WO2024036112A1 - Promédicaments d'amide et leurs utilisations - Google Patents

Promédicaments d'amide et leurs utilisations Download PDF

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WO2024036112A1
WO2024036112A1 PCT/US2023/071789 US2023071789W WO2024036112A1 WO 2024036112 A1 WO2024036112 A1 WO 2024036112A1 US 2023071789 W US2023071789 W US 2023071789W WO 2024036112 A1 WO2024036112 A1 WO 2024036112A1
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compound
pharmaceutically acceptable
solvate
acceptable salt
alkyl
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PCT/US2023/071789
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Jason Randall HARRIS
Jill Melissa Baccei
Brian Andrew Stearns
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Autobahn Therapeutics, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • R 1 is selected from hydrogen, -OR 7 , -NR 7 R 8 , C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 1-9 heteroaryl, phenyl, and -C 1 -C 6 alkyl- phenyl, wherein C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 2 - C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 5 and R 6 are hydrogen.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 9a and R 9b are independently selected from hydrogen and C 1-6 alkyl.
  • R 9c is C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • R 9c is unsubstituted C 1-6 alkyl.
  • R 9c is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9c is -CH3.
  • R 3 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • R 3 is selected from C1-6alkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C6-10aryl, and C1- 9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1- 6 alkyl, C 1-6 haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • R 3 is C6-10aryl WSGR Docket No.60179-726.601 optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1- 6haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 3 is phenyl optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1- 6haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • R 3 is phenyl optionally substituted with one, two, or three groups selected from C 1-6 alkyl and -OR 10 , wherein R 10 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.
  • R 3 is C 1-9 heteroaryl optionally substituted with one, two, or three groups selected from halogen, C 1- 6 alkyl, C 1-6 haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • R 3 is pyridyl optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1- 6 haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • R 3 is pyridyl optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1- 6 haloalkyl, and -OR 10 , wherein R 10 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 3 is C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • R 3 is C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -OR 10 , and -N(R 10 )(R 11 ).
  • R 3 is a compound of Formula , or a salt or R 3 , , , , , or .
  • R 3 is a compound of acceptable salt or solvate thereof, wherein R 3 is .
  • WSGR Docket No.60179-726.601 [0005]
  • R 2 is C 2 -C 6 alkyl optionally substituted with one or more groups selected from halogen, C 1 -C 6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and - S(O)2R 13 .
  • a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is C2-C6alkyl substituted with one or more groups selected from halogen, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • R 2 is C2-C6alkyl substituted with one or more -OH.
  • a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is C 2 -C 6 alkyl substituted with one or more of halogen.
  • a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is C 3 -C 6 cycloalkyl optionally substituted with one or more groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • R 2 is C 3 -C 6 cycloalkyl optionally substituted with one or more groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • R 2 is unsubstituted C 3 -C 6 cycloalkyl.
  • R 2 is C1-9heteroaryl optionally substituted with one or more groups selected from halogen, C 1 -C 6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and - S(O) 2 R 13 .
  • R 2 is C1-9heteroaryl optionally substituted with one or more groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and - S(O) 2 R 13 , wherein C 1-9 heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • R 2 is selected from unsubstituted pyridyl, WSGR Docket No.60179-726.601 unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl.
  • a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 and R 2 are combined to form a C2-C9heterocycloalkyl optionally substituted with one or more groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , - N(R 10 )(R 11 ), and -S(O)2R 13 .
  • R 1 and R 2 are combined to form an unsubstituted C 2 -C 9 heterocycloalkyl.
  • a pharmaceutical composition comprising a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, further comprising a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor.
  • FAAH peripherally restricted fatty acid amide hydrolase
  • a pharmaceutical composition comprising a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, further comprising a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652.
  • FAAH peripherally restricted fatty acid amide hydrolase
  • a method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis (AHL or AHLE), adult Refsum disease, infantile Refsum disease, Alexander disease, Alzheimer's disease, Balo concentric sclerosis, Canavan disease, central pontine myelinolysis (CPM), cerebral palsy, cerebrotendineous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic's syndrome, diffuse myelinoclastic sclerosis, encephalomyelitis, Guillain-Barre syndrome, Huntington’s disease (HD), idiopathic inflammatory demyelinating disease (HDD), Krabbe disease, Leber
  • WSGR Docket No.60179-726.601 embodiments is a method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from multiple sclerosis and X-linked adrenoleukodystrophy.
  • a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein the CNS disease or disorder is selected from multiple sclerosis and X-linked adrenoleukodystrophy.
  • S1P1 Five members of this family have been identified across a variety of cell types, S1P1 (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6) and S1P5 (EDG-8).
  • the receptor subtypes S1P1, S1P2 and S1P3 are expressed widely in both peripheral tissues and in the central nervous system (CNS) and play key roles in cardiovascular regulation, lymphocyte trafficking and neurogenesis.
  • the S1P4 receptor is expressed mainly in the immune and hematopoietic systems and mediates immune cell proliferation and cytokine production typically in the presence of high concentrations of S1P.
  • S1P1 and S1P5 receptors simultaneously within the brain tissue of patients with nervous system diseases should provide neuroprotective and remyelinating benefits.
  • S1P1/5 receptors are expressed on astrocytes, microglia, neurons and oligodendroglia and have been shown to modulate processes relevant to demyelinating neuropathologies, including astrocyte activation, microglial activation, oligodendrocyte precursor cell migration and maturation, and oligodendroglial cell survival.
  • Studies in EAE mouse models of MS have shown that genetic deletion or pharmacological functional antagonism of S1P1 reduces demyelination, axonal loss, and astrogliosis.
  • S1P5 is highly expressed on myelin-forming oligodendrocytes and S1P5 stimulation/modulation has been shown to promote survival of mature oligodendrocytes.
  • Fatty acid amide hydrolase is an integral membrane serine hydrolase that degrades the fatty acid amide family of signaling lipids and can hydrolyze select amide prodrugs. FAAH is highly conserved between species and is expressed in many tissues, including the central nervous system (CNS), to varying degrees.
  • Select carboxylic acids can be converted to more permeable amide prodrugs which are then capable of passing through the blood brain barrier where they can be converted to active molecules through the action of FAAH upon the prodrug. This results in the delivery of higher amounts of the carboxylic acid to the CNS as compared to dosing the parent alone.
  • peripherally expressed FAAH simultaneously hydrolyzes the prodrug resulting in a considerable amount of non-productive prodrug conversion.
  • Co-administration of a peripherally restricted FAAH inhibitor with a CNS permeable FAAH convertible prodrug increases the selectivity of prodrug delivery to the CNS. It also results in lower exposures of the parent molecule in plasma and peripheral tissue than what is observed when dosing the prodrug alone.
  • C1-Cx includes C1-C2, C1-C3... C1-Cx.
  • a group designated as “C 1 -C 4 " indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
  • C1-C4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e. a C1- C 10 alkyl.
  • a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon WSGR Docket No.60179-726.601 atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • an alkyl is a C1- C 6 alkyl.
  • the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, or t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
  • An “alkylene” group refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl.
  • an alkylene is a C1-C6alkylene. In other embodiments, an alkylene is a C 1 -C 4 alkylene. In certain embodiments, an alkylene comprises one to four carbon atoms (e.g., C 1 -C 4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C1 alkylene).
  • an alkylene comprises two carbon atoms (e.g., C 2 alkylene). In other embodiments, an alkylene comprises two to four carbon atoms (e.g., C2-C4 alkylene).
  • Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2- , -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and the like.
  • alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present.
  • R is H or an alkyl.
  • an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like.
  • alkynyl refers to a type of alkyl group in which at least one carbon-carbon triple bond is present.
  • an alkenyl group has the formula -C ⁇ C-R, wherein R refers to the remaining portions of the alkynyl group.
  • R is H or an alkyl.
  • an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Non-limiting examples of an alkynyl group include -C ⁇ CH, -C ⁇ CCH 3 - C ⁇ CCH2CH3, -CH2C ⁇ CH.
  • An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.
  • alkylamine refers to the –N(alkyl) x H y group, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.
  • aromatic refers to a planar ring having a delocalized ⁇ -electron system containing 4n+2 ⁇ electrons, where n is an integer.
  • aromatic includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine).
  • aryl e.g., phenyl
  • heterocyclic aryl or “heteroaryl” or “heteroaromatic” groups (e.g., pyridine).
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon or nitrogen atoms) groups.
  • carbocyclic or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms.
  • carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon.
  • at least one of the two rings of a bicyclic carbocycle is aromatic.
  • both rings of a bicyclic carbocycle are aromatic.
  • Carbocycle includes cycloalkyl and aryl.
  • aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
  • aryl is phenyl or a naphthyl.
  • an aryl is a phenyl.
  • an aryl is a C6-C10aryl.
  • an aryl group is a monoradical or a diradical (i.e., an arylene group).
  • cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • cycloalkyls are spirocyclic or bridged compounds.
  • cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom.
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicyclo[1.1.1]pentyl.
  • a cycloalkyl is a C 3 - C6cycloalkyl.
  • a cycloalkyl is a monocyclic cycloalkyl.
  • Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.2]octyl and bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • halo or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
  • haloalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a halogen atom. In one aspect, a fluoroalkyl is a C1-C6fluoroalkyl.
  • fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.
  • a fluoroalkyl is a C 1 -C 6 fluoroalkyl.
  • a fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. –NH-, - N(alkyl)-, sulfur, or combinations thereof.
  • heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C1-C6heteroalkyl.
  • heteroalkylene refers to a divalent heteroalkyl radical.
  • heterocycle refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms.
  • heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic or bridged compounds.
  • Non- aromatic heterocyclic groups include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system.
  • the heterocyclic groups include benzo-fused ring systems.
  • non- aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • a WSGR Docket No.60179-726.601 group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N- attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached).
  • the heterocyclic groups include benzo-fused ring systems.
  • at least one of the two rings of a bicyclic heterocycle is aromatic.
  • both rings of a bicyclic heterocycle are aromatic.
  • heteroaryl or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls.
  • Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
  • Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.
  • a heteroaryl contains 0-4 N atoms in the ring.
  • a heteroaryl contains 1-4 N atoms in the ring.
  • a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
  • a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
  • heteroaryl is a C 1 -C 9 heteroaryl.
  • monocyclic heteroaryl is a C 1 -C 5 heteroaryl.
  • monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl.
  • bicyclic heteroaryl is a C6-C9heteroaryl.
  • a “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur.
  • a heterocycloalkyl is fused with an aryl or heteroaryl.
  • the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl.
  • heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
  • a heterocycloalkyl is a C 2 - C10heterocycloalkyl.
  • a heterocycloalkyl is a C4-C10heterocycloalkyl.
  • a heterocycloalkyl contains 0-2 N atoms in the ring.
  • a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.
  • bond refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.
  • moiety refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • optional substituents are independently selected from D, halogen, -CN, -NH 2 , -OH, -NH(CH 3 ), -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CF 3 , -OCH 3 , and -OCF 3 .
  • substituted groups are substituted with one or two of the preceding groups.
  • modulate means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • modulator refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an agonist.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.
  • the terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • the terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.
  • the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g.
  • a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent are administered to a patient as separate entities either simultaneously, concurrently or sequentially WSGR Docket No.60179-726.601 with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • kit and “article of manufacture” are used as synonyms.
  • the term “subject” or “patient” encompasses mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • the terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • Compounds [0050] Compounds described herein, including pharmaceutically acceptable salts, active metabolites and pharmaceutically acceptable solvates thereof, are amide prodrugs of dual S1P1 and S1P5 receptor agonists.
  • R 1 is selected from hydrogen, -OR 7 , -NR 7 R 8 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl- phenyl, wherein C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 2 - C 9 heterocycloalkyl, C 1-9 heteroaryl, phenyl, and -C 1 -C 6 alkyl-phenyl are optionally substituted with one or more groups selected from halogen,
  • substituents are selected from among a subset of the listed alternatives.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 5 and R 6 are hydrogen.
  • R 5 is C1-6alkyl and R 6 are hydrogen.
  • R 9a and R 9b are independently selected from hydrogen and C1- 6 alkyl.
  • R 9a is hydrogen and R 9b is C1-6alkyl.
  • R 9a is hydrogen and R 9b is -CH 3 .
  • R 9a and R 9b are C1-6alkyl.
  • WSGR Docket No.60179-726.601 embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b are -CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b are hydrogen.
  • R 9c is C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • R 9c is unsubstituted C1-6alkyl.
  • R 9c is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9c is -CH3.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 9c is -CH 2 CH 3 .
  • R 3 is selected from C1-6alkyl, C3-6cycloalkyl, C2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • R 3 is selected from C 1-6 alkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1- 6alkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • R 3 is C6-10aryl optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 3 is phenyl optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • R 3 is phenyl optionally substituted with one, two, or three groups selected from C 1-6 alkyl and - OR 10 , wherein R 10 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 3 is phenyl optionally substituted with one, two, or three groups selected from C1-6alkyl and -OR 10 , wherein R 10 is C1-6alkyl.
  • R 3 is phenyl substituted with one or two groups selected from C 1-6 alkyl and -OR 10 , wherein R 10 is C 1-6 alkyl.
  • WSGR Docket No.60179-726.601 In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C1-9heteroaryl optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • R 3 is pyridyl optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • R 3 is pyridyl optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, and -OR 10 , wherein R 10 is selected from hydrogen, C1-6alkyl, and C 1-6 haloalkyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 3 is C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • R 3 is C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -OR 10 , and -N(R 10 )(R 11 ).
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 3 is unsubstituted C 1-6 alkyl.
  • R 3 is , , , , , , .
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein m is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 3.
  • each R 4 is independently selected from halogen, -CN, C1-6alkyl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -C(O)R 13 , -C(O)N(R 10 )(R 11 ), -S(O)2R 13 , and - S(O) 2 N(R 10 )(R 11 )-, wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from halogen, C1-6haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • each R 4 is independently selected from halogen, -CN, C1-6alkyl, -OR 10 , and - N(R 10 )(R 11 ), wherein C1-6alkyl is optionally substituted with one, two, or three groups selected from halogen, C 1-6 haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • each R 4 is independently selected from halogen, C1-6alkyl, -OR 10 , wherein C1-6alkyl is optionally substituted with one, two, or three groups selected from halogen, C 1-6 haloalkyl, and -OR 10 .
  • R 1 is selected from hydrogen and C1-C6alkyl.
  • R 1 is hydrogen.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is C1-C6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -CH 3 . [0062] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C2-C6alkyl optionally substituted with one or more groups selected from halogen, C 1 -C 6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O) 2 R 13 .
  • R 2 is C2-C6alkyl optionally substituted with one or more groups selected from halogen, C 1 -C 6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O) 2 R 13 .
  • R 2 is C2-C6alkyl optionally substituted with one, two, or three groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 .
  • R 2 is C2-C6alkyl substituted with one or more groups selected from halogen, C1-6haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is C 2 -C 6 alkyl substituted with one, two, or three groups selected from halogen, C 1-6 haloalkyl, -OR 10 , and - N(R 10 )(R 11 ).
  • R 2 is C2-C6alkyl substituted with one, two, or three halogen.
  • R 2 is C2-C6alkyl substituted with one, two, or three C1-6haloalkyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is C 2 -C 6 alkyl substituted with one, two, or three -OR 10 .
  • R 2 is C2-C6alkyl substituted with one, two, or three -N(R 10 )(R 11 ).
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is unsubstituted C2-C6alkyl.
  • R 2 is C 3 -C 6 cycloalkyl optionally substituted with one or more groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and - S(O)2R 13 .
  • R 2 is C 3 -C 6 cycloalkyl optionally substituted with one or more groups selected from halogen, C 1 -C 6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and - S(O)2R 13 .
  • R 2 is C3-C6cycloalkyl optionally substituted with one, two, or three groups selected from halogen, C 1 -C 6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and - S(O)2R 13 .
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is C3-C6cycloalkyl substituted with one or more groups selected from halogen, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • R 2 is C3-C6cycloalkyl substituted with one, two, or three groups selected from halogen, C1-6haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is C 3 -C 6 cycloalkyl substituted with one, two, or three halogen.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is C3-C6cycloalkyl substituted with one, two, or three C 1-6 haloalkyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is C 3 -C 6 cycloalkyl substituted with one, two, or three -OH.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is C3-C6cycloalkyl substituted with one, two, or three -N(R 10 )(R 11 ).
  • R 2 is unsubstituted C3-C6cycloalkyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is -C1-C6alkyl-C3-C6cycloalkyl optionally substituted with one or more groups selected from halogen, C 1 -C 6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 .
  • R 2 is unsubstituted -C1-C6alkyl-C3-C6cycloalkyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is -CH 2 -C 3 -C 6 cycloalkyl optionally substituted with one or more groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and - S(O)2R 13 .
  • R 2 is unsubstituted -CH 2 -C 3 -C 6 cycloalkyl.
  • R 2 is C1-9heteroaryl optionally substituted with one or more groups selected from halogen, C 1 -C 6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and - S(O) 2 R 13 .
  • R 2 is C1-9heteroaryl optionally substituted with one or more groups selected from halogen, C 1 -C 6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and - S(O) 2 R 13 , wherein C 1-9 heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • R 2 is pyridyl optionally substituted with one or more groups selected from halogen, C 1 -C 6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O) 2 R 13 .
  • R 2 is pyridazinyl optionally substituted with one or more groups selected from halogen, C 1 -C 6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O) 2 R 13 .
  • R 2 is pyrimidinyl optionally substituted with one or more groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 .
  • R 2 is pyrazinyl optionally substituted with one or more groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 .
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is selected from unsubstituted pyridyl, unsubstituted WSGR Docket No.60179-726.601 pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl.
  • R 2 is unsubstituted pyridyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is unsubstituted pyridazinyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is unsubstituted pyrimidinyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is unsubstituted pyrazinyl.
  • [0069] is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 are combined to form a C 2 -C 9 heterocycloalkyl optionally substituted with one or more groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, - OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 .
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 and R 2 are combined to form a C 2 -C 9 heterocycloalkyl optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 .
  • R 1 and R 2 are combined to form an unsubstituted C 2 -C 9 heterocycloalkyl.
  • R 1 is selected from hydrogen, -OR 7 , -NR 7 R 8 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 1-9 heteroaryl, phenyl, and -C 1 -C 6 alkyl- phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C 9 heterocycloalkyl, C 1-9 heteroaryl, phenyl, and -C 1 -C 6 alkyl-phenyl are optionally substituted with one or more groups selected from halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 2
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is selected from hydrogen and C 1 -C 6 alkyl.
  • R 1 is hydrogen.
  • R 1 is C 1 -C 6 alkyl.
  • R 1 is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -CH3.
  • R 2 is C 2 -C 6 alkyl optionally substituted with one or more groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 .
  • R 2 is C 2 -C 6 alkyl optionally substituted with one or more groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 .
  • some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C2-C6alkyl optionally substituted with one, two, or three groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 .
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is C2-C6alkyl substituted with one or more groups selected from halogen, C1-6haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • R 2 is C 2 -C 6 alkyl substituted with one, two, or three groups selected from halogen, C1-6haloalkyl, -OR 10 , and - N(R 10 )(R 11 ).
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is C 2 -C 6 alkyl substituted with one, two, or three halogen.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is C2-C6alkyl substituted with one, two, or three C1-6haloalkyl.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is C2-C6alkyl substituted with one, two, or three -OH.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is C 2 -C 6 alkyl substituted with one, two, or three -N(R 10 )(R 11 ).
  • R 2 is unsubstituted C 2 -C 6 alkyl.
  • R 2 is C3-C6cycloalkyl optionally substituted with one or more groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and - S(O) 2 R 13 .
  • R 2 is C3-C6cycloalkyl optionally substituted with one or more groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O) 2 R 13 .
  • R 2 is C 3 -C 6 cycloalkyl optionally substituted with one, two, or three groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 .
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is C 3 -C 6 cycloalkyl substituted with one or more groups selected from halogen, C1-6haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • R 2 is C 3 -C 6 cycloalkyl substituted with one, two, or three groups selected from halogen, C 1- 6haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • R 2 is C3-C6cycloalkyl substituted with one, two, or three -OR 10 .
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is C 3 -C 6 cycloalkyl substituted with one, two, or three -OH.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is C3-C6cycloalkyl substituted with one, two, or three -N(R 10 )(R 11 ).
  • R 2 is unsubstituted C3-C6cycloalkyl.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is -C 1 -C 6 alkyl-C 3 -C 6 cycloalkyl optionally substituted with one or more groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 .
  • R 2 is unsubstituted -C 1 -C 6 alkyl-C 3 -C 6 cycloalkyl.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is -CH2-C3-C6cycloalkyl optionally substituted with one or more groups selected from halogen, C 1 -C 6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and - S(O) 2 R 13 .
  • R 2 is unsubstituted -CH2-C3-C6cycloalkyl.
  • R 2 is C 1-9 heteroaryl optionally substituted with one or more groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and - S(O)2R 13 .
  • R 2 is C 1-9 heteroaryl optionally substituted with one or more groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and - WSGR Docket No.60179-726.601 S(O) 2 R 13 , wherein C 1-9 heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • R 2 is pyridyl optionally substituted with one or more groups selected from halogen, C 1 -C 6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and - S(O)2R 13 .
  • R 2 is pyridazinyl optionally substituted with one or more groups selected from halogen, C 1 -C 6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and - S(O)2R 13 .
  • R 2 is pyrimidinyl optionally substituted with one or more groups selected from halogen, C 1 -C 6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and - S(O) 2 R 13 .
  • R 2 is pyrazinyl optionally substituted with one or more groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and - S(O) 2 R 13 .
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is selected from unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl.
  • R 2 is selected from unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl.
  • R 2 is selected from unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl.
  • R 2 is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted pyridazinyl.
  • [0079] is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 are combined to form a C2-C9heterocycloalkyl optionally substituted with one or more groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, - OR 10 , -N(R 10 )(R 11 ), and -S(O) 2 R 13 .
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 and R 2 are combined to form a C2-C9heterocycloalkyl optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -S(O) 2 R 13 .
  • R 1 and R 2 are combined to form an unsubstituted C2-C9heterocycloalkyl.
  • WSGR Docket No.60179-726.601 Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. [0081] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from: , , , , , . [0082] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate , , WSGR Docket No.60179-726.601 , pharmaceutically acceptable salt or solvate thereof. [0083] In some embodiments, compounds described herein are in the form of pharmaceutically acceptable salts.
  • “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable salt refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation.
  • Handbook of Pharmaceutical Salts Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci.1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zürich: Wiley-VCH/VHCA, 2002.
  • Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible, and this capability can be manipulated as WSGR Docket No.60179-726.601 one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted. [0086] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid to provide a "pharmaceutically acceptable acid addition salt.” In some embodiments, the compound described herein (i.e.
  • Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid.
  • Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); glu
  • a compound described herein is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base to provide a "pharmaceutically acceptable base addition salt.”
  • the compound described herein is acidic and is reacted with a base. In such situations, an acidic proton of the compound described herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion.
  • compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine.
  • compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like.
  • Acceptable inorganic bases used to form salts with compounds that include an acidic proton, WSGR Docket No.60179-726.601 include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like.
  • the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.
  • a reference to a pharmaceutically acceptable salt includes the solvent addition forms.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of isolating or purifying the compound with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein.
  • the compounds provided herein optionally exist in unsolvated as well as solvated forms.
  • the methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity.
  • sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway.
  • the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.
  • the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl.
  • isotopically-labeled compounds described herein for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, WSGR Docket No.60179-726.601 increased in vivo half-life or reduced dosage requirements.
  • one or more hydrogen atoms of the compounds described herein is replaced with deuterium.
  • the compounds described herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration.
  • the compounds presented herein include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • E
  • Z
  • Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns.
  • compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure enantiomers.
  • resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
  • diastereomers are separated by separation/resolution techniques based upon differences in solubility.
  • separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof.
  • stereoisomers are obtained by stereoselective synthesis.
  • Synthesis of Compounds [0097] Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein. [0098] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed. [0099] Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6 th Edition, John Wiley and Sons, Inc.
  • compounds are prepared as described in the Examples.
  • Methods of Treatment [00102] In some embodiments, described herein is a method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis (AHL or AHLE), adult Refsum disease, infantile Refsum disease, Alexander disease, Alzheimer's disease, Balo concentric sclerosis, Canavan disease, central pontine myelinolysis (CPM), cerebral palsy, cerebrotendineous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic's syndrome, diffuse myelinoclastic sclerosis, encephalomyelitis, Guillain-Barre syndrome, WSGR Docket No.60179-726.601 Huntington’s disease (HD), idiopathic inflammatory demye
  • AD acute
  • a method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from multiple sclerosis.
  • a method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is X- linked adrenoleukodystrophy.
  • a method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor.
  • a compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor.
  • FAAH peripherally restricted fatty acid amide hydrolase
  • a method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis (AHL or AHLE), adult Refsum disease, infantile Refsum disease, Alexander disease, Alzheimer's disease, Balo concentric sclerosis, Canavan disease, central pontine myelinolysis (CPM), cerebral palsy, cerebrotendineous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic's syndrome, diffuse myelinoclastic sclerosis, encephalomyelitis, Guillain-Barre syndrome, Huntington’s disease (HD), idiopathic inflammatory demyelinating disease (HDD), Krabbe disease, Leber
  • a method of WSGR Docket No.60179-726.601 treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from multiple sclerosis, further comprising administering to the patient a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor.
  • a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein the CNS disease or disorder is selected from multiple sclerosis, further comprising administering to the patient a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor.
  • FAAH peripherally restricted fatty acid amide hydrolase
  • a method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is X-linked adrenoleukodystrophy, further comprising administering to the patient a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor.
  • the peripherally restricted FAAH inhibitor is ASP-3652.
  • Pharmaceutical compositions [00105] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions.
  • compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.
  • the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition.
  • the pharmaceutical composition further comprises a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor.
  • the pharmaceutical composition further comprises a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652.
  • Administration of the compounds and compositions described herein can be affected by any method that enables delivery of the compounds to the site of action.
  • enteral routes including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema
  • parenteral routes injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, WSGR Docket No.60179-726.601 intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient is presented as a bolus, electuary or paste.
  • Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • Tablets may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers are added.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, WSGR Docket No.60179-726.601 stabilizing and/or dispersing agents.
  • compositions may be presented in unit-dose or multi- dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • compositions for parenteral administration include aqueous and non- aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • Pharmaceutical compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • Pharmaceutical compositions may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • Pharmaceutical compositions may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • compositions suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation.
  • Pharmaceutical compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • a compound disclosed herein is formulated in such a manner that delivery of the compound to a particular region of the gastrointestinal tract is achieved.
  • a compound disclosed herein is formulated for oral delivery with bioadhesive polymers, pH-sensitive coatings, time dependent, biodegradable polymers, microflora activated systems, and the like, in order to effect delivering of the compound to a particular region of the gastrointestinal tract.
  • a compound disclosed herein is formulated to provide a controlled release of the compound. Controlled release refers to the release of the compound described herein from a dosage form in which it is incorporated according to a desired profile over an extended period of time.
  • Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles.
  • controlled release compositions allow delivery of an agent to a subject over an extended period of time according to a predetermined profile.
  • Such release rates can provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacologic response while minimizing side effects as compared to conventional rapid release dosage forms.
  • Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations.
  • WSGR Docket No.60179-726.601 Approaches to deliver the intact therapeutic compound to the particular regions of the gastrointestinal tract (e.g.
  • Matrix-Based Systems such as multi-matrix (MMX)-based delayed-release tablets, ensure the drug release in the colon.
  • MMX multi-matrix
  • the compounds and compositions described herein may include other agents conventional WSGR Docket No.60179-726.601 in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the compounds described herein, or a pharmaceutically acceptable salt thereof are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from administration of a dual S1P1 and S1P5 receptor agonist.
  • Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment involves administration of pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.
  • compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments.
  • compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial. [00138] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.
  • prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the WSGR Docket No.60179-726.601 disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
  • the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
  • the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days.
  • the dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
  • a maintenance dose is administered if necessary.
  • the dosage or the frequency of administration, or both is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day.
  • the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an WSGR Docket No.60179-726.601 individual treatment regime.
  • the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50.
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED 50 .
  • the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans.
  • the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED 50 with minimal toxicity.
  • the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
  • the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non- systemically or locally to the mammal.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
  • further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours.
  • the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is WSGR Docket No.60179-726.601 temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
  • the length of the drug holiday varies from 2 days to 1 year.
  • it is appropriate to administer at least one compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.
  • the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • a compound described herein, or a pharmaceutically acceptable salt thereof is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
  • the overall benefit experienced by the patient may be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like.
  • additional agent such as an additional therapeutically effective drug, an adjuvant or the like.
  • Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens is optionally determined by means similar to those set forth hereinabove for the actives themselves.
  • the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects.
  • a combination treatment regimen encompasses treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period.
  • Combination treatment WSGR Docket No.60179-726.601 further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
  • the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought is modified in accordance with a variety of factors (e.g. the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject).
  • the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.
  • dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth.
  • the compound provided herein when co- administered with one or more other therapeutic agents, is administered either simultaneously with the one or more other therapeutic agents, or sequentially.
  • the multiple therapeutic agents are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).
  • the compounds described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapies are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies.
  • the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms.
  • a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject.
  • a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.
  • EXAMPLES WSGR Docket No.60179-726.601 [00158] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.
  • a solution of the A-3 (13 g, 51.9 mmol) in DCM (30 mL) was added and stirred at rt for 3 h.
  • the reaction mixture was poured into ice and extracted with EtOAc (20 mL ⁇ 3).
  • the combined organic phase was washed with water, brine, dried over Na2SO4, and concentrated.
  • the residue was purified by flash chromatography over silica gel to afford A-4 (8.2 g, 57% yield) as a yellow solid.
  • WSGR Docket No.60179-726.601 [00163] To a mixture of A-4 (5 g, 18 mmol) in DCM (50 mL) was added BCl 3 (4.21 g, 35.9 mmol) at 0 °C.
  • reaction mixture was stirred at rt for 0.5 h.
  • Paraformaldehyde (3.31 g, 110 mmol) was added and the reaction mixture was stirred at 85 °C overnight.
  • the mixture was poured into water and extracted with EtOAc (50 mLx3).
  • the combined organic phase was washed with water, brine, dried over Na 2 SO 4 , filtered and concentrated in vacuum.
  • the residue was purified by flash chromatography over silica gel to afford A-7 (3.1 g, 86% yield) as a colorless oil.
  • A-10 (1.6 g, 39% yield) as a yellow solid.
  • a mixture of A-10 (1.6 g, 4.57 mmol), DIEA (708 mg, 5.48 mmol), AcOH (27.4 mg, 457 ⁇ mol) and A-11 (831 mg, 5.48 mmol) in DCE (20 mL) was stirred at room temperature overnight.
  • NaBH(OAc) 3 (2.9 g, 13.7 mmol) was added and the mixture was stirred at room temperature for 4 h.
  • Example 2 Synthesis of 1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4- dihydronaphthalen-2-yl)methyl)-N-methylazetidine-3-carboxamide (Compound 2) [00171] To a mixture of Compound 1 (50 mg, 115 ⁇ mol) and DIEA (44.5 mg, 344 ⁇ mol) in DMF (5 mL) was added HATU (65.5 mg, 172 ⁇ mol) at 0 °C. The mixture was stirred at 0 °C for 1 h and methanamine (17.8 mg, 574 ⁇ mol) was added. The mixture was stirred at rt overnight.
  • Example 3 Synthesis of 1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4- dihydronaphthalen-2-yl)methyl)-N-(pyridin-3-yl)azetidine-3-carboxamide (Compound 3) [00172] 1-((6-((2-Methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2- yl)methyl)-N-(pyridin-3-yl)azetidine-3-carboxamide (Compound 3) was prepared as described in Example 2 starting from Compound 1 and pyridin-3-amine. MS (ESI): 510.2 (M+H).
  • Example 4 Synthesis of 1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4- dihydronaphthalen-2-yl)methyl)-N-(pyridazin-3-yl)azetidine-3-carboxamide (Compound 4) WSGR Docket No.60179-726.601 [00173] 1-((6-((2- - 2- yl)methyl)-N-(pyridazin-3-yl)azetidine-3-carboxamide (Compound 4) was prepared as described in Example 2 starting from Compound 1 and pyridazin-3-amine. MS (ESI): 511.2 (M+H).
  • Example 5 Synthesis of N-(3-fluoropropyl)-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1- methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 5) [00174] N-(3-Fluoropropyl)-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4- dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 5) was prepared as described in Example 2 starting from Compound 1 and 3-fluoropropan-1-amine. MS (ESI): 495.3 (M+H).
  • Example 6 Synthesis of 1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4- dihydronaphthalen-2-yl)methyl)-N-(2,2,2-trifluoroethyl)azetidine-3-carboxamide (Compound 6) [00175] 1-((6-((2-Methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2- yl)methyl)-N-(2,2,2-trifluoroethyl)azetidine-3-carboxamide (Compound 6) was prepared as described in Example 2 starting from Compound 1 and 2,2,2-trifluoroethan-1-amine.
  • Example 8 Synthesis of N-cyclopropyl-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl- 3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 8) [00177] N-Cyclopropyl-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4- dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 8) was prepared as described in Example 2 starting from Compound 1 cyclopropanamine. MS (ESI): 475.4 (M+H).
  • Example 9 Synthesis of (R)-N-(sec-butyl)-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1- methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 9) [00178] (R)-N-(sec-butyl)-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4- dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 9) was prepared as described in Example 2 starting from Compound 1 and (2R)-butan-2-amine. MS (ESI): 491.4 (M+H).
  • Example 10 Synthesis of (S)-N-(sec-butyl)-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1- methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 10) [00179] (S)-N-(sec-butyl)-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4- dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 10) was prepared as described in Example 2 starting from Compound 1 and (2S)-butan-2-amine. MS (ESI): 491.4 (M+H).
  • Example 11 Synthesis of 1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4- dihydronaphthalen-2-yl)methyl)-N-(3,3,3-trifluoropropyl)azetidine-3-carboxamide (Compound 11) [00180] 1-((6-((2- - 2-yl)methyl)- N-(3,3,3-trifluoropropyl)azetidine-3-carboxamide (Compound 11) was prepared as described in Example 2 starting from Compound 1 and 3,3,3-trifluoropropan-1-amine.
  • Example 12 Synthesis of azetidin-1-yl(1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl- 3,4-dihydronaphthalen-2-yl)methyl)azetidin-3-yl)methanone (Compound 12) [00181] Azetidin-1-yl(1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4- dihydronaphthalen-2-yl)methyl)azetidin-3-yl)methanone (Compound 12) was prepared as described in Example 2 starting from Compound 1 and azetidine. MS (ESI): 475.2 (M+H).
  • the chromatography was performed on a reverse phase Kinetex 2.6 ⁇ m C18 column, 2.1 x 30 mm, 100 ⁇ .
  • the mobile phase A comprised of 0.1% formic acid in water
  • mobile phase B WSGR Docket No.60179-726.601 comprised of 0.1% formic acid in acetonitrile with a 1.5 min run time at the flow rate of 0.9 mL/min for the acid metabolite of test compounds.
  • the mass spectrometer API-5500 and API Q Trap 4000 Applied Biosystems/MDS SCIEX Instruments, Framingham, MA, USA) was operated under ESI positive or negative ion MRM mode.

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Abstract

L'invention concerne des promédicaments d'amide, des procédés de fabrication de tels composés, des compositions pharmaceutiques et des médicaments comprenant de tels composés, et des procédés d'utilisation de tels composés dans le traitement d'une maladie ou d'un trouble du SNC.
PCT/US2023/071789 2022-08-08 2023-08-07 Promédicaments d'amide et leurs utilisations WO2024036112A1 (fr)

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AU2005314938A1 (en) * 2004-12-13 2006-06-22 Ono Pharmaceutical Co., Ltd. Aminocarboxylic acid derivative and medicinal use thereof

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* Cited by examiner, † Cited by third party
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AU2005314938A1 (en) * 2004-12-13 2006-06-22 Ono Pharmaceutical Co., Ltd. Aminocarboxylic acid derivative and medicinal use thereof

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