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WO2024206153A1 - Inhibiteurs de l'homologue 2 de spinster (spns2) destinés à être utilisés en thérapie - Google Patents

Inhibiteurs de l'homologue 2 de spinster (spns2) destinés à être utilisés en thérapie Download PDF

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WO2024206153A1
WO2024206153A1 PCT/US2024/021158 US2024021158W WO2024206153A1 WO 2024206153 A1 WO2024206153 A1 WO 2024206153A1 US 2024021158 W US2024021158 W US 2024021158W WO 2024206153 A1 WO2024206153 A1 WO 2024206153A1
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nmr
mhz
alkyl
cdcl
compound
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Kevin R. Lynch
Yugesh Kharel
Tao Huang
Webster L. Santos
Christopher SHRADER
Kyle DUNNAVANT
Ariel Louise BURGIO
Andrew D. BAGE
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Virginia Tech Intellectual Properties Inc
UVA Licensing and Ventures Group
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Virginia Tech Intellectual Properties Inc
University of Virginia Patent Foundation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/195—Radicals derived from nitrogen analogues of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • S1P transporters There are two well characterized S1P transporters, SPNS2 (endothelium, microglia) and MFSD2B (erythrocytes, platelets).
  • SPNS2 endothelium, microglia
  • MFSD2B erythrocytes, platelets.
  • S1P release is coupled with S1P degradation in tissue parenchyma, a differential is generated between the extracellular (high) and intracellular (low) S1P concentrations.
  • the S1P gradient in blood functions to maintain endothelial barrier integrity, while other S1P concentration gradients control immune cell positioning.
  • S1P is particularly important for egress of lymphocytes from secondary lymphoid tissue into efferent lymph cells.
  • S1P receptor modulator (SRM) drugs mask lymphocytes from S1P by desensitizing S1P1 receptors.
  • SRM agonist activity at endothelial and cardiac S1P1 receptors drives adverse events such as first dose bradycardia and macular edema. Therefore, other methods to modulate immune cell trafficking by interdicting S1P signaling are needed.
  • X is a C 6 -C 10 -aryl or 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl ring members are independently selected from N, O, and S).
  • R 1 and R 2 are independently selected from the group consisting of H, C 1 -C 6- alkyl, C 1 - C 6 -alkoxy, C 1 -C 6 -haloalkoxy,C 3 -C 8 -cycloalkyl, C 1 -C 6 -haloalkyl, CN, and halo.
  • U is (A) an optionally fused, bridged, or spiro-fused 6- to 8- membered heterocycloalkyl wherein 2 ring atoms are N.
  • V is selected from the group consisting of H, C 1 -C 14 -alkyl,C 2 -C 12 -alkenyl, (C 6 -C 10 )aryl, (C 6 - C 10 )heteroaryl, -C 1 -C 10 -alkyl-(C 6 -C 10 )aryl, -C 2 -C 12 -alkenyl-(C 6 -C 10 )aryl, -C 1 -C 10 -alkyl-(C 3 - C 8 )cycloalkyl, -(3- to 14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S), -(C 1 -C 10
  • U is (B) a monocyclic 4- to 7-membered heterocycloalkyl (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S).
  • V is selected from the group consisting of H, -C 1 -C 14 -alkyl, -C 1 -C 10 - alkyl-O-(C 3 -C 14 )cycloalkyl, -C 1 -C 10 -alkyl-O-(C 6 -C 10 )aryl, -C 1 -C 10 -alkyl-NR x -(C 6 -C 10 )aryl, - C 1 -C 10 -alkyl-NR x C(O)(C 6 -C 10 )aryl, -C 1 -C 10 -alkyl-C(O)NR x (C 6 -C 10 )aryl, -C 2 -C 12 -alkenyl
  • T is -C(O)- or -NR x C(O)-.
  • R x is H or C 1 -C 6 -alkyl.
  • m is an integer selected from 0, 1, 2, 3, 4, 5, and 6.
  • each alkyl, alkoxy, alkenyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl is optionally substituted with 1 – 5 substituents independently selected from the group consisting of hydroxy, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkoxy, C 1 -C 6 -haloalkyl, -NR’2, - NHC(O)(OC 1 -C 6 -alkyl), -NO 2 , -CN, oxo, -C(O)OH, -C(O)O(C 1 -C 6 -alkyl), -C 1 -C 6 -alkyl(C 1 - C 6 -alkoxy), -C(O)NH 2 , C 1 -C 6 -alkoxy, C 3 -C 14 -cycloalkyl, -C(O)C 1 -C 6
  • Each R’ is independently selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl, C 6 -C 10 -aryl, 3- to 14-membered heterocycloalkyl and -(C 1 -C 6 -alkyl)- (3- to 14-membered heterocycloalkyl) (wherein 1-4 ring members are independently selected from N, O, and S), and 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S.
  • Another embodiment of the disclosure is a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as described herein.
  • the disclosure also provides, in an embodiment, a method of inhibiting spinster homolog 2 (SPNS2), comprising contacting SPNS2 with an effective amount of a compound or a pharmaceutically acceptable salt thereof as described herein.
  • SPNS2 spinster homolog 2
  • the present disclosure provides a method of treating a patient afflicted by a neoplastic disease, comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described herein.
  • the present disclosure provides a method of treating a patient afflicted by an allergic disease, comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described herein.
  • the disclosure provides a method of treating a patient afflicted with an autoimmune disease, comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described herein.
  • the disclosure provides a method of treating a patient afflicted with a fibrotic disease, comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described herein.
  • FIG.1. shows a representative data set for Spns2-dependent S1P transport blockers (STBs) in the EAE (Experimental Autoimmune Encephalomyelitis) model of multiple sclerosis.
  • the chemotactic lipid, sphingosine 1-phosphate (S1P), is required for the correct positioning of immune cells. Lymphocyte egress from secondary lymphoid tissues such as lymph nodes is, for example, dependent on S1P signaling. S1P’s role in lymphocyte trafficking was discovered when the mechanism of action of the immunosuppressive drug fingolimod (FTY720) was investigated. Fingolimod’s active metabolite, phospho-FTY720, desensitizes lymphocyte S1P1 receptors; thereby, rendering these cells unable to detect S1P 1 . The resulting lymphopenia is a pharmacodynamic marker of such S1P1 receptor agonists.
  • FTY720 immunosuppressive drug fingolimod
  • the S1P in lymph is nearly undetectable in mouse strains deficient in the S1P transporter SPNS2, suggesting that lymph endothelial cells extrude S1P into lymph via SPNS2 3 , resulting in a lymph - LN S1P concentration gradient.
  • Plasma S1P gradients are likewise maintained by prominent S1P catabolic activity in tissue parenchyma (excepting blood) coupled with the extrusion of S1P into plasma by red blood cells (RBCs).
  • RBCs red blood cells
  • Mfsd2b null mice do not have diminished numbers for circulating lymphocytes 4 .
  • the plasma – tissue S1P concentration gradient is important for maintaining endothelial barrier integrity 6,7 .
  • S1P lyase inhibitors will eliminate the lymph-LN S1P gradient, which will modulate the immune system by disrupting lymphocyte trafficking analogous to S1P1 agonists.
  • S1P lyase deficiency whether accomplished through genetic manipulation of mice or S1P lyase inhibitor administration, raises S1P levels in tissues, including lymph nodes, with a resulting lymphopenia 1,8 .
  • administering a selective S1P lyase inhibitor to rats and inducing global deletion of the S1P lyase gene (Sgpl1) in mice were both found to be nephrotoxic 8 .
  • Spns2 inhibitors 16 Use of an Spns2 inhibitor in anti-fibrotic therapy can arise from another study employing both mutant mouse strains and one of the present inventors’ Spns2 inhibitors 16 . Specifically, in two models of kidney fibrosis, mice rendered deficient in Spns2 in kidney pericytes as well as mice treated with an Spns2 inhibitor (SLF1081851) 13 , had significantly less fibrosis and improved function of the injured kidney 16 .
  • Alkyl refers to straight or branched chain hydrocarbyl including from 1 to about 20 carbon atoms. For instance, an alkyl can have from 1 to 14 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Exemplary alkyl includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like, and also includes branched chain isomers of straight chain alkyl groups, for example without limitation, -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH(CH 2 CH 3 ) 2 , - C(CH 3 ) 3 , -C(CH 2 CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 2 CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 C(CH 3 ) 3 , -CH 2 C(CH 3 )(CH 2 CH 3 ) 3
  • a “haloalkyl” is an alkyl, as defined herein, that is substituted with at least one, such as 1 – 8, halo substituents.
  • Each of the terms “halogen,” “halide,” and “halo” refers to -F, -Cl, -Br, or -I.
  • alkenyl refers to straight or branched chain hydrocarbyl groups including from 2 to about 20 carbon atoms having 1-3, 1-2, or at least one carbon to carbon double bond. An alkenyl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.
  • Substituted alkenyl refers to alkenyl substituted at 1 or more, e.g., 1, 2, 3, 4, 5, or even 6 positions, which substituents are attached at any available atom to produce a stable compound, with substitution as described herein. “Optionally substituted alkenyl” refers to alkenyl or substituted alkenyl. [0037] “Alkyne or “alkynyl” refers to a straight or branched chain unsaturated hydrocarbon having the indicated number of carbon atoms and at least one triple bond.
  • Examples of a (C 2 - C 8 )alkynyl group include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, 1- pentyne, 2-pentyne, 1-hexyne, 2-hexyne, 3-hexyne, 1-heptyne, 2-heptyne, 3-heptyne, 1- octyne, 2-octyne, 3-octyne and 4-octyne.
  • An alkynyl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.
  • Substituted alkynyl refers to an alkynyl substituted at 1 or more, e.g., 1, 2, 3, 4, 5, or even 6 positions, which substituents are attached at any available atom to produce a stable compound, with substitution as described herein.
  • Optionally substituted alkynyl refers to alkynyl or substituted alkynyl.
  • alkoxy refers to an -O-alkyl group having the indicated number of carbon atoms.
  • a (C 1 -C 6 )alkoxy group includes -O-methyl, -O-ethyl, -O-propyl, -O- isopropyl, -O-butyl, -O-sec-butyl, -O-tert-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl, -O- hexyl, -O-isohexyl, and -O-neohexyl.
  • a “haloalkoxy” is an alkoxy, as defined herein, that is substituted with at least one, such as 1 – 8, halo substituents.
  • cycloalkyl refers to a monocyclic, bicyclic, tricyclic, or polycyclic, 3- to 14-membered ring system, which is either saturated, such as “cycloalkyl,” or unsaturated, such as “cycloalkenyl.”
  • cycloalkenyl refers specifically to cyclic alkenyl, such as C 3 -C 6 -cycloalkenyl.
  • the cycloalkyl may be attached via any atom. Cycloalkyl, for instance, also contemplates fused rings wherein, for instance, a cycloalkyl is fused to an aryl or heteroaryl ring as defined herein.
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl.
  • a cycloalkyl group can be unsubstituted or optionally substituted with one or more substituents as described herein.
  • “Substituted cycloalkyl” refers to cycloalkyl substituted at 1 or more, e.g., 1, 2, 3, 4, 5, or even 6 positions, which substituents are attached at any available atom to produce a stable compound, with substitution as described herein.
  • Optionally substituted cycloalkyl refers to cycloalkyl or substituted cycloalkyl.
  • Aryl when used alone or as part of another term means a carbocyclic aromatic group whether or not fused having the number of carbon atoms designated or if no number is designated, up to 14 carbon atoms, such as a C 6 -C 14 -aryl. Particular aryl groups are phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like (see e.g. Lang’s Handbook of Chemistry (Dean, J. A., ed) 13 th ed. Table 7-2 [1985]).
  • a particular aryl is phenyl.
  • “Aryl” also includes aromatic ring systems that are optionally fused with a cycloalkyl ring, as herein defined.
  • An aryl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.
  • a “substituted aryl” is an aryl that is independently substituted with one or more substituents attached at any available atom to produce a stable compound, wherein the substituents are as described herein.
  • “Optionally substituted aryl” refers to aryl or substituted aryl.
  • the term “heteroatom” refers to N, O, and S.
  • Heteroaryl alone or in combination with any other moiety described herein, refers to a monocyclic aromatic ring structure containing 5 to 10, such as 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, such as 1-4, 1-3, or 1-2, heteroatoms independently selected from the group consisting of O, S, and N.
  • Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen.
  • a carbon or heteroatom is the point of attachment of the heteroaryl ring structure such that a stable compound is produced.
  • heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, and indolyl.
  • a heteroaryl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.
  • a “substituted heteroaryl” is a heteroaryl that is independently substituted, unless indicated otherwise, with one or more, e.g., 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, also 1 substituent, attached at any available atom to produce a stable compound, wherein the substituents are as described herein.
  • “Optionally substituted heteroaryl” refers to heteroaryl or substituted heteroaryl.
  • Heterocycloalkyl means a saturated or unsaturated non-aromatic monocyclic, bicyclic, tricyclic or polycyclic ring system that has from 3 to 14, such as 3 to 6, atoms in which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N.
  • a heterocycloalkyl is optionally fused with aryl or heteroaryl of 5-6 ring members, and includes oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen.
  • the point of attachment of the heterocycloalkyl ring is at a carbon or heteroatom such that a stable ring is retained.
  • heterocycloalkyl groups include without limitation morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuryl, and dihydroindolyl.
  • a hetercycloalkyl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.
  • “Optionally substituted heterocycloalkyl” denotes a heterocycloalkyl that is substituted with 1 to 3 substituents, e.g., 1, 2 or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are as described herein.
  • nitrile or “cyano” can be used interchangeably and refer to a -CN group which is bound to a carbon atom of a heteroaryl ring, aryl ring and a heterocycloalkyl ring.
  • a “hydroxyl” or “hydroxy” refers to an –OH group.
  • the substituent -CO 2 H may be replaced with bioisosteric replacements such as: and the like, wherein R has the same definition as R A as defined herein. See, e.g., THE PRACTICE OF MEDICINAL CHEMISTRY (Academic Press: New York, 1996), at page 203.
  • R has the same definition as R A as defined herein. See, e.g., THE PRACTICE OF MEDICINAL CHEMISTRY (Academic Press: New York, 1996), at page 203.
  • Compounds described herein can exist in various isomeric forms, including configurational, geometric, and conformational isomers, including, for example, cis- or trans- conformations.
  • the compounds may also exist in one or more tautomeric forms, including both single tautomers and mixtures of tautomers.
  • the term “isomer” is intended to encompass all isomeric forms of a compound of this disclosure, including tautomeric forms of the compound.
  • the compounds of the present disclosure may also exist in open-chain or cyclized forms. In some cases one or more of the cyclized forms may result from the loss of water.
  • the specific composition of the open-chain and cyclized forms may be dependent on how the compound is isolated, stored or administered. For example, the compound may exist primarily in an open-chained form under acidic conditions but cyclize under neutral conditions. All forms are included in the disclosure. [0055] Some compounds described herein can have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms.
  • a compound as described herein can be in the form of an optical isomer or a diastereomer. Accordingly, the disclosure encompasses compounds and their uses as described herein in the form of their optical isomers, diastereoisomers and mixtures thereof, including a racemic mixture.
  • Optical isomers of the compounds of the disclosure can be obtained by known techniques such as asymmetric synthesis, chiral chromatography, simulated moving bed technology or via chemical separation of stereoisomers through the employment of optically active resolving agents.
  • stereoisomer means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound.
  • a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, for example greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, or greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of the other stereoisomers of the compound.
  • the stereoisomer as described above can be viewed as composition comprising two stereoisomers that are present in their respective weight percentages described herein.
  • the depicted structure controls. Additionally, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. In some cases, however, where more than one chiral center exists, the structures and names may be represented as single enantiomers to help describe the relative stereochemistry. Those skilled in the art of organic synthesis will know if the compounds are prepared as single enantiomers from the methods used to prepare them.
  • a compound of Formula I includes a pharmaceutically acceptable salt of the compound.
  • a “pharmaceutically acceptable salt” is a pharmaceutically acceptable, organic or inorganic acid or base salt of a compound described herein.
  • Representative pharmaceutically acceptable salts include, e.g., alkali metal salts, alkali earth salts, ammonium salts, water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2, 2 -disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, iso
  • a pharmaceutically acceptable salt can have more than one charged atom in its structure.
  • the pharmaceutically acceptable salt can have multiple counterions.
  • a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counterions.
  • the terms “treat”, “treating” and “treatment” refer to the amelioration or eradication of a disease or symptoms associated with a disease. In certain embodiments, such terms refer to minimizing the spread or worsening of the disease resulting from the administration of one or more prophylactic or therapeutic agents to a patient with such a disease.
  • the terms “prevent,” “preventing,” and “prevention” refer to the prevention of the onset, recurrence, or spread of the disease in a patient resulting from the administration of a prophylactic or therapeutic agent.
  • the term “effective amount” refers to an amount of a compound as described herein or other active ingredient sufficient to provide a therapeutic or prophylactic benefit in the treatment or prevention of a disease or to delay or minimize symptoms associated with a disease. Further, a therapeutically effective amount with respect to a compound as described herein means that amount of therapeutic agent alone, or in combination with other therapies, that provides a therapeutic benefit in the treatment or prevention of a disease.
  • a “patient” or subject” includes an animal, such as a human, cow, horse, sheep, lamb, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig.
  • the animal is a mammal such as a non-primate and a primate (e.g., monkey and human).
  • a patient is a human, such as a human infant, child, adolescent or adult.
  • “Inhibitor” means a compound that induces dose dependent lymphopenia and a modest decrease in plasma S1P. In an embodiment, an inhibitor binds to SPNS2.
  • COMPOUNDS [0065] As described generally above, the present disclosure provides compounds, pharmaceutically acceptable salts, and/or tautomers thereof, wherein the compounds conform to Formula I: , [0066] X is a C 6 -C 10 -aryl or 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl ring members are independently selected from N, O, and S).
  • R 1 and R 2 are independently selected from the group consisting of H, C 1 -C 6 -alkyl, C 1 - C 6- alkoxy, C 1 -C 6- haloalkoxy, C 3 -C 8 -cycloalkyl, C 1 -C 6 -haloalkyl, CN, and halo.
  • U is (A) an optionally fused, bridged, or spiro-fused 6- to 8- membered heterocycloalkyl wherein 2 ring atoms are N.
  • V is selected from the group consisting of H, C 1 -C 14 -alkyl, C 2 -C 12 -alkenyl, (C 6 -C 10 )aryl, (C 6 - C 10 )heteroaryl, -C 1 -C 10 -alkyl-(C 6 -C 10 )aryl, -C 2 -C 12 -alkenyl-(C 6 -C 10 )aryl, -C 1 -C 10 -alkyl-(C 3 - C 8 )cycloalkyl, -(3- to 14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S), -(C 1 -C 10
  • V is selected from the group consisting of H, -C 1 -C 14 -alkyl, -C 1 -C 10 - alkyl-O-(C 6 -C 10 )aryl, -C 1 -C 10 - alkyl-NR x -(C 6 -C 10 )aryl, -C 1 -C 10 -alkyl-NR x C(O)(C 6 -C 10 )aryl, - C 1 -C 10 -alkyl-C(O)NR x (C 6 -C 10 )aryl,-C 2 -C 12 -alkenyl-O-(C 6 -C 10 )aryl, -C 1 -C 10 -alkyl-O-(C 6 - C 10 )heteroaryl (wherein 1 to 4 heteroaryl ring members are independently selected from N, O, and S), and -C 2 -C 12 -alkenyl-O-(C 6 -
  • T is -C(O)- or -NR x C(O)-.
  • R x is H or C 1 -C 6 -alkyl.
  • m is an integer selected from 0, 1, 2, 3, 4, 5, and 6.
  • each alkyl, alkoxy, alkenyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl is optionally substituted with 1 – 5 substituents independently selected from the group consisting of hydroxy, halo, C 1 -C 6 -alkyl, C 1 -C 6- haloalkoxy, C 1 -C 6 -haloalkyl, -NR’ 2 , - NHC(O)(OC 1 -C 6 -alkyl), -NO 2 , -CN, oxo, -C(O)OH, -C(O)O(C 1 -C 6 -alkyl), -C 1 -C 6 -alkyl(C 1 - C 6 -alkoxy), -C(O)NH 2 , C 1 -C 6 -alkoxy, C 1 -C 6 -alkyl, C 3 -C 14 -cycloalkyl,
  • Each R’ is independently selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl, C 6 -C 10 -aryl, 3- to 14-membered heterocycloalkyl and -(C 1 -C 6 -alkyl)- (3- to 14-membered heterocycloalkyl) (wherein 1-4 ring members are independently selected from N, O, and S), and 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S.
  • U is (A) an optionally substituted and optionally fused, bridged, or spiro-fused 6- to 8-membered heterocycloalkyl wherein 2 ring atoms are N, and V is selected from the group consisting of H, C 1 -C 14 -alkyl, C 2 -C 12 -alkenyl, (C 6 -C 10 )aryl, (C 6 - C 10 )heteroaryl, -C 1 -C 10 -alkyl-(C 6 -C 10 )aryl, -C 2 -C 12 -alkenyl-(C 6 -C 10 )aryl, -C 1 -C 10 -alkyl-(C 3 - C 8 )cycloalkyl, -(3- to 14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S), -(C 1 -C 1 -C
  • V is C 1 -C 14 -alkyl. In an illustrative embodiment, V is C 8 -C 12 -alkyl. [0078] In additional embodiments wherein U conforms to (A), U is selected from the group consisting of optionally substituted: [0079] In various embodiments, U is (B) an optionally substituted monocyclic 4- to 7- membered heterocycloalkyl (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S), and V is selected from the group consisting of H, -C 1 -C 14 -alkyl, - C 1 -C 10 -alkyl-O-(C 3 -C 14 )cycloalkyl, -C 1 -C 10 -alkyl-O-(C 6 -C 10 )aryl, -C 1 -C 10 -alkyl-NR x -(C 6 - C 10
  • U is a monocyclic 5- to 7- membered heterocycloalkyl (wherein 1 or 2 heterocycloalkyl members are independently selected from N and O).
  • heterocycloalkyl include optionally substituted pyrrolidinyl, oxazolidinyl, isoxazolidinyl, imidazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl.
  • U is piperazinyl.
  • V is -C 1 -C 10 -alkyl-O-(C 6 -C 10 )aryl.
  • V is -C 3 -C 8 -alkyl-O-phenyl.
  • V is -C 3 -C 8 -alkyl-O-phenyl and the phenyl is substituted with a C 3 -C 14 -cycloalkyl.
  • the cycloalkyl is a cyclopropyl.
  • X is C 6 -C 10 -aryl.
  • X is phenyl.
  • W is a bond or O.
  • W is a bond.
  • T is -NR x C(O)-.
  • R x is H.
  • T is -C(O)-.
  • m is 0.
  • the present disclosure provides a compound or pharmaceutically acceptable salt thereof wherein: U is (A) an optionally substituted and optionally fused, bridged, or spiro-fused 6- to 8- membered heterocycloalkyl wherein 2 ring atoms are N; X is C 6 -C 10 -aryl; T is -NR x C(O)- wherein R x is H; V is C 8 -C 12 -alkyl; and W is a bond; and m is 0.
  • the present disclosure also provides a compound or pharmaceutically acceptable salt thereof wherein: U is (B) an optionally substituted 5- to 7-membered heterocycloalkyl (wherein 1 or 2 heterocycloalkyl members are independently selected from N and O); X is C 6 -C 10 -aryl; T is -NR x C(O)- wherein R x is H; V is -C 1 -C 10 -alkyl-O-(C 6 -C 10 )aryl; and W is a bond; and m is 0. [0089] The present disclosure provides specific examples of Formula I compounds, and their pharmaceutically acceptable salts, and/or tautomers thereof as set forth in Table 1 and Table 2 below.
  • Table 2 Examples of Formula I Compounds (A: IC 50 ⁇ 1 ⁇ M; B: IC 50 > 1 ⁇ M)
  • the disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds according to Formula I or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof in admixture with a pharmaceutically acceptable carrier.
  • the composition further contains, in accordance with accepted practices of pharmaceutical compounding, one or more additional therapeutic agents, pharmaceutically acceptable excipients, diluents, adjuvants, stabilizers, emulsifiers, preservatives, colorants, buffers, flavor imparting agents.
  • the pharmaceutical composition comprises a compound selected from those illustrated in Table 1 or Table 2 or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, and a pharmaceutically acceptable carrier.
  • composition of the present disclosure is formulated, dosed, and administered in a manner consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular subject being treated, the clinical condition of the subject, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the “therapeutically effective amount” of a compound (or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof that is administered is governed by such considerations, and is the minimum amount necessary to induce dose dependent lymphopenia and a modest decrease in plasma SIP, or to inhibit SPNS2 activity, or both. Such amount may be below the amount that is toxic to normal cells, or the subject as a whole.
  • the initial therapeutically effective amount of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure that is administered is in the range of about 0.01 to about 200 mg/kg or about 0.1 to about 20 mg/kg of patient body weight per day, with the typical initial range being about 0.3 to about 15 mg/kg/day.
  • Oral unit dosage forms, such as tablets and capsules may contain from about 1 mg to about 1000 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure. In another embodiment, such dosage forms contain from about 50 mg to about 500 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure.
  • such dosage forms contain from about 25 mg to about 200 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure. In still another embodiment, such dosage forms contain from about 10 mg to about 100 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure. In a further embodiment such dosage forms contain from about 5 mg to about 50 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure.
  • compositions can be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • Suitable oral compositions as described herein include without limitation tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, syrups or elixirs.
  • compositions suitable for single unit dosages that comprise a compound of the disclosure or its pharmaceutically acceptable stereoisomer, salt, or tautomer and a pharmaceutically acceptable carrier.
  • compositions suitable for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions.
  • liquid formulations of the inventive compounds contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically palatable preparations of the SPNS2 inhibitor.
  • a compound of the present disclosure in admixture with non-toxic pharmaceutically acceptable excipients is used for the manufacture of tablets.
  • excipients include without limitation inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known coating techniques to delay disintegration and absorption in the gastrointestinal tract and thereby to provide a sustained therapeutic action over a desired time period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example peanut oil, liquid paraffin or olive oil.
  • a compound of the present disclosure is admixed with excipients suitable for maintaining a stable suspension.
  • excipients include without limitation are sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia.
  • Oral suspensions can also contain dispersing or wetting agents, such as naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • dispersing or wetting agents such as naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycet
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending a compound of the present disclosure in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide a compound of the present disclosure in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., sodium EDTA
  • suspending agent e.g., sodium EDTA
  • preservatives e.g., sodium sulfate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation reaction products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable, an aqueous suspension or an oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of Formula I may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • compositions for parenteral administrations are administered in a sterile medium.
  • the parenteral formulation can either be a suspension or a solution containing dissolved drug.
  • Adjuvants such as local anesthetics, preservatives and buffering agents can also be added to parenteral compositions.
  • SIP gradients are chemotactic, a property that enables correct positioning of immune cells, and they help to maintain endothelial barrier integrity. Accordingly, SIP gradients are manipulated for therapeutic benefit using Formula I compounds because they target the endothelial SIP exporter, SPNS2.
  • the disclosure provides a method of inhibiting spinster homolog 2 (SPNS2).
  • SPNS2 spinster homolog 2
  • the method comprises contacting SPNS2 with an effective amount of a compound as described herein.
  • the contacting occurs in vitro. In other embodiments, the contacting occurs ex vivo or in vivo.
  • Another embodiment is a method of treating a patient afflicted by a neoplastic disease, comprising administering to the patient a therapeutically effective amount a compound as described herein.
  • the neoplastic disease is metastatic neoplasms.
  • An additional embodiment is a method of treating a patient afflicted with an allergic disease, comprising administering to the patient a therapeutically effective amount of a compound as described herein.
  • An illustrative allergic disease is asthma.
  • Formula I compounds also are useful in a method of treating a patient afflicted with an autoimmune disease, comprising administering to the patient a therapeutically effective amount of the compound.
  • the autoimmune disease is chosen from multiple sclerosis, type I diabetes, inflammatory bowel diseases including Crohn’s disease and ulcerative colitis, Grave’s disease, Addison’s disease, dermatomyositis, myasthenia gravis, systemic lupus erythematosus, scleroderma, psoriasis, and atopic dermatitis.
  • An exemplary autoimmune disease is multiple sclerosis.
  • multiple sclerosis comprises one or more progressive forms of multiple sclerosis as well as the remitting relapsing form of the disease.
  • Additional embodiments include a method of treating a patient afflicted with atherosclerosis or pulmonary arterial hypertension.
  • the present disclosure provides a method for treating a patient afflicted with a fibrotic disease.
  • the method comprises administering to the patient a therapeutically effective amount of a compound as described herein.
  • the fibrotic disease is a renal fibrosis, such as chronic kidney disease. 10,11
  • LITERATURE CITED IN THE DISCLOSURE [00119] Numbered citations in the present disclosure are as follows, and are incorporated by reference as if fully set forth herein: 1. Schwab SR, Pereira JP, Matloubian M, Xu Y, Huan, Y, Cyster JG.
  • MFSD2B is essential for the sphingosine-1-phosphate export in erythrocytes and platelets Nature 550, 524-528 (2017) 5.
  • Kobayashi N, Kawasaki-Nishi S, Otsuka M, Hisano Y, Yamaguchi A, Nishi T MFSD2B is a sphingosine 1-phosphate transporter in erythroid cells.
  • Mfsd2b and Spns2 are essential for maintenance of blood vessels during development and in anaphylactic shock.
  • Van der Weyden L Arends MJ, Campbell AD, Bald T, Wardle-Jones H, Griggs N, Velasco-Herrera MD, Tüting T, Sansom OJ, Karp NA, Clare S, Gleeson D, Rider E, Galli A, Tuck E, Cambridge EL, Voet T, Macaulay IC, Wong K, Sanger Mouse Genetics Project, Spiegel S, Speak AO, Adams DJ. Genome-wide in vio screen identifies novel new regulators for metastatic colonization. Nature 531, 233-236 (2017) 15.
  • reaction was stirred for 30 minutes, then ketone (1.0 equiv.) was added, and the reaction was allowed to warm to 25 °C and stirred, monitoring by TLC.
  • the reaction was quenched with water, extracted with ethyl acetate (3x), and the organic extracts were combined, washed with brine (2x) dried with MgSO 4 , filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give the desired compound.
  • N-(pent-4-en-1-yl)benzamide, 1az To a stirring solution of hex-5-en-1-ol (0.20 g, 0.24 mL, 1.0 eq., 2.0 mmol), triethylsilane (0.47 g, 0.64 mL, 2.0 eq., 4.0 mmol) and ytterbium(III) trifluoromethanesulfonate hydrate (51 mg, 0.04 eq., 80 ⁇ mol) in 1,2-Dichloroethane (8.0 mL) was added cyclohexanone (0.39 g, 0.41 mL, 2.0 eq., 4.0 mmol) under a nitrogen atmosphere.
  • reaction was stirred at 25 °C for 30 minutes, then aqueous hydrogen chloride (21 mg, 0.57 mL, 1.0 molar, 0.70 eq., 0.57 mmol) was added and the reaction was stirred at 25 °C for 24 hours.
  • the reaction was diluted with water (25 mL) and extracted with ethyl acetate (3 x 25 mL). The organic extracts were combined, washed with brine (2 x 50 mL), dried with sodium sulfate, filtered, and concentrated in vacuo.
  • reaction mixture was stirred at 110 °C for 16 hours.
  • the reaction mixture was allowed to cool to room temperature, then concentrated in vacuo.
  • 6-bromo-2-chlorobenzo[d]oxazole, 10 [00676] To a stirring solution of 6-bromobenzo[d]oxazole-2-thiol 9 (0.45 g, 1 Eq, 2.0 mmol) in dichloromethane (6 mL) was added sequentially sulfurous dichloride (0.58 g, 0.36 mL, 2.5 Eq, 4.9 mmol) and N,N-dimethylformamide (5.7 mg, 6.1 ⁇ L, 0.04 Eq, 78 ⁇ mol) under a nitrogen atmosphere.
  • reaction was stirred at room temperature for 3 hours, monitoring by TLC.
  • the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 5 mL). The organic extracts were combined, washed with brine (3 x 10 mL), dried with sodium sulfate, filtered, and concentrated in vacuo.
  • tert-butyl (R)-3-(((6-bromobenzo[d]oxazol-2-yl)amino)methyl)pyrrolidine- 1-carboxylate [00678] To a stirred solution of 6-bromo-2-chlorobenzo[d]oxazole 10 (0.66 g, 1.0 Eq, 2.8 mmol) in N,N-dimethylformamide (9.5 mL) was added potassium carbonate (0.78 g, 2.0 Eq, 5.7 mmol) and tert-butyl (R)-3-(aminomethyl)pyrrolidine-1-carboxylate (0.68 g, 1.2 Eq, 3.4 mmol).
  • reaction was heated to 120 °C for 16 hours, monitoring by TLC.
  • the reaction mixture was diluted with ethyl acetate (20 mL), washed with saturated lithium bromide solution (3 x 20 mL), dried with sodium sulfate, filtered, and concentrated in vacuo.
  • reaction was stirred at room temperature, monitoring by TLC, then diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic extracts were combined, washed with brine (2 x 15 mL), dried with sodium sulfate, filtered, and concentrated in vacuo.
  • tert-butyl (S)-3-(((tert-butoxycarbonyl)(6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzo[d]oxazol-2-yl)amino)methyl)pyrrolidine-1-carboxylate Synthesized according to General Procedure 14.0.107 g, 65%, off-white amorphous solid.
  • drugs that interfere with S1P signaling modulate the immune response at the level of lymphocyte trafficking.
  • Such drugs are approved for treatment of autoimmune diseases such as multiple sclerosis and ulcerative colitis.
  • the new chemical entities claimed herein modulate lymphocyte trafficking by blocking a different node in the S1P signaling pathway. Therefore, these molecules are expected to be efficacious in treating patients suffering from a condition requiring immunosuppression such as autoimmune disorders and organ transplantation.
  • autoimmune disorders are multiple sclerosis, inflammatory bowel diseases (for example, ulcerative colitis and Crohn’s disease), systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, scleroderma, Sjogren’s syndrome, atopic dermatitis, uveitis, vasculitis, and so forth.
  • Transplanted organs include kidney, heart, liver, lung, intestine, stomach, pancreatic beta cells, and stem cells. Included are complications such as graft vs host disease that can arise from organ or stem cell transplants.
  • FIG. 1 graft vs host disease that can arise from organ or stem cell transplants.
  • STBs Spns2-dependent SIP transport blockers

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Abstract

La présente divulgation concerne des composés inhibiteurs de SPNS2 selon la formule I : T, U, V, W, X, R1, R2 et m étant tels que définis dans la description. La présente invention concerne également des sels pharmaceutiquement acceptables et/ou des tautomères de composés de formule I tels que décrits dans la description. L'invention concerne en outre leurs procédés d'utilisation en thérapie, par exemple dans des maladies pour lesquelles une activité immunomodulatrice et/ou anti-fibrotique est indiquée.
PCT/US2024/021158 2023-03-24 2024-03-22 Inhibiteurs de l'homologue 2 de spinster (spns2) destinés à être utilisés en thérapie Pending WO2024206153A1 (fr)

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