WO2017004608A1 - Modulateurs d'oxadiazole de s1p, ainsi que procédés de fabrication et d'utilisation correspondants - Google Patents

Modulateurs d'oxadiazole de s1p, ainsi que procédés de fabrication et d'utilisation correspondants Download PDF

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WO2017004608A1
WO2017004608A1 PCT/US2016/040892 US2016040892W WO2017004608A1 WO 2017004608 A1 WO2017004608 A1 WO 2017004608A1 US 2016040892 W US2016040892 W US 2016040892W WO 2017004608 A1 WO2017004608 A1 WO 2017004608A1
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compound
hydrogen
alkyl
mmol
amino
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PCT/US2016/040892
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English (en)
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Wei Xu
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Exelixis, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • 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
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to the field of agonists of Sphingosine 1 -Phosphate Type 1 Receptor (S1P1R or SI PI) and/or Type 5 Receptor (S1P5R or S1P5), and methods of their use.
  • S1P1R or SI PI Sphingosine 1 -Phosphate Type 1 Receptor
  • S1P5R Type 5 Receptor
  • Sphingosine 1 -phosphate is a biologically active lysophospholipid that serves as a key regulator of cellular differentiation and survival. Circulation of mature lymphocytes between blood and secondary lymphoid tissues plays an important role in the immune system. Agonism of S1P1R has been shown to lead to the sequestration of peripheral lymphocytes into secondary lymphoid tissue. Such sequestration of lymphocytes has been shown to result in immunosuppressive activity in animal models. Known S1P1 receptor agonists, such as FTY720, have been shown to markedly decrease peripheral blood lymphocytes through the sequestration of lymphocytes into secondary lymphoid tissues.
  • Potent agonists of the SI PI receptor are thought to induce long-term down-regulation of S1P1 on lymphocytes, thereby inhibiting the migration of lymphocytes toward SIP.
  • the consequential decrease in trafficking and infiltration of antigen-specific T cells provides a means of immunomodulating activity that can be useful in the treatment of various immune- related conditions such as graft versus host disease and autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosis. Therefore, agonists of S1P1R are potentially useful immunosuppressants for the treatment of a variety of autoimmune conditions.
  • the myelin sheath that surrounds neural cell axons is required to insulate neural axons and allow rapid movement of electrical impulses through the myelinated nerve fiber. Demyelination, or loss of the integrity of the myelin sheath is the hallmark of autoimmune neurodegenerative diseases, including multiple sclerosis.
  • the myelin sheath in the central nervous system is produced by oligodendrocytes. Mature, myelin-producing
  • oligodendrocytes express SIP receptor transcripts in relative abundance of
  • Fingolimod a sphingosine- 1 -phosphate (SIP) analogue that has been used successfully in clinical trials as a systemic immunomodulatory therapy for multiple sclerosis, readily accesses the central nervous system.
  • Fingolimod a sphingosine- 1 -phosphate (SIP) analogue that has been used successfully in clinical trials as a systemic immunomodulatory therapy for multiple sclerosis, readily accesses the central nervous system.
  • SIP sphingosine- 1 -phosphate
  • Sphingosine-1 -phosphate has been shown to regulate the migration of osteoclast precursors, demonstrating a role in bone mineral homeostasis and suggesting a role in treating bone-destroying disorders such as rheumatoid arthritis and osteoporosis ⁇ Nature 2009, 458(7237), 524-528).
  • S1P3 has been associated with acute toxicty and bradycardia in rodents (Hale, et. al. Bioorganic & Med Chem Lett., 2004, 14(13), 3501-3505; J. Pharmacol. Exp. Ther. 2004, 309(2), 758-768; J. Med Chem 2005, 48(20), 6168-6173; J Biol. Chem. 2004, 279(14), 13839-13848). Therefore agonists which are selective for S 1P1 and/or S1P5, without being active for S1P3, are desirable.
  • the invention provides compounds that are agonists of SI PI and/or S1P5 and that are useful in the treatment of graft versus host disease and autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and systemic lupus erythematosis, in mammals.
  • This invention also provides methods of making the compound, methods of using such compounds in the treatment of graft versus host disease and autoimmune diseases, especially in humans, and to pharmaceutical compositions containing such compounds.
  • a first aspect of the invention provides compounds of embodiment (1) of Formula I:
  • R 1 is hydrogen or -P(0)(OR 6 ) 2 ;
  • R 2 and R 2a are independently hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, or haloalkoxy; Ring A is phenyl or 6-membered heteroaryl;
  • each R 3 is independently cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy,
  • n 0, 1, or 2;
  • R 4 is hydrogen, alkyl, cyano, halo, haloalkyl, or hydroxyalkyl;
  • R 5 is hydrogen or alkyl
  • R 5a is hydrogen, alkyl, alkylcarbonyl, or alkoxycarbonyl
  • each R 6 is independently hydrogen or alkyl
  • R 7 , R 7a , R 7b , and R 7c are independently hydrogen or alkyl
  • R is hydrogen, alkyl, or hydroxyalkyl.
  • the invention is directed to a pharmaceutical composition which comprises 1) a compound of Formula I or a single stereoisomer or mixture of isomers thereof, optionally as a pharmaceutically acceptable salt thereof and 2) a pharmaceutically acceptable carrier, excipient, or diluent.
  • the invention provides a method for treating a disease, disorder, or syndrome which method comprises administering to a patient a therapeutically effective amount of a compound of Formula I or a single stereoisomer or mixture of isomers thereof, optionally as a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a single stereoisomer or mixture of isomers thereof, optionally as a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.
  • the Invention is directed to a method of making a Compound of the Invention which method comprises:
  • R 2 , R 2a , R 3 , R 4 , R 7c , ring A, and n are as defined for Formula I, and optionally separating individual isomers; and optionally modifying any of the R 2 , R 2a , R 3 , R 4 , and R 7c groups; and optionally forming a pharmaceutically acceptable salt, hydrate, solvate or combination thereof.
  • the symbol "-" means a single bond
  • " ⁇ ” means a triple bond
  • the symbol ' ⁇ /" refers to a group on a double-bond as occupying either position on the terminus of a double bond to which the symbol is attached; that is, the geometry, E- or Z-, of the double bond is ambiguous.
  • the " ⁇ " symbol will be used at the end of the bond which was theoretically cleaved in order to separate the group from its parent structural formula.
  • a substituent "R” may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.
  • the "R” group may reside on either the 5-membered or the 6-membered ring of the fused ring system.
  • alkyl can refer to a monovalent alkyl radical or a divalent radical (i.e., alkylene).
  • administering and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, and chemotherapy, etc.)
  • “administration” and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • Alkyl means a linear saturated hydrocarbon radical of one to six carbon atoms or a branched saturated hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), or pentyl (including all isomeric forms), and the like.
  • Alkenyl means a linear hydrocarbon radical of two to six carbon atoms or a branched hydrocarbon radical of three to 6 carbon atoms which radical contains at least one double bond, e.g., ethenyl, propenyl, l-but-3-enyl, and l-pent-3-enyl, and the like.
  • Alkoxy means an -OR group where R is alkyl group as defined herein.
  • Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like.
  • Alkoxyalkyl means an alkyl group, as defined herein, substituted with at least one, specifically one, two, or three, alkoxy groups as defined herein. Representative examples include methoxymethyl and the like.
  • Alkoxyalkyloxy means an -OR group where R is alkoxyalkyl as defined herein.
  • Alkoxycarbonyl means a -C(0)R group where R is alkoxy, as defined herein.
  • Alkoxycarbonylamino means an -NHR group where R is alkoxycarbonyl as defined herein.
  • Alkylamino means an -NHR group where R is alkyl, as defined herein.
  • Alkylaminoalkyl means an alkyl group substituted with one or two alkylamino groups, as defined herein.
  • Alkylcarbonyl means a -C(0)R group where R is alkyl, as defined herein.
  • Alkylcarbonylamino means an -NHR group where R is alkylcarbonyl, as defined herein.
  • Alkylsulfonyl means an -S(0) 2 R group where R is alkyl, as defined herein, e.g. methylsulfonyl, isopropylsulfonyl.
  • Alkynyl means a linear hydrocarbon radical of two to six carbon atoms or a branched hydrocarbon radical of three to 6 carbon atoms which radical contains at least one triple bond, e.g., ethynyl, propynyl, butynyl, pentyn-2-yl and the like.
  • Amino means -NH 2 .
  • Aminocarbonyl means a -C(0)NH 2 group.
  • Aryl means a six- to fourteen-membered, mono- or bi-carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. Representative examples include phenyl, naphthyl, and indanyl, and the like.
  • Arylalkyl means an alkyl radical, as defined herein, substituted with one or two aryl groups, as defined herein, e.g., benzyl and phenethyl, and the like.
  • Carboxy means a -C(0)OH group.
  • Cycloalkyl means a monocyclic or fused bicyclic, saturated or partially unsaturated (but not aromatic), hydrocarbon radical of three to ten carbon ring atoms.
  • Fused bicyclic hydrocarbon radical includes bridged ring systems.
  • the valency of the group may be located on any atom of any ring within the radical, valency rules permitting.
  • cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, or cyclohex-3-enyl, and the like.
  • Cycloalkyloxy means an -OR group where R is cycloalkyl as defined herein.
  • Dialkylamino means a -NRR' radical where R and R' are alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino, diethylamino, N,N-methylpropylamino or N.N-methylethylamino, and the like.
  • fused ring means a polycyclic ring that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures.
  • fused ring systems are not necessarily all aromatic ring systems.
  • fused rings share a vicinal set of atoms, for example naphthalene or 1,2,3,4- tetrahydro-naphthalene.
  • a spiro ring system is not a fused ring system by this definition, but fused ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused ring system.
  • two adjacent groups on an aromatic system may be fused together to form a ring structure.
  • the fused ring structure may contain heteroatoms and may be optionally substituted with one or more groups.
  • saturated carbons of such fused groups i.e. saturated ring structures
  • Halogen or "halo” refers to fluorine, chlorine, bromine and iodine.
  • Haloalkoxy means an -OR' group where R' is haloalkyl as defined herein, e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.
  • Haloalkyl mean an alkyl group substituted with one or more halogens, specifically one to five halo atoms, e.g., trifluoromethyl, 2-chloroethyl, and 2,2-difluoroethyl, and the like.
  • Heteroaryl means a monocyclic, fused bicyclic, or fused tricyclic, radical of 5 to 14 ring atoms containing one or more, specifically one, two, three, or four ring heteroatoms independently selected from -0-, -S(0) n - (n is 0, 1 , or 2), -N-, -N(R X )-, and the remaining ring atoms being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic.
  • R is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl.
  • Fused bicyclic radical includes bridged ring systems. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting. When the point of valency is located on the nitrogen, R x is absent.
  • heteroaryl includes, but is not limited to, 1 ,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-lH-indolyl (including, for example, 2,3-dihydro-lH-indol-2-yl or 2,3-dihydro- lH-indol-5-yI, and the like), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol- 4-yl, benzofuranyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4- yl, pteridinyl, purinyl, quina
  • Heteroatom refers to O, S, N, and P.
  • Heterocycloalkyl means a saturated or partially unsaturated (but not aromatic) monocyclic group of 3 to 8 ring atoms or a saturated or partially unsaturated (but not aromatic) fused bicyclic group of 5 to 12 ring atoms in which one or more, specifically one, two, three, or four ring heteroatoms independently selected from O, S(0) n (n is 0, 1, or 2), N, N(R y ) (where R y is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl), the remaining ring atoms being carbon.
  • Fused bicyclic radical includes bridged ring systems. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. When the point of valency is located on a nitrogen atom, R y is absent.
  • heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, piperidinyl, 4-piperidony , morpholinyl, piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl,
  • Heterocycloalkyloxy means an -OR group where R is hetero cycloalkyl as defined herein.
  • Hydroxyalkyl means an alkyl group substituted with at least one, in another example with one, two, or three, hydroxy groups.
  • Spirocyclyl or "spirocyclic ring” refers to a ring originating from a particular annular carbon of another ring.
  • a ring atom of a saturated bridged ring system (rings B and B'), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spirocyclyl (ring A) attached thereto.
  • a spirocyclyl can be carbocyclic or heteroalicyclic.
  • Patient for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In a specific embodiment the patient is a mammal, and in a more specific embodiment the patient is human.
  • a "pharmaceutically acceptable salt” of a compound means a salt that is
  • Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,
  • 2-naphthalenesulfonic acid 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylic acid and the like.
  • Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Specific salts are the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins.
  • Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol,
  • 2-diethylaminoethanol dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine,
  • N-methylglucamine N-methylglucamine, polyamine resins, and the like.
  • Exemplary organic bases are
  • Platinum(s)," and “platin-containing agent(s)” include, for example, cisplatin, carboplatin, and oxaliplatin.
  • Prodrug refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood.
  • esters of the compounds of this invention include, but are not limited to, alkyl esters (for example with between about one and about six carbons) the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl.
  • pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (for example with between about one and about six carbons).
  • Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S.
  • Stepoisomer means any of two or more isomers containing the same atoms bonded to each other in an identical manner but differing from each other in the spatial arrangement of the atoms or groups of atoms.
  • Stepreoisomer includes, for example, an enantiomer, a geometric isomer, a diastereomer, a rotamer, cis-isomer, trans-isomer, and conformational isomer.
  • the names and illustration used in this application to describe compounds of the invention, unless indicated otherwise, are meant to encompass all possible stereoisomers and any mixture, racemic or otherwise, thereof.
  • “Therapeutically effective amount” is an amount of a compound of the invention, that when administered to a patient, ameliorates a symptom of the disease.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like.
  • the therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and to this disclosure.
  • Treating" or "treatment” of a disease, disorder, or syndrome includes (i) preventing the disease, disorder, or syndrome from occurring in a human, i.e. causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome.
  • Yield for each of the reactions described herein is expressed as a percentage of the theoretical yield.
  • the invention further comprises subgenera of embodiment (1) in which the substituents are selected as any and all combinations of structural formula (I), R 1 , R 2 , R 2a , R 3 , R 4 , R 5 , R 5a , R 7 , R 7a , R 7b , R 7c , R 8 and n as defined herein, including without limitation, the following: [°°65] Structural Formula I is one of formulae (I-a) - (i-b). (Il-a - fll-d). (Hl-a) -
  • R 1 is selected from one of the following groups (la) - (lg):
  • R 2 and R 2a are selected from one of the following groups (2a) - (2m):
  • R 2 and R 2a are independently cyano, halo, or alkyl.
  • R 2 and R 2a are independently halo or alkyl.
  • R 2 and R 2a are each independently halo.
  • R 2 and R 2a are each chloro.
  • R 2 is chloro or fluoro and R 2a is chloro or fluoro.
  • R 2 is chloro and R 2a is fluoro.
  • R 2 and R 2a are each independently alkyl.
  • R 2 and R 2a are each methyl.
  • R 2 is alkyl and R 2a is halo.
  • R z is methyl and R is halo.
  • R ⁇ is methyl and R a is chloro or fluoro
  • R is methyl and R is fluoro.
  • R is methyl and R is chloro.
  • each R is independently selected from one of the following groups (3a) -
  • each R 3 is independently alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyloxy, cycloalkyloxy, heterocycloalkyloxy, alkylamino, or dialkylamino.
  • each R 3 is independently alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, or dialkylamino.
  • each R 3 is independently alkyl, alkoxy, or alkylamino.
  • each R 3 is independently alkyl or alkoxy.
  • each R is independently alkyl or alkylamino.
  • each R 3 is independently alkoxy or alkylamino.
  • each R 3 is independently alkyl.
  • each R 3 is independently alkoxy.
  • each R 3 is independently alkylamino.
  • each R 3 is isopropoxy, isopropylamino, or isobutyl.
  • each R 3 is isopropoxy or isopropylamino.
  • each R 3 is isopropoxy or isobutyl.
  • each R 3 is isopropylamino or isobutyl.
  • each R 3 is isopropoxy.
  • each R is isobutyl.
  • R 4 is selected from one of the following groups (4a) - (4m);
  • R 4 is alkyl, cyano, halo, haloalkyl, or hydroxyalkyl.
  • R 4 is methyl, cyano, chloro, or hydroxymethyl.
  • R 4 is alkyl, cyano, halo, or hydroxyalkyl.
  • R 4 is alkyl, cyano, halo;
  • R 4 is methyl, cyano, halo.
  • R 4 is methyl, cyano, chloro.
  • R 4 is alkyl
  • R 4 is methyl.
  • R 4 is cyano. (4j) R 4 is halo.
  • R 4 is chloro
  • R 4 is hydroxyalkyl
  • R 4 is hydroxymethyl
  • R 5 and R 5a are selected from one of the following groups (5a) - f5 ⁇ T);
  • R 5 is hydrogen and R 5a is hydrogen, alkyl, alkylcarbonyl, or alkoxycarbonyl.
  • R 5 is hydrogen and R 5a is alkylcarbonyl or alkoxycarbonyl.
  • R 5 is hydrogen and R 5a is hydrogen or alkyl.
  • R 5 is hydrogen; R 5a is hydrogen.
  • n when present, is selected from one of the following groups (6a) - (6f):
  • n 0, 1, or 2.
  • n O or l .
  • n 1 or 2.
  • R 7c and R 8 are selected from one of the following groups (7a) - (7g):
  • R 7 and R 7a are each hydrogen; R 7b and R 7c are independently hydrogen or alkyl; and R 8 is hydrogen, alkyl, or hydroxyalkyl.
  • R 7 , R 7a , and R 7b are each hydrogen; R 7c is hydrogen or alkyl; and R 8 is hydrogen, alkyl, or hydroxyalkyl.
  • R 7 , R 7a , R 7b and R 8 are each hydrogen; and R 7c is hydrogen or alkyl.
  • R 7 , R 7a , R 7b and R 8 are each hydrogen; and R 7c is hydrogen or methyl.
  • R 7 , R 7 , R 7b and R 8 are each hydrogen; and R 7c is alkyl.
  • R 7 , R 7a , R 7b and R 8 are each hydrogen; and R 7c is methyl.
  • R 7 , R 7a , R 7b , R 7c and R 8 are hydrogen.articular embodiments of this aspect of the invention include compounds of any one of the formulae (I), (I-a) - (I-b), (Il-a) - (II-d), (III- a) - (III-c), (IV-a) - (IV-i), (V-a) - (V-f), and (Vl-a) - (Vl-f), each as defined in each of the following rows, wherein each entry is a group number as defined above (e.g., (6e) refers to n is 1), and a dash "-" indicates that the variable is as defined for formula (I) or defined according to any one of the applicable variable definitions l(a)-7(g) [e.g., when R 1 is a dash, it can be either as defined for Formula (I) or any one of definitions (la)-(lg)]: E bidt momen ⁇
  • Another aspect of the Invention provides a pharmaceutical composition which comprises a compound of any one of Formulae I, (I-a) - (I-b), (Il-a) - (Il-d), (Ill-a) - (III-c), (IV- a) - (IV-i), (V-a) - (V-f), and (Vl-a) - (Vl-f), or a compound selected from Table 1 or Table 2 (below), or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier, excipient, or diluent.
  • Another aspect of the Invention is a method of treating disease, disorder, or syndrome where the disease is associated with uncontrolled, abnormal, and/or unwanted cellular activities effected directly or indirectly by S1P1 and/or S1P5 which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of Formulae I, (I-a) - (I-b), (Il-a) - (Il-d), (Ill-a) - (III-c), (IV-a) - (IV-i), (V-a) - (V-f), and (Vl-a) - (Vl-f), or a compound selected from Table 1 or Table 2 (below), or selected from any of the above embodiments, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.
  • a compound of Formulae I (I-a) - (I-b), (Il-a) - (Il-d), (Ill-a) - (III-c), (IV-a) - (IV-
  • Another aspect of the invention is directed to a method of treating an autoimmune disease, disorder, or syndrome comprising administering to a patient a therapeutically effective amount of a compound of Formulae I, (I-a) - (I-b), (Il-a) - (Il-d), (Ill-a) - (III-c), (IV-a) - (IV-i), (V-a) - (V-f), and (Vl-a) - (Vl-f), or a compound selected from Table 1 or Table 2 (below), or selected from any of the above embodiments, optionally as a pharmaceutically acceptable salt or pharmaceutical composition thereof.
  • the autoimmune disease is multiple sclerosis.
  • the disease is psoriasis.
  • the disease is inflammatory bowel disease.
  • the autoimmune disease is graft-versus-host disease.
  • the disease is inflammation caused by an autoimmune disease.
  • compositions for treating an autoimmune disease, disorder, or syndrome which composition comprises a pharmaceutically acceptable carrier, excipient, and/or diluent together with a therapeutically effective amount of a compound of Formulae I, (I-a) - (I-b), (Il-a) - (Il-d), (Ill-a) - (III-c), (IV-a) - (IV-i), (V-a) - (V-f), and (VI- a) - (Vl-f), or a compound selected from Table 1 or Table 2 (below), or selected from any of the above embodiments, optionally as a pharmaceutically acceptable salt or pharmaceutical composition thereof.
  • the disease is an autoimmune disease.
  • the autoimmune disease is multiple sclerosis. In another embodiment, the disease is psoriasis. In another embodiment, the disease is inflammatory bowel disease. In another embodiment the autoimmune disease is graft-versus-host disease. In another embodiment, the disease is inflammation caused by an autoimmune disease.
  • Another aspect of the invention comprises use of a compound of Formulae I, (I-a) - (I-b), (Il-a) - (Il-d), (Ill-a) - (III-c), (IV-a) - (IV-i), (V-a) - (V-f), and (Vl-a) - (Vl-f), or a compound selected from Table 1 or Table 2 (below), or selected from any of the above embodiments, optionally as a pharmaceutically acceptable salt or pharmaceutical composition thereof for the preparation of a medicament for the treatment of an autoimmune disease, disorder, or syndrome.
  • the disease is an autoimmune disease.
  • the autoimmune disease is multiple sclerosis.
  • the disease is psoriasis.
  • the disease is inflammatory bowel disease.
  • the autoimmune disease is graft-versus-host disease.
  • the disease is inflammation caused by an autoimmune disease.
  • the invention provides pharmaceutical compositions comprising an inhibitor of SI PI and/or S1P5 according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent.
  • administration is by the oral route.
  • Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, specifically in unit dosage forms suitable for simple administration of precise dosages.
  • compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include carriers and adjuvants, etc.
  • Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
  • formulations depend on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules) and the bioavailability of the drug substance.
  • pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1 ,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • aqueous and nonaqueous carriers, diluents, solvents or vehicles examples include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • a coating such as lecithin
  • surfactants for example
  • One specific route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate
  • solution retarders as for example paraffin
  • absorption accelerators as for example,
  • Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients. [0089] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present invention with for example suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • Compressed gases may be used to disperse a compound of this invention in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient.
  • the composition will be between about 5% and about 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
  • composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this invention.
  • the compounds of the invention are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy.
  • the compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary.
  • the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used.
  • the determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.
  • Compounds of this invention can be made by the synthetic procedures described below.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis.), or Bachem (Torrance, Calif.), or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4 th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
  • the reactions described herein take place at atmospheric pressure and over a temperature range from about -78 °C to about 150 °C, more specifically from about 0 °C to about 125 °C and more specifically at about room (or ambient) temperature, e.g., about 20 °C. Unless otherwise stated (as in the case of a hydrogenation), all reactions are performed under an atmosphere of nitrogen.
  • Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups regenerate original functional groups by routine manipulation or in vivo. Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.
  • the compounds of the invention may have asymmetric carbon atoms or quaternized nitrogen atoms in their structure.
  • Compounds of the Invention that may be prepared through the syntheses described herein may exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers.
  • the compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention.
  • Some of the compounds of the invention may exist as tautomers.
  • the molecule may exist in the enol form; where an amide is present, the molecule may exist as the imidic acid; and where an enamine is present, the molecule may exist as an imine. All such tautomers are within the scope of the invention.
  • the present invention also includes isotopically-labeled compounds, which are identical to those recited in Formula I, 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 compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, l4 C, 15 N, 18 0, ,7 0, 31 P, 32 P, 35 S, l8 F, and 36 C1, respectively.
  • Isotopically-labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically-labelled reagent for a non-isotopically-labelled reagent.
  • the present invention also includes N-oxide derivatives and protected derivatives of compounds of the Invention.
  • compounds of the Invention when compounds of the Invention contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art.
  • groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s)
  • these groups can be protected with a suitable "protecting group” or "protective group”.
  • suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1991, the disclosure of which is incorporated herein by reference in its entirety.
  • nitrogen protecting groups include, but are not limited to Boc, Fmoc, benzyl, trityl, and the like.
  • the protected derivatives of compounds of the Invention can be prepared by methods well known in the art.
  • optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • Enantiomers may be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation.
  • enantiomer enriched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield) by recrystallization.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • the invention additionally provides methods for making compounds of formula I.
  • the compounds of the invention may be prepared by the general methods and examples presented below, and methods known to those of ordinary skill in the art and reported in the chemical literature. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Intermediate substituted benzoic acids and their precursors (benzoic acids esters, benzamides or benzonitriles) are commercially available or are prepared by methods known to those skilled in the art (see WO201011316). Intermediate pyridyl carboxylic acids are commercially available or are prepared by methods known to those skilled in the art (see WO2009024905 and WO200802937). Intermediate substituted N-hydroxyamidines of formula III and IV are prepared from the corresponding substituted nitrile by methods known to those skilled in the art.
  • R 2 , R 2a , R 3 , R 4 , R 7c , ring A, and n shall have the meanings defined in the detailed description of formula I, and optionally separating individual isomers; and optionally modifying any of the R 2 , R 2a , R 3 , R 4 , and R 7c groups; and optionally forming a pharmaceutically acceptable salt, hydrate, solvate or combination thereof.
  • a carboxylic acid of formula II is reacted with a N- hydroxyamidine of formula HI under coupling conditions well known in the art such as by treatment with SOCl 2 or, N-(3-dimethylaminopropyl)-A -ethylcarbodiimide hydrochloride (EDCI) in the presence of 1 -hydroxylbenzotriazole (HOBt) or, benzotriazol-1- yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PyBOP) or, O-(7-azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or, 0-(benzotriazol-l-yl- N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) in the presence of a base such as Et 3 N or
  • a carboxylic acid of formula II is reacted with and N- hydroxyamidine of formula V, where X is a halogen such as fluorine, under coupling conditions well known in the art such as by treatment with SOCl 2 or, N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride in the presence of 1-hydroxylbenzotriazole (HOBt) or, benzotriazol-l-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PyBOP) or, O-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or, O- (benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) in the presence
  • HOBt 1-hydroxy
  • intermediate IV reacting intermediate VIII and an alcohol Vila (X is OH) under Mitsunobu conditions in the presence of PPh 3 and di-tert-butyl azodicarboxylate in a suitable solvent such as THF provides intermediate IV.
  • Reacting intermediate IV as shown in Scheme I with a suitable acid such as HCl in a suitable solvent such as dioxane, THF or methanol provides the desired compound of formula I.
  • Step 1 (2R,3R)-Methyl 2-amino-3-hydroxybutanoate (4).
  • MeOH 120 niL
  • acetyl chloride 20 mL, 282 mmol
  • D-allothreonine 3 1 1.31 g, 94.9 mmol
  • the reaction mixture was removed from the ice bath and heated to reflux for several hours. After cooling to RT, the reaction mixture was concentrated in vacuo. The crude product was used as is in the next reaction.
  • Step 2 (2R,3R)-Methyl 2-(tert-butoxycarbonylamino)-3-hydroxybutanoate (5).
  • Step 3 (4R,5R)-3-tert-Butyl 4-methyl 2,2,5-trimethyloxazolidine-3,4- dicarboxylate (6).
  • Compound 5 (12.68 g, 54.4 mmol), toluene (150 mL), dimethoxypropane (75 mL, 610 mmol) and p-toluenesulfonic acid monohydrate (1.4 g, 7.4 mmol) were combined and stirred at 80 °C for 6 h. After cooling to RT, the reaction mixture was concentrated in vacuo and the resulting oil was partitioned between sat'd NaHC0 3 and diethyl ether.
  • Step 4 (4S,5R)-tert-Butyl 4-(hydroxymethyl)-2,2,5-trimethyloxazolidine-3- carboxylate (7).
  • Compound 6 (1 1.7 g, 42.8 mmol) was dissolved in THF (80 mL) and cooled in an ice bath.
  • Lithium borohydride (1.87 g, 85.8 mmol) was added followed by the dropwise addition of a 1 :1 solution of THF:MeOH (22 mL) with stirring. After the addition was complete, the reaction mixture was removed from the ice bath and stirred at RT overnight.
  • reaction was followed by LC-MS and NMR and additional lithium borohydride was added in 500 mg aliquots as needed until the reaction was complete. Once reaction was complete, the reaction mixture was cooled in an ice bath then slowly added to a cold solution of 7.5% aqueous citric acid solution. The mixture was stirred for 30 min then extracted with EtOAc (3x). The combined
  • Step 1 Ethyl 2-(isopropylamino)-6-methylisonicotinate (9).
  • Ethyl 2-chloro-6- methylpyridine-4-carboxylate 8 550 mg, 2.75 mmol
  • Pd(OAc) 2 28 mg, 0.13 mmol
  • BINAP 156 mg, 0.25 mmol
  • Cs 2 C0 3 2.4 g, 7.5 mmol
  • 1,4-dioxane 25 mL
  • N 2 was bubbled into the mixture for a few minutes and isopropylamine (885 mg, 15 mmol) was added.
  • the sealed mixture was heated to 85 °C for 20 h.
  • the mixture was filtered through Celite and washed with EtOAc.
  • the solvents were removed in vacuo. Purification by flash column chromatography gave 9 (530 mg, 86%).
  • Step 2 2-(IsopropyIamino)-6-methyIisonicotinic acid (10).
  • Ethyl 2- (isopropylamino)-6-methylisonicotinate 9 (530 mg, 2.38 mmol) was dissolved in a mixture of MeOH (5 mL) and water (5 mL) and then treated with NaOH (480 mg, 1 .9 mmol) at RT for 4 h. MeOH was removed in vacuo and the resulting aqueous mixture was neutralized to pH 6 by addition of 20% aqueous HC1 solution. The resulting solids were filtered and dried to give 10 (384 mg, 83%).
  • Step 1 (4S,5R)-tert-Butyl 4-((2,6-dichloro-4-cyanophenoxy)methyl)-2,2,5- trimethyloxazolidine-3-carboxyIate (12).
  • 3,5-dichloro-4-fluorobenzonitrile 11 (836 mg, 4.40 mmol) and intermediate 7 (1.19 g, 4.84 mmol) in 10 mL of anhydrous THF, cooled at 0 °C with an ice bath, was added NaH (194 mg, 60% in mineral oil) in portions with stirring over 2 min.
  • the reaction mixture was warmed to RT and stirred at RT for 4 h.
  • the reaction was quenched by addition of ice water.
  • Step 2 (4S,5R)-tert-Butyl 4-((2,6-dichloro-4-(N- hydroxycarbamimidoyl)phenoxy)-methyl)-2,2,5-trimethyloxazolidine-3-carboxylate (13).
  • Step 3 (4S,5R)-tert-Butyl 4-((2,6-dichloro-4-(5-(2-(isopropylamino)-6- methylpyridin-4-yl)-l,2,4-oxadiazol-3-yl)phenoxy)methyl)-2,2,5-trimethyloxazolidine-3- carboxylate (14).
  • Step 4 (2R,3S)-3-Amino-4-(2,6-dichloro-4- ⁇ 5-[2-(isopropylamino)-6- methylpyridin-4-yl]-l,2,4-oxadiazol-3-yl ⁇ phenoxy)butan-2-ol.
  • Compound 14 (545 mg, 0.90 mmol) was dissolved in 10 mL of 4M HCl in dioxane with stirring at RT followed by addition of 5 mL of MeOH. After stirring at RT for 30 min, the resulting yellow solution was concentrated in vacuo. The residue was dissolved in water, basified with 1 M NaOH to pH>13, and extracted with EtOAc (3x).
  • Step 1 l-Bromo-4,5-difluoro-2-methylbenzene (16).
  • 3,4-difluorotoluene 15 27 g, 210 mmol
  • iron powder 600 mg, 10 mmol
  • Br 2 40 g, 250 mmol
  • the reaction was stirred for 12 h while it was slowly warmed to RT. Water was added and the resulting mixture was extracted with diethyl ether. The ether layer was washed with sodium thiosulfate solution, brine and dried over Na 2 S0 4 . Removal of ether gave the desired bromotoluene 16 (36 g, 83%).
  • ⁇ -NMR 400MHz, DMSO-d6):D D 8 7.78 (t, 1H), 7.52 (t, 1H), 2.29 (s, 3H).
  • Step 2 4,5-Difluoro-2-methylbenzonitriIe (17).
  • 1 -Bromo-4,5-difluoro-2- methylbenzene 16 (2 g, 9.6 mmol), CuCN (1.0 g, 1 1 mmol) and NMP (5 mL) were combined in a sealed tube and heated to 160 °C with stirring for 12 h. Due to the volatility of the resulting benzonitrile 13, the crude reaction mixture was used as is in the next reaction.
  • Step 3 (S)-tert-Butyl 4-((4-cyano-2-fluoro-5-methylphenoxy)methyl)-2,2- dimethyloxazolidine-3-carboxylate (18).
  • the crude reaction mixture of compound 17 was cooled to 0 °C.
  • the alcohol 2 2.0 g, 8.7 mmol
  • KO l Bu 2.2 g, 20 mmol
  • the mixture was stirred for 3 h at RT. Water was added to quench the reaction.
  • the crude product was extracted with EtOAc. Purification by flash column chromatography gave compound 18 (1.36 g, 43%).
  • Step 4 (S)-tert-Butyl 4-((2-fluoro-4-(N'-hydroxycarbamimidoyl)-5- methylphenoxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (19).
  • Intermediate 19 was synthesized from intermediate 18 in good yield (>90%) using the same or an analogous synthetic procedure to that of intermediate 13 in Example 1.
  • Step 5 (S)-tert-Butyl 4-((2-fluoro-4-(5-(2-(isopropylamino)-6-methylpyridin-4- yl)-l,2,4-oxadiazol-3-yl)-5-methylphenoxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (20).
  • carboxylic acid 10 582 mg, 3 mmol
  • HOBT 445 mg, 3.3 mmol
  • DCM (30 mL) was added N,N'-diisopropylcarbodiimide (415 mg, 3.3 mmol).
  • Step 6 (2R)-2-Amino-3-(2-fluoro-4- ⁇ 5-[2-(isopropylamino)-6-methyIpyridin-4- yI]-l,2,4-oxadiazol-3-yl ⁇ -5-methylphenoxy)propan-l-ol.
  • MeOH MeOH
  • 4 N HC1 dioxane
  • the mixture was stirred for 4 h. Volatiles were removed in vacuo. The residue was diluted with water (25 mL) and was washed with diethyl ether (2 x 15 mL).
  • Step 1 2-ChIoro-4-bromo-6-methylphenol (22).
  • 2-chloro-6- methylphenol 21 5 g, 35 mmol
  • AcOH 70 mL
  • NBS 6.2 g, 35 mmol
  • the solution was stirred at RT for 12 h.
  • AcOH was removed under reduced pressure.
  • the residue was diluted with EtOAc, washed with saturated Na 2 C0 3 solution and dried over Na 2 S0 4 . Removal of the solvents gave desired compound 22 (4 g, 52%) which was used in the next step without further purification.
  • Step 2 (S)-tert-Butyl 4-((4-bromo-2-chIoro-6-methylphenoxy)methyl)-2,2- dimethyIoxazolidine-3-carboxylate (23).
  • intermediate 2 4.8 g, 21.7 mmol
  • triphenylphosphine 7.0 g, 27 mmol
  • diisopropylazodicarboxylate 5.4 g, 27 mmol
  • Step 3 (S)-tert-Butyl 4-((2-chloro-4-cyano-6-methylphenoxy)methyl)-2,2- dimethyloxazoIidine-3-carboxylate (24).
  • Compound 23 (5.68 g, 13 mmol), Zn(CN) 2 (920 mg, 7.8 mmol), Pd(dppf)Cl 2 , DCM (475 mg, 0.65 mmol) and polymethylhydrosiloxane (390 mg) were dissolved in DMA/H 2 0 (30 mL/0.3 mL). The reaction mixture was stirred at 90 °C for 6 h. Water was added and the product was extracted with EtOAc. Concentration and purification by flash column chromatography gave the desired compound 24 (4.5 g, 91%).
  • Step 4 (S)-tert-Butyl 4-((2-chloro-4-(N'-hydroxycarbamimidoyl)-6- methylphenoxy)methyl)-2,2-dimethyIoxazolidine-3-carboxylate (25).
  • Intermediate 25 was synthesized from intermediate 24 using the same or an analogous synthetic procedure to that of intermediate 13 in Example 1.
  • Step 5 (S)-tert-Butyl 4-((2-chloro-4-(5-(2-(isopropylamino)-6-methylpyridin-4- yl)-l,2,4-oxadiazol-3-yl)-6-methylphenoxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (26).
  • Intermediate 26 was synthesized from intermediates 10 and 25 using the same or an analogous synthetic procedure to that of intermediate 14 in Example 1.
  • Step 6 (2R)-2-Amino-3- ⁇ [2-chloro-6-methyl-4-(5- ⁇ 2-methyl-6-[(l- methylethyI)amino]pyridin-4-yl ⁇ -l,2,4-oxadiazol-3-yl)phenyl]oxy ⁇ propan-l-ol.
  • the title compound was synthesized from intermediate 26 using the same or an analogous synthetic procedure to that of (2R)-2-amino-3-(2-fluoro-4- ⁇ 5-[2-(isopropylamino)-6-methylpyridin-4-yl]- l,2,4-oxadiazol-3-yl ⁇ -5-methylphenoxy)propan-l -ol in Example 2.
  • Step 1 (4S,5S)-tert-Butyl 4-((5-chIoro-4-cyano-2-fluorophenoxy)methyl)-2,2,5- trimethyloxazolidine-3-carboxylate (29).
  • Intermediate 28 was made in an analogous manner to intermediate 7 using the appropriate enantiomerically pure starting material in place of compound 3.
  • Intermediate 29 was synthesized from commercially available 27 using the same or an analogous synthetic procedure to that of intermediate 12 in Example 1.
  • Step 2 (4S,5S)-tert-Butyl 4-((5-chIoro-2-fluoro-4-(N'- hydroxycarbamimidoyl)phenoxy)-methyl)-2,2,5-trimethyIoxazolidine-3-carboxylate (30).
  • Intermediate 30 was synthesized from intermediate 29 using the same or an analogous synthetic procedure to that of intermediate 13 in Example 1.
  • Step 3 (4S,5S)-tert-Butyl 4-((5-chloro-2-fluoro-4-(5-(2-(isopropylamino)-6- methylpyridin-4-yl)-l,2,4-oxadiazol-3-yl)phenoxy)methyl)-2,2,5-trimethyloxazolidine-3- carboxylate (31).
  • Intermediate 31 was synthesized from intermediates 10 and 30 using the same or an analogous synthetic procedure to that of intermediate 14 in Example 1.
  • Step 4 (2S,3S)-3-Amino-4- ⁇ [5-chloro-2-fluoro-4-(5- ⁇ 2-methyl-6-[(l- methylethyl)amino]pyridin-4-yl ⁇ -l,2,4-oxadiazol-3-yl)phenyl]oxy ⁇ butan-2-ol
  • Step 1 3-Chloro-4-isopropoxybenzonitrile (33).
  • a stirring suspension of 32 (20.0 g, 128 mmol) and NaH (6.17 g, 154 mmol) in THF (200 mL) was cooled to -10 °C and isopropyl alcohol (12.8 mL, 167 mmol) was added very slowly over a period of 1 h such that the internal reaction temperature did not exceed 10 °C.
  • the reaction mixture was cooled and quenched with ice. THF was removed under reduced pressure, water was added to the residue and the resulting mixture was extracted with EtOAc. The organic phases were dried and concentrated in vacuo to afford 33 (24 g, 95.6%) which was used as such for the next step.
  • Step 2 3-Chloro-4-isopropoxybenzoic acid (34).
  • 33 57 g, 291 mmol
  • EtOH 120 mL
  • 12% aqueous KOH solution 300 mL
  • the reaction mixture was then cooled and acidified with HC1 to pH 5.
  • a yellow solid precipitated out which was filtered, washed with water and dried.
  • the resulting solid was stirred with hexane for 5 min and the hexane decanted.
  • the resulting solid was resuspended in hexane, filtered, and washed with hexane to afford 34 as a white solid (45 g, 72%).
  • Step 3 (4S,5R)-tert-Butyl 4-((5-chloro-4-(5-(3-chloro-4-isopropoxyphenyl)-l,2,4- oxadiazol-3-yI)-2-fluorophenoxy)methyl)-2,2,5-trimethyloxazolidine-3-carboxylate (36).
  • Intermediate 35 was synthesized using the same or an analogous synthetic procedure to that of intermediate 30 in Example 4, substituting intermediate 7 for intermediate 28.
  • Intermediate 36 was synthesized from intermediates 34 and 35 using the same or an analogous synthetic procedure to that of intermediate 14 in Example 1.
  • Step 4 (2R,3S)-3-Amino-4- ⁇ [5-chloro-4-(5- ⁇ 3-chloro-4-[(l- methylethyl)oxy]phenyl ⁇ -l,2,4-oxadiazol-3-yl)-2-fluorophenyl]oxy ⁇ butan-2-ol
  • Step 1 Methyl 4-hydroxy-3-iodobenzoate (38).
  • a stirred solution of methyl-4- hydroxybenzoate 37 (20 g, 132 mmol) in AcOH (100 mL) was heated to 65 °C.
  • a solution of IC1 (21.3g, 7.0 mL, 132 mmol) in AcOH (25 mL) was added dropwise over 40 min. Stirring at 65 °C was continued for 8 h followed by stirring at RT for 16 h. The precipitated product was isolated via filtration, washed with water and dried under vacuum to give 38 (20 g, 55%) as a white solid.
  • Step 2 Methyl 3-cyano-4-hydroxybenzoate (39). To a stirred solution of 38 (12 g, 44 mmol) in DMF (60 mL) was added CuCN (4.4 g, 48 mmol) and NaCN (0.24g, 4.8 mmol) followed by heating to 105 °C for 18 h. The reaction mixture was allowed to cool to RT, and any precipitates were removed via filteration and washed with ethyl acetate. The filtrate was diluted with water (200 mL), extracted with EtOAc, dried over Na 2 S0 4 and concentrated in vacuo to afford 39 (6.2 g, 80%) as a light yellow solid.
  • Step 3 Methyl 3-cyano-4-isopropoxybenzoate (40). To as stirred solution of compound 39 (6.2 g, 34 mmol) in DMF (25 mL) was added 2-bromopropane (6.34 g, 52 mmol) and K 2 C0 3 (14 g, 103 mmol) and the resulting mixture was heated to 90 °C for 14 h. After cooling to RT, the reaction mixture was diluted with water (200 mL) and extracted with DCM. The combined organic layers were dried over Na 2 S0 4 , concentrated, and purified by column chromatography to give 40 (7.0 g, 91%) as a thick oil.
  • Step 4 3-Cyano-4-isopropoxybenzoic acid (41).
  • 40 7.0 g, 315 mmol
  • THF a mixture of EtOH (30 mL) and THF (30 mL)
  • 2M NaOH 20 mL, 41 mmol
  • the solvent was removed in vacuo and water (100 mL) was added to the resulting residue.
  • the resulting aqueous mixture was acidified with 2N HC1 and extracted with EtOAc.
  • the EtOAc phase was washed with water and brine and dried over Na 2 S0 4 .
  • Step 5 (4S,5R)-tert-Butyl 4-((5-chloro-4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4- oxadiazol-3-yl)-2-fluorophenoxy)methyl)-2,2,5-trimethyIoxazolidine-3-carboxylate (42).
  • Step 6 5-[3-(4- ⁇ [(2S,3R)-2-Amino-3-hydroxybutyl]oxy ⁇ -2-chloro-5- fluorophenyl)-l,2,4-oxadiazol-5-yl]-2-[(l-methylethyl)oxy]benzonitrile hydrochloride salt.
  • Step 1 6-Chloro-2-methylpyridin-3-amine (44). To a stirred solution of 43 (5 g, 29 mmol) in EtOH (20 mL) and cone. HCI (20 mL) was added Fe powder (16.2 g, 289 mmole) in small portions at RT over 30 min. Stirring was continued at RT for another 30 min. The solvent was distilled off under reduced pressure. Water was added and the resulting mixture was neutralized with NaHC0 3 . EtOAc was added and the biphasic mixture was filtered through Celite and washed with EtOAc. The phases of the filtrate were separated and the organic layer was washed with water, brine, dried over Na 2 S0 4 , and concentrated to afford 44 (4.1 g, 99 %) as a yellow solid.
  • Step 2 6-Chloro-N-isopropyl-2-methylpyridin-3-amine (45).
  • 44 (4.81 g, 33.75 mmol) and acetone (2.74 g, 47.2 mmol) in dichloroethane (60 mL) was added NaBH(OAc) 3 (10.713 g, 50.53 mmol) and AcOH (3.44 g, 57.2 mmol) at RT.
  • the reaction was stirred for 16 h followed by dilution with IN NaOH.
  • the aqueous solution was extracted with DCM and the organic layer was washed with water, brine, dried over Na 2 S0 4 and concentrated to afford 45 (6.16 g, 98%).
  • Step 3 5-(Isopropylamino)-6-methylpicolinonitrile (46).
  • 45 6.2 g, 33.5 mmol
  • DMF 50 mL
  • Zn(CN) 2 5.5 g, 46.84 mmol
  • tetrakis(triphenylphosphine)palladium (0) 5.8 g, 5.01 mmol
  • the reaction was stirred at 130 °C for 16 h. After completion, the reaction mixture was absorbed on silica gel and chromatographed to obtain 46 (5 g, 85 %) as thick liquid.
  • Step 4 5-(Isopropylamino)-6-methylpicolinic acid (47).
  • 46 5.0 g, 28.4 mmol
  • EtOH 40 mL
  • 20 % aqueous KOH 40 mL
  • the reaction mixture was refluxed for 12 h.
  • Solvent was removed in vacuo.
  • the resulting aqueous mixture was neutralized to pH 5 with citric acid solution and extracted with EtOAc. Organic layer was dried, concentrated and washed with pentane to afford 47 (2.8 g, 50%) as a white solid.
  • Step 5 (4S,5R)-tert-Butyl 4-((2,6-dichIoro-4-(5-(5-(isopropylamino)-6- methylpyridin-2-yl)-l,2,4-oxadiazol -yl)phenoxy)methyl)-2,2,5-trimethyloxazolidine-3- carboxylate (48).
  • Intermediate 48 was synthesized from intermediates 47 and 13 using the same or an analogous synthetic procedure to that of intermediate 14 in Example 1.
  • Step 6 (2R,3S)-3-amino-4-(2,6-dichloro-4-(5-(5-(isopropylamino)-6- methylpyridin-2-yl)-l ⁇ ,4-oxadiazol-3-yl)phenoxy)butan-2-ol dihydrochloride salt.
  • Step 1 Methyl 6-fluoro-5-methylnicotinate (50).
  • a mixture of 5-methyl-6-fluoro- nicotinic acid 49 (7.0 g, 45 mmol), K 2 C0 3 (13.7 g, 99 mmol), methyl iodide (9.58 g, 67 mmol) and DMF (200 mL) was stirred for 16 h at RT. After dilution with water (50 mL), the reaction mixture was extracted with EtOAc (50 mL). The organic phase was washed successively with saturated aqueous NaHC0 3 (20 mL), brine (2 x 20 mL) and dried (Na 2 S0 4 ). Filtration and evaporation of the solvent gave 50 (6.5 g, 85%).
  • Step 2 Methyl 6-(isopropylamino)-5-methylnicotinate (51).
  • Isopropylamine (50 mL) and 50 (6.5 g, 38 mmol) were combined in a sealed tube and heated at 90 °C for 12 h. After cooling to RT, volatiles were removed in vacuo. The resulting residue was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na 2 S0 4 and concentrated to afford 51 (7.9 g, 98.4%).
  • Step 3 6-(Isopropylamino)-5-methylnicotinic acid (52).
  • HCI (20 mL) was heated to 80 °C for 12 h. After cooling to RT, the reaction mixture was concentrated in vacuo. The resulting residue was dried under high vacuum, washed with pentane and diethyl ether and azeotroped with toluene to afford 52 (4.0 g, 95%) as the hydrochloride salt.
  • Step 4 (4S,5R)-tert-Butyl 4-((2,6-dichloro-4-(5-(6-(isopropylamino)-5- methylpyridin-3-yl)-l,2,4-oxad.azol-3-yl)phenoxy)methy ⁇
  • Step 5 (2R,3S)-3-amino-4-(2,6-dichIoro-4-(5-(6-(isopropylamino)-5- methylpyridin-3-yl)-l,2,4-oxadiazol-3-yl)phenoxy)butan-2-ol dihydrochloride salt
  • Step 1 6-Methyl-4-nitropicolinonitriIe (55).
  • a mixture of 4-nitro-2-picoline-N- oxide 54 (6 g, 38 mmol) and dimethyl sulfate (5.3 g, 42 mmol) was heated to 65-70 °C for 2 h. After cooling, the resulting solid was filtered and washed with 30 mL of n-hexane. The solid was then dissolved in 80 mL of water, cooled to -10 °C and a solution of sodium cyanide (7.7 g, 152 mmol) in water (55 mL) added dropwise with stirring over 40 min under an atmosphere of N 2 .
  • Step 2 6-Methyl-4-nitropicolinic acid (56).
  • a solution 55 (7 g, 42 mmol) in 90% H 2 S0 4 (40 mL) was heated at 120 °C for 2 h and then allowed to cool to RT.
  • Step 3 4-Bromo-6-methylpicolinic acid (57).
  • a solution of 56 (6 g, 32.7 mmol) in 48% hydrobromic acid (65 mL ) was heated at 100 °C overnight and was then cool to RT. The solution was then evaporated to dryness in vacuo to give crude 57 in near quantative yield which was directly used in the next step.
  • Step 4 4 ⁇ (Isopropylamino)-6-methylpicoIinic acid (58).
  • crude 57 (32.7 mmol) in butanol (120 mL) was added isopropylamine (8.2 g, 139 mmol) and the mixture was heated to 1 17 °C for 2 days. The solvent was removed in vacuo and the resulting residue was purified by column chromatography to afford 58 (5.0 g, 78% over 2 steps from compound 56) as a brown solid.
  • Step 5 (4S,5R)-tert-ButyI 4 (2,6-dichloro-4 ⁇ 5-(4-(isopropylamino)-6- methylpyridin-2-yl)-l,2,4-oxadiazol-3-yl)phenoxy)m
  • Step 6 (2R,3S)-3-amino-4-(2,6-dichloro-4-(5-(4-(isopropyIamino)-6- methylpyridin-2-yl)-l,2,4-oxadiazol-3-yl)phenoxy)butan-2-ol dihydrochloride salt
  • the title compound was synthesized from intermediate 59 using the same or an analogous synthetic procedure to that of (2S,3S)-3-amino-4- ⁇ [5-chloro-2-fluoro-4-(5- ⁇ 2-methyl-6-[(l- methylethyl)amino]pyridin-4-yl ⁇ -l ,2,4-oxadiazol-3-yl)phenyl]oxy ⁇ butan-2-ol dihydrochloride salt in Example 4.
  • Step 1 Methyl 5-bromo-6-chloronicotinate (61).
  • a mixture of 5-bromo-6- chloronicotinic acid 60 (0.2 g, 0.84 mmol), K 2 C0 3 (0.3 g, 2.1 mmol) and methyl iodide (0.178 g, 1.2 mmol) in DMF (10 mL) was stirred for 16 h at RT. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL).
  • Step 2 Methyl 5-bromo-6-(isopropyIamino)nicotinate (62).
  • 61 10 g, 39.9 mmol
  • triethylamine 5 mL
  • the obtained residue was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na 2 S0 4 and concentrated to afford 62 (10 g, 91.8%).
  • Step 3 Methyl 5-cyano-6-(isopropylamino)nicotinate (63). To a stirred solution of 62 (1.5 g, 5.4 mmol) in DMF (5 mL) was added Zn(CN) 2 (1.59 g, 13.6 mmol) and tetrakis(tirphenylphosphine)palladium (0) (0.78 g, 0.68 mmol) at 25 °C. The reaction mixture was stirred at 90 °C for 4 h. After completion, the reaction mixture was absorbed onto silica gel and chromatographed to afford 63 (1.0 g, 83 %).
  • Step 4 5-Cyano-6-(isopropylamino)nicotinic acid (64).
  • 63 4.8 g, 20.4 mmol
  • MeOH 50 mL
  • LiOH 1.367 g, 32.4 mmol
  • water 5 mL
  • the pH was adjusted to 2-3 with IN HC1 and extracted with EtOAc.
  • the EtOAc phase was dried over Na 2 S0 4 and concentrated under reduced pressure to obtain compound 64 (3.8 g, 84% yield) as a white solid.
  • Step 6 5-[3-(4- ⁇ [(2S,3R)-2-Amino-3-hydroxybutyl]oxy ⁇ -3,5-dichlorophenyl)- l,2,4-oxadiazol-5-yI]-2-[(l-methylethyl)amino]pyridine-3-carbonitrile di-trifluoroacetate salt.
  • Steps 1-4 5-Cyano-6-isopropoxynicotinic acid (68).
  • Intermediate 68 can be prepared by one skilled in the art from commercially available 60 in four steps using the standard procedures outlined in the scheme above.
  • Step 5 (4S,5R)-tert-ButyI 4-((2,6-dichloro-4-(5-(5-cyano-6-isopropoxypyridin-3- yI)-l,2,4-oxadiazol-3-yl)phenoxy)methyl)-2,2,5-trimethyloxazolidine-3-carboxylate (69).
  • Step 6 5-(3-(4-((2S,3R)-2-amino-3-hydroxybutoxy)-3,5-dichlorophenyl)-l,2,4- oxadiazol-5-yl)-2-isopropoxynicotinonitrile trifluoroacetic acid salt
  • the title compound was synthesized from intermediate 69 using the same or an analogous synthetic procedure to that of (2S,3S)-3-amino-4- ⁇ [5-chloro-2-fluoro-4-(5- ⁇ 2-methyl-6-[(l-methylethyl)amino]pyridin-4-yl ⁇ - l,2,4-oxadiazol-3-yl)phenyl]oxy ⁇ butan-2-ol dihydrochloride salt in Example 4, substituting TFA for HCI and DCM for EtOH and without converting the resulting TFA salt from the preparative HPLC purif i cation to the corresponding HCl salt.
  • Step 1 tert-Butyl (2S,3R)-l-(5-chloro-2-fluoro-4-(5-(2-(isopropylamino)-6- methyIpyridin-4-yl)-l,2,4-oxadiazol-3-yl)phenoxy)-3-hydroxybutan-2-ylcarbamate (70).
  • Step 2 tert-Butyl (2S,3 )-l-(5-chIoro-2-fluoro-4-(5-(2-(isopropylamino)-6- methyIpyridin-4-yl)-l,2,4-oxadiazol-3-yl)phenoxy)-3-(di-tert-butoxyphosphoryloxy)butan- 2-yIcarbamate (71).
  • Step 3 (lR,2S)-2-Amino-3- ⁇ [5-chloro-2-fluoro-4-(5- ⁇ 2-methyl-6-[(l- methylethyl)amino]pyridin-4-yl ⁇ -l,2,4-oxadiazoI-3-yI)phenyl]oxy ⁇ -l-methylpropyl dihydrogen phosphate dihydrochloride salt.
  • A-1 (2.0 g, 8.5 mmol) was heated in SOCl 2 (8 mL, 110 mmol) at 80°C for 1 hour. Excess SOCl 2 was removed under reduced pressure to afford A-2.
  • A-2 (2.2 g, 8.5 mmol) was heated in /-PrOH (10 mL) at 80°C for 1 hour. Excess i- PrOH was removed under reduced pressure. The residue was purified by flash chromatography (using a solvent gradient of 0-20% EtOAc in heptane) to afford A-3.
  • A-3 (2.5 g, 8.8 mmol) and z-PrOH (2.7 mL, 35.2 mmol) were dissolved in dry THF (25 mL) under N 2 .
  • the mixture was cooled to 0°C and a 1M solution of KOtBu in THF (10.6 mL, 10.56 mmol) was added.
  • the reaction was stirred for 1 hour at 0°C.
  • saturated aqueous NH 4 C1 solution (30 mL) and EtOAc (50 mL).
  • the layers were separated and the organic phase was extracted with EtOAc (50 mL).
  • the combined organic layer was washed with brine (10 mL), dried over Na 2 S0 4 and concentrated.
  • the residue was purified by flash chromatography (using a solvent gradient of 0-20% EtOAc in heptane) to afford A-4 (2.5 g) as colorless oil.
  • A-4 (1 g, 3.31 mmol), Zn(CN) 2 (805 mg, 6.86 mmol), and Pd[P(Ph) 3 ] 4 (1 15 mg, 0.1 mmol) in DMF (10 mL) was heated at 120°C for 3 hours. The mixture was cooled to room temperature, saturated aqueous NaHC0 3 (15 mL) was added and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by flash chromatography (using a solvent gradient of 0-30% EtOAc in heptane) to afford A-5.
  • A-6 (31 mg, 0.15 mmol) in DMF (1 mL) was added EDC-HC1 (29 mg, 0.15 mmol) and HOBt (24 mg, 0.18 mmol). The mixture was stirred for 50 minutes, and compound B-l (63 mg, 0.15 mmol) was added. After 50 minutes, the mixture was warmed at 95°C for 6 hours. The reaction was diluted with saturated aqueous NaHC0 3 and extracted with EtOAc. The organic phase was washed with water, brine, dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by flash chromatography (using a solvent gradient of 0-25% EtOAc in heptane) to afford compound A-7.
  • Suitable in vitro assays for measuring S1P1 and S1P5 agonist activity are known in the art. All Compounds in Table 1 were tested in one or more of the following biological assays and were found to be agonists of S I PI and/or S1P5. As such compounds of Formula I are useful for treating diseases, particularly autoimmune disease in which SI PI and/or S1P5 activity contributes to the pathology and/or symptomatology of the disease, for example, multiple sclerosis and graft-versus host disease. Suitable in vivo models for autoimmune diseases are known to those of ordinary skill in the art and are also described below, e.g.
  • HEK293 cells expressing the CNG channel and SIP] are thawed and plated into the wells of a black, clear bottom, 384-well CellBind plate (Corning, Corning, NY) at 14,000 cells per well.
  • HEK293 cells expressing the CNG channel and CB1 are cultured and plated under the same conditions.
  • the cells are incubated for 16 h at 37 °C in complete DMEM medium (Invitrogen Carlsbad, CA) containing 10% FBS (HyClone Logan, UT), 250 ⁇ g/mL geneticin (Invitrogen), and 1 ⁇ g/mL puromycin (Sigma-Aldrich, St. Louis, MO).
  • FBS HyClone Logan, UT
  • GPI GPI-Aldrich
  • puromycin Sigma-Aldrich, St. Louis, MO
  • a membrane potential dye (BD Biosciences) is added and the plates are incubated for 2-2.5 h at room temperature.
  • Test compounds are tested at maximum concentrations of 10 ⁇ . Compounds are diluted in DMSO (10 concentration points, 3 -fold each) and added to the assay plate at final DMSO concentrations of 1.8%. For each compound, there are duplicate assay plates and each assay plate have duplicate wells per concentration point. Test compounds are added to the cells in a DPBS solution containing 25 ⁇ Ro 20-1724 (Sigma-Aldrich), 500 nM of the A2b receptor agonist NEC A (Sigma-Aldrich) and 10 nM (EC 95 ) of SIP (Avanti Alabaster, AL) and incubated for 90 min.
  • the assay plate is read before compound addition (To) and after the 90 min incubation (T 90 ) using an EnVision plate reader (PerkinElmer, Waltham, MA) at an excitation wavelength of 350 nm and an emission wavelength of 590 nm.
  • the T 9 o/T 0 ratio is determined for each concentration of the test compounds.
  • the percent agonist activity is determined as [(test compound - DMSO alone control) / (NEC A alone control- DMSO alone control) * 100].
  • the percent activities are plotted against compound concentration to determine EC 50 using XLFit (IDBS, Alameda, CA).
  • the control used for calculating rEC50 in the SIPi CNG agonist assay is DMSO.
  • the cytoplasmic C-terminus of SI Pi was tethered to the tTA transcriptional activator with a linker that contains a cleavage site for the Nla protease from tobacco etch virus (TEV protease).
  • TEV protease tobacco etch virus
  • the C-terminus of the human P-arrestin2 protein was fused to TEV protease. Binding of an agonist recruits the ⁇ -arrestin-TEV fusion protein to the receptor resulting in cleavage of the linker and released of tTA to enter the nucleus and subsequently activated a tTA-dependent luciferase reporter gene.
  • Assay 2a Frozen HEK293 cells transiently transfected with receptor cDNAs for SI Pi (Invitrogen) are thawed and suspended in 10 mL of Pro293a-CDM culture medium (Invitrogen) supplemented with 4 mM L-Glutamine (Invitrogen), IX Pen/Strep (100 units/mL penicillin and 100 ⁇ g/mL streptomycin, Invitrogen) and 0.1% fatty acid free BSA (Sigma- Aldrich).
  • Cells are added to the wells of a 384-well white opaque bottom assay plate (PerkinElmer) at 3,000-6,000 cells per well and the plate is incubated for approximately 4 h in a 37 °C incubator.
  • Test compounds are tested at maximum concentrations of 10 ⁇ for the agonist assays.
  • Compounds are diluted in DMSO (10 concentration points, 3-fold each) and added to the assay plate at a 1% final DMSO concentration. For each compound, there are duplicate assay plates and each assay plate has duplicate wells per concentration point. The plate is incubated at 37 °C for 30 min.
  • the efficacy control is 5 ⁇ SIP (Avanti).
  • the assay plates are incubated in a 37 °C incubator for 16-18 h. Luciferase assay reagent is added and luminescence measured in an En Vision plate reader (PerkinElmer). To determine agonist activity, percent activity is calculated as [(test compound - background) / (positive control- background) * 100], where background is the luminescence of the DMSO alone control and the positive control is the luminescence from cells incubated with the efficacy control 5 ⁇ SIP. The percent activities are plotted against compound concentration to determine EC50 using XLFit (IDBS).
  • IDBS XLFit
  • Assay 2b Alternatively, U20S cells expressing the reporter gene and SI Pi (Invitrogen) were added to the wells of a 384-well white opaque bottom assay plate (PerkinElmer) at 0.3125 X 10 6 cells per well. The cells were serum starved for 48 h in Freestyle medium (Invitrogen). Test compounds were tested at maximum concentrations of 1 ⁇ for the agonist assay. Compounds were diluted in DMSO (10 concentration points, 3-fold each) and added to the assay plate at a 1% final DMSO concentration. The efficacy control was 1 ⁇ SIP 6 040892
  • Percent activity was calculated as [(test compound ratio - DMSO ratio) / (positive control ratio - DMSO ratio) * 100], where the positive control and DMSO ratios are from cells incubated with the efficacy control 1 ⁇ SIP and 1% DMSO, respectively. The percent activities were plotted against compound concentration to determine EC 50 using XLFit (IDBS).
  • Assay 3a The hSIPIR GTPyS binding assay was carried out at room temperature in 96 well non-binding surface assay plates. The reaction in each well contained 4 ⁇ g hSIPIR (hEdgl) membrane protein (Lonza), 30 ⁇ GDP, 0.1 nM [ 35 S]GTPyS, 0.25% fatty acid free BSA, and serially diluted hSIPIR agonist compound in 200 ⁇ , assay buffer (25mM Tris-HCl PH 7.9, 100 mM NaCl, 3 mM MgC12, and 0.2 niM EGTA).
  • assay buffer 25mM Tris-HCl PH 7.9, 100 mM NaCl, 3 mM MgC12, and 0.2 niM EGTA.
  • Assay 3b The DELFIA GTP-Eu binding assay (PerkinElmer) is a time-resolved fluorometric assay based on GDP-GTP exchange.
  • CHO cell membranes (Lonza) expressing human SIP] are incubated in 96-well filter plates (Pall, East Hills, NY) in a final volume of 100 ⁇ ⁇ buffer containing 40 ⁇ g/mL membrane, 50 mM HEPES, 2 ⁇ GDP, 10 mM MgCl 2 , 100 mM NaCl, 500 ⁇ g/mL Saponin and test compound. Test compounds are tested at maximum concentrations of 10 ⁇ .
  • Compounds are diluted (10 concentration points, 3-fold each) and added to the assay plate at a 1% final DMSO concentration. For each compound, there are duplicate assay plates and each assay plate has duplicate wells per concentration point. The plates are incubated for 30 min at room temperature on a plate shaker at low speed. GTP-Eu is added to each well (10 ⁇ , 10 nM final concentration) and the plate is incubated for an additional 30 min with slow shaking. The wells are washed with ice cold GTP washing buffer (3 X 150 ⁇ ,) using a vacuum manifold and the assay plates read in an EnVision plate reader (PerkinElmer) at an excitation wavelength of 340 nm and an emission wavelength of 615 ran.
  • EnVision plate reader PerkinElmer
  • percent activity is calculated as [(test compound - background)/ (positive control- background) * 100], where background is the fluorescence in absence of compound and the positive control is the fluorescence from membranes incubated with 1 ⁇ SIP (Avanti). The percent activities are plotted against compound concentration to determine IC 50 or EC 50 using XLFit (IDBS).
  • the hSlPR5 GTPyS binding assay was carried out at room temperature in 96-well non-binding surface assay plates.
  • the reaction in each well contained 5 ⁇ g hSlPR5 (hEdg8) membrane protein from CHO cells expressing hSlPR5, 30 ⁇ GDP, 0.1 nM [ 35 S]GTPyS, 0.25% fatty acid free BSA, and serially-diluted Compound of the Invention in 200 xL assay buffer (25 mM Tris-HCl PH 7.9, 100 mM NaCl, 3 mM MgC12, and 0.2 mM EGTA).
  • Table 4 gives EC 50 data (unless otherwise indicated) for the compounds in Tables 1 and 2 and are in nM units.
  • Assay 2b is the TangoTM ⁇ -arrestin Recruitment Assay in U20S cells, as described in Biological Example 2.
  • Assay 3a is the hSIPIR GTPyS Binding Assay as described in Biological Example 3.
  • Assay 4 is the hSlP5R GTPyS Binding Assay as described in Biological Example 4.
  • Assay 5 is the TangoTM ⁇ -arrestin Recruitment Assay in HEK293 cells, as described in Biological Example 5.
  • F means the compound has an EC 50 or relative EC 50 of less than or equal to 250 nM and G means the compound has an EC50 or relative EC50 of greater than 250 nM.
  • A means the compound has an EC50 or relative EC 50 of less than or equal to 10 nM.
  • B means the compound has an EC 50 or relative EC 50 greater than 10 nM but less than or equal to 50 nM.
  • C means the compound has an EC 50 or relative EC o greater than 50 nM but less than or equal to 250 nM.
  • D means the compound has an EC 50 or relative EC 50 greater than 250 nM but less than or equal to 2800 nM.
  • E means the compound has an EC 50 or relative EC 50 greater than 2800 nM but less than 10000 nM.
  • nt means the Compound was not tested and "na” means the compound was tested but had no measurable activity under the assay conditions employed.
  • 26 isopropoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)-2- nt A nt nt fluorophenoxy)propan-l -ol
  • mice Suppression of circulating lymphocytes is assessed as a pharmacodynamic (PD) endpoint in 6-10 week old C57B1/6 male mice (Taconic Farms, Germantown, NY). Upon arrival, mice are acclimated to the vivarium (12 h light cycle, 12 h dark cycle) for a minimum of 3 days prior to the initiation of a study. During the study, animals are provided food and water ad libitum and housed in a room conditioned at 70-75 °F. All animals are examined daily for health assessment.
  • PD pharmacodynamic
  • Compounds of the Invention are suspended or dissolved in vehicle for administration of 0.1 mL/animal based on mean body weight of group.
  • Compounds are administered using a disposable gavage needle (20G, Braintree Scientific, Braintree, MA). Blood is collected into EDTA-coated tubes (Microvette 100 with EDTA, Sarstedt, Newton, NC) from the retro-orbital sinus of isoflurane-anesthetized animals 24 or 32 h post-dose. Mice are then euthanized by cervical dislocation. For some experiments, samples of tissues are collected for measurement of compound levels. Samples are frozen immediately on dry ice and stored at -18 °C until assayed.
  • CBC complete blood count
  • CBC readouts include white blood cells; total and % of total for the following: neutrophils, lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells (RBC); RBC; hemoglobin; hematocrit; mean corpuscular volume, hemoglobin (HGB) total and concentration; RBC distribution width; platelets; and mean platelet volume.
  • All mouse PD data consists of group sizes of 8 and are expressed as means ⁇ SEM.
  • the compounds of the invention are formulated and animals are dosed at a volume of 4 mL/kg.
  • whole blood is collected via jugular vein canulas into EDTA-coated tubes and hematology analysis is performed on an Abbott Cell-Dyn 3700 hematology analyzer.
  • Readouts include white blood cells (total, differential, and % of total), neutrophils, lymphocytes, monocytes, eosinophils, basophils, RBC, HGB, hematocrit, mean corpuscule volume, mean corpuscule HGB concentration, RBC distribution width, platelets, and mean platelet volume.
  • DTH Delayed-type hypersensitivity
  • This second phase results in recruitment of inflammatory cells such as neutrophils and macrophages to the injection site of an intradermally applied antigen in a previously sensitized host, which causes swelling 24 h to 48 h post antigen challenge.
  • the DTH assay (primarily done in mice) is an in vivo manifestation of a cell-mediated immunity reaction, and the response to antigen representation modulated by immunosuppressive treatment can be measured.
  • mice C57B1/6 male mice (10 mice per group) are immunized on day zero by subcutaneous injection at the base of the tail with 100 iL of 2 mg/mL methylated BSA emulsified with Complete Freunds Adjuvans (CFA, Sigma). Once-daily for twice-daily administration of a Compound of the Invention occurrs for 10 days. On day 10 after immunization, mice receive a second booster injection at the base of tail of an emulsified mixture of 2 mg/mL methylated BSA in Incomplete Freund's Adjuvans. On day 13 animals are challenged subcutaneously in the left hind footpad with 20 of 10 mg/mL methylated BSA in sterile water (water for injection).
  • CFA Complete Freunds Adjuvans
  • Animals are injected with an equal volume of sterile water into the right hind footpad as a control. Twenty four hours later (dose day 14) the right and left hind foot paws are transected at the medial and lateral malleolus, weighed, and the weight difference induced by injected antigen determined and compared to weight differences of vehicle treated non-sensitized and sensitized control groups. The increase in paw weights comparing left and right hind paw for each treatment group are analyzed for differences of treatment with a Compound of the Invention compared to vehicle control group using the Mann- Whitney non-parametric test statistic with minimal significance level set at p ⁇ 0.05.
  • the rodent allograft model is an in vivo assay for assessing tissue rejection (ie, from transplantation) in response to chronic and/or sub-chronic immunosuppressive treatment (Chiba et al, 2005). Rejection is caused by T lymphocytes of the recipient responding to the foreign major histocompatibility complex of the donor graft.
  • the transplanted organ eg, skin
  • the transplanted organ represents a continuous source of HLA alloantigens capable of inducing a rejection response at any time post transplantation. Because it cannot be eliminated, the allograft continuously activates the immune system, resulting in lifelong overproduction of cytokines, constant cytotoxic activity, and sustained alteration in the graft vasculature.
  • Multiple sclerosis is a demyelinating disease of the CNS.
  • the main features of the disease are focal areas of demyelination and inflammation mediated by macrophages and t-lymphocytes. These cells develop in the peripheral lymphoid organs and travel to the CNS causing an autoimmune response.
  • the development of T cells is controlled largely by the expression of various cytokines as well as cellular adhesion molecules.
  • the EAE model today is the most thoroughly studied animal model for human autoimmune diseases. Mice are immunized with myelin-derived peptide PLP and clinical parameters of disease (bodyweight loss and paralysis) are monitored daily. The endpoint is the analysis of the extent of inflammation in brain and spinal cord.
  • C57B1/6 mice develop chronic paralysis after immunization with MOG 35 - 55 peptide. Mice develop EAE 8-14 days after immunization and stay chronically paralyzed for 30-40 days after onset of disease.
  • Female C57B1/6 mice are subcutaneously injected with MOG35-55 peptide emulsified in Complete Freund's Adjuvant at two sites on the back, injecting 0.1 mL at each site.
  • pertussis toxin (aids in brain penetration of the MOG peptide) is administered intraperitoneally. A second injection of pertussis toxin is administered 22-26 h after the MOG 3 5-5 5 peptide injection.
  • EAE Onset of EAE is typically 7 days after immunization. EAE is scored on a scale of 0-5 with 0 being no obvious changes in motor functions, while 5 indicates complete paralysis. Mice are administered a Compound of the Invention (once-daily or twice- daily) on the day of MOG 35- 55 peptide injection and monitored for paralysis and compared to vehicle-treated control animals. A positive effect in this model is delayed onset/severity of EAE.
  • Biological Example 12 Osteoporosis model

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Abstract

L'invention concerne des composés de Formule (I) : dans laquelle chaque variable est telle que définie dans la description, ainsi que des procédés de fabrication et d'utilisation des composés en tant qu'agonistes de S1P1 et/ou de S1P5, par exemple pour traiter la maladie du greffon contre l'hôte et des maladies auto-immunes.
PCT/US2016/040892 2015-07-02 2016-07-02 Modulateurs d'oxadiazole de s1p, ainsi que procédés de fabrication et d'utilisation correspondants WO2017004608A1 (fr)

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