 ⁇ M, at least 25 ⁇ M, at least 30 ⁇ M, at least 35 ⁇ M, at least 40 ⁇ M, at least 45 ⁇ M, or at least 50 ⁇ M.
- a compound disclosed herein does not substantially inhibit CYP3A4 (e.g., less than 20%, 15%, 10%, 5%, or 1%inhibition) at 5 ⁇ M, 10 ⁇ M, 15 ⁇ M, 20 ⁇ M, 25 ⁇ M, 30 ⁇ M, 35 ⁇ M, 40 ⁇ M, 45 ⁇ M, or 50 ⁇ M.
- a compound disclosed herein does not cause CYP-mediated drug-drug interactions such as CYP3A4-mediated drug-drug interactions.
- a compound disclosed herein has a half-life of at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 1 hour, or at least 2 hours in human.
- the present disclosure further provides articles of manufacture comprising a compound described herein, a composition described herein, or one or more unit dosages described herein in suitable packaging.
- the article of manufacture is for use in any of the methods described herein.
- suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like.
- An article of manufacture may further be sterilized and/or sealed.
- kits for carrying out the methods of the present disclosure which comprises one or more compounds described herein or a composition comprising a compound described herein.
- the kits may employ any of the compounds disclosed herein.
- the kit employs a compound described herein or a salt thereof.
- the kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of any condition or described herein, for example for the treatment of cancer.
- Kits generally comprise suitable packaging.
- the kits may comprise one or more containers comprising any compound described herein.
- Each component if there is more than one component
- kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses.
- kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or an additional pharmaceutically active compound useful for a condition detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
- Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies) .
- kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component (s) of the methods of the present disclosure.
- the instructions included with the kit generally include information as to the components and their administration to an individual.
- the compounds of the present disclosure may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below) .
- the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.
- enantiomer of a compound may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers.
- diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High-Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
- Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
- Solvates of a compound provided herein or a salt thereof are also contemplated. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
- R a is a C 1 -C 6 alkyl group (e.g., ethyl) ;
- X is a leaving group (e.g., I) ;
- R 2’ is equivalent to R 2 except that R 2’ does not include hydrogen (i.e., R 2’ is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl) ; and
- R 1 , R 2 , R 3 , and n are as detailed herein.
- a diazoacetate of general formula 1a can be reacted with an aldehyde of general formula 1b in the presence of a Lewis acid, such as e.g., SnCl 2 or SnCl 4 to yield ⁇ -keto esters of general formula 1e.
- a Lewis acid such as e.g., SnCl 2 or SnCl 4
- an acid of general formula 1c can be reacted with malonic acid derivative 1d, which can be decarboxylated to yield ⁇ -keto esters of general formula 1e.
- Compound of general formula 1e can optionally be alkylated with compounds of general formula 1f to yield compound of general formula 1g. Condensation of compounds of general formula 1e or 1g with benzoimidazolamines of general formula 1h yields compounds of formula (I) .
- R 1 is C 1 -C 6 alkyl, C 4 -C 12 cycloalkyl, or 3-12 membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 4 -C 12 cycloalkyl, and 3-12 membered heterocyclyl are each independently optionally substituted by halo, -OH, or C 1 -C 6 alkoxy;
- R 2 is hydrogen, -CN, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl are each independently optionally substituted by halo, -OH, or C 1 -C 6 alkoxy;
- each R 3 is independently halo, C 1 -C 6 alkyl, -CN, or -OH;
- n is an integer from 0-4.
- Embodiment 2 The compound of embodiment 1, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
- R 1 is wherein:
- R 1a is methyl substituted by 0-3 halo
- R 1b is hydrogen or halo
- R 1c is C 2 -C 4 alkyl or C 2 -C 4 haloalkyl.
- Embodiment 3 The compound of embodiment 2, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 1 is
- Embodiment 4 The compound of embodiment 2 or 3, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 1a is methyl.
- Embodiment 5 The compound of embodiment 2 or 3, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 1a is methyl substituted by 1-3 halo.
- Embodiment 6 The compound of embodiment 5, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 1a is -CF 3 .
- Embodiment 7 The compound of any one of embodiments 2-6, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 1b is hydrogen.
- Embodiment 8 The compound of any one of embodiments 2-6, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 1b is halo.
- Embodiment 9 The compound of any one of embodiments 2-6, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 1b is F.
- Embodiment 10 The compound of any one of embodiments 2-9, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 1c is C 2 -C 4 alkyl.
- Embodiment 11 The compound of embodiment 10, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 1c is ethyl.
- Embodiment 12 The compound of any one of embodiments 2-9, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 1c is C 2 -C 4 haloalkyl.
- Embodiment 13 The compound of embodiment 12, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 1c is -CH 2 CF 3 or - CH 2 CH 2 F.
- Embodiment 14 The compound of embodiment 1, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclopropyl, cyclobutyl, or oxetanyl.
- Embodiment 15 The compound of any one of embodiments 1-14, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
- Embodiment 16 The compound of any one of embodiments 1-14, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1 -C 6 alkyl.
- Embodiment 17 The compound of embodiment 16, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl, ethyl, n-propyl, isopropyl, or sec-butyl.
- Embodiment 18 The compound of any one of embodiments 1-14, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1 -C 6 haloalkyl.
- Embodiment 19 The compound of embodiment 18, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 2 is -CH 2 F, -CF 3 , -CH 2 CH 2 F, -CH 2 CH 2 CH 2 F or -CH 2 CF 3 .
- Embodiment 20 The compound of any one of embodiments 1-19, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein n is 0.
- Embodiment 21 The compound of any one of embodiments 1-19, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein n is 1-4.
- Embodiment 22 The compound of embodiment 21, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently F, Cl, C 1 -C 3 alkyl, -CN, or -OH.
- Embodiment 23 A compound selected from the group consisting of
- Embodiment 24 A pharmaceutical composition comprising the compound of any one of embodiments 1-23, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
- Embodiment 25 A method of treating a condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of the compound of any one of embodiments 1-23, or an isotopically enriched form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the condition is mediated by IgE-independent mast cell activation, which is mediated by activation of MRGPRX2.
- Embodiment 26 The method of embodiment 25, wherein MRGPRX2 is human MRGPRX2.
- Embodiment 27 The method of embodiment 26, wherein the condition is itch, an inflammatory disorder (e.g., asthma, irritable bowel syndrome, periodontitis, neurogenic inflammation, inflammatory pain, chronic idiopathic urticaria, atopic dermatitis, or rosacea) , or a drug or food anaphylaxis (e.g., drug anaphylaxis caused by a muscle relaxant, a fluoroquinolone antibiotic, a phenothiazine antipsychotic, or an opioid) .
- an inflammatory disorder e.g., asthma, irritable bowel syndrome, periodontitis, neurogenic inflammation, inflammatory pain, chronic idiopathic urticaria, atopic dermatitis, or rosacea
- a drug or food anaphylaxis e.g., drug anaphylaxis caused by a muscle relaxant, a fluoroquinolone antibiotic, a phenothiazine antipsychotic,
- Embodiment 28 The method of embodiment 27, wherein the condition is itch.
- Embodiment 29 The method of any one of embodiments 25-28, wherein the compound does not cause CYP3A4-mediated drug-drug interactions.
- Embodiment 30 The method of any one of embodiments 25-29, wherein the compound is administered topically or orally.
- Embodiment 31 The method of any one of embodiments 25-30, further comprising administering to the individual an additional therapeutic agent, wherein the additional therapeutic agent is an anti-histamine.
- IP-1 myo-inositol 1-phosphate
- Step B To a solution of ethyl 4-methyl-3-oxopentanoate (700 mg, 4.0 mmol) in THF (10 mL) was added potassium tert-butoxide (455.8 mg, 4.0 mmol) at 0 °C. After 30 minutes, iodoethane (1.27 mg, 8.1 mmol) was added to the reaction mixture at 0 °C. The mixture was stirred for 16 h at 80 °C. After letting cool to rt, the mixture was filtered, and water (30 mL) was added to the filtrate. The resulting mixture was extracted with ethyl acetate (30 mL) .
- Step C A solution of 1H-benzo [d] imidazol-2-amine (532 mg, 4.0 mmol) and ethyl 2-ethyl-4-methyl-3-oxohexanoate (800 mg, 4.0 mmol) in DMF (10 mL) was stirred under nitrogen at 140 °C for 20 h. After letting cool to rt, water (30 mL) was added. The resulting mixture was extracted with ethyl acetate (30 mL) . The organic layers were dried over anhyd. sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by chromatography on silica gel (0-40%EA in PE) to afford the title compound as an off-white solid.
- Example S01, Step C The title compound was obtained as described in Example S01, Step C, using ethyl 4-methyl-3-oxohexanoate obtained in Example S01, Step A.
- Step A To a solution of diisopropylamine (3.46 g, 34 mmol) in THF (30 ml) was added a solution of n-BuLi (14.3 ml, 2.4 M in hexane) at -20°C under nitrogen atmosphere, followed by a solution of butanoic acid (1 g, 11.4 mmol) in THF (10 ml) . The mixture was stirred at -15 °C for 1.5 h. 1, 3-dimethylpropyleneurea (DMPU) (1.46 g, 11.4 mmol) was added dropwise over a period of 5 min. Then, the mixture was stirred at room temperature for 1 h and cooled again to -15 °C.
- DMPU 3-dimethylpropyleneurea
- Step B To solution of 2- (methyl-d3) butanoic acid (1 g, 9 mmol) in THF (10 mL) was added CDI (1.85 g, 11 mmol) at rt, and the mixture was stirred under N 2 for 1 h. Then potassium 3-methoxy-3-oxopropanoate (2.32 g, 14 mmol) and MgCl 2 (1.09 g, 11 mmol) were added to the above solution. The resulting mixture was stirred at rt overnight. The resulting mixture was quenched by addition of aqueous HCl (1.0 N) and extracted with EtOAc. The combined organic layers were dried over anhyd. Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. This resulted in 850 mg of methyl 4- (methyl-d3) -3-oxohexanoate as a light-yellow oil, which was used directly in the next step without further purification.
- Step C Potassium tert-butoxide (553.8 mg, 4.93 mmol) was added to a solution of methyl 4- (methyl-d3) -3-oxohexanoate (850 mg, 4.93 mmol) at 0 °C. After 30 minutes, iodomethane (1.40 g, 9.87 mmol) was added to the reaction mixture at 0 °C. The mixture was stirred for 16 h at 80 °C. After cooling to rt, the mixture was filtered, and water (30 mL) was added to the filtrate. The resulting mixture was extracted with ethyl acetate (30 mL) . The organic layers were dried over anhyd.
- Step D A solution of 1H-benzo [d] imidazol-2-amine (600 mg, 4.50 mmol) and methyl 2-methyl-4- (methyl-d3) -3-oxohexanoate (800 mg, 4.56 mmol) in DMF (10 mL) was stirred at 140 °C under nitrogen for 20 h. After the reaction mixture was cooled to rt, water (30 mL) was added to the filtrate. The resulting mixture was extracted with ethyl acetate (30 mL) . The organic layers were dried over anhyd. Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0 -40%EA /PE) to afford 60 mg of the title compound as a solid.
- Step A A solution of 1H-benzo [d] imidazol-2-amine (5 g, 37.6 mmol) and ethyl 4-methyl-3-oxohexanoate (6.47 g, 37.6 mmol) in DMF (10 mL) was stirred under nitrogen at 140 °C for 20 h. After the reaction mixture was cooled to RT, water (30 mL) was added to the mixture. The resulting mixture was extracted with ethyl acetate (30 mL) . The organic layers were dried over anhyd. sodium sulfate, filtered, and the filtrate was concentrated.
- Step B To a solution of 2- (sec-butyl) benzo [4, 5] imidazo [1, 2-a] pyrimidin-4 (10H) -one (3 g, 12.4 mmol) in AcOH (30 mL) was added iodine monochloride (2.42 g, 14.8 mmol) in DCM (10 mL) . The mixture was stirred for 16 h at rt. The mixture was concentrated, then MeOH (30 mL) was added. The resulting mixture was filtered, and the filter cake was collected.
- Step C To a solution of 2- (sec-butyl) -3-iodobenzo [4, 5] imidazo [1, 2-a] pyrimidin-4 (10H) -one (250 mg, 0.68mmol. ) in DMA (5 mL) , Zn powder (9 mg, 0.14 mmol. ) and Zn (CN) 2 (79 mg, 0.68 mmol. ) was added. Then Pd 2 (dba) 3 (70 mg, 0.068 mmol. ) and dppf [1, 1'-bis (diphenylphosphino) ferrocene, 39 mg, 0.068 mmol] were added. The reaction was stirred at 110 °C for 6h.
- Step A Potassium tert-butoxide (650 mg, 5.8 mmol) was added to a solution of ethyl 4-methyl-3-oxohexanoate (1 g, 5.8 mmol) at 0 °C. After 30 minutes, ( (2-iodoethoxy) methyl) benzene (2.28 g, 8.7 mmol) was added to the reaction mixture at 0 °C. The mixture was stirred for 16 h at 80 °C. After allowing to cool to rt, the mixture was filtered, and water (30 mL) was added to the filtrate. The resulting mixture was extracted with ethyl acetate (30 mL) .
- Step B A solution of 1H-benzo [d] imidazol-2-amine (500 mg, 1.71 mmol) and methyl 2- (2- (benzyloxy) ethyl) -4-methyl-3-oxohexanoate (227 mg, 1.71 mmol) in DMA (10 mL) was stirred under nitrogen at 140 °C for 20 h. After allowing to cool to rt, the mixture was filtered, and water (30 mL) was added to the filtrate. The resulting mixture was extracted with ethyl acetate (30 mL) . The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated.
- Step C A mixture of 3- (2- (benzyloxy) ethyl) -2- (sec-butyl) benzo [4, 5] imidazo [1, 2-a] pyrimidin-4 (10H) -one (200 mg, 0.532 mmol) and Pd/C (28.32 g, 0.266 mmol) in EA (10 mL) was stirred under an atmosphere of H 2 at rt for 16 h. The mixture was filtered, and the filtrate was concentrated.
- Step A To a solution of 2- (sec-butyl) -3- (2-hydroxyethyl) benzo [4, 5] imidazo [1, 2-a] pyrimidin-4 (10H) -one (120 mg, 0.420 mmol) and triethylamine (63.8 g, 0.630 mmol) in DCM (10 mL) at 0°C under Argon, was added methanesulfonyl chloride (52.9 g, 0.462 mmol) dropwise. The mixture was stirred for 1 h at 0 °C. Water (10 mL) was added and the resulting mixture was extracted with ethyl acetate (30 mL) .
- Step A To a solution of ethyl 4-methyl-3-oxopentanoate (1.5 g, 8.7 mmol; Example S01, Step A) in THF (10 mL) was added sodium hydride (349 mg, 8.7 mmol) at 0 °C. After 30 minutes, 2, 2, 2-trifluoroethyl trifluoromethanesulfonate (4.0 g, 17.4 mmol) was added to the reaction mixture at 0 °C. The mixture was stirred at 60 °C for 16 h. After cooling to RT, water (30 mL) was added. The resulting mixture was extracted with ethyl acetate (50 mL) two times.
- Step B A solution of 1H-benzo [d] imidazol-2-amine (262 mg, 1.97 mmol) and ethyl 4-methyl-3-oxo-2- (2, 2, 2-trifluoroethyl) hexanoate (500 mg, 1.97 mmol) in DMF (10 mL) was stirred under nitrogen at 140 °C for 20 h. After cooling to RT, water (30 mL) was added. The resulting mixture was extracted with ethyl acetate (30 mL) . The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was recrystallized from MeOH to afford (100 mg, 15.7) of the title compound as a yellow solid.
- the residue was purified by prep-HPLC (Column: Gemini-C18 150 x 21.2 mm, 5 um, mobile phase: gradient of (water, 0.1%TFA) /ACN from 70: 30 to 50: 50) to give the title compound as a solid.
- Step A To a solution of ethyl 4-methyl-3-oxopentanoate (200 mg, 1.2 mmol) in THF (10 mL) was added NaOH (48 mg, 1.2 mmol) at 0 °C. After 30 minutes, iodoethane (561.5 mg, 3.6 mmol) was added to the reaction mixture at 0 °C. The mixture was stirred for 16 h at 25 °C. Water (10 mL) was added and the mixture was extracted with ethyl acetate (15 mL) . The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated.
- Step B A solution of 1H-benzo [d] imidazol-2-amine (70 mg, 0.5 mmol) and ethyl 2- (cyclobutanecarbonyl) butanoate (100 mg, 0.5 mmol) in dioxane (5 mL) was stirred under nitrogen at 100 °C for 20 h. After cooling to RT, water (10 mL) was added. The resulting mixture was extracted with ethyl acetate (15 mL) . The organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was applied onto a silica gel column (0 -40%EA/PE) to afford (16 mg, 12%) of the title compound as a white solid.
- Example S17 The title compound was obtained in Example S17, Step B. Purification by chromatography on silica gel (0-10%EA/PE) gave the title compound as a light yellow solid.
- Step A To a solution of 2-methoxyethan-1-ol (760 mg, 10 mmol) and TEA (1 g, 10 mmol) in DCM (20 mL) was added triphosgene (1 g, 3.38 mmol) at 0 °C. The mixture was warmed to RT and stirred for 3 h. Then methylamine (620 mg, 20 mmol) was added, and the mixture was stirred overnight at rt and concentrated to afford 2-methoxyethyl methylcarbamate (500 mg, 38%) as yellow oil.
- Mass Spectrum (ESI) m/z 134 (M+1) .
- Step C To a solution of 2- (sec-butyl) -3-ethylbenzo [4, 5] imidazo [1, 2-a] pyrimidin-4-ol (97 mg, 0.36 mmol) , K 2 CO 3 (147 mg, 1.07 mmol) and KI (17 mg, 0.1 mmol) in DMF (20 mL) was added 2-methoxyethyl (chloromethyl) (methyl) carbamate (500 mg, 2.2 mmol) . The mixture was stirred at RT for overnight. The reaction was treated with water (20 mL) and extracted with ethyl acetate (50 mL x 2) .
- Examples S48 –S53 below were also prepared by procedures similar to the one described in Example S47, replacing acetyl chloride with the reagents shown in the table below.
- Chloromethyl 3- (2-methoxyethoxy) propanoate was prepared according to a procedure similar to the one described for chloromethyl 3-methoxypropanoate.
- Examples below were also prepared by procedures similar to the one described in Example S67, replacing 2- (sec-butyl) -3-ethylbenzo [4, 5] imidazo [1, 2-a] pyrimidin-4 (10H) -one with (S) -2- (sec-butyl) -3-ethylbenzo [4, 5] imidazo [1, 2-a] pyrimidin-4 (10H) -one and chloromethyl propionate with the reagents shown in the table below.
- Step B To a solution of 2-hydroxyethyl methylcarbamate (600 mg, 5.04 mmol) in DMF (10 mL) was added imidazole (1 g, 15.12 mmol) and TBDMSCl (989.4 mg, 6.55 mmol) at 25 °C. The mixture was stirred at room temperature for 24 h. The mixture was treated with DCM (50 mL) and washed with aqueous citric acid (20 mL) .
- Step C To a solution of 2- ( (tert-butyldimethylsilyl) oxy) ethyl methylcarbamate (1 g, 4.3 mmol) in TMSCl (5 mL) was added paraformaldehyde (219 mg, 7.31 mmol) at 25 °C. The mixture was refluxing with CaCl 2 in a drying tube on top of the water condenser for 2.5 hours. The mixture was treated with water (50 mL) and extracted with ethyl acetate (50 mL x 2) .
- Step D To a solution of 2- ( (tert-butyldimethylsilyl) oxy) ethyl (chloromethyl) (methyl) carbamate (300 mg, 1.07mmol) in DMF (10 mL) was added 2- (sec-butyl) -3-ethylbenzo [4, 5] imidazo [1, 2-a] pyrimidin-4-ol (97 mg, 0.36 mmol) , K 2 CO 3 (147 mg, 1.07 mmol) and KI (17 mg, 0.1 mmol) at 25 °C. The mixture was stirred at room temperature for 18 h.
- Example S86 was prepared by procedures similar to the ones described in Example S46, replacing 2-methoxyethan-1-ol in step A with ethanol.
- Example S87 was prepared by procedures similar to the ones described in Example S46, replacing 2-methoxyethan-1-ol in step A with 2- (2-methoxyethoxy) ethan-1-ol.
- Example S88 was prepared by procedures similar to the ones described for Example S63, replacing 2- (sec-butyl) -3-ethylbenzo [4, 5] imidazo [1, 2-a] pyrimidin-4 (10H) -one with (S) -2- (sec-butyl) -3-ethylbenzo [4, 5] imidazo [1, 2-a] pyrimidin-4 (10H) -one.
- a variety of assays can be used to evaluate inhibition of compounds for hMRGPRX2.
- Compounds of the present disclosure display inhibition of hMRGPRX2 in the following assays.
- HEK293 cells stably expressing human MAS-related G protein–coupled receptor X2 were used for this assay.
- Fluo-8 dye (CAS 1345980-40-6) is a fluorescent calcium binding dye used as an indicator of cellular calcium concentration.
- Cells expressing hMRGPRX2 are pre-loaded with Fluo-8 AM which can cross the cell membrane. Once inside the cell, the lipophilic blocking groups of Fluo-8 AM are cleaved by non-specific cell esterase, resulting in a negatively charged fluorescent dye that stays inside cells. Its fluorescence is greatly enhanced upon binding to calcium. When cells are stimulated with agonist compounds, the receptor signals through the release of intracellular calcium, which greatly increase the fluorescence of Fluo-8.
- HEK293 cells stably expressing hMRGPRX2 were plated at 10000 cells/well (20 ⁇ L/well) in a 384-well black plate (Corning #3712) and incubated overnight. The next day, media was removed and replaced with 20 ⁇ L/well of 1X Fluo-8 dye loading solution. Cells were incubated at 37°C for 30 minutes. Subsequently 5 ⁇ L/well of test compounds at 5X concentration were added and real time calcium signals were captured by FLIPR plate reader (Molecular Devices) . Cells were incubated at 37°C for another 30 minutes.
- the percent (%) inhibition at each concentration of a compound was calculated relative to the responses in the Max and Min control wells contained within each assay plate.
- the Max control wells contained cells only as 0%inhibition
- the Min control wells contained cells and MRGPRX2 agonist as 100%inhibition.
- the concentrations and percent inhibition values for a test compound were plotted and the concentration of the compound required to achieve 50%inhibition (IC 50 ) was determined with a four-parameter logistic dose response equation. Results for certain compounds are provided in Table B1 below.
- a means an IC 50 of ⁇ 10 nM
- b means an IC 50 of 10 ⁇ 100 nM
- c means an IC 50 of 100 ⁇ 1000 nM
- d means IC 50 of >1000 nM
- IP1 myo-Inositol 1 phosphate
- the principle is based on HTRF technology. Native IP1 produced by cells or unlabeled IP1 (standard curve) compete with d2-labeled IP1 (acceptor) for binding to anti-IP1-Cryptate (donor) .
- the specific signal i.e. energy transfer
- test compounds at 200X concentration were added to a 384-well assay plate (Corning #4512) .
- 10 ⁇ L/well of cells resuspended in HBSS were added.
- Cells were incubated with compounds at 37 °C for 15 minutes.
- 4 ⁇ L/well of hMRGPRX2 agonist at 3.5X concentration (Final concentration ⁇ EC 80 of hMRGPRX2 agonist) were added.
- Cells were incubated at 37°C for 2 hours.
- 3 ⁇ L/well of IP1-d2 was added followed by 3 ⁇ L/well of Anti-IP1-Cryptate.
- the assay plate was incubated at 25°C for 60 minutes.
- the HTRF signals were measured on an Envision plate reader (Perkin Elmer) .
- the percent (%) inhibition at each concentration of a compound was calculated relative to the responses in the Max and Min control wells contained within each assay plate.
- the Max control wells contained cells and MRGPRX2 agonist as 0%inhibition
- the Min control wells contained cells and MRGPRX2 agonist plus maximum concentration of reference antagonist as 100%inhibition.
- the concentrations and percent inhibition values for a test compound were plotted and the concentration of the compound required to achieve 50%inhibition (IC 50 ) was determined with a four-parameter logistic dose response equation. Results for certain compounds are provided in Table B2 below.
- a means an IC 50 of ⁇ 100 nM
- b means an IC 50 of 100 -1000 nM
- c means an IC 50 of >1000 nM
- the CYP3A4 isoform-specific substrate Midazolam was incubated with human liver microsomes at a single concentration or at a range of test compound concentrations (typically 0.1 –25 ⁇ M) . At the end of the incubation, the amount of parent compound remaining was monitored by LC-MS/MS at each of the test compound concentrations. Typical experiments for determining IC 50 values involved incubating the substrate at concentrations below its K M . The MS detection was performed by using a Sciex API 4000 Q trap instrument. Each tested compound was analyzed by reversed phase HPLC using a Kinetex 2.6u C18 column (3.0 mm X 30 mm, Phenomenex) . Mobile phase -solvent A: water with 0.1%formic acid, solvent B: acetonitrile with 0.1%formic acid. The amount of parent compound was determined on the basis of the peak area ratio (compound area to IS area) .
- IC 50 values for the compounds prepared according to Examples S02, S07, S36, and S37 were determined. Each of these compounds has an IC 50 >30 uM.
- These in vitro data are generally predictive of the potential for drug-drug interactions in vivo (see e.g.: Obach, R.S., et al. “The Utility of in Vitro Cytochrome P450 Inhibition Data in the Prediction of Drug-Drug Interactions” ; J. Pharmacol. Exp. Ther., 316, 336 -348, (2006) ) and suggest that these compounds are not likely to cause CYP3A4-mediated drug-drug interactions.
- a variety of assays can be used to evaluate the properties of the compounds such as solubility and as a predictive tool for the oral absorption of drug candidates and permeability across biorelevant membranes.
- the Caco-2 cell culture model is widely used during drug discovery and development as a predictive tool for the oral absorption of drug candidates (e.g. Y. Sambuy, et al., Cell Biol. Toxicol., 21, 1-26, 2005; S. Skolnik, et al., J. Pharm. Sci., 99, 3246-3265, 2010) .
- several models are available to predict the skin permeability of topical drugs (e.g. C. Alonso, et al., Eur. J. Pharm Sciences, 136, 104945, 2019; R. Neupane, et al., Pharmaceutics, 12, 152, 2020) .
- test compound and control compound were evaluated by LC-MS/MS analysis.
- the samples were analyzed and quantified against the standards of known concentration using LC coupled with mass spectral peak identification and quantitation. Solubility values of the test compound and control compound were calculated as follows:
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Abstract
L'invention concerne des composés qui sont des antagonistes de MRGPRX2 et sont utiles dans le traitement d'états associés à MRGPRX2. L'invention concerne également des compositions contenant les composés.
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Citations (4)
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WO2009050348A1 (fr) * | 2007-08-02 | 2009-04-23 | Sanofis-Aventis | Dérivés de λ/-hétéroaryl-carboxamides tricycliques, leur préparation et leur application en thérapeutique |
WO2017168137A1 (fr) * | 2016-03-29 | 2017-10-05 | Great Matter Pharma Ab | Pyrimidobenzimidazoles pour utilisation dans le traitement et la prévention de troubles neurodégénératifs |
WO2019181997A1 (fr) * | 2018-03-23 | 2019-09-26 | 保土谷化学工業株式会社 | Composé comprenant une structure cyclique de benzimidazole et élément électroluminescent organique |
US20210128561A1 (en) * | 2019-10-31 | 2021-05-06 | Rheinische-Friedrich-Wilhelms-Universität Bonn | MRGX Receptor Antagonists |
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WO2009050348A1 (fr) * | 2007-08-02 | 2009-04-23 | Sanofis-Aventis | Dérivés de λ/-hétéroaryl-carboxamides tricycliques, leur préparation et leur application en thérapeutique |
WO2017168137A1 (fr) * | 2016-03-29 | 2017-10-05 | Great Matter Pharma Ab | Pyrimidobenzimidazoles pour utilisation dans le traitement et la prévention de troubles neurodégénératifs |
WO2019181997A1 (fr) * | 2018-03-23 | 2019-09-26 | 保土谷化学工業株式会社 | Composé comprenant une structure cyclique de benzimidazole et élément électroluminescent organique |
US20210128561A1 (en) * | 2019-10-31 | 2021-05-06 | Rheinische-Friedrich-Wilhelms-Universität Bonn | MRGX Receptor Antagonists |
Non-Patent Citations (3)
Title |
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ASIYE MERIÇ, ARZU KARAYEL , ZERRIN INCESU, ARZU KARAYEL, SUHEYLA OZBEY : " Synthesis of Some 2,4-Di- and 2,3,4-Trisubstituted Benzimidazo<1,2-a>Pyrimidines and Evaluation of Their Cytotoxicities Towards F2408 and 5RP7 Cells", JOURNAL OF NEUROLOGY NEUROSURGERY & PSYCHIATRY., BMJ PUBLISHING GROUP, GB, vol. 57, no. 11, 1 January 2006 (2006-01-01), GB , pages 1090 - 1097, XP055934328, ISSN: 0022-3050, DOI: 10.1136/jnnp-2018-319267 * |
DATABASE REGISTRY STN; ANONYMOUS : "Pyrimido[1,2-a]benzimidazol-4-ol, 3-butyl-2-methyl-(CA INDEX NAME) ", XP055934376, retrieved from EXTERNAL * |
DATABASE Registry STN; ANONYMOUS : "-Pyrimido[1,2-a]benzimidazolesulfonic acid, 4-hydroxy-2-methyl-(CA INDEX NAME) ", XP055934366, retrieved from External * |
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