WO2023114977A1 - Antagonistes du récepteur s1pr4 et leurs procédés d'utilisation - Google Patents

Antagonistes du récepteur s1pr4 et leurs procédés d'utilisation Download PDF

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WO2023114977A1
WO2023114977A1 PCT/US2022/081762 US2022081762W WO2023114977A1 WO 2023114977 A1 WO2023114977 A1 WO 2023114977A1 US 2022081762 W US2022081762 W US 2022081762W WO 2023114977 A1 WO2023114977 A1 WO 2023114977A1
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alkyl
alkoxy
halo
optionally substituted
independent occurrences
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PCT/US2022/081762
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Andrew Cridland
Emanuela Gancia
Jamie Knight
George Hynd
Philip Jackson
Neil JENNINGS
Richard Bull
Thomas Allen MILLER
Jonathan Max Levenson
Lauren MARTENS
Kelley Cronin LARSON
Suzanne Bruhn
Barbara TATE
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Tiaki Therapeutics, Inc.
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Publication of WO2023114977A1 publication Critical patent/WO2023114977A1/fr

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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Definitions

  • Sphingosine 1-phosphate is a lysophospholipid mediator that evokes a variety of cellular responses by stimulation of five members of the endothelial cell differentiation gene (EDG) receptor family.
  • EDG endothelial cell differentiation gene
  • GPCRs G-protein coupled receptors
  • on stimulation propagate second messenger signals via activation of heterotrimeric G-protein alpha (Ga) subunits and beta-gamma ( ⁇ ) dimers.
  • GPCRs G-protein coupled receptors
  • this S1P-driven signaling results in cell survival, increased cell migration and, often, mitogenesis.
  • S1P has been demonstrated to induce many cellular processes, including those that result in platelet aggregation, cell proliferation, cell morphology, tumor-cell invasion, endothelial cell chemotaxis and angiogenesis.
  • S1P receptors are good targets for therapeutic applications such as wound healing, tumor growth inhibition, and autoimmune diseases.
  • Sphingosine-1-phosphate signals cells in part via a set of G protein- coupled receptors named S1P1, S1P2, S1P3, S1P4, and S1P5 (formerly EDG1, EDG5, EDG3, EDG6 and EDG8).
  • the EDG receptors are G-protein coupled receptors (GPCRs) and on stimulation propagate second messenger signals via activation of heterotrimeric G-protein alpha (G a ) subunits and beta-gamma (Gp 7 ) dimers. These receptors share 50-55% amino acid sequence identity and cluster with three other receptors (LPA1; LPA2, and LPA (formerly EDG2, EDG4 and EDG7) for the structurally related lysophosphatidic acid (LPA).
  • S1P type 4 receptors S1PR4 are expressed mainly in leukocytes, and specifically S1PR4 mediates immunosuppressive effects of S1P by inhibiting proliferation and secretion of effector cytokines, while enhancing secretion of the suppressive cytokine IL-10.
  • S1PR4 receptors make good drug targets because individual receptors are both tissue and response specific. Tissue specificity of the S1P4 receptors is desirable because development of an agonist or antagonist selective for one receptor localizes the cellular response to tissues containing that receptor, limiting unwanted side effects.
  • Microglia the resident CNS immune cells, are multifunctional and display robust plasticity of functional state. In the presence of chronic neuroinflammation, functional plasticity is significantly decreased thereby promoting cytotoxicity, as well as, loss of protective functions (Song and Colonna 2018). S1PR4 is expressed on cells of myeloid lineage, which includes microglia (Olesch, Ringel et al.2017).
  • S1PR4 The gene for S1PR4 is expressed specifically in microglia in the CNS and its expression is stable over time, as shown in Olesch, C., et al. (2017). "Beyond Immune Cell Migration: The Emerging Role of the Sphingosine-1-phosphate Receptor S1PR4 as a Modulator of Innate Immune Cell Activation.” Mediators Inflamm 2017: 6059203.
  • S1PR4 is a G-protein coupled receptor that is linked to Rho/ROCK signaling via G12/13 and Ras-ERK Mapk signaling through Gi. Signaling through G12/13 ultimately activates NF- ⁇ B-mediated transcription, resulting in production of pro-inflammatory cytokines (Olesch, Ringel et al.2017).
  • ring A is a 5-6 membered aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, wherein ring A is optionally substituted with one or more independent occurrences of halo, -OH, -CN, - N(R a ) 2 , -C 1 -C 6 alkyl, -C 1- C 6 alkoxy, or -C(O)-N(R a ) 2 , and wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b
  • R 1 is halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1-6 alkoxy, or -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1-6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ;
  • R 2 is halo, -OH, -CN, -N(R a ) 2 , -C 1 -
  • R 1 is halo, -OH, -CN, -N(R a ) 2 , - C 1 -C 6 alkyl, -C 1-6 alkoxy, or -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1-6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , or -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ;
  • R 2 is halo, -OH, -CN, -N(R a ) 2 , -C 1 -
  • R 1 is halo, -OH, -CN, -N(R a ) 2 , - C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , or -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ;
  • R 2 is halo, -OH, -CN, -N(R a ) 2 ,
  • ring A is a sulfur-containing 5- 10 membered heteroaryl, wherein ring A is optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1-6 alkoxy, and - C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, - N(R b ) 2 , -C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d
  • R 3 is H or -C 1 -C 6 alkyl
  • each of R 4 and R 5 is independently halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or - C(O)-N(R a ) 2
  • each -C 1 -C 6 alkyl and -C 1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , - C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ;
  • R 6 is halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl
  • ring B is a nitrogen-containing 5-10 membered heteroaryl, a nitrogen- containing 3-10 membered heterocyclyl, or phenyl, wherein ring B is optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(R a ) 2 , - C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo, - OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , -N(R b ) 2 C(O)R c , or -N(R b )S(O) 2 R d ; each
  • each of R 1 , R 2 , R 9 , R 10 , and R 11 is independently H, halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)- N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , - C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ;
  • R 3 is H or -
  • the compound is a compound as shown in Table 1, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable excipient.
  • a method of treating or preventing a neurological, neurodegenerative, or cognitive disorder e.g., a neurological, neurodegenerative, or cognitive disorder described herein, in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
  • a lysosomal storage disorder e.g., a lysosomal storage disorder described herein
  • a method of treating or preventing a lysosomal storage disorder comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
  • CMT Charcot-Marie-Tooth disease
  • Sjogren-Larsson syndrome Refsum disease
  • Krabbe disease Canavan disease
  • Alexander disease Friedreich's ataxia
  • Pelizaeus-Merzbacher disease Bassen- Kornzweig syndrome
  • MLD metachromatic leukodystrophy
  • Leber’s optic neuropathy and nerve damage due to pernicious anemia
  • a method of treating a lysosomal storage disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of compound described herein or a pharmaceutically acceptable salt thereof.
  • Activator deficiency Alpha-mannosidosis, AB variant, Aspartylglucosaminuria, Batten–Shmeyer– Vogt disease, Beta-galactosidase / GM1 gangliosidosis, Beta-mannosidosis, Chronic hexosaminidase A deficiency, cystinosis, CLN7 disease, Congenital cathepsin D deficiency, Cholesteryl ester storage disease, Cystinosis, Danon disease, Fabry disease, fucosidosis, I-cell disease, Krabbe disease, Farber disease, Finnish Variant, gangliosidosis, galactosialidosis,
  • the present disclosure provides compounds that can act as antagonists of the S1PR4 receptor and can be useful in the treatment of disorders including but not limited to those described herein.
  • Compounds [00021] Another feature of the present disclosure relates to compounds that act as antagonists of the S1PR4 receptor.
  • a compound of Formula X or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-6 membered aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, wherein ring A is optionally substituted with one or more independent occurrences of halo, -OH, -CN, - N(R a ) 2 , -C 1 -C 6 alkyl, -C 1- C 6 alkoxy, or -C(O)-N(R a ) 2 , and wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2
  • R 1 is halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1-6 alkoxy, or -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1-6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ;
  • R 2 is halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1-6 alkoxy, or -C(O)-N(R a
  • a compound of Formula II or a pharmaceutically acceptable salt thereof, wherein R 1 is halo, -OH, -CN, -N(R a ) 2 , - C 1 -C 6 alkyl, -C 1-6 alkoxy, or -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1-6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , or -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ; R 2 is halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1-6 alk
  • L 1 is [00026]
  • the compound is a compound of Formula I or Formula II is Formula II-a: [00027]
  • the compound is a compound of Formula I or Formula II is Formula II-b: [00028]
  • R 6 is 7 wherein each occurrence of R is independently H, halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , C(O)N(R b ) 2 , and -N(R b )C(O)R c , - N(R b )S(O) 2 R d , or 3-10 membered heterocyclyl optionally substituted with oxo, or two R 7 are joined together to form oxo; and R 8 is H, halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(
  • R 1 and R 2 is independently chloro, bromo, iodo, fluoro, -CN, -C 1 -C 6 alkyl, or -C 1 -C 6 alkoxy. In embodiments, R 1 and R 2 is independently chloro, bromo, iodo, or fluoro. In an embodiment, R 1 and R 2 are chloro.
  • ring B is , , , [00030] In some embodiments, ring B is , , , [00031] In some embodiments, ring B is , , , [ 00032] In an embodiment, R 6 is , , , , , , [ 00033] In an embodiment, R 6 is , , , , , , ,
  • R 1 is halo, -OH, -CN, -N(R a ) 2 , - C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , or -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ;
  • R 2 is halo, -OH, -CN, -N(R a ) 2 ,
  • the compound is a compound of Formula III-a, Formula III-b, or Formula III-c: wherein each of R 9 , R 10 , R 11 , and R 12 is independently H, halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1-6 alkoxy, and -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , or -N(R b ) 2 C(O)R c , and -N(R b )S(O) 2 R d .
  • each of R 9 , R 10 , R 11 , and R 12 is independently H or -C 1 -C 6 alkyl, wherein -C 1 -C 6 alkyl is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , or -N(R b ) 2 C(O)R c , and - N(R b )S(O) 2 R d .
  • the compound is a compound Formula III-d or Formula III-e: wherein each of R 17 and R 18 is independently H, halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1-6 alkoxy, and -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1-6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , - C(O)N(R b ) 2 , or -N(R b ) 2 C(O)R c , and -N(R b )S(O) 2 R d ; and R x is H, halo, -OH, -CN, -N(R a )
  • ring B is .
  • R 1 is chloro.
  • R 2 is chloro.
  • R 9 is -CH 3 .
  • R 11 is -CHF 2 .
  • R 12 is -CH 3 .
  • R 17 is -CH 3 .
  • R 18 is -CH 3 .
  • R x is -C 1 -C 6 alkyl substituted with -OH or -NH 2 .
  • ring A is a sulfur-containing 5- 10 membered heteroaryl, wherein ring A is optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1-6 alkoxy, and - C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, - N(R b ) 2 , -C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d
  • each of R 15 , R 16 , and R 17 is independently H, halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1-6 alkoxy, or -C(O)- N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , - C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ;
  • R 3 is H or -C 1 -C 6 alkyl
  • the ring B is .
  • R 15 , R 16 , and R 17 are H.
  • R 3 is H.
  • R 4 and R 5 are unsubstituted -C 1 -C 6 alkyl.
  • R 4 and R 5 are unsubstituted methyl.
  • R 6 is methyl substituted with hydroxyl.
  • the compound of Formula IV is Formula IV-B: or a pharmaceutically acceptable salt thereof, wherein each of R 15 and R 17 is independently H, halo, -OH, -CN, -N(R a )2, -C 1 -C 6 alkyl, -C 1-6 alkoxy, and -C(O)-N(R a )2, wherein each -C 1 - C 6 alkyl and -C 1 -C 6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , or -N(R b )C(O)R c , or - N(R b )S(O) 2 R d ; R 3 is H or -C 1 -C 6 alkyl; each of R 4 and R 5 is independently
  • R 3 is H or -C 1 -C 6 alkyl
  • each of R 4 and R 5 is independently halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or - C(O)-N(R a ) 2
  • each -C 1 -C 6 alkyl and -C 1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , - C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ;
  • R 6 is halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl
  • ring B is a nitrogen-containing 5-10 membered heteroaryl, a nitrogen- containing 3-10 membered heterocyclyl, or phenyl, wherein ring B is optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(R a ) 2 , - C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo, - OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , -N(R b ) 2 C(O)R c , or -N(R b )S(O) 2 R d ; each
  • ring B is .
  • ring E is N-linked piperidinyl.
  • ring E is N-linked pyrrolidinyl.
  • R 3 is H.
  • R 4 and R 5 are unsubstituted -C 1 -C 6 alkyl.
  • R 4 and R 5 are unsubstituted methyl.
  • R 6 is methyl substituted with hydroxyl.
  • each of R 1 , R 2 , R 9 , R 10 , and R 11 is independently H, halo, -OH, -CN, -N(R a )2, -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)- N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , - C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ;
  • R 3 is H or -C 1
  • ring B is .
  • R 3 is H.
  • R 4 and R 5 are unsubstituted -C 1 -C 6 alkyl.
  • R 4 and R 5 are unsubstituted methyl.
  • R 6 is methyl substituted with hydroxyl.
  • R 1 is H.
  • R 9 is H, chloro, fluoro, or -C 1 -C 6 alkyl, wherein the -C 1 - C 6 alkyl can be optionally substituted with one or more independent occurrences of halo.
  • R 9 is -CF 3 .
  • R 10 is H, -C 1 -C 6 alkyl, fluoro, or chloro.
  • R 2 is H, fluoro, or -C 1 -C 6 alkyl.
  • R 11 is H, chloro, fluoro, -C 1 -C 6 alkoxy, or -C 1 -C 6 alkyl, wherein the , -C 1 -C 6 alkoxy and -C 1 -C 6 alkyl can be optionally substituted with one or more independent occurrences of halo.
  • R 11 is -OCH 3 , -OCH 2 CH 3 , or - OCF 3 , .
  • R 11 is -CF 3 .
  • the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds.
  • compounds of Formula I, II, III, IV, V, VI, or subgenera thereof may also comprise one or more isotopic substitutions.
  • hydrogen may be 2 H (D or deuterium) or 3 H (T or tritium); carbon may be, for example, 13 C or 14 C; oxygen may be, for example, 18 O; nitrogen may be, for example, 15 N, and the like.
  • a particular isotope (e.g., 3 H, 13 C, 14 C, 18 O, or 15 N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.
  • Chemical Definitions [00062] Definitions of specific functional groups and chemical terms are described in more detail below.
  • analogue means one analogue or more than one analogue.
  • C 1–6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1–6 , C 1–5 , C 1–4 , C 1–3 , C 1–2 , C 2–6 , C 2–5 , C 2–4 , C 2–3 , C 3–6 , C 3–5 , C 3–4 , C 4–6 , C 4–5 , and C 5–6 alkyl.
  • the following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.
  • Alkyl refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C 1–20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C 1–12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1–7 alkyl”).
  • an alkyl group has 1 to 6 carbon atoms (“C 1–6 alkyl”, also referred to herein as “lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1– 5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”).
  • an alkyl group has 2 to 6 carbon atoms (“C 2–6 alkyl”).
  • C 1–6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), n–propyl (C 3 ), isopropyl (C 3 ), n–butyl (C 4 ), tert–butyl (C 4 ), sec–butyl (C 4 ), iso–butyl (C 4 ), n– pentyl (C 5 ), 3–pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3–methyl–2–butanyl (C 5 ), tertiary amyl (C 5 ), and n–hexyl (C 6 ).
  • alkyl groups include n–heptyl (C 7 ), n– octyl (C 8 ) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C 1–10 alkyl (e.g., –CH 3 ). In certain embodiments, the alkyl group is substituted C 1–10 alkyl.
  • Alkylene refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted.
  • Unsubstituted alkylene groups include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene (-CH 2 CH 2 CH 2 CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 - ), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -), and the like.
  • substituted alkylene groups e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (-CH(CH 3 )-, (-C(CH 3 ) 2 -), substituted ethylene (-CH(CH 3 )CH 2 -,- CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -,-CH 2 C(CH 3 ) 2 -), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, - CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, - CH 2 CH 2 C(CH 3 ) 2 -), and the like.
  • alkylene groups may be substituted or unsubstituted with one or more substituents as described herein.
  • Alkenyl refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds), and optionally one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds) (“C 2–20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds.
  • an alkenyl group has 2 to 10 carbon atoms (“C 2–10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2–8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2–7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2–6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2–5 alkenyl”).
  • an alkenyl group has 2 to 4 carbon atoms (“C 2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2–3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”).
  • the one or more carbon–carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1– butenyl).
  • Examples of C 2–4 alkenyl groups include ethenyl (C 2 ), 1–propenyl (C 3 ), 2–propenyl (C 3 ), 1–butenyl (C 4 ), 2–butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2–6 alkenyl groups include the aforementioned C 2–4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like.
  • alkenyl examples include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
  • each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkenyl group is unsubstituted C 2–10 alkenyl.
  • alkenyl group is substituted C 2–10 alkenyl.
  • Alkynyl refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds), and optionally one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds) (“C 2–20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C 2–10 alkynyl”).
  • an alkynyl group has 2 to 9 carbon atoms (“C 2–9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2–8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2–7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2–6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2–5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2–4 alkynyl”).
  • an alkynyl group has 2 to 3 carbon atoms (“C 2–3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 alkynyl”).
  • the one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl).
  • Examples of C 2–4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1–propynyl (C 3 ), 2–propynyl (C 3 ), 1–butynyl (C 4 ), 2–butynyl (C 4 ), and the like.
  • C 2–6 alkenyl groups include the aforementioned C 2–4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like.
  • each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkynyl group is unsubstituted C 2–10 alkynyl.
  • the alkynyl group is substituted C 2–10 alkynyl.
  • Aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6–14 aryl”).
  • an aryl group has six ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C 14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.
  • aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
  • each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
  • the aryl group is unsubstituted C 6–14 aryl.
  • the aryl group is substituted C6–14 aryl.
  • R 56 and R 57 may be hydrogen and at least one of R 56 and R 57 is each independently selected from C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C 1 -C 8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , NR 58 SOR 59 NR 58 SO 2 R 59 , COOalkyl, COOaryl, CONR 58 R 59 , CONR 58 OR 59 , NR 58 R 59 , SO 2 NR 58 R 59 , S-alkyl, SOalkyl, SO 2 alkyl, Saryl, SOaryl, SO 2 aryl; or R 56 and R 57 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to
  • R 60 and R 61 are independently hydrogen, C 1 -C 8 alkyl, C 1 -C 4 haloalkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, substituted C 6 -C 10 aryl, 5-10 membered heteroaryl, or substituted 5- 10 membered heteroaryl .
  • Heteroaryl refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5–10 membered heteroaryl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl).
  • a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”).
  • a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”).
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotri azolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadi azolyl, benzthiazolyl, benzisothiazolyl, benzthiadi azolyl, indolizinyl, and purinyl.
  • Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Examples of representative heteroaryls include the following: wherein each Z is selected from carbonyl, N, NR 65 , O, and S; and R 65 is independently hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, and 5-10 membered heteroaryl.
  • Carbocyclyl or “carbocyclic” refers to a radical of a non–aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C 3–10 carbocyclyl”) and zero heteroatoms in the non–aromatic ring system.
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3–8 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3–6 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3–6 carbocyclyl”).
  • a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5–10 carbocyclyl”).
  • Exemplary C 3–6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3–8 carbocyclyl groups include, without limitation, the aforementioned C 3–6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C8), and the like.
  • Exemplary C 3–10 carbocyclyl groups include, without limitation, the aforementioned C 3–8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro–1H–indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated.
  • “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is unsubstituted C 3–10 carbocyclyl.
  • the carbocyclyl group is a substituted C 3–10 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C 3–10 cycloalkyl”).
  • a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3–8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5–10 cycloalkyl”). Examples of C 5–6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
  • C 3–6 cycloalkyl groups include the aforementioned C 5–6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • Examples of C 3–8 cycloalkyl groups include the aforementioned C 3–6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is unsubstituted C 3–10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C 3–10 cycloalkyl.
  • “Heterocyclyl” or “heterocyclic” refers to a radical of a 3– to 10–membered non– aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3–10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is unsubstituted 3–10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3–10 membered heterocyclyl.
  • a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5–10 membered heterocyclyl”).
  • a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”).
  • a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”).
  • the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
  • Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl–2,5–dione.
  • Exemplary 5– membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6– membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C 6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • Nonrogen-containing heterocyclyl means a 4- to 7- membered non- aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g.2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N- methyl piperazine. Particular examples include azetidine, piperidone and piperazone.
  • Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g,. heteroaryl, cycloalkenyl, e.g,. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
  • alkyl e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g,. heteroaryl, cycloalkenyl, e.g,. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
  • Alkoxy refers to the group –OR 29 where R 29 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n- hexoxy, and 1,2-dimethylbutoxy.
  • R 29 is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C 6 -C 10 aryl, aryloxy, carboxyl, cyano, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl–S(O)-, alkyl–S(O) 2 - and aryl-S(O) 2 -.
  • substituents for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C 6 -C 10 aryl, aryloxy, carboxyl, cyano, C 3 -
  • Exemplary ‘substituted alkoxy’ groups include, but are not limited to, –O-(CH 2 ) t (C 6 -C 10 aryl), –O-(CH 2 ) t (5-10 membered heteroaryl), –O-(CH 2 ) t (C 3 -C 10 cycloalkyl), and –O-(CH 2 ) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 - C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • Particular exemplary ‘substituted alkoxy’ groups are -OCF 3 , -OCH 2 CF 3 , -OCH 2 Ph, -OCH 2 -cyclopropyl, -OCH 2 CH 2 OH, and -OCH 2 CH 2 NMe 2 .
  • “Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.
  • Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group).
  • substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
  • the present invention contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group).
  • Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), 2–methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), t–butyldimethylsilyl (TBDMS), t–butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), and tosylate (Ts).
  • MOM methoxylmethyl
  • MEM 2–methoxyethoxymethyl
  • Bn benzyl
  • TIPS triisopropylsilyl
  • TDMS t–butyldimethylsilyl
  • TMPS t
  • the substituent present on an sulfur atom is an sulfur protecting group (also referred to as a thiol protecting group).
  • the substituent present on a nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group).
  • Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • compositions comprising a compound described herein (e.g., a compound of Formula (I) or Formula (II)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the compound of the present invention is provided in an effective amount in the pharmaceutical composition.
  • the compound of the present invention is provided in a therapeutically effective amount.
  • the compound of the present invention is provided in a prophylactically effective amount.
  • the pharmaceutical composition comprises an effective amount of the active ingredient.
  • the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient.
  • the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.
  • the pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.
  • the compounds provided herein are administered in an effective amount.
  • the amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.
  • the compounds provided herein When used to prevent the onset of a neurological-disorder, the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Subjects at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • the pharmaceutical compositions provided herein can also be administered chronically (“chronic administration”).
  • Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc, or may be continued indefinitely, for example, for the rest of the subject’s life.
  • the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.
  • the pharmaceutical compositions of the present invention may be further delivered using a variety of dosing methods.
  • the pharmaceutical composition may be given as a bolus, e.g., in order to raise the concentration of the compound in the blood to an effective level.
  • the placement of the bolus dose depends on the systemic levels of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingredient, while a bolus delivered directly to the veins (e.g., through an IV drip) allows a much faster delivery which quickly raises the concentration of the active ingredient in the blood to an effective level.
  • the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV drip, to provide maintenance of a steady-state concentration of the active ingredient in the subject’s body.
  • the pharmaceutical composition may be administered as first as a bolus dose, followed by continuous infusion.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.
  • a minor component from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight
  • the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.
  • each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses, generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • Injection dose levels range from about 0.1 mg/kg/hour to at least 20 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 5 g/day for a 40 to 80 kg human patient.
  • Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art.
  • the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable excipient and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s).
  • the active ingredients When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.
  • transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • the acid which may be used to prepare the pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, e.g., a composition suitable for injection, such as for intravenous (IV) administration.
  • compositions agents include any and all diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, preservatives, lubricants and the like, as suited to the particular dosage form desired, e.g., injection.
  • General considerations in the formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21 st Edition (Lippincott Williams & Wilkins, 2005).
  • injectable preparations such as sterile injectable aqueous suspensions
  • suitable dispersing or wetting agents and suspending agents include, but are not limited to, water, sterile saline or phosphate–buffered saline, or Ringer's solution.
  • the injectable composition can be sterilized, for example, by filtration through a bacterial–retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the compounds provided herein are administered in an effective amount.
  • the amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, response of the individual patient, the severity of the patient’s symptoms, and the like.
  • the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include pre–filled, pre– measured ampules or syringes of the liquid compositions.
  • kits comprising a composition (e.g., a solid composition) comprising a compound of Formula I, II, III, IV, V, VI, or subgenera thereof.
  • composition e.g., a solid composition
  • Pharmaceutical Composition Definitions “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non–toxic may be inorganic or organic acid addition salts and base addition salts.
  • 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, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, formic acid, tartaric acid, citric acid, benzoic acid, 3–(4–hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2–ethane–disulfonic acid, 2– hydroxyethanesulfonic acid, benzenesulfonic acid, 4
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, formate, oxalate and the like.
  • pharmaceutically acceptable cation refers to an acceptable cationic counter–ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J.
  • a neurological, neurodegenerative, or cognitive disorder e.g., a neurological, neurodegenerative, or cognitive disorder described herein, in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
  • a lysosomal storage disorder e.g., a lysosomal storage disorder described herein
  • a method of treating or preventing a lysosomal storage disorder comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.
  • a method of preventing a neurological, neurodegenerative, or cognitive disorder comprising administering to the subject a prophylactically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof
  • a method of treating a neurological, neurodegenerative, or cognitive disorder e.g., a neurological, neurodegenerative, or cognitive disorder described herein, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
  • a lysosomal storage disorder e.g., a lysosomal storage disorder described herein
  • a method of treating a lysosomal storage disorder comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.
  • exemplary disorders that can be treated by the compounds described herein include but are not limited to: Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Huntington's disease, lysosomal storage diseases including Gaucher, spinocerebellar ataxias (e.g., SCA1, SCA2, SCA3, SCA6, SCAT, and SCA17), spinobulbar muscular atrophy (SBMA) or Kennedy disease, dentatorubropallidoluysian atrophy (DRPLA), ALS, AIDS dementia, frontotemporal dementia, corticobasal ganglionic degeneration, progressive supranuclear palsy, Creutzfeldt-Jakob disease, Gerstmann- St Hurssler-Scheinker syndrome, fatal familial insomnia, corticobasal ganglionic degeneration, hereditary spas
  • CMT Charcot-Marie-Tooth disease
  • Sjogren-Larsson syndrome Refsum disease
  • Krabbe disease Canavan disease
  • Alexander disease Friedreich's ataxia
  • Pelizaeus-Merzbacher disease Bassen-Kornzweig syndrome
  • MLD metachromatic leukodystrophy
  • Leber’s optic neuropathy and nerve damage due to pernicious anemia
  • Exemplary disorders that can be treated by the methods described herein include lysosomal storage diseases and related disorders. Accordingly, in some embodiments, exemplary disorders that can be treated by the compounds described herein, e.g., a compound of Formula I, II, III, IV, V, VI, or subgenera thereof, include but are not limited to lysosomal storage diseases, such as Activator deficiency, Alpha-mannosidosis, AB variant, Aspartylglucosaminuria, Batten– Saintmeyer–Vogt disease, Beta-galactosidase / GM1 gangliosidosis, Beta-mannosidosis, Chronic hexosaminidase A deficiency, cystinosis, CLN7 disease, Congenital cathepsin D deficiency, Cholesteryl ester storage disease, Cystinosis, Danon disease, Fabry disease, fucosidosis, I-cell disease, Krabbe disease, Farber disease, Finnish Vari
  • a method of treating a neuroinflammatory disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.
  • described herein is a method of preventing a neuroinflammatory disorder in a subject in need thereof, comprising administering to the subject a prophylactically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.
  • a method of treating neuroinflammation in a subject in need thereof the method comprising administering to the subject a therapeutically effective amount of a compound described herein.
  • described herein is a method of preventing neuroinflammation in a subject in need thereof, the method comprising administering to the subject a prophylactically effective amount of a compound described herein.
  • the neuroinflammation is associated with a separate disorder in the subject.
  • described herein is a method of treating a genetic disorder resulting in loss-of-function in the ras signaling pathway in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.
  • described herein is a method of preventing a genetic disorder resulting in loss-of-function in the ras signaling pathway in a subject in need thereof, comprising administering to the subject a prophylactically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.
  • the genetic disorder resulting in loss-of-function in the ras signaling pathway is Legius syndrome.
  • the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition .
  • the present invention contemplates administration of the compounds of the present invention as a prophylactic before a subject begins to suffer from the specified disease, disorder or condition.
  • the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a CNS-related disorder, is sufficient to induce anesthesia or sedation.
  • the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.
  • An effective amount encompasses therapeutic and prophylactic treatment.
  • a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition.
  • the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g, young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • compound A is hydrolyzed with lithium hydroxide monohydrate to form carboxylic acid B.
  • carboxylic acid B is reacted with amine C in the presence of HATU to provide compound D.
  • R 6 of amine C is protected with a protecting group.
  • SCHEME 1 [000145]
  • the synthetic route illustrated in Scheme 2 depicts an exemplary procedure for preparing compound I.
  • compound E is reacted with hexamethylenetetramine to form F, which is consequently reacted with ethyl chlorooxoacetate to provide carbamate G.
  • phosphoryl chloride-mediated cyclization of G affords oxazole H.
  • Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.
  • All starting materials are commercially available from Sigma-Aldrich (including Fluka and Discovery CPR) or Acros unless otherwise noted after the chemical name.
  • Reagent/reactant names given are as named on the commercial bottle or as generated by IUPAC conventions or ChemDraw 16.0. None of the specific conditions and reagents noted herein is to be construed as limiting the scope of the invention and are provided for illustrative purposes only.
  • conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • LC/MS was also performed on an Agilent 1260 (binary pump/DAD detector) coupled to Agilent 6120 Mass Spectrometer. LC/MS data is referenced to LC/MS conditions using the method number provided in Table 2. Table 2. LC/MS analysis methods Purification Methods [000157] For the general procedures, intermediate and final compounds may be purified by any technique or combination of techniques known to one skilled in the art.
  • Some examples that are not limiting include flash chromatography with a solid phase (silica gel, alumina, etc.) and a solvent (or combination of solvents (heptane, EtOAc, DCM, MeOH, MeCN, water, etc.) that elutes the desired compounds; RP-HPLC purification performed on Agilent Technologies 1260 Infinity purification system, Agilent 6120 series Single Quadrupole Mass Spectrometer, Gilson purification system (306 pump and GX-281 fraction collector), Shimadzu LC20Ap and Waters MS triggered purification system (see Table 2 for some non- limiting conditions); recrystallization from an appropriate solvent (MeOH, EtOH, i-PrOH, EtOAc, toluene, etc.) or combination of solvents (EtOAc/heptane, EtOAc/MeOH, etc.); precipitation from a combination of solvents (DMF/water, DMSO/DCM, EtOAc/heptane, etc.); tri
  • ACN or MeCN acetonitrile
  • DAD dimethylacetamide
  • DIEA N,N- diisopropylethylamine
  • DIPEA N,N-diisopropylethylamine
  • DMF dimethylformamide
  • DMSO dimethyl sulfoxide
  • EA or EtOAc ethyl acetate
  • EDG6 endothelial differentiation G-protein coupled receptor 6
  • ESI electrospray ionization
  • DCM dichloromethane
  • MeOH methanol
  • HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate
  • HPLC high-performance liquid chromatography
  • i-PrOH isopropyl alcohol
  • Ir[dF(CF 3 )ppy](dtbbpy)PF 6 [4,4′-
  • Example 1.2-(2,5-dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylphenyl)oxazole-5- carboxamide (i) Ethyl 2-(2,5-dichlorophenyl)oxazole-5-carboxylate [000159] A reaction vessel was charged ethyl 2-bromooxazole-5-carboxylate (100 mg, 0.455 mmol), 2,5-dichlorophenylboronic acid (104 mg, 0.545 mmol), tetrakis(triphenylphosphine)palladium(0) (53 mg, 0.0455 mmol), cesium carbonate (222 mg, 0.682 mmol) and solvated in 1,4-dioxane (3.0 mL) and distilled water (0.5 mL).
  • the reaction was degassed and placed under argon. The reaction was set to stir at RT and next warmed to 100 oC. The reaction was heated at 100oC for 18 h. The reaction was allowed to cool to RT and next partitioned between distilled water and ethyl acetate. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to cyclohexane : ethyl acetate, 80 : 20, gradient elution) to afford the title product (58 mg, 45%).
  • a reaction vessel was charged with 2-(2,5-dichlorophenyl)oxazole-5-carboxylic acid (45 mg, 0.174 mmol), (4-amino-3,5-dimethylphenyl)methanol (Preparation 1, 32 mg, 0.209 mmol), HATU (93 mg, 0.244 mmol) and solvated in DMF (2.0 mL).
  • Triethylamine 49 ⁇ L, 0.349 mmol
  • the reaction was stirred at RT for 0.5 h.
  • the reaction was next partitioned between distilled water and ethyl acetate.
  • the reaction was degassed and placed under argon. The reaction was set to stir at RT and next warmed to 80 oC. The reaction was heated at 80 oC for 1 h. The reaction was allowed to cool to RT and next partitioned between distilled water and ethyl acetate. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to cyclohexane : ethyl acetate, 50 : 50, gradient elution) to afford the title compound (520 mg, 70%).
  • Example 4.5-(2,5-dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylphenyl)nicotinamide (i) Ethyl 5-(2,5-dichlorophenyl)nicotinate [000171] A reaction vessel was charged with ethyl 5-bromonicotinate (603 mg, 2.62 mmol), 2,5-dichlorophenylboronic acid (500 mg, 2.62 mmol), tetrakis(triphenylphosphine)palladium(0) (303 mg, 0.262 mmol), cesium carbonate (2.56 g, 7.86 mmol) and solvated in 1,4-dioxane (10.0 mL) and distilled water (2.0 mL).
  • the reaction was degassed and placed under argon. The reaction was set to stir at RT and next warmed to 80 oC. The reaction was heated at 80 oC for 1.5 h. The reaction was allowed to cool to RT and partitioned between distilled water and ethyl acetate. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to diethyl ether, gradient elution) to afford the title compound (740 mg, 95%).
  • the reaction was degassed and placed under argon. The reaction was set to stir at RT and next warmed to 80 oC. The reaction was heated at 80 oC for 1.5 h. The reaction was stopped and allowed to cool to RT. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to tert-butyl methyl ether gradient elution) to afford the title compound as a white solid (170 mg, 23%).
  • lithium hydroxide monohydrate (101 mg, 2.41 mmol) was added.
  • the reaction was set to stir at RT and next warmed to 50 oC.
  • the reaction was heated at 50 oC for 0.5 h.
  • the reaction was allowed to cool to RT and the organics removed in vacuo.
  • the aqueous layer was acidified with 1N hydrochloric acid to pH ⁇ 7 and the resulting precipitate filtered and dried in vacuo to afford the title compound as a white solid (89 mg, 55%).
  • the reaction was heated at 150 oC under microwave irradiation for 1.5 h.
  • the reaction was allowed to cool to RT and next partitioned between ethyl acetate and distilled water.
  • the organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo.
  • the reaction was degassed and placed under argon. The reaction was set to stir at RT and next warmed to 80 oC. The reaction was heated at 80 oC for 1 h. The reaction was allowed to cool to RT and next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to cyclohexane : ethyl acetate, 50 : 50, gradient elution) to afford the title product (270 mg, 35%).
  • the reaction was set to stir at RT and next cooled to 0 oC
  • Sodium nitrite (1.41 g, 20.37 mmol) in distilled water (3.0 mL) was added dropwise at 0 oC. This reaction was stirred at 0 oC for 0.5 h.
  • ethyl 2- chloroacetoacetate (3.36 g, 2.82 mL, 20.37 mmol) and sodium acetate (3.03 g, 37.04 mmol) were added at 0 oC.
  • the reaction was allowed to warm to RT and stirred at RT for 1.5 h.
  • the reaction was next partitioned between ethyl acetate and distilled water.
  • the reaction was degassed and placed under an argon. The reaction was set to stir at RT and next warmed to 90 oC. The reaction was heated at 90 oC for 10 h. The reaction was allowed to cool to RT. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (petroleum spirit 40-60 oC to petroleum spirit 40-60 oC : ethyl acetate, 80 : 20, gradient elution) to give the title compound as a yellow oil (8.5 g, 81%).
  • the reaction was stirred at 80 oC for 24 h and next cooled to RT.
  • the reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo.
  • the crude material was purified by reverse phase HPLC (Table 3, Method 5) to afford the title compound as a white solid (7 mg, 1.98 %).
  • Racemic 1-(2,5-dichlorophenyl)-N-(4-(hydroxymethyl)-2,6- dimethylphenyl)pyrrolidine-3-carboxamide (i) Racemic ethyl 1-(2,5-dichlorophenyl)pyrrolidine-3-carboxylate [000195] A reaction vessel was charged with ethyl pyrrolidine-3-carboxylate hydrochloride (307 mg, 1.71 mmol), 2-bromo-1,4-dichlorobenzene (347 mg, 1.54 mmol), Xphos (81 mg, 0.171 mmol), tris(dibenzylideneacetone)dipalladium(0) (78 mg, 0.0854 mmol), cesium carbonate (1.76 g, 5.13 mmol) and solvated in 1,4-dioxane (11.0 mL).
  • the reaction was degassed and placed under argon. The reaction was set to stir at RT and next warmed to 80 oC. The reaction was stirred at 80 oC for 18 h. The reaction was allowed to cool to RT. The reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to cyclohexane : ethyl acetate, 95 : 5, gradient elution) to afford the title compound as a yellow oil (259 mg, 58%).
  • the reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to cyclohexane : ethyl acetate, 25 : 75, gradient elution).
  • nickel pre-catalyst itself prepared by stirring nickel (II) chloride ethylene glycol dimethyl ether complex (0.5 mg, 0.0025 mmol) and 4,4’-di-tert-butyl-2,2’-dipyridyl (0.8 mg, 0.0030 mmol) in 1,2-dimethoxyyethane (0.2 mL) under an argon atmosphere for 10 mins.
  • the reaction was degassed and placed under an argon atmosphere.
  • the reaction was next irradiated in an LED photoreactor for 2 h.
  • the reaction was partitioned between ethyl acetate and distilled water.
  • the reaction was next allowed to cool to RT.
  • the reaction was partitioned between ethyl acetate and distilled water.
  • the organic layer was separated and the combined organic layers were washed with 10% citric acid solution, saturated sodium hydrogen carbonate solution, brine, dried (MgSO 4 ) and concentrated in vacuo.
  • the crude material was purified by reverse phase HPLC (Table 3, Method 1) to afford the title compound as a white solid (29 mg, 25%).
  • the reaction was degassed and placed under argon. The reaction was set to stir at RT and next warmed to 80 oC. The reaction was stirred at 80 oC 3 h. The reaction was allowed to cool to RT. The reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to cyclohexane : ethyl acetate, 50 : 50, gradient elution) to afford the title compound (30 mg, 9.2%).
  • the reaction was set to stir at RT.
  • the reaction was stirred at RT for 16 h.
  • the reaction was next partitioned between ethyl acetate and distilled water.
  • the organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo.
  • the crude material was purified by preparative TLC (petroleum spirit 40-60 oC to petroleum spirit 40-60 oC : ethyl acetate, 50 : 50, gradient elution) to afford the title compound as an off-white solid (27 mg, 22.9%).
  • Example 17.4-(2,5-Dichlorophenyl)-N-(2,6-dimethyl-4-(2-(methylamino)-2- oxoethoxy)phenyl)pyrimidine-2-carboxamide (i) Ethyl 2-(4-(4-(2,5-dichlorophenyl)pyrimidine-2-carboxamido)-3,5- dimethylphenoxy)acetate [000215] A reaction vessel was charged with 4-(2,5-dichlorophenyl)-N-(4-hydroxy-2,6- dimethylphenyl)pyrimidine-2-carboxamide ((Example 16, step (i), 268 mg, 0.69 mmol)), cesium carbonate (450 mg, 1.38 mmol) and solvated in DMF (15 mL).
  • the reaction was allowed to warm to RT and stirred at RT for 16 h.
  • the reaction was next cooled to 0 oC and quenched with MeOH (1 mL) and 10% aqueous NaOH solution (1 mL).
  • the organics were removed in vacuo.
  • the aqueous layer was acidified to pH ⁇ 6-7 with 1N hydrochloric acid solution.
  • the reaction was partitioned with ethyl acetate.
  • the organic layer was separated and the combined organic layers were dried (MgSO 4 ) and concentrated in vacuo.
  • the residue was purified by preparative TLC (neat ethyl acetate) to afford the title compound as an orange solid (83 mg, 51%) as an orange solid.
  • the reaction was set to stir at RT under a nitrogen atmosphere. The reaction was stirred at RT for 16 h. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography reverse phase HPLC (Table 3, Method 6) to afford the title compound as a white solid (53.4 mg, 31.3%).
  • the reaction was heated at 110 oC for 24 h. The reaction was allowed to cool to RT. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by preparative TLC (DCM to DCM : ethyl acetate, 97 : 3, gradient elution) to give the title product as a white solid (101.9 mg, 18% yield).
  • a reaction vessel was charged with N-[4-(aminomethyl)-2,6-dimethylphenyl]-4- (2,5-dichlorophenyl)pyrimidine ((Example 20, step (i), 80 mg, 0.2 mmol)) and solvated in DCM (2 mL). The reaction was set to stir at RT and next cooled to 0 oC.
  • the reaction was stirred at RT for 3 h.
  • the reaction was partitioned between ethyl acetate and distilled water.
  • the organic layer was separated and the combined organics were dried (MgSO4) and concentrated in vacuo.
  • the crude material was purified by preparative TLC (petroleum spirit 40-60 oC to petroleum spirit 40-60 oC : ethyl acetate, 50 : 50, gradient elution) to afford the title compound as a white solid (80 mg, 57.4%).
  • N-(4-(4-(2,5-Dichlorophenyl)pyrimidine-2-carboxamido)-3,5-dimethylbenzyl)- 2-fluoroethan-1-aminium formate [000233] To a solution of N-[4-(chloromethyl)-2,6-dimethylphenyl]-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide ((Example 13, step (i), 130 mg, 0.31 mmol)) in DMF (4 mL) was added 2-fluoroethanamine (55 ⁇ L, 0.775 mmol), K 2 CO 3 (215 mg, 1.55 mmol) and KI (3 mg, 0.018 mmol).
  • the reaction was set to stir at RT under a nitrogen atmosphere. The reaction was next warmed to reflux. The reaction was heated at reflux for 4 h. The reaction was allowed to cool to RT. The reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Table 3, Method 6) to afford the title compound as white solid (22.9 mg, 15% yield).
  • Example 27 4-(2,5-Dichlorophenyl)-N-(2,6-dimethyl-3- (methylcarbamoyl)phenyl)pyrimidine-2-carboxamide (i) N,2,4-Trimethyl-3-nitrobenzamide
  • a reaction vessel was charged with 2,4-dimethyl-3-nitrobenzoic acid (200 mg, 0.02 mmol), HATU (581 mg, 1.53 mmol) and solvated in DMF (3.0 mL). DIPEA (534 ⁇ L, 3.06 mmol) was added and the reaction was set to stir at RT under a nitrogen atmosphere. The reaction was stirred at RT for 2 h. The reaction was partitioned between ethyl acetate and distilled water.
  • the reaction was next allowed to warm to 110 oC and stirred at 110 °C for 24 h. The reaction was allowed to cool to RT. The reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Table 3, Method 6) to afford the title compound as a white solid (25 mg, 16% yield).
  • Example 28.4-(2,5-Dichlorophenyl)-N-(4-(dimethylcarbamoyl)-2,6- dimethylphenyl)pyrimidine-2-carboxamide [000240] The title compound was prepared by using an analogous reaction protocol as described for N-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylphenyl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(4-(2,5- dichlorophenyl)pyrimidine-2-carboxamido)-3,5-dimethylbenzoic acid and 2M dimethylamine in THF.
  • Example 29.4-(2,5-Dichlorophenyl)-N-(5-(hydroxymethyl)-2,4-dimethylphenyl)pyrimidine-2- carboxamide [000241] The title compound was prepared by using an analogous reaction protocol as described for N-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylphenyl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(2,5- dichlorophenyl)pyrimidine-2-carboxylic acid and (5-amino-2,4-dimethylphenyl)methanol).
  • Example 44.4-(2,5-Dichlorophenyl)-N-(2-ethyl-4-(hydroxymethyl)-6- methylphenyl)pyrimidine-2-carboxamide (i) 4-Amino-3-ethyl-5-methylbenzaldehyde [000270] A mixture of 2-ethyl-6-methylaniline (CAS: 24549-06-2, 2.0 g, 14.8 mmol) and hexamethylenetetramine (CAS: 100-97-0, 2.0 g, 14.8 mmol) in acetic acid (20 mL) and distilled water (5 mL) was set to stir at RT and next heated at 120°C for 2 h.
  • 2-ethyl-6-methylaniline CAS: 24549-06-2, 2.0 g, 14.8 mmol
  • hexamethylenetetramine CAS: 100-97-0, 2.0 g, 14.8 mmol
  • Example 61.4-(2,5-Dichlorophenyl)-N-(2-ethyl-4-(2-hydroxyethoxy)-6- methylphenyl)picolinamide [000302] A solution of 4-(2,5-dichlorophenyl)picolinoyl chloride (265 mg, 0.92 mmol) and 2-(4-amino-3-ethyl-5-methylphenoxy)ethan-1-ol (150 mg, 0.77 mmol) in THF (50 mL) at 0°C was treated with DIPEA (380 ⁇ L, 2.31 mmol), and the resulting mixture was stirred at the RT for 2 h.
  • DIPEA 380 ⁇ L, 2.31 mmol
  • the title compound was prepared by using an analogous reaction protocol as described for 4-(2,5-dichlorophenyl)-N-(2,6-dimethyl-3- (methylcarbamoyl)phenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(2,5-dichlorophenyl)pyrimidine-2-carbonyl chloride and 1-(difluoromethyl)-3,5-dimethyl- 1H-pyrazol-4-amine (CAS: 1005633-15-7)).
  • the title compound was prepared by using an analogous reaction protocol as described for N-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylphenyl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(2,5- dichlorophenyl)pyrimidine-2-carboxylic acid and (5-amino-2,4-dimethylphenyl)methanol (CAS: 1334148-06-9)).
  • PathHunter® CHO-K1 EDG6 ⁇ -Arrestin cells (10000 cells/well (20 ⁇ l/well) in a white, tissue cultured treated 384 well plate) were seeded in AssayCompleteTM Cell Plating 11 Reagent (93-0563R11A, DiscoverX) and incubated overnight at 37 ⁇ C, 5% CO 2 .
  • PathHunter® CHO-K1 EDG6 ⁇ -Arrestin cells were pre-incubated for 30 minutes with a concentration range of test compounds (addition: 2.5 ⁇ L of 10X) at 37 ⁇ C, 5% CO 2 before addition of Sphingosine 1-phosphate (2.5 ⁇ L of 100 ⁇ M, final assay concentration: 10 ⁇ M) for 3 hours (37 ⁇ C, 5% CO2 for 150 minutes and room temperature for 30 minutes).
  • PathHunter® Working Detection Solution was prepared as the manufacturer’s user manual. 12.5 ⁇ L of PathHunter® Working Detection Solution was added to all the wells in the assay plate and incubated at room temperature for 1 hour in the dark.
  • IC 50 data are reported in Table 5 for compounds in Table 1.
  • A indicates a B-arrestin IC 50 ( ⁇ M) 0.01 ⁇ M to ⁇ 0.1 ⁇ M
  • B indicates a ⁇ -arrestin IC 50 ( ⁇ M) 0.1 ⁇ M to ⁇ 1.0 ⁇ M
  • C indicates a B-arrestin IC 50 ( ⁇ M) 1.0 ⁇ M to ⁇ 10 ⁇ M
  • D indicates a B-arrestin IC 50 ( ⁇ M) 10 ⁇ ⁇ M.
  • the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features.

Abstract

L'invention concerne des composés utiles en tant qu'antagonistes du récepteur S1PR4, des compositions pharmaceutiques comprenant lesdits composés, des procédés de fabrication desdits composés et des compositions pharmaceutiques, ainsi que des procédés d'utilisation desdits composés et compositions pharmaceutiques dans le traitement de troubles comprenant des troubles neurologiques, des troubles cognitifs et des troubles neurodégénératifs.
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