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US20190119236A1 - Compounds for binding proprotein convertase subtilisin/kexin type 9 (pcsk9) - Google Patents

Compounds for binding proprotein convertase subtilisin/kexin type 9 (pcsk9) Download PDF

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US20190119236A1
US20190119236A1 US16/078,578 US201716078578A US2019119236A1 US 20190119236 A1 US20190119236 A1 US 20190119236A1 US 201716078578 A US201716078578 A US 201716078578A US 2019119236 A1 US2019119236 A1 US 2019119236A1
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alkyl
compound
hydrogen
cycloalkyl
tert
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US16/078,578
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Anjali Pandey
Simeon Bowers
Thomas E. Barta
Jonathan William Bourne
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SRX Cardio LLC
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Portola Pharmaceuticals LLC
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Assigned to PORTOLA PHARMACEUTICALS, INC. reassignment PORTOLA PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BOWERS, SIMEON, PANDEY, ANJALI, BARTA, THOMAS E., BOURNE, Jonathan William
Publication of US20190119236A1 publication Critical patent/US20190119236A1/en
Assigned to PORTOLA PHARMACEUTICALS, INC. reassignment PORTOLA PHARMACEUTICALS, INC. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: HCR COLLATERAL MANAGEMENT, LLC
Assigned to SRX CARDIO, LLC reassignment SRX CARDIO, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PORTOLA PHARMACEUTICALS, INC.
Assigned to SRX CARDIO, LLC reassignment SRX CARDIO, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PORTOLA PHARMACEUTICALS, INC.
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    • 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
    • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/40—Oxygen atoms
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    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
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    • 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
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • the present disclosure relates to novel compounds, methods, and compositions capable of binding to proprotein convertase subtilisin/kexin type 9 (PCSK9), thereby modulating PCSK9 proprotein convertase enzyme activity.
  • PCSK9 proprotein convertase subtilisin/kexin type 9
  • LDL-C low density lipoprotein cholesterol
  • LDLRs low density lipoprotein receptors
  • ADH Autosomal dominant hypercholesterolemia
  • the low density lipoprotein receptor mediates efficient endocytosis of very low density lipoprotein (VLDL), VLDL remnants, and LDL. As part of the endocytic process, the LDLR releases lipoproteins into hepatic endosomes.
  • PCSK9 Proprotein convertase subtilisin/kexin type 9
  • EGF-A epidermal growth factor-like repeat A
  • LDLR low-density lipoprotein receptor
  • PCSK9 A drug that could modulate the activity of PCSK9 would be useful in controlling LDL-cholesterol levels. Therefore, there remains a need for compounds that are effective in the treatment and prevention of conditions and disorders associated with PCSK9, including hypercholesterolemia and hypocholesterolemia.
  • the compounds provided herein bind to PCSK9, thereby modulating PCSK9 proprotein convertase enzyme activity, and can be used to treat and prevent PCSK9-associated conditions and disorders.
  • compositions including pharmaceutical compositions, kits that include the compounds, and methods of using (or administering) and making the compounds.
  • the disclosure further provides compounds or compositions thereof for use in a method of treating a disease, disorder, or condition that is mediated by PCSK9.
  • the disclosure provides uses of the compounds or compositions thereof in the manufacture of a medicament for the treatment of a disease, disorder or condition that is mediated, at least in part, by PCSK9.
  • n 0, 1, or 2;
  • X 1 is absent, CR 2 , CR 2 R 2 , C(O), N, NR 2 , S, SO 2 , or O;
  • X 2 , X 3 , and X 4 are each independently CR 2 , CR 2 R 2 , C(O), N, NR 2 , S, SO 2 , or O;
  • ring B is a five- or six-membered ring comprising one or more double bonds
  • X 5 and X 6 are either CR 2 or N;
  • X 7 is C or N
  • ring A is selected from:
  • L is a bond, C 1-6 -alkylene, —O—, —C(O)—, —SO 2 —, —N(R a )—, —N(R a )SO 2 —, or —SO 2 N(R a )—
  • R a is hydrogen, C 1-6 alkyl, or C 1-6 heteroalkyl, wherein the C 1-6 alkyl or C 1-6 heteroalkyl are optionally substituted with 1 to 3 substituents independently selected from halo, oxo, hydroxy, C 1-6 alkyl, or C 1-6 heteroalkyl;
  • R 1 in each instance is independently halo, cyano, C 1-6 alkyl optionally substituted with halo or hydroxy, C 3-6 cycloalkyl, —NR b C(O)NR b R b , or —NR b S(O) 2 R b ;
  • R 2 in each instance is independently hydrogen, halo, C 1-6 alkyl optionally substituted with halo or hydroxy, C 3-6 cycloalkyl, C 2-6 hydroxyalkyl, cyano, —C(O)OR c , or —C(O)NR c R c ;
  • R 3 is hydrogen, halo, cyano, amino, C 1-12 alkyl, C 1-12 alkenyl, C 1-12 alkynyl, C 3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl, or heteroaryl;
  • R 4 in each instance is independently hydrogen, C 1-6 alkyl, —C(O)NR d R d , —C(NR d )NR d R d , —C(O)R d , or —S(O) 2 NR d R d ;
  • R 4 is hydrogen, X 1 , X 2 , X 3 , X 4 are all CH, then L-R 3 is not CF 3 ;
  • L-R 3 is not hydrogen, —CH 2 -aryl, or —CH 2 -heteroaryl
  • L-R 3 is not —SO 2 -aryl, wherein the aryl is optionally substituted;
  • the compound is not 3-bromo-8-(4-methylpiperidin-1-yl)quinoline or 4-methyl-1-(naphthalen-1-yl)piperidine;
  • R 4 is not C(O)NH 2 .
  • diseases or conditions include cardiovascular diseases (e.g., coronary disease, hypertension, hypercholesterolemia, or atherosclerosis), a metabolic diseases (e.g., diabetes), hypocholesterolemia, a disease or condition where the mammal has elevated plasma levels of low density lipoprotein cholesterol, and a disease or condition where the mammal has suppressed plasma levels of low density lipoprotein cholesterol. Therefore, in certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof are of use as a medicament for the treatment of the aforementioned diseases or conditions.
  • a dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —C(O)NH 2 is attached through the carbon atom.
  • a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • a wavy line or a dashed line drawn through a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.
  • C u-v indicates that the following group has from u to v carbon atoms.
  • C 1-6 alkyl indicates that the alkyl group has from 1 to 6 carbon atoms.
  • references to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • the term “about” includes the indicated amount ⁇ 10%.
  • the term “about” includes the indicated amount ⁇ 5%.
  • the term “about” includes the indicated amount ⁇ 1%.
  • to the term “about X” includes description of “X”.
  • the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise.
  • reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.
  • Alkyl refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl), or 1 to 4 carbon atoms (i.e., C 1-4 alkyl).
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
  • alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.
  • Alkenyl refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 alkenyl).
  • alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).
  • Alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 alkynyl).
  • alkynyl also includes those groups having one triple bond and one double bond.
  • Alkoxy refers to the group “alkyl-O—”. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
  • Alkylthio refers to the group “alkyl-S—”.
  • acyl refers to a group —C(O)R, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Examples of acyl include formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.
  • “Amido” refers to both a “C-amido” group which refers to the group —C(O)NR y R z and an “N-amido” group which refers to the group —NR y C(O)R z , wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Amino refers to the group —NR y R z wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Aryl refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems.
  • aryl has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl).
  • Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl.
  • Aryl does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl.
  • Carbamoyl refers to both an “O-carbamoyl” group which refers to the group —O—C(O)NR y R z and an “N-carbamoyl” group which refers to the group —NR y C(O)OR z , wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Carboxyl ester refers to both —OC(O)R and —C(O)OR, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Cycloalkyl refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • the term “cycloalkyl” includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond).
  • cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl).
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • the term cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule.
  • Imino refers to a group —C(NR)R, wherein each R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Halogen or “halo” includes fluoro, chloro, bromo, and iodo.
  • Haloalkyl refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached.
  • Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (—CHF 2 ) and trifluoromethyl (—CF 3 ).
  • Haloalkoxy refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
  • Hydroalkyl refers to an alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a hydroxyl group.
  • Heteroalkyl refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group.
  • the term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group.
  • Heteroatomic groups include, but are not limited to, —NR—, —O—, —S—, —S(O)—, —S(O) 2 —, and the like, where hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • heteroalkyl groups include —OCH 3 , —CH 2 OCH 3 , —SCH 3 , —CH 2 SCH 3 , —NRCH 3 , and —CH 2 NRCH 3 , where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
  • Heteroaryl refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl includes 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8 heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl.
  • fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system.
  • Heterocyclyl refers to a saturated or unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • the term “heterocyclyl” includes heterocycloalkenyl groups (i.e. the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups.
  • a heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro.
  • any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom).
  • heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule.
  • heterocyclyl has 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen.
  • ring carbon atoms i.e., C 2-20 heterocyclyl
  • 2 to 12 ring carbon atoms i.
  • heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.
  • spiro-heterocyclyl refers to a ring system in which a three- to ten-membered heterocyclyl has one or more additional ring, wherein the one or more additional ring is three- to ten-membered cycloalkyl or three- to ten-membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three- to ten-membered heterocyclyl.
  • spiro-heterocyclyl rings include bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl.
  • fused-heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.
  • “Sulfonyl” refers to the group —S(O) 2 R, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.
  • “Sulfinyl” refers to the group —S(O)R, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.
  • Alkylsulfonyl refers to the group —S(O) 2 R, where R is alkyl.
  • Alkylsulfinyl refers to the group —S(O)R, where R is alkyl.
  • “Sulfinic acid” refers to the group —S(O)R, where R is alkyl.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.
  • substituted means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom's normal valence is not exceeded.
  • the one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.
  • impermissible substitution patterns e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms.
  • impermissible substitution patterns are well known to the skilled artisan.
  • substituted may describe other chemical groups defined herein. Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.
  • substituted alkyl refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, acyl, oxo, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted.
  • the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.
  • any formula or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • isotopically labeled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H, 13 C and 14 C are incorporated.
  • isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • the disclosure also includes “deuterated analogs” of compounds of Formula I in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule.
  • deuterated analogs of compounds of Formula I in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule.
  • Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984).
  • Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
  • Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index.
  • An 18 F, 3 H, 11 C labeled compound may be useful for PET or SPECT or other imaging studies.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I.
  • the concentration of such a heavier isotope, specifically deuterium may be defined by an isotopic enrichment factor.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • pharmaceutically acceptable salt of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable.
  • “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt, particularly a pharmaceutically acceptable addition salt may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
  • pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH 2 (alkyl)), dialkyl amines (i.e., HN(alkyl) 2 ), trialkyl amines (i.e., N(alkyl) 3 ), substituted alkyl amines (i.e., NH 2 (substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl) 2 ), tri(substituted alkyl) amines (i.e., N(substituted alkyl) 3 ), alkenyl amines (i.e., NH 2 (alkenyl)), dialkenyl amines (i.e., HN(alkenyl) 2 ), trialkenyl amines (i.e.,
  • Suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • hydrate refers to the complex formed by the combining of a compound of Formula I and water.
  • a “solvate” refers to an association or complex of one or more solvent molecules and a compound of the disclosure.
  • solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid, and ethanolamine.
  • Tautomers are in equilibrium with one another.
  • amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.
  • Stepoisomers are isomers that differ only in the way the atoms are arranged in space and include enantiomers and diastereomers.
  • Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture.
  • “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • Prodrugs means any compound which releases an active parent drug according to Formula I in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of Formula I are prepared by modifying functional groups present in the compound of Formula I in such a way that the modifications may be cleaved in vivo to release the parent compound.
  • Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include compounds of Formula I wherein a hydroxy, amino, carboxyl or sulfhydryl group in a compound of Formula I is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula I, and the like. Preparation, selection, and use of prodrugs is discussed in T. Higuchi and V.
  • “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • n 0, 1, or 2;
  • X 1 is absent, CR 2 , CR 2 R 2 , C(O), N, NR 2 , S, SO 2 , or O;
  • X 2 , X 3 , and X 4 are each independently CR 2 , CR 2 R 2 , C(O), N, NR 2 , S, SO 2 , or O;
  • ring B is a five- or six-membered ring comprising one or more double bonds
  • X 5 and X 6 are either CR 2 or N;
  • X 7 is C or N
  • ring A is selected from:
  • L is a bond, C 1-6 -alkylene, —O—, —C(O)—, —SO 2 —, —N(R a )—, —N(R a )SO 2 —, or —SO 2 N(R a )—
  • R a is hydrogen, C 1-6 alkyl, or C 1-6 heteroalkyl, wherein the C 1-6 alkyl or C 1-6 heteroalkyl are optionally substituted with 1 to 3 substituents independently selected from halo, oxo, hydroxy, C 1-6 alkyl, or C 1-6 heteroalkyl;
  • R 1 in each instance is independently halo, cyano, C 1-6 alkyl optionally substituted with halo or hydroxy, C 3-6 cycloalkyl, —NR b C(O)NR b R b , or —NR b S(O) 2 R b ;
  • R 2 in each instance is independently hydrogen, halo, C 1-6 alkyl optionally substituted with halo or hydroxy, C 3-6 cycloalkyl, C 2-6 hydroxyalkyl, cyano, —C(O)OR c , or —C(O)NR c R c ;
  • R 3 is hydrogen, halo, cyano, amino, C 1-12 alkyl, C 1-12 alkenyl, C 1-12 alkynyl, C 3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl, or heteroaryl;
  • R 4 in each instance is independently hydrogen, C 1-6 alkyl, —C(O)NR d R d , —C(NR d )NR d R d , —C(O)R d , or —S(O) 2 NR d R d ;
  • R 4 is hydrogen, X 1 , X 2 , X 3 , X 4 are all CH, then L-R 3 is not CF 3 ;
  • L-R 3 is not hydrogen, —CH 2 -aryl, or —CH 2 — heteroaryl
  • L-R 3 is not —SO 2 -aryl, wherein the aryl is optionally substituted;
  • the compound is not 3-bromo-8-(4-methylpiperidin-1-yl)quinoline or 4-methyl-1-(naphthalen-1-yl)piperidine;
  • R 4 is not C(O)NH 2 .
  • n 0, 1, or 2;
  • n 0, 1, or 2;
  • X 1 , X 2 , X 3 , and X 4 are each independently CH, C(O), N, NH, S, SO 2 , or O; or
  • X 1 is absent and X 2 , X 3 , and X 4 are each independently CH, C(O), N, NH, S, SO 2 , or O;
  • X 5 and X 6 are either CH or N;
  • ring A is selected from:
  • L is a bond, C 1-6 -alkylene, —O—, —C(O)—, —SO 2 —, or —N(R a )—, where R a is hydrogen, C 1-6 alkyl, or C 1-6 heteroalkyl, wherein the C 1-6 alkyl or C 1-6 heteroalkyl are optionally substituted with 1 to 3 substituents independently selected from halo, oxo, hydroxy, C 1-6 alkyl, or C 1-6 heteroalkyl;
  • R 1 in each instance is independently, halo, cyano, C 1-6 alkyl optionally substituted with halo or hydroxy, C 3-6 cycloalkyl, —NR b C(O)NR b R b , —NR b S(O) 2 R b , —N(R b ) 2 , or —NR b C(O)R b ;
  • R 2 in each instance is independently, halo, C 1-6 alkyl optionally substituted with halo or hydroxy, C 3-6 cycloalkyl, C 2-6 hydroxyalkyl, cyano, —C(O)OR c , or —C(O)NR c R c ;
  • R 3 is hydrogen, halo, cyano, C 1-12 alkyl, C 1-12 alkenyl, C 1-12 alkynyl, C 3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl, or heteroaryl,
  • R 4 in each instance is independently, hydrogen, C 1-6 alkyl, —C(O)NR d R d , —C(NR d )NR d R d , —C(O)R d , or —S(O) 2 NR d R d ;
  • R 4 is hydrogen, X 1 , X 2 , X 3 , X 4 are all CH, then either L-R 3 is not CF 3 or n is not 0.
  • the compound is of Formula (Ia) with the further proviso that when m is 0, n is 0, R 4 is hydrogen, X 1 , X 2 , X 3 , X 4 are all CH, then L-R 3 is not hydrogen.
  • the bicyclic ring may be optionally substituted with one or more R 2 selected from the group consisting of hydrogen, halo, C 1-6 alkyl optionally substituted with halo or hydroxy, C 3-6 cycloalkyl, C 2-6 hydroxyalkyl, cyano, —C(O)OR c , and —C(O)NR c R c .
  • the bicyclic ring may be optionally substituted with one or more R 2 selected from the group consisting of hydrogen, halo, C 1-6 alkyl optionally substituted with halo or hydroxy, C 3-6 cycloalkyl, C 2-6 hydroxyalkyl, cyano, —C(O)OR c , and —C(O)NR c R c .
  • ring A is:
  • ring A is:
  • ring A is:
  • m is 0 or 1.
  • R 4 is hydrogen, —C(O)NH 2 , or —C(NH)NH 2 . In certain embodiments, R 4 is hydrogen.
  • R 1 is —NHC(O)NH 2 , —NHS(O) 2 CH 3 , or —NHC(O)CH 3 . In certain embodiments, R 1 is —NHS(O) 2 CH 3 , or —NHC(O)CH 3 .
  • R 2 is hydrogen, C 1-6 alkyl, —CO 2 H or —C(O)NH 2 . In certain embodiments, R 2 is —CO 2 H or —C(O)NH 2 . In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is hydrogen or methyl.
  • R 4 is hydrogen, —C(O)NH 2 , or —C(NH)NH 2 . In certain embodiments, R 4 is hydrogen.
  • L is a bond, —CH 2 —, —O—, —C(O)—, —S(O) 2 —, —S(O) 2 NH—, or —NH—.
  • L is —CH 2 —, —O—, —C(O)—, —S(O) 2 —, —S(O) 2 NH—, or —NH—.
  • L is —CH 2 —, —O—, —C(O)—, —S(O) 2 —, or —NH—.
  • L is a bond.
  • R 3 is hydrogen, amino, halo, C 1-6 alkyl, aryl, or C 3-10 heterocyclyl, wherein C 1-6 alkyl, aryl, or C 3-10 heterocyclyl is optionally substituted with one or more halo.
  • R 3 is hydrogen, C 1-6 alkyl, or C 3-10 heterocyclyl, wherein C 1-6 alkyl or C 3-10 heterocyclyl is optionally substituted with one or more halo.
  • R 3 is hydrogen.
  • R 3 is CH 3 .
  • R 3 is CF 3 .
  • R 3 is F.
  • R 3 is Cl.
  • R 3 is NH 2 .
  • R 3 is cyclohexyl.
  • R 3 is aryl.
  • R 3 is C 3-10 heterocyclyl.
  • L is a bond and R 3 is hydrogen, C 1-6 alkyl, haloalkyl, halo, C 3-10 cycloalkyl, heterocyclyl, or aryl.
  • L is a bond and R 3 is hydrogen.
  • L is a bond and R 3 is CH 3 .
  • L is a bond and R 3 is CF 3 .
  • L is a bond and R 3 is F.
  • L is a bond and R 3 is Cl.
  • L is a bond and R 3 is cyclohexyl.
  • L is a bond, and R 3 is phenyl.
  • R 3 is:
  • Y is —O—, —N(R e )—, —CH((CH 2 ) f OH), or —N((CH 2 ) f OH);
  • each R e is independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or C 2-6 alkyl where the C 2-6 alkyl is substituted with a hydroxy;
  • f 0, 1, 2, 3, or 4.
  • Y is —N(R e )—.
  • n 0, 1, or 2;
  • n 0, 1, or 2;
  • X 1 , X 2 , X 3 , and X 4 are each independently CH, C(O), N, NH, S, SO 2 , or O; or
  • X 1 is absent and X 2 , X 3 , and X 4 are each independently CH, C(O), N, NH, S, SO 2 , or O;
  • X 5 and X 6 are either CH or N;
  • ring A is selected from:
  • R 1 in each instance is independently, halo, cyano, C 1-6 alkyl optionally substituted with halo or hydroxy, C 3-6 cycloalkyl, —NR b C(O)NR b R b , —NR b S(O) 2 R b , —N(R b ) 2 , or —NR b C(O)R b ;
  • R 2 in each instance is independently, halo, C 1-6 alkyl optionally substituted with halo or hydroxy, C 3-6 cycloalkyl, C 2-6 hydroxyalkyl, cyano, —C(O)OR c , or —C(O)NR c R c ;
  • R 4 in each instance is independently, hydrogen, C 1-6 alkyl, —C(O)NR d R d , —C(NR d )NR d R d , —C(O)R d , or —S(O) 2 NR d R d ;
  • J is selected from the group consisting of —O—, —CO—, —CH 2 —, —CF 2 —, —SO 2 —;
  • Ring C is a 5 or 6 membered saturated or unsaturated aryl, heteroaryl, carbocyclic or heterocyclic ring. And ring C may be fused via R 11 , R 12 to form a 5-6 membered aryl, heteroaryl, carbocyclic or heterocyclic ring;
  • E 1 , E 2 , and E 3 are independently selected from C or N;
  • R 11 and R 12 are independently selected from the group consisting of lower alkyl, halo, hydroxy, amino, aminoalkyl, hydroxylalkyl, haloalkyl, carboxy, —C(O)NH 2 , nitrile, —S-alkyl, —O-alkyl, acyl, and oxo; and
  • R 10 , R 11 , and R 12 are independently selected from the group consisting of lower alkyl, halo, hydroxy, amino, aminoalkyl, hydroxylalky, haloalkyl, carboxy, —C(O)NH 2 , —C(O)N-alkyl, nitrile, —S-alkyl, —O-alkyl, acyl, oxo; and R 10 and R 11 may be joined to form a 5-6 membered fused saturated or unsaturated ring D containing 0-3 heteroatoms where Ring D may further be substituted at positions at least two atoms away from the juncture with Ring C,
  • a compound may be selected from those compounds in Table 1 or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof.
  • a compound may be selected from those compounds in Table 2 or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof.
  • the compounds provided herein are useful for binding to PCSK9 and modulating PCSK9 proprotein convertase enzyme activity.
  • Treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
  • a) inhibiting the disease or condition e.g., decreasing one or more symptoms resulting from the disease or condition
  • Prevention means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop.
  • Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
  • Subject refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications.
  • the subject is a mammal. In one embodiment, the subject is a human.
  • terapéuticaally effective amount or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression.
  • a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition of as described herein.
  • the therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one or ordinary skill in the art.
  • ex vivo means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual.
  • Ex vivo means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes.
  • the compounds and compositions described herein may be used ex vivo to determine the optimal schedule and/or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suited are described below or will become apparent to those skilled in the art.
  • the selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.
  • Proprotein convertase subtilisin/kexin type 9 also known as PCSK9, is an enzyme that in humans is encoded by the PCSK9 gene. Seidah et al., “The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation,” Proc. Natl. Acad. Sci. U.S.A. 100 (3): 928-933 (2003). Similar genes (orthologs) are found across many species. Many enzymes, including PCSK9, are inactive when they are first synthesized, because they have a section of peptide chains that blocks their activity; proprotein convertases remove that section to activate the enzyme.
  • the PCSK9 gene encodes a proprotein convertase belonging to the proteinase K subfamily of the secretory subtilase family.
  • the encoded protein is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum.
  • the protein may function as a proprotein convertase.
  • a human PCSK9 amino acid sequence is:
  • PCSK9 is believed to play a regulatory role in cholesterol homeostasis.
  • PCSK9 can bind to the epidermal growth factor-like repeat A (EGF-A) domain of the low-density lipoprotein receptor (LDL-R) resulting in LDL-R internalization and degradation.
  • EGF-A epidermal growth factor-like repeat A
  • LDL-R low-density lipoprotein receptor
  • PCSK9 inhibitors could result in such widespread usage having the potential to replace statins in certain conditions.
  • PCSK9 has medical significance because it acts in cholesterol homeostasis. Drugs that block PCSK9 biological actions are believed to lower circulating low-density lipoprotein cholesterol (LDL-C) levels (e.g., by increasing the availability of LDL-Rs and, consequently, LDL-C clearance).
  • LDL-C low-density lipoprotein cholesterol
  • Evolocumab (trade name RepathaTM from Amgen, Inc.) and Alirocumab (tradename PraluentTM from Sanofi U.S., LLC and Regeneron Pharmaceuticals, Inc.) have been FDA approved, but are still in clinical trials to determine if they can improve outcomes in heart disease.
  • Variants of PCSK9 can reduce or increase circulating cholesterol.
  • Abifadel et al. “Mutations in PCSK9 cause autosomal dominant hypercholesterolemia” Nat. Genet. 34 (2): 154-156 (2003).
  • LDL-C is normally removed from the blood when it binds to an LDL-R on the surface of liver cells, and is internalized within the hepatocyte as a receptor-ligand complex.
  • the LDL-R is concomitantly degraded along with the complexed LDL particle.
  • the LDL-R is recycled after internalization thereby returning to the surface of the cell for removal of more cholesterol.
  • compounds contemplated to have a modulation effect on PCSK9's ability to form an LDL-R/PCSK9 complex may bind to a PCSK9 protein and modulate the protein's biological activity.
  • compounds decrease LDL-R/PCSK9 complex formation and are thereby useful to treat various diseases involving lipid dysregulation.
  • compounds increase LDL-R/PCSK9 complex formation and are thereby useful in research and development of therapies relevant to LDL dysregulation.
  • gain-of-function PCSK9 mutants may result in conditions including, but not limited to, hypercholesterolemia.
  • compounds that bind to a PCSK9 and increase the affinity of PCSK9's low density lipoprotein receptor for a low density lipoprotein receptor on the surface of a cell would be expected to increase the symptoms of hypercholesterolemia by increasing low density lipoprotein receptor internalization and degradation.
  • LEF loss-of-function
  • PCSK9 mutants may result in conditions comprising reduced low density lipoproteins and would be expected to result in hypocholesterolemia thereby reducing the risk of cardiovascular diseases, including but not limited to, coronary heart disease.
  • compounds that bind to a PCSK9 that decrease the affinity of PCSK9's low density lipoprotein receptor binding site for a low density lipoprotein receptor on the surface of a cell e.g., a hepatocyte
  • the compounds of the present disclosure are therefore useful for treating diseases and conditions mediated, at least in part by, PCSK9, including but not limited to cardiovascular diseases (e.g., a coronary disease) and metabolic diseases.
  • cardiovascular diseases e.g., a coronary disease
  • metabolic diseases e.g., cardiovascular diseases, e.g., a coronary disease
  • the compounds of the present disclosure are useful for treating diseases and conditions including, but not limited to hypercholesterolemia, atherosclerosis, and hypertension.
  • the compounds of the present disclosure are useful for reducing symptoms including, but not limited to elevated low density lipoprotein receptor density, reduced low density lipoprotein receptor density, symptoms of liver disease.
  • the administration of a compound of the present disclosure induces a conformational shift of the PCSK9 protein such that the affinity of the low density lipoprotein binding site for a low density lipoprotein receptor is decreased, wherein PCSK9/LDL-R complex formation is decreased.
  • the decrease in PCSK9/LDL-R complex formation results in an increase in the bioavailability of LDL-R receptors for binding to circulating LDL, thereby increasing the internalization and clearance of LDL by LDL-R.
  • administration of the compound may result in increased bioavailability of hepatocyte cell LDL-Rs.
  • the administration of a compound of the present disclosure induces a conformational shift of the PCSK9 protein such that the affinity of the low density lipoprotein binding site for a low density lipoprotein receptor is increased, wherein PCSK9/LDL-R complex formation is increased or stabilized.
  • the increase or stabilization in PCSK9/LDL-R complex formation results in a decrease in the bioavailability of LDL-R receptors for binding to circulating LDL, thereby decreasing the internalization and clearance of LDL by LDL-R.
  • a PCSK9 allosteric activator compound may result in decreased bioavailability of hepatocyte cell LDL-Rs.
  • provided herein is a method of treating a disease or condition mediated, at least in part, by PCSK9, the method comprising administering to a patient in need thereof a compound of Formula (I):
  • n 0, 1, or 2;
  • X 1 is absent, CR 2 , CR 2 R 2 , C(O), N, NR 2 , S, SO 2 , or O;
  • X 2 , X 3 , and X 4 are each independently CR 2 , CR 2 R 2 , C(O), N, NR 2 , S, SO 2 , or O;
  • ring B is a five- or six-membered ring comprising one or more double bonds
  • X 5 and X 6 are either CR 2 or N;
  • X 7 is C or N
  • ring A is selected from:
  • L is a bond, C 1-6 -alkylene, —O—, —C(O)—, —N(R a )—, —N(R a )SO 2 —, or —SO 2 N(R a )-where R a is hydrogen, C 1-6 alkyl, or C 1-6 heteroalkyl, wherein the C 1-6 alkyl or C 1-6 heteroalkyl are optionally substituted with 1 to 3 substituents independently selected from halo, oxo, hydroxy, C 1-6 alkyl, or C 1-6 heteroalkyl;
  • R 1 in each instance is independently halo, cyano, C 1-6 alkyl optionally substituted with halo or hydroxy, C 3-6 cycloalkyl, —NR b C(O)NR b R b , or —NR b S(O) 2 R b ;
  • R 2 in each instance is independently hydrogen, halo, C 1-6 alkyl optionally substituted with halo or hydroxy, C 3-6 cycloalkyl, C 2-6 hydroxyalkyl, cyano, —C(O)OR c , or —C(O)NR c R c ;
  • R 3 is hydrogen, halo, cyano, amino, C 1-12 alkyl, C 1-12 alkenyl, C 1-12 alkynyl, C 3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl, or heteroaryl;
  • R 4 in each instance is independently hydrogen, C 1-6 alkyl, —C(O)NR d R d , —C(NR d )NR d R d , —C(O)R d , or —S(O) 2 NR d R d ;
  • a method of treating a disease or condition mediated, at least in part, by PCSK9 comprising administering to a patient in need thereof a compound of Formula (I), as defined herein, with the following provisos:
  • R 4 is hydrogen, X 1 , X 2 , X 3 , X 4 are all CH, then either L-R 3 is not CF 3 or n is not 0;
  • L-R 3 is not hydrogen, —CH 2 -aryl, or —CH 2 -heteroaryl
  • L-R 3 is not —SO 2 -aryl, wherein the aryl is optionally substituted;
  • the compound is not 3-bromo-8-(4-methylpiperidin-1-yl)quinoline or 4-methyl-1-(naphthalen-1-yl)piperidine;
  • R 4 is not C(O)NH 2 .
  • provided herein is a method of treating a disease or condition mediated, at least in part, by PCSK9, the method comprising administering to a patient in need thereof a compound selected from Table 1 or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof.
  • a method of treating a disease or condition mediated, at least in part, by PCSK9 the method comprising administering to a patient in need thereof a compound selected from Table 2 or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof.
  • a compound for use in the treatment of a disease or condition mediated, at least in part, by PCSK9 wherein the compound is of Formula (I), as defined herein, with the following provisos:
  • R 4 is hydrogen, X 1 , X 2 , X 3 , X 4 are all CH, then either L-R 3 is not CF 3 or n is not 0;
  • L-R 3 is not hydrogen, —CH 2 -aryl, or —CH 2 -heteroaryl
  • L-R 3 is not —SO 2 -aryl, wherein the aryl is optionally substituted;
  • the compound is not 3-bromo-8-(4-methylpiperidin-1-yl)quinoline or 4-methyl-1-(naphthalen-1-yl)piperidine;
  • R 4 is not C(O)NH 2 .
  • R 4 is hydrogen, X 1 , X 2 , X 3 , X 4 are all CH, then either L-R 3 is not CF 3 or n is not 0;
  • L-R 3 is not hydrogen, —CH 2 -aryl, or —CH 2 -heteroaryl
  • L-R 3 is not —SO 2 -aryl, wherein the aryl is optionally substituted;
  • the compound is not 3-bromo-8-(4-methylpiperidin-1-yl)quinoline or 4-methyl-1-(naphthalen-1-yl)piperidine;
  • R 4 is not C(O)NH 2 .
  • a compound of Formula (Ia), (Ib) or any other Formula, as defined herein for the treatment of a disease or condition mediated, at least in part, by PCSK9.
  • a compound for the manufacture of a medicament for treating a disease or condition mediated, at least in part, by PCSK9 wherein the compound is of Formula (I), as defined herein, with the following provisos:
  • R 4 is hydrogen, X 1 , X 2 , X 3 , X 4 are all CH, then either L-R 3 is not CF 3 or n is not 0;
  • L-R 3 is not hydrogen, —CH 2 -aryl, or —CH 2 -heteroaryl
  • L-R 3 is not —SO 2 -aryl, wherein the aryl is optionally substituted;
  • the compound is not 3-bromo-8-(4-methylpiperidin-1-yl)quinoline or 4-methyl-1-(naphthalen-1-yl)piperidine;
  • R 4 is not C(O)NH 2 .
  • a compound of Formula (Ia), (Ib) or any other Formula, as defined herein for the manufacture of a medicament for treating a disease or condition mediated, at least in part, by PCSK9.
  • a method of inhibiting the activity of PCSK9 where the method comprising binding a compound to PCSK9, thereby inhibiting the activity of PCSK9, where the compound is of Formula (I), as defined herein, with the following provisos:
  • R 4 is hydrogen, X 1 , X 2 , X 3 , X 4 are all CH, then either L-R 3 is not CF 3 or n is not 0;
  • L-R 3 is not hydrogen, —CH 2 -aryl, or —CH 2 -heteroaryl
  • L-R 3 is not —SO 2 -aryl, wherein the aryl is optionally substituted;
  • the compound is not 3-bromo-8-(4-methylpiperidin-1-yl)quinoline or 4-methyl-1-(naphthalen-1-yl)piperidine;
  • R 4 is not C(O)NH 2 .
  • Hypercholesterolemia (also spelled hypercholesterolaemia) is the presence of high levels of cholesterol in the blood. It is a form of “hyperlipidemia” (elevated levels of lipids in the blood) and “hyperlipoproteinemia” (elevated levels of lipoproteins in the blood). Durrington, P “Dyslipidaemia” The Lancet 2003; 362(9385):717-731. Hypercholesterolemia is typically due to a combination of environmental and genetic factors. Environmental factors include obesity and dietary choices. Genetic contributions are usually due to the additive effects of multiple genes, though occasionally may be due to a single gene defect such as in the case of familial hypercholesterolaemia.
  • Hypercholesterolemia Genetic abnormalities are in some cases completely responsible for hypercholesterolemia, such as in familial hypercholesterolemia where there is one or more genetic mutations in the autosomal dominant APOB gene, the autosomal recessive LDLRAP1 gene, autosomal dominant familial hypercholesterolemia (HCHOLA3) variant of the PCSK9 gene, or the LDL receptor gene.
  • Cholesterol is a sterol. It is one of three major classes of lipids which all animal cells utilize to construct their membranes and is thus manufactured by all animal cells. Plant cells do not manufacture cholesterol. It is also the precursor of the steroid hormones, bile acids and vitamin D. Since cholesterol is insoluble in water, it is transported in the blood plasma within protein particles (lipoproteins). Lipoproteins are classified by their density: very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL). Biggerstaff et al., (2004). “Understanding lipoproteins as transporters of cholesterol and other lipids” Adv Physiol Educ 28 (1-4): 105-6.
  • VLDL very low density lipoprotein
  • IDL intermediate density lipoprotein
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • All the lipoproteins carry cholesterol, but elevated levels of the lipoproteins other than HDL (termed non-HDL cholesterol), particularly LDL-cholesterol are associated with an increased risk of atherosclerosis and coronary heart disease.
  • LDL-cholesterol is associated with an increased risk of atherosclerosis and coronary heart disease.
  • Cera et al. (2004) “Atherogenic lipoprotein particles in atherosclerosis” Circulation 109(23 Suppl 1): III 2-7.
  • higher levels of HDL cholesterol are protective.
  • Kontush et al. (2006) “Antiatherogenic small, dense HDL-guardian angel of the arterial wall?” Nat Clin Pract Cardiovasc Med 3(3):144-153.
  • Elevated levels of non-HDL cholesterol and LDL in the blood may be a consequence of diet, obesity, inherited (genetic) diseases (such as LDL receptor mutations in familial hypercholesterolemia), or the presence of other diseases such as diabetes and an underactive thyroid.
  • Total cholesterol is the amount of all of the fats in your blood. These fats are called lipids.
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • Cholesterol is measured in milligrams per deciliter (mg/dL). In conditions such as heart disease or diabetes, LDL cholesterol should stay below 100 mg/dL. If there is a risk for heart disease, LDL cholesterol should be lower than 130 mg/dL. In general, LDL cholesterol should be lower than 160-190 mg/dL. Alternative, HDL “good” cholesterol should be high. For example, HDL levels in men should be above 40 mg/dL, while HDL levels should be above 50 mg/dL for women.
  • hypercholesterolemia comprises a longstanding elevation of serum cholesterol that can lead to atherosclerosis.
  • Chronically elevated serum cholesterol contributes to formation of atheromatous plaques in the arteries. This can lead to progressive stenosis (narrowing) or even complete occlusion (blockage) of the involved arteries.
  • smaller plaques may rupture and cause a clot to form and obstruct blood flow.
  • tissue ischemia may manifest as specific symptoms including, but not limited to, temporary ischemia of the brain (commonly referred to as a transient ischemic attack) may manifest as temporary loss of vision, dizziness and impairment of balance, aphasia (difficulty speaking), paresis (weakness) and paresthesia (numbness or tingling), usually on one side of the body.
  • Insufficient blood supply to the heart may manifest as chest pain
  • ischemia of the eye may manifest as transient visual loss in one eye.
  • Insufficient blood supply to the legs may manifest as calf pain when walking, while in the intestines it may present as abdominal pain after eating a meal.
  • hypocholesterolemia is the presence of abnormally low (hypo-) levels of cholesterol in the blood (-emia). Although the presence of high total cholesterol (hyper-cholesterolemia) correlates with cardiovascular disease, a defect in the body's production of cholesterol can lead to adverse consequences as well. Cholesterol is an essential component of mammalian cell membranes and is required to establish proper membrane permeability and fluidity. It is not clear if a lower than average cholesterol level is directly harmful; it is often encountered in particular illnesses.
  • Possible causes of low cholesterol include, but are not limited to, statins, hyperthyroidism, or an overactive thyroid gland, adrenal insufficiency, liver disease, malabsorption (inadequate absorption of nutrients from the intestines), such as in celiac disease, malnutrition, abetalipoproteinemia (a genetic disease that causes cholesterol readings below 50 mg/dl), hypobetalipoproteinemia (a genetic disease that causes cholesterol readings below 50 mg/dl, manganese deficiency, Smith-Lemli-Opitz syndrome, Marfan syndrome, leukemias and other hematological diseases.
  • statins a genetic disease that causes cholesterol readings below 50 mg/dl
  • hypobetalipoproteinemia a genetic disease that causes cholesterol readings below 50 mg/dl
  • manganese deficiency Smith-Lemli-Opitz syndrome
  • Marfan syndrome leukemias and other hematological diseases.
  • Diabetes affects more than 20 million Americans. Over 40 million Americans have pre-diabetes (which often develops before type 2 diabetes). Diabetes is usually a lifelong (chronic) disease in which there is a high level of sugar in the blood. Insulin is a hormone produced by the pancreas to control blood sugar. Diabetes can be caused by too little insulin, resistance to insulin, or both. To understand diabetes, it is important to first understand the normal process by which food is broken down and used by the body for energy.
  • glucose enters the bloodstream.
  • Glucose is a source of fuel for the body.
  • An organ called the pancreas makes insulin. The role of insulin is to move glucose from the bloodstream into muscle, fat, and liver cells, where it can be used as fuel.
  • Type 1 diabetes can occur at any age, but it is most often diagnosed in children, teens, or young adults. In this disease, the body makes little or no insulin. Daily injections of insulin are needed. The exact cause is unknown.
  • Type 2 diabetes makes up most diabetes cases. It most often occurs in adulthood. But because of high obesity rates, teens and young adults are now being diagnosed with it. Many people with type 2 diabetes do not know they have it.
  • Gestational diabetes is high blood sugar that develops at any time during pregnancy in a woman who does not have diabetes.
  • Diabetes symptoms may result from high blood sugar level and include, but are not limited to, blurry vision, excess thirst, fatigue, hunger, urinating often and weight loss.
  • diseases or conditions that benefit from treatment with other therapeutic agents.
  • diseases or conditions can be of cardiovascular nature or can be related to pulmonary disorders, metabolic disorders, gastrointestinal disorders and the like.
  • Cardiovascular related diseases or conditions that can benefit from a combination treatment of the compounds of the disclosure with other therapeutic agents include, without limitation, angina including stable angina, unstable angina (UA), exercised-induced angina, variant angina, arrhythmias, intermittent claudication, myocardial infarction including non-STE myocardial infarction (NSTEMI), pulmonary hypertension including pulmonary arterial hypertension, heart failure including congestive (or chronic) heart failure and diastolic heart failure and heart failure with preserved ejection fraction (diastolic dysfunction), acute heart failure, or recurrent ischemia.
  • angina including stable angina, unstable angina (UA), exercised-induced angina, variant angina, arrhythmias, intermittent claudication, myocardial infarction including non-STE myocardial infarction (NSTEMI), pulmonary hypertension including pulmonary arterial hypertension, heart failure including congestive (or chronic) heart failure and diastolic heart failure and heart failure with preserved ejection fraction (dia
  • Therapeutic agents suitable for treating cardiovascular related diseases or conditions include anti-anginals, heart failure agents, antithrombotic agents, antiarrhythmic agents, antihypertensive agents, and lipid lowering agents.
  • the co-administration of the compounds of the disclosure with therapeutic agents suitable for treating cardiovascular related conditions allows enhancement in the standard of care therapy the patient is currently receiving.
  • the compounds of the disclosure are co-administered with ranolazine (RANEXA®).
  • Anti-anginals include beta-blockers, calcium channel blockers, and nitrates. Beta blockers reduce the heart's need for oxygen by reducing its workload resulting in a decreased heart rate and less vigorous heart contraction.
  • beta-blockers include acebutolol (Sectral®), atenolol (Tenormin®), betaxolol (Kerlone®), bisoprolol/hydrochlorothiazide (Ziac®), bisoprolol (Zebeta®), carteolol (Cartrol®), esmolol (Brevibloc®), labetalol (Normodyne®, Trandate®), metoprolol (Lopressor®, Toprol® XL), nadolol (Corgard®), propranolol (Inderal®), sotalol (Badorece®), and timolol (Blocadren®).
  • Nitrates dilate the arteries and veins thereby increasing coronary blood flow and decreasing blood pressure.
  • examples of nitrates include nitroglycerin, nitrate patches, isosorbide dinitrate, and isosorbide-5-mononitrate.
  • Calcium channel blockers prevent the normal flow of calcium into the cells of the heart and blood vessels causing the blood vessels to relax thereby increasing the supply of blood and oxygen to the heart.
  • Examples of calcium channel blockers include amlodipine (Norvasc®, Lotrel®), bepridil (Vascor®), diltiazem (Cardizem®, Tiazac®), felodipine (Plendil®), nifedipine (Adalat®, Procardia®), nimodipine (Nimotop®), nisoldipine (Sular®), verapamil (Calan®, Isoptin®, Verelan®), and nicardipine.
  • Diuretics eliminate excess fluids in the tissues and circulation thereby relieving many of the symptoms of heart failure.
  • diuretics include hydrochlorothiazide, metolazone (Zaroxolyn®), furosemide (Lasix®), bumetanide (Bumex®), spironolactone (Aldactone®), and eplerenone (Inspra®).
  • Angiotensin converting enzyme (ACE) inhibitors reduce the workload on the heart by expanding the blood vessels and decreasing resistance to blood flow.
  • ACE inhibitors include benazepril (Lotensin®), captopril (Capoten®), enalapril (Vasotec®), fosinopril (Monopril®), lisinopril (Prinivil®, Zestril®), moexipril (Univasc®), perindopril (Aceon®), quinapril (Accupril®), ramipril (Altace®), and trandolapril (Mavik®).
  • Vasodilators reduce pressure on the blood vessels by making them relax and expand.
  • vasodilators include hydralazine, diazoxide, prazosin, clonidine, and methyldopa.
  • ACE inhibitors, nitrates, potassium channel activators, and calcium channel blockers also act as vasodilators.
  • Cardiac glycosides are compounds that increase the force of the heart's contractions. These compounds strengthen the pumping capacity of the heart and improve irregular heartbeat activity. Examples of cardiac glycosides include digitalis, digoxin, and digitoxin.
  • Antithrombotics inhibit the clotting ability of the blood.
  • Platelet inhibitors inhibit the clotting activity of platelets, thereby reducing clotting in the arteries.
  • platelet inhibitors include acetylsalicylic acid (aspirin), ticlopidine, clopidogrel (Plavix®), prasugrel (Effient®), dipyridamole, cilostazol, persantine sulfinpyrazone, dipyridamole, indomethacin, and glycoprotein llb/llla inhibitors, such as abciximab, tirofiban, and eptifibatide (Integrelin®).
  • Beta blockers and calcium channel blockers also have a platelet-inhibiting effect.
  • Anticoagulants prevent blood clots from growing larger and prevent the formation of new clots.
  • anticoagulants include bivalirudin (Angiomax®), warfarin (Coumadin®), unfractionated heparin, low molecular weight heparin, danaparoid, lepirudin, and argatroban.
  • Thrombolytic agents act to break down an existing blood clot.
  • examples of thrombolytic agents include streptokinase, urokinase, and tenecteplase (TNK), and tissue plasminogen activator (t-PA).
  • Antiarrhythmic agents are used to treat disorders of the heart rate and rhythm.
  • Examples of antiarrhythmic agents include amiodarone, dronedarone, quinidine, procainamide, lidocaine, and propafenone.
  • Cardiac glycosides and beta blockers are also used as antiarrhythmic agents.
  • Antihypertensive agents are used to treat hypertension, a condition in which the blood pressure is consistently higher than normal. Hypertension is associated with many aspects of cardiovascular disease, including congestive heart failure, atherosclerosis, and clot formation.
  • antihypertensive agents include alpha-1-adrenergic antagonists, such as prazosin (Minipress®), doxazosin mesylate (Cardura®), prazosin hydrochloride (Minipress®), prazosin, polythiazide (Minizide®), and terazosin hydrochloride (Hytrin®); beta-adrenergic antagonists, such as propranolol (Inderal®), nadolol (Corgard®), timolol (Blocadren®), metoprolol (Lopressor®), and pindolol (Visken®); central alpha-adrenoceptor agonists, such as clonidine hydrochloride (Catapres®
  • Lipid lowering agents are used to lower the amounts of cholesterol or fatty sugars present in the blood.
  • lipid lowering agents include bezafibrate (Bezalip®), ciprofibrate (Modalim®), and statins, such as atorvastatin (Lipitor®), fluvastatin (Lescol®), lovastatin (Mevacor®, Altocor®), mevastatin, pitavastatin (Livalo®, Pitava®) pravastatin (Lipostat®), rosuvastatin (Crestor®), and simvastatin (Zocor®).
  • statins such as atorvastatin (Lipitor®), fluvastatin (Lescol®), lovastatin (Mevacor®, Altocor®), mevastatin, pitavastatin (Livalo®, Pitava®) pravastatin (Lipostat®), rosuvastatin (Crestor®), and simvastatin (Z
  • LDL-C low-density lipoprotein cholesterol
  • Examples include FDA approved Evolocumab (trade name RepathaTM from Amgen, Inc.) and FDA approved Alirocumab (tradename PraluentTM from Sanofi U.S., LLC and Regeneron Pharmaceuticals, Inc.).
  • a patient presenting with an acute coronary disease event often suffers from secondary medical conditions such as one or more of a metabolic disorder, a pulmonary disorder, or a peripheral vascular disorder.
  • Such patients can benefit from treatment of a combination therapy comprising administering to the patient a compound of the disclosure in combination with at least one therapeutic agent.
  • Pulmonary disorder refers to any disease or condition related to the lungs.
  • pulmonary disorders include, without limitation, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and emphysema.
  • COPD chronic obstructive pulmonary disease
  • bronchitis bronchitis
  • emphysema emphysema
  • therapeutics agents used to treat pulmonary disorders include bronchodilators including beta2 agonists and anticholinergics, corticosteroids, and electrolyte supplements.
  • Specific examples of therapeutic agents used to treat pulmonary disorders include epinephrine, terbutaline (Brethaire®, Bricanyl®), albuterol (Proventil®), salmeterol (Serevent®, Serevent Diskus®), theophylline, ipratropium bromide (Atrovent®), tiotropium (Spiriva®), methylprednisolone (Solu-Medrol®, Medrol®), magnesium, and potassium.
  • metabolic disorders include, without limitation, diabetes, including type I and type II diabetes, metabolic syndrome, dyslipidemia, obesity, glucose intolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.
  • therapeutic agents used to treat metabolic disorders include antihypertensive agents and lipid lowering agents, as described in the section “Cardiovascular Agent Combination Therapy” above.
  • Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretin mimetics.
  • Peripheral vascular disorders are disorders related to the blood vessels (arteries and veins) located outside the heart and brain, including, for example peripheral arterial disease (PAD), a condition that develops when the arteries that supply blood to the internal organs, arms, and legs become completely or partially blocked as a result of atherosclerosis.
  • PAD peripheral arterial disease
  • compositions comprising the compounds of the disclosure and at least one therapeutic agent.
  • the composition comprises the compounds of the disclosure and at least two therapeutic agents.
  • the composition comprises the compounds of the disclosure and at least three therapeutic agents, the compounds of the disclosure and at least four therapeutic agents, or the compounds of the disclosure and at least five therapeutic agents.
  • the methods of combination therapy include co-administration of a single formulation containing the compounds of the disclosure and therapeutic agent or agents, essentially contemporaneous administration of more than one formulation comprising the compounds of the disclosure and therapeutic agent or agents, and consecutive administration of a compound of the disclosure and therapeutic agent or agents, in any order, wherein preferably there is a time period where the compounds of the disclosure and therapeutic agent or agents simultaneously exert their therapeutic effect.
  • kits that include a compound of the disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and suitable packaging.
  • a kit further includes instructions for use.
  • a kit includes a compound of the disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.
  • articles of manufacture that include a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof in a suitable container.
  • the container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag.
  • compositions that contain one or more of the compounds described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients.
  • Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • Such compositions are prepared in a manner well known in the pharmaceutical art.
  • the pharmaceutical compositions may be administered in either single or multiple doses.
  • the pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes.
  • the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets.
  • the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • compositions that include at least one compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345.
  • Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”).
  • transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139.
  • Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof.
  • a pharmaceutical excipient for preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof.
  • the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • the tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
  • the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject's body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate.
  • Normalizing according to the subject's body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.
  • the daily dosage may also be described as a total amount of a compound described herein administered per dose or per day.
  • Daily dosage of a compound of Formula I may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 10 to 500 mg/day, between about 20 to 500 mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day, or between about 15 to 150 mg/day.
  • the total daily dosage for a human subject may be between 1 mg and 1,000 mg, between about 1,000-2,000 mg/day, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day.
  • the compounds of the present application or the compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known in cancer chemotherapy, and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous.
  • the method comprises administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week.
  • the compounds may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers.
  • the compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006). Greene's protective groups in organic synthesis. Hoboken, N.J., Wiley-Interscience, and references cited therein.
  • the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce or Sigma (St. Louis, Mo., USA).
  • solvent refers to a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like).
  • solvent inert including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like).
  • Scheme 1 shows exemplary synthetic routes (Route A and Route B) for preparing compounds of Formula I, wherein ring A, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 1 , R 2 , R 3 , m, n, and L are as defined herein and Z 1 , Z 2 , Z 3 , and Z 4 are functional groups suitable for coupling reactions (e.g., halogen, hydroxyl, etc.).
  • compound 1-b can be provided by contacting compound 1-a with compound 1-e under reaction conditions suitable for coupling, where Z 3 and Z 4 are functional groups that are complementary with respect to a particular coupling reaction.
  • Compounds of formula I can then be provided from compound 1-b by contacting compound 1-b with compound 1-d under reaction conditions suitable for coupling, where Z 1 and Z 2 are functional groups that are complementary with respect to a particular coupling reaction.
  • the coupling can be a cross coupling reaction, such as a Heck reaction, Negishi coupling, Stille coupling, Suzuki reaction, Kumada coupling, and the like.
  • compound 1-c can be provided by contacting compound 1-a with compound 1-d under reaction conditions suitable for coupling, where Z 1 and Z 2 are functional groups that are complementary with respect to a particular coupling reaction.
  • the coupling can be a cross coupling reaction, such as a Heck reaction, Negishi coupling, Stille coupling, Suzuki reaction, Kumada coupling, and the like.
  • Compounds of formula I can then be provided from compound 1-c by contacting compound 1-e with compound 1-e under reaction conditions suitable for coupling, where Z 3 and Z 4 are functional groups that are complementary with respect to a particular coupling reaction.
  • each Z 5 is a leaving group (e.g., chloro, bromo, iodo, or any other suitable leaving group) and R 13 is an alkylene or heteroalkylene.
  • any one of compounds 1-a, 1-b, 1-c, 1-d, 1-e, or 1-f may be purchased from commercial sources or prepared according to literature methods available to the skilled artisan, and may be optionally further functionalized (e.g., with one or more R 2 moieties) for use in Scheme 1 or Scheme 2.
  • 1-(4-(Trifluoromethyl)naphthalen-1-yl)piperazine (1) can also be prepared via the following alternative synthesis.
  • the title compound may be synthesized using methods similar to Example 1 using 4-bromo-5,6,7,8-tetrahydronaphthalen-1-amine as the starting material.
  • 1-(4-(piperidin-4-yloxy)naphthalen-1-yl)piperazine (4) can also be prepared by the following alternative synthesis.
  • the title compound may be synthesized using methods similar to Example 1, except using tert-butyl 4-(4-bromonaphthalen-1-yl)piperazine-1-carboxylate and tert-butyl 4-aminopiperidine-1-carboxylate as the starting materials.
  • N-(4-(Piperazin-1-yl)naphthalen-1-yl)piperidin-4-amine (5) can also be prepared using the following alternative synthesis.
  • 1-(4-(Piperidin-4-ylsulfonyl)naphthalen-1-yl)piperazine (7) can also be prepared by the following alternative synthesis.
  • Piperazin-1-yl(4-(piperazin-1-yl)naphthalen-1-yl)methanone (8) can also be prepared by the following alternative synthesis.
  • tert-Butyl 4-(4-bromonaphthalen-1-yl)piperazine-1-carboxylate (0.3 g, 0.000765 mol) was dissolved in EtOH (30 mL) in a pressure vessel and NaOAc (0.125 g, 0.00153 mol) and Pd(dppf)Cl 2 (0.0279 g, 0.000038 mol) were added.
  • the reaction was degassed with N 2 and the vessel was pressurized with CO gas (2 BAR). The temperature was slowly raised to 110° C. and the resulting solution was stirred overnight. After completion of the reaction the solution was filtered through a small pad of celite and washed with EtOH (3 ⁇ 50 mL).
  • the title compound may be synthesized using the same methods similar to of Example 11, except using 8-bromoisoquinolin-5-amine as the starting material.
  • the nitro group is reduced to the amine; the amine is converted the diazonium salt using sodium nitrite and, subsequently, to the iodide (Knochel, P. et al Synthesis, 2007, 81-84).
  • the iodide may be coupled using palladium catalysts with either 2-ketopiperazine (Ford, D. et al WO 2013096051) or (2-methoxypyridin-4-yl)boronic acid (Marsilje, T. H. et al J. Med. Chem. 2013, 56, 5675-90) to afford, after deprotection, either 4-(8-(piperidin-4-yloxy)isoquinolin-5-yl)piperazin-2-one (16) or 4-(8-(piperidin-4-yloxy)isoquinolin-5-yl)piperidin-2-one (27).
  • 2-ketopiperazine Form, D. et al WO 2013096051
  • (2-methoxypyridin-4-yl)boronic acid Marsilje, T. H. et al J. Med. Chem. 2013, 56, 5675-90
  • 4-(8-(piperidin-4-yloxy)isoquinolin-5-yl)piperazin-2-one can also be prepared by the following alternative synthesis (16).
  • 4-bromonaphthalen-1-ol is converted to a dimethyaminoisothiourea intermediate, which rearranges on vigorous heating to give, on hydrolysis, 4-bromonaphthalene-1-thiol.
  • the thiol is reacted with N-BOC-piperidine-4-Br and the sulfur oxidized to the corresponding sulfone.
  • the aryl bromide is coupled to a second piperidine subunit. Reduction/deprotection leads to the desired 4-bromonaphthalene-1-thiolen-1-yl)sulfonyl)piperidine (23).
  • the commercial 8-methoxyisoquinoline is N-oxidized (Dirnberger, D. et al Archiv der Pharmazie 1990, 323, 323) and treated with TMS-CN (Norrby, T. et al Acta Chemica Scand. 1998, 52, 77), affording 8-methoxyisoquinoline-3-carbonitrile.
  • the carbonitrile is brominated.
  • the key bromide, 5-bromo-8-methoxyisoquinoline-3-carbonitrile may be coupled using palladium reagents and subsequently modified and deprotected to give piperazine (5-(piperazin-1-yl)-8-(piperidin-4-yloxy)isoquinoline-3-carboxylic acid (22)), piperazone (5-(3-oxopiperazin-1-yl)-8-(piperidin-4-yloxy)isoquinoline-3-carboxamide (15)), piperidone (5-(2-oxopiperidin-4-yl)-8-(piperidin-4-yloxy)isoquinoline-3-carboxylic acid (110)), and piperidine (5-(piperidin-4-yl)-8-(piperidin-4-yloxy)isoquinoline-3-carboxylic acid (25)) analogs.
  • tert-Butyl 4-(4-bromonaphthalen-1-yl)piperazine-1-carboxylate is lithiated and reacted with the carboxaldehyde derived from N-BOC-isonipecotic acid.
  • the carbinol is cleaved by catalytic reduction, and deprotection affords 1-(4-(piperidin-4-ylmethyl)naphthalen-1-yl)piperazine (22).
  • the ultimate indolines 4-(piperidin-4-yl)-7-(piperidin-4-yloxy)indolin-2-one (24) or 4-(piperazin-1-yl)-7-(piperidin-4-yloxy)indolin-2-one (12), can be targeted by oxidizing the indole rings to indolines using, for example, NBS, and performing the appropriate palladium couplings and deprotections according to the scheme.
  • 3-Chloroacrolein is condensed with 1-BOC-piperidin-ol by means of a Michael reaction, giving N-BOC-(E)-3-(piperidin-4-yloxy)acrylaldehyde.
  • the aldehyde can dibromoolefinated using CBr 4 /PPh 3 , giving a diene which can undergo a thermal or Lewis acid catalyzed Diels-Alder cyclization, followed by aromatization with loss of HBr.
  • the aryl bromide may be coupled to BOC-piperazine. Reduction of the nitrile induces cyclization to the indicated lactam affording, on deprotection, the isoindolone, 4-(piperazin-1-yl)-7-(piperidin-4-yloxy)isoindolin-1-one (13).
  • the resulting reaction mixture was heated to 110° C. for 4 h.
  • the reaction was monitored by TLC and LCMS.
  • the reaction mixture was filtered through a celite pad and was washed with ethyl acetate.
  • the filtrate was concentrated under reduced pressure and the residue was purified on basic alumina with a gradient elution of 3% MeOH in DCM to furnish 1-(naphthalen-1-yl)piperazine.
  • LCMS purity: 93.356%, m/z 213.3 [M+H] + .
  • 4-(piperidin-4-yl)-1H-benzo[d]imidazole (20) may be prepared by methods similar to those described in Example 18, using 4-bromo-1H-benzo[d]imidazole as the aryl halide starting material.
  • 4-(Piperidin-4-yl)benzo[d]thiazole (21) may be prepared by methods similar to those described in Example 18, using 4-bromobenzo[d]thiazole as the aryl halide starting material.
  • 5-(piperidin-4-yl)isoquinoline (109) may be prepared by methods similar to those described in Example 18, using 5-bromoisoquinoline as the aryl halide starting material.
  • 4-(4-methoxynaphthalen-1-yl)piperidine (47) may be prepared using similar methods as described in Example 18, except using 1-bromo-4-methoxynaphthalene as the aryl halide starting material.
  • 8-(Piperidin-4-yl)isoquinoline (110) may be prepared by methods similar to those described in Example 18, using 8-bromoisoquinoline as the aryl halide starting material.
  • 4-(piperidin-4-yl)isoquinoline (45) may be prepared by methods similar to those described in Example 18, using 4-bromoisoquinoline as the aryl halide starting material.
  • 1-(piperidin-4-yl)isoquinoline (46) may be prepared by methods similar to those described in Example 18, using 1-bromoisoquinoline as the aryl halide starting material.
  • 4-(piperidin-4-yl)naphthalen-1-ol (47) may be prepared by methods similar to those described in Example 18, using 4-bromonaphthalen-1-ol as the aryl halide starting material.
  • 4-(piperidin-4-yl)quinazoline (48) may be prepared by methods similar to those described in Example 18, using 4-chloroquinazoline as the aryl halide starting material.
  • LCMS m/z 214.2 [M+H] + (Method 1).
  • 4-(4-fluoronaphthalen-1-yl)piperidine (49) may be prepared by methods similar to those described in Example 18, using 1-bromo-4-fluoronaphthalene as aryl halide starting material.
  • 5-(piperidin-4-yl)quinoline (111) may be prepared by methods similar to those described in Example 18, using 5-bromoquinoline as the aryl halide starting material.
  • 4-(piperidin-4-yl)quinoline (50) may be prepared by methods similar to those described in Example 18, using 4-bromoquinoline as the aryl halide starting material.
  • 8-fluoro-5-(piperidin-4-yl)quinoline may be prepared by methods similar to those described in Example 18, using 5-bromo-8-fluoroquinoline as the aryl halide starting material.
  • 8-fluoro-5-(piperidin-4-yl)isoquinoline may be prepared by methods similar to those described in Example 18, using 5-bromo-8-fluoroisoquinoline as the aryl halide starting material.
  • Phosphorus tribromide (0.89 g, 3.3 mmol, 1.2 eq) was added to the solution of (5-bromonaphthalen-1-yl) methanol (0.65 g, 2.75 mmol, 1.0 eq) in CHCl 3 (20 mL) under nitrogen atmosphere at 0° C. and the solution was stirred at ambient temperature for 2 h. After complete consumption of starting material, the reaction mixture was diluted with dichloromethane and washed with water, saturated aqueous sodium bicarbonate and brine. The organic extract was then dried over anhydrous sodium sulfate, filtered, and solvent evaporated from the filtrate under reduced pressure to afford 1-bromo-5-(bromomethyl)naphthalene.
  • Lithium borohydride (0.89 g, 4.12 mmol, 5.0 eq) was added to the solution of tert-butyl 4-(5-(methoxycarbonyl)naphthalen-1-yl)piperidine-1-carboxylate (0.3 g, 0.82 mmol, 1.0 eq) in THF (10 mL) under nitrogen atmosphere at 0° C. and the reaction mixture was stirred under nitrogen atmosphere, at 60° C. for 4 h. After complete consumption of starting material, saturated aqueous ammonium chloride was added drop-wise at 0° C., the mixture was diluted with water and extracted with ethyl acetate.
  • Boc anhydride(1.5 g, 6.75 mmol, 1.0 eq) was added to the solution of 4-bromonaphthalen-1-amine (1.0 g, 4.5 mmol, 1.1 eq), Et 3 N (0.68 g, 6.75 mmol, 1.5 eq), DMAP (0.1 g) in dichloromethane (20 mL) under nitrogen atmosphere at 0° C. and the solution was stirred at ambient temperature for 12 h. After complete consumption of starting material, the reaction mixture was diluted with dichloromethane and washed with water followed by brine. The organic extract was then dried over anhydrous sodium sulfate, filtered, and solvent evaporated from the filtrated under reduced pressure to afford diboc protected 4-bromonaphthalen-1-amine.
  • LCMS Purity 48.07%.
  • Pd—C (10% w/w, 50% moisture, 0.5 g) was added to the solution of tert-butyl 4-(5-fluoroquinolin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.85 g, 2.59 mmol, 1.0 eq) in mixture of EtOH (1 mL) and THF (3 mL). The reaction was allowed to stir at room temperature under hydrogen atmosphere (balloon pressure) for 12 h.
  • DDQ (1.63 g, 7.18 mmol, 3.0 eq) was added to the solution of tert-butyl 4-(5-fluoro-1,2,3,4-tetrahydroquinolin-8-yl)piperidine-1-carboxylate (0.8 g, 2.39 mmol, 1.0 eq) in toluene (10 mL).
  • the reaction mixture was heated at 110° C. for 12 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate.
  • Triflic anhydride (6.63 g, 23.59 mmol, 1.4 eq) was added dropwise to the solution of 4-chloronaphthalen-1-ol (3.0 g, 16.85 mmol, 1.0 eq) and Et 3 N (6.8 g, 64.41 mmol, 4.0 eq) in dichloromethane (30 mL) under nitrogen atmosphere at 0° C. and the solution was stirred at ambient temperature for 2 h. After complete consumption of starting material, the reaction mixture was diluted with dichloromethane and washed with water and brine. The organic extract was then dried over anhydrous sodium sulfate, filtered, and solvent evaporated under reduced pressure to afford 4-chloronaphthalen-1-yl trifluoromethanesulfonate.
  • LCMS Purity 80.81%.
  • Triflic anhydride (1.76 g, 6.25 mmol, 2.0 eq) was added dropwise to the solution of 4-(cyclohex-1-en-1-yl)naphthalen-1-ol (0.7 g, 3.12 mmol, 1.0 eq) in pyridine (5 mL) at 0° C.
  • the reaction mixture was stirred under nitrogen atmosphere, at room temperature for 2 h. After complete consumption of starting material, 1N HCl was added to the reaction mixture, diluted with water and extracted with ethyl acetate.
  • Pd—C (10% w/w, 50% moisture, 0.6 g) was added to the solution of tert-butyl 4-(4-(cyclohex-1-en-1-yl)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.6 g, 1.54 mmol, 1.0 eq) in MeOH (50 mL) and reaction was allowed to stir at room temperature under hydrogen atmosphere (balloon pressure) for 4 h.
  • 4-(piperazin-1-yl)benzo[d]thiazole (41) may be prepared by methods similar to those described in Example 41, using 4-bromobenzo[d]thiazole as the aryl halide starting material.
  • 7-(piperazin-1-yl)benzo[d]thiazole (42) may be prepared methods similar to those described in Example 41, using 7-bromobenzo[d]thiazole as the aryl halide starting material.
  • Pd—C (10% w/w, 50% moisture, 0.1 g) was added to the solution of tert-butyl 4-(4-(N-(5,6,7,8-tetrahydronaphthalen-2-yl)sulfamoyl)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.2 g, 0.386 mmol, 1.0 eq) in a mixture of EtOH (5 mL) and THF (10 mL). The reaction was allowed to stir at room temperature under hydrogen atmosphere (balloon pressure) for 16 h.
  • N-phenyl-4-(piperidin-4-yl)naphthalene-1-sulfonamide may be prepared by methods similar to those described in Example 44, using aniline as the arylamine in step 2.
  • Chlorosulphonic acid (5.63 g, 48.3 mmol, 2.0 eq) was added drop-wise to the solution of 1-bromonaphthalene (5.0 g, 24.1 mmol, 1.0 eq) in chloroform (50 mL) under nitrogen atmosphere at 0° C. and the solution was stirred at ambient temperature for 1 h. After complete consumption of starting material, the reaction mixture was poured into chilled water and extracted with dichloromethane. The organic extract was separated and the aqueous extract was again extracted with dichloromethane.
  • Pd(PPh 3 ) 2 Cl 2 (0.203 g, 0.289 mmol, 0.1 eq) was added to the reaction mixture and was stirred under nitrogen atmosphere, at 100° C. for 16 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate.
  • Pd(PPh 3 ) 2 Cl 2 (0.33 g, 0.471 mmol, 0.1 eq) was added to the reaction mixture and was stirred under nitrogen atmosphere, at 85° C. for 16 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate.
  • Pd—C (10% w/w, 50% moisture, 0.25 g) was added to the solution of tert-butyl 4-(5-(trifluoromethyl)quinolin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.5 g, 1.29 mmol, 1.0 eq) in MeOH (7 mL). The reaction was allowed to stir at room temperature under hydrogen atmosphere (balloon pressure) for 1 h.
  • 5-(piperidin-4-yl)-8-(trifluoromethyl)quinoline may be prepared by methods similar to those described in Example 47, using 5-bromo-2-(trifluoromethyl)aniline as the arylamine starting material in step 1.
  • Lithium hydroxide (0.085 g, 2.02 mmol, 1.5 eq) was added to the solution of tert-butyl 4-(6-(methoxycarbonyl)naphthalen-1-yl)piperidine-1-carboxylate (0.3 g, 1.35 mmol, 1.0 eq) in a mixture of THF (2 mL), MeOH (2 mL) and water (2 mL) and the reaction mixture was stirred at room temperature for 4 h. After complete consumption of starting material, the reaction mixture was evaporated under reduced pressure, the residue was dissolved in water, acidified with 10% aqueous citric acid and extracted with ethyl acetate.
  • HATU (0.32 g, 0.84 mmol, 1.5 eq) was added to a solution of 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-naphthoic acid (0.2 g, 0.56 mmol, 1.0 eq) and DIPEA (0.32 g, 0.84 mmol, 1.5 eq) in DMF (5 mL) at 0° C.
  • the reaction mixture was stirred at 0° C. for 15 min.
  • Ammonium chloride (0.29 g, 5.6 mmol, 10.0 eq) was added and the reaction mixture was stirred at room temperature for 4 h. After complete consumption of starting material, the reaction mixture was poured into chilled water.

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Abstract

The present disclosure relates to novel compounds, methods, and compositions capable of binding to PCSK9, thereby modulating PCSK9 proprotein convertase enzyme activity. The compounds of the disclosure include compounds Formula (I).

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application Ser. No. 62/298,920, filed Feb. 23, 2016, the contents of which are hereby incorporated by reference in their entirety.
    • FIELD
  • The present disclosure relates to novel compounds, methods, and compositions capable of binding to proprotein convertase subtilisin/kexin type 9 (PCSK9), thereby modulating PCSK9 proprotein convertase enzyme activity.
    • STATE OF THE ART
  • Elevated plasma levels of low density lipoprotein cholesterol (LDL-C) represent a great risk factor for the development of coronary heart disease. Clearance of LDL-C from the plasma occurs primarily by the liver through the action of low density lipoprotein receptors (LDLRs), which are cell surface glycoproteins that bind to apolipoprotein B100 (apoB100) on LDL particles with high affinity and mediate their endocytic uptake. Goldstein et al., Annu. Rev. Cell Biol. 1:1-39 (1985). Autosomal dominant hypercholesterolemia (ADH) is associated with mutations that reduce plasma LDL clearance that are found in genes encoding the LDLR (familial hypercholesterolemia (FH)) or apoB100 (familial defective apoB100). Hobbs et al., Annu. Rev. Genet. 24, 133-170 (1990); and Innerarity et al., J. Lipid Res. 31:1337-1349 (1990), respectively.
  • The low density lipoprotein receptor (LDLR) mediates efficient endocytosis of very low density lipoprotein (VLDL), VLDL remnants, and LDL. As part of the endocytic process, the LDLR releases lipoproteins into hepatic endosomes.
  • Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans. PCSK9 is believed to play a regulatory role in cholesterol homeostasis. For example, PCSK9 can bind to the epidermal growth factor-like repeat A (EGF-A) domain of the low-density lipoprotein receptor (LDLR) resulting in LDLR internalization and degradation.
  • A drug that could modulate the activity of PCSK9 would be useful in controlling LDL-cholesterol levels. Therefore, there remains a need for compounds that are effective in the treatment and prevention of conditions and disorders associated with PCSK9, including hypercholesterolemia and hypocholesterolemia. The compounds provided herein bind to PCSK9, thereby modulating PCSK9 proprotein convertase enzyme activity, and can be used to treat and prevent PCSK9-associated conditions and disorders.
    • SUMMARY
  • Provided herein are compounds that are useful for binding and modulating PCSK9 enzyme activity. The disclosure also provides compositions, including pharmaceutical compositions, kits that include the compounds, and methods of using (or administering) and making the compounds. The disclosure further provides compounds or compositions thereof for use in a method of treating a disease, disorder, or condition that is mediated by PCSK9. Moreover, the disclosure provides uses of the compounds or compositions thereof in the manufacture of a medicament for the treatment of a disease, disorder or condition that is mediated, at least in part, by PCSK9.
  • Accordingly, in one embodiment provided is a compound of Formula (I):
  • Figure US20190119236A1-20190425-C00001
  • or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof;
    • wherein:
  • m is 0, 1, or 2;
  • X1 is absent, CR2, CR2R2, C(O), N, NR2, S, SO2, or O;
  • X2, X3, and X4 are each independently CR2, CR2R2, C(O), N, NR2, S, SO2, or O;
  • ring B is a five- or six-membered ring comprising one or more double bonds;
  • X5 and X6 are either CR2 or N;
  • X7 is C or N;
  • ring A is selected from:
  • Figure US20190119236A1-20190425-C00002
  • where the wavy line in ring A indicates the point of attachment to
  • Figure US20190119236A1-20190425-C00003
  • L is a bond, C1-6-alkylene, —O—, —C(O)—, —SO2—, —N(Ra)—, —N(Ra)SO2—, or —SO2N(Ra)— where Ra is hydrogen, C1-6 alkyl, or C1-6 heteroalkyl, wherein the C1-6 alkyl or C1-6 heteroalkyl are optionally substituted with 1 to 3 substituents independently selected from halo, oxo, hydroxy, C1-6 alkyl, or C1-6 heteroalkyl;
  • R1 in each instance is independently halo, cyano, C1-6 alkyl optionally substituted with halo or hydroxy, C3-6 cycloalkyl, —NRbC(O)NRbRb, or —NRbS(O)2Rb;
      • wherein each Rb is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl;
  • R2 in each instance is independently hydrogen, halo, C1-6 alkyl optionally substituted with halo or hydroxy, C3-6 cycloalkyl, C2-6 hydroxyalkyl, cyano, —C(O)ORc, or —C(O)NRcRc;
      • wherein each Rc is independently, hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl;
  • R3 is hydrogen, halo, cyano, amino, C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl, or heteroaryl;
      • wherein each C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl and heteroaryl of R3 is optionally substituted with 1 to 3 substituents independently selected from halo, hydroxy, cyano, C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, C1-6 alkoxy, acyl, C3-10 cycloalkyl, heteroalkyl, heteroaryl, heterocyclyl, aryl, oxo, —N3, —NO2, —N(Rf)2, —C(O)N(Rf)2, —C(NRf)(N(Rf)2), —NRfC(O)ORf, —C(O)N(Rf)2, —CO2H, —CO2Rf, —NRfC(NRf)(N(Rf)2), haloalkyl, haloalkoxy, —N(Rf)N(Rf)2, —C(NRf)Rf, —S(O)Rf, —SO2H, —S(O)2Rf, —SCN, —SH, or (═S), and where each Rf is independently H or C1-6 alkyl;
  • or when X7 is N, then L-R3 is absent;
  • R4 in each instance is independently hydrogen, C1-6 alkyl, —C(O)NRdRd, —C(NRd)NRdRd, —C(O)Rd, or —S(O)2NRdRd;
      • wherein each Rd is independently, hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl;
  • with the following provisos:
  • 1) when m is 0, then both R4 and L-R3 cannot be hydrogen;
  • 2) when m is 0, R4 is hydrogen, X1, X2, X3, X4 are all CH, then L-R3 is not CF3;
  • 3) when X5 and X6 are both nitrogen, then L-R3 is not hydrogen, —CH2-aryl, or —CH2-heteroaryl;
  • 4) when X1, X2, X3, and X4 are all CH or X1 is nitrogen and X2, X3, and X4 are all CH, then L-R3 is not —SO2-aryl, wherein the aryl is optionally substituted;
  • 5) when A is attached via a carbon atom to the remainder of the molecule and m is other than 0, then R1 is not appended to the same carbon;
  • 6) the compound is not 3-bromo-8-(4-methylpiperidin-1-yl)quinoline or 4-methyl-1-(naphthalen-1-yl)piperidine; and
  • 7) when A is piperidinyl and L-R3 is hydrogen, then R4 is not C(O)NH2.
  • In certain embodiments, provided herein is a method of using a compound of Formula I or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof in the treatment of a disease or condition in a mammal that is mediated, at least in part, by PCSK9. Such diseases or conditions include cardiovascular diseases (e.g., coronary disease, hypertension, hypercholesterolemia, or atherosclerosis), a metabolic diseases (e.g., diabetes), hypocholesterolemia, a disease or condition where the mammal has elevated plasma levels of low density lipoprotein cholesterol, and a disease or condition where the mammal has suppressed plasma levels of low density lipoprotein cholesterol. Therefore, in certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof are of use as a medicament for the treatment of the aforementioned diseases or conditions.
    • DETAILED DESCRIPTION
  • Before the present compositions and methods are described, it is to be understood that the disclosure is not limited to the particular compounds, compositions, methodologies, protocols, cell lines, assays, and reagents described, as these may vary. It is also to be understood that the terminology used herein is intended to describe particular embodiments of the present disclosure, and is in no way intended to limit the scope of the present disclosure as set forth in the appended claims.
    • 1. Definitions
  • The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.
  • As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
  • A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —C(O)NH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line or a dashed line drawn through a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.
  • The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “C1-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.
  • Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount±10%. In other embodiments, the term “about” includes the indicated amount±5%. In certain other embodiments, the term “about” includes the indicated amount±1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.
  • “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e. —(CH2)3CH3), sec-butyl (i.e. —CH(CH3)CH2CH3), isobutyl (i.e. —CH2CH(CH3)2) and tert-butyl (i.e. —C(CH3)3); and “propyl” includes n-propyl (i.e. —(CH2)2CH3) and isopropyl (i.e. —CH(CH3)2).
  • Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group or an “arylenyl” group, respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.
  • “Alkenyl” refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).
  • “Alkynyl” refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond.
  • “Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
  • “Alkylthio” refers to the group “alkyl-S—”.
  • “Acyl” refers to a group —C(O)R, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.
  • “Amido” refers to both a “C-amido” group which refers to the group —C(O)NRyRz and an “N-amido” group which refers to the group —NRyC(O)Rz, wherein Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • “Amino” refers to the group —NRyRz wherein Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C6-10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl.
  • “Carbamoyl” refers to both an “O-carbamoyl” group which refers to the group —O—C(O)NRyRz and an “N-carbamoyl” group which refers to the group —NRyC(O)ORz, wherein Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • “Carboxyl ester” refers to both —OC(O)R and —C(O)OR, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Further, the term cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule.
  • “Imino” refers to a group —C(NR)R, wherein each R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • “Halogen” or “halo” includes fluoro, chloro, bromo, and iodo. “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (—CHF2) and trifluoromethyl (—CF3).
  • “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
  • “Hydroxyalkyl” refers to an alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a hydroxyl group.
  • “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, —NR—, —O—, —S—, —S(O)—, —S(O)2—, and the like, where hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of heteroalkyl groups include —OCH3, —CH2OCH3, —SCH3, —CH2SCH3, —NRCH3, and —CH2NRCH3, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
  • “Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.
  • “Heterocyclyl” refers to a saturated or unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e. the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. Also used herein, the term “spiro-heterocyclyl” refers to a ring system in which a three- to ten-membered heterocyclyl has one or more additional ring, wherein the one or more additional ring is three- to ten-membered cycloalkyl or three- to ten-membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three- to ten-membered heterocyclyl. Examples of the spiro-heterocyclyl rings include bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.
  • “Sulfonyl” refers to the group —S(O)2R, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.
  • “Sulfinyl” refers to the group —S(O)R, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.
  • “Alkylsulfonyl” refers to the group —S(O)2R, where R is alkyl.
  • “Alkylsulfinyl” refers to the group —S(O)R, where R is alkyl.
  • “Sulfinic acid” refers to the group —S(O)R, where R is alkyl.
  • Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group or an “arylenyl” group, respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.
  • The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.
  • The term “substituted” means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom's normal valence is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.
  • Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted. For example, in some embodiments, the term “substituted alkyl” refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, acyl, oxo, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.
  • Any formula or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl and 125I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 3H, 13C and 14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • The disclosure also includes “deuterated analogs” of compounds of Formula I in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
  • Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. An 18F, 3H, 11C labeled compound may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I.
  • The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • In many cases, the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, stereoisomers, and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substituted alkyl)3), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)3, mono-, di- or tri-cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • The term “hydrate” refers to the complex formed by the combining of a compound of Formula I and water.
  • A “solvate” refers to an association or complex of one or more solvent molecules and a compound of the disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid, and ethanolamine.
  • Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.
  • “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space and include enantiomers and diastereomers.
  • “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture.
  • “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • “Prodrugs” means any compound which releases an active parent drug according to Formula I in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula I are prepared by modifying functional groups present in the compound of Formula I in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds of Formula I wherein a hydroxy, amino, carboxyl or sulfhydryl group in a compound of Formula I is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula I, and the like. Preparation, selection, and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby incorporated by reference in their entirety.
  • As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
    • 2. List of Abbreviations and Acronyms
      • Abbreviation Meaning
      • Ac Acetyl
      • acid Protic acid or Lewis acid
      • ACN Acetonitrile
      • AIBN Azobisisobutyronitrile
      • aq. Aqueous
      • base Organic base (e.g., amine base) or inorganic base
      • BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)
      • BH3-DMS Borane dimethyl sulfide
      • BOC Tert-butyloxycarbonyl-
      • BuLi n-Butyllithium
      • BuOH n-butanol
      • DCM Dichloromethane
      • DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
      • DEAD Diethyl azodicarboxylate
      • DIPEA N,N-Diisopropylethylamine
      • DMAP 4-dimethylaminopyridine
      • DMF Dimethylformamide
      • DME Dimethyl ether
      • DMSO Dimethylsulfoxide
      • dppf 1,1′-Bis(diphenylphosphino)ferrocene
      • EDC.HCL N′-ethylcarbodiimide hydrochloride
      • Et Ethyl
      • EtOAc Ethyl acetate
      • EtOH Ethanol
      • HA Protic acid
      • HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
      • HBTU N,N,N′,N′-Tetramethyl-( )-(1H-benzotriazol-1-yl)uronium hexafluorophosphate
      • HOBt 1-hydroxybenzotriazole
      • hrs or h Hours
      • i-PrMgCl Isopropylmagnesium chloride
      • LCMS Liquid chromatography—mass spectrometry
      • MCPBA or m-CPBA m-Chloroperoxybenzoic acid
      • Me Methyl
      • MeCN(CH3CN) Acetonitrile
      • MeOH Methanol
      • min Minute(s)
      • MS Mass spectrometry
      • N Normal (Normality)
      • NaOAc Sodium acetate
      • NBS N-bromosuccinimide
      • OAc Acetate
      • PCC Pyridinium chlrochromate
      • Pd/C Palladium on carbon
      • Pd(dba)2 Bis(dibenzylideneacetone)palladium(0)
      • Pd(dba)3 Tris(dibenzylideneacetone)dipalladium(0)
      • Ph Phosphine
      • p-TsOH p-toluenesulfonic acid
      • rt Room temperature
      • s Second(s)
      • TBAI Tetrabutylammonium iodide
      • t-Bu (tBu) Tert-butyl
      • t-BuOK (tBuOK) Potassium tert-butoxide
      • TEA Triethanolamine
      • Tf Trifluoromethanesulfonyl
      • TFA Trifluoroacetic acid
      • THF Tetrahydrofuran
      • TLC Thin layer chromotography
      • TMS-CN Trimethylsilyl cyanide
      • TMSCF3 Trifluoromethyltrimethylsilane
      • TMS-NCO Trimethylsilyl isocyanate
      • Tr Trityl
      • Ts p-Toluenesulphonyl
    3. Compounds
  • Provided herein are compounds that are useful for binding PCSK9. In one embodiment, provided is a compound of Formula (I):
  • Figure US20190119236A1-20190425-C00004
  • or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof; wherein:
  • m is 0, 1, or 2;
  • X1 is absent, CR2, CR2R2, C(O), N, NR2, S, SO2, or O;
  • X2, X3, and X4 are each independently CR2, CR2R2, C(O), N, NR2, S, SO2, or O;
  • ring B is a five- or six-membered ring comprising one or more double bonds;
  • X5 and X6 are either CR2 or N;
  • X7 is C or N;
  • ring A is selected from:
  • Figure US20190119236A1-20190425-C00005
  • where the wavy line in ring A indicates the point of attachment to
  • Figure US20190119236A1-20190425-C00006
  • L is a bond, C1-6-alkylene, —O—, —C(O)—, —SO2—, —N(Ra)—, —N(Ra)SO2—, or —SO2N(Ra)— where Ra is hydrogen, C1-6 alkyl, or C1-6 heteroalkyl, wherein the C1-6 alkyl or C1-6 heteroalkyl are optionally substituted with 1 to 3 substituents independently selected from halo, oxo, hydroxy, C1-6 alkyl, or C1-6 heteroalkyl;
  • R1 in each instance is independently halo, cyano, C1-6 alkyl optionally substituted with halo or hydroxy, C3-6 cycloalkyl, —NRbC(O)NRbRb, or —NRbS(O)2Rb;
      • wherein each Rb is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl;
  • R2 in each instance is independently hydrogen, halo, C1-6 alkyl optionally substituted with halo or hydroxy, C3-6 cycloalkyl, C2-6 hydroxyalkyl, cyano, —C(O)ORc, or —C(O)NRcRc;
      • wherein each Rc is independently, hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl;
  • R3 is hydrogen, halo, cyano, amino, C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl, or heteroaryl;
      • wherein each C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl and heteroaryl of R3 is optionally substituted with 1 to 3 substituents independently selected from halo, hydroxy, cyano, C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, C1-6 alkoxy, acyl, C3-10 cycloalkyl, heteroalkyl, heteroaryl, heterocyclyl, aryl, oxo, —N3, —NO2, —N(Rf)2, —C(O)N(Rf)2, —C(NRf)(N(Rf)2), —NRfC(O)ORf, —C(O)N(Rf)2, —CO2H, —CO2Rf, —NRfC(NRf)(N(Rf)2), haloalkyl, haloalkoxy, —N(Rf)N(Rf)2, —C(NRf)Rf, —S(O)Rf, —SO2H, —S(O)2Rf, —SCN, —SH, or (═S), and where each Rf is independently H or C1-6 alkyl;
  • or when X7 is N, then L-R3 is absent;
  • R4 in each instance is independently hydrogen, C1-6 alkyl, —C(O)NRdRd, —C(NRd)NRdRd, —C(O)Rd, or —S(O)2NRdRd;
      • wherein each Rd is independently, hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl;
  • with the following provisos:
  • 1) when m is 0, then both R4 and L-R3 cannot be hydrogen;
  • 2) when m is 0, R4 is hydrogen, X1, X2, X3, X4 are all CH, then L-R3 is not CF3;
  • 3) when X5 and X6 are both nitrogen, then L-R3 is not hydrogen, —CH2-aryl, or —CH2— heteroaryl;
  • 4) when X1, X2, X3, and X4 are all CH or X1 is nitrogen and X2, X3, and X4 are all CH, then L-R3 is not —SO2-aryl, wherein the aryl is optionally substituted;
  • 5) when A is attached via a carbon atom to the remainder of the molecule and m is other than 0, then R1 is not appended to the same carbon;
  • 6) the compound is not 3-bromo-8-(4-methylpiperidin-1-yl)quinoline or 4-methyl-1-(naphthalen-1-yl)piperidine; and
  • 7) when A is piperidinyl and L-R3 is hydrogen, then R4 is not C(O)NH2.
  • In certain embodiments, provided is a compound of Formula (Ia):
  • Figure US20190119236A1-20190425-C00007
  • wherein:
  • m is 0, 1, or 2;
  • n is 0, 1, or 2;
  • X1, X2, X3, and X4 are each independently CH, C(O), N, NH, S, SO2, or O; or
  • X1 is absent and X2, X3, and X4 are each independently CH, C(O), N, NH, S, SO2, or O;
  • and the dotted line can represent one or more double bonds;
  • X5 and X6 are either CH or N;
  • ring A is selected from:
  • Figure US20190119236A1-20190425-C00008
  • where the wavy line in ring A indicates the point of attachment to
  • Figure US20190119236A1-20190425-C00009
  • L is a bond, C1-6-alkylene, —O—, —C(O)—, —SO2—, or —N(Ra)—, where Ra is hydrogen, C1-6 alkyl, or C1-6 heteroalkyl, wherein the C1-6 alkyl or C1-6 heteroalkyl are optionally substituted with 1 to 3 substituents independently selected from halo, oxo, hydroxy, C1-6 alkyl, or C1-6 heteroalkyl;
  • R1 in each instance is independently, halo, cyano, C1-6 alkyl optionally substituted with halo or hydroxy, C3-6 cycloalkyl, —NRbC(O)NRbRb, —NRbS(O)2Rb, —N(Rb)2, or —NRbC(O)Rb;
      • where each Rb is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl;
  • R2 in each instance is independently, halo, C1-6 alkyl optionally substituted with halo or hydroxy, C3-6 cycloalkyl, C2-6 hydroxyalkyl, cyano, —C(O)ORc, or —C(O)NRcRc;
      • where each Rc is independently, hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl;
  • R3 is hydrogen, halo, cyano, C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl, or heteroaryl,
      • where each C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl and heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, hydroxy, cyano, C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, C1-6 alkoxy, acyl, C3-10 cycloalkyl, heteroalkyl, heteroaryl, heterocyclyl, aryl, oxo, —N3, —NO2, —N(Rf)2, —C(O)N(Rf)2, —C(NRf)(N(Rf)2), —NRfC(O)ORf, —C(O)N(Rf)2, —CO2H, —CO2Rf, —NRfC(NRf)(N(Rf)2), haloalkyl, haloalkoxy, —N(Rf)N(Rf)2, —C(NRf)Rf, —S(O)Rf, —SO2H, —S(O)2Rf, —SCN, —SH, or (═S), and where each Rf is independently H or C1-6 alkyl;
  • R4 in each instance is independently, hydrogen, C1-6 alkyl, —C(O)NRdRd, —C(NRd)NRdRd, —C(O)Rd, or —S(O)2NRdRd;
      • where each Rd is independently, hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl;
  • or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof, with the following provisos:
  • 1) when A is piperazin-4-yl, m is 0, R4 is hydrogen, and L-R3 is hydrogen, then
  • Figure US20190119236A1-20190425-C00010
  • is not benzimidazole, benzoxazole, benzothiazole; and
  • 2) when m is 0, R4 is hydrogen, X1, X2, X3, X4 are all CH, then either L-R3 is not CF3 or n is not 0.
  • In certain embodiments, the compound is of Formula (Ia) with the further proviso that when m is 0, n is 0, R4 is hydrogen, X1, X2, X3, X4 are all CH, then L-R3 is not hydrogen.
  • In certain embodiments, the moiety
  • Figure US20190119236A1-20190425-C00011
  • is:
  • Figure US20190119236A1-20190425-C00012
    Figure US20190119236A1-20190425-C00013
    Figure US20190119236A1-20190425-C00014
    Figure US20190119236A1-20190425-C00015
  • wherein the wavy line indicates the point of attachment to L and the dashed line represents the point of attachment to ring A.
  • In certain embodiments, the moiety
  • Figure US20190119236A1-20190425-C00016
  • is:
  • Figure US20190119236A1-20190425-C00017
    Figure US20190119236A1-20190425-C00018
  • wherein the wavy line indicates the point of attachment to L and the dashed line represents the point of attachment to ring A, and further wherein the bicyclic ring may be optionally substituted with one or more R2 selected from the group consisting of hydrogen, halo, C1-6 alkyl optionally substituted with halo or hydroxy, C3-6 cycloalkyl, C2-6 hydroxyalkyl, cyano, —C(O)ORc, and —C(O)NRcRc.
  • In certain embodiments, the moiety
  • Figure US20190119236A1-20190425-C00019
  • is:
  • Figure US20190119236A1-20190425-C00020
  • wherein the wavy line indicates the point of attachment to L and the dashed line represents the point of attachment to ring A, and further wherein the bicyclic ring may be optionally substituted with one or more R2 selected from the group consisting of hydrogen, halo, C1-6 alkyl optionally substituted with halo or hydroxy, C3-6 cycloalkyl, C2-6 hydroxyalkyl, cyano, —C(O)ORc, and —C(O)NRcRc.
  • In certain embodiments, the moiety
  • Figure US20190119236A1-20190425-C00021
  • is:
  • Figure US20190119236A1-20190425-C00022
  • optionally substituted with 1, 2, or 3 R2 as described herein.
  • In certain embodiments, the moiety
  • Figure US20190119236A1-20190425-C00023
  • is:
  • Figure US20190119236A1-20190425-C00024
    Figure US20190119236A1-20190425-C00025
    Figure US20190119236A1-20190425-C00026
    Figure US20190119236A1-20190425-C00027
    Figure US20190119236A1-20190425-C00028
  • wherein the wavy line indicates the point of attachment to L and the dashed line represents the point of attachment to ring A.
  • In certain embodiments, the moiety
  • Figure US20190119236A1-20190425-C00029
  • is:
  • Figure US20190119236A1-20190425-C00030
  • wherein the wavy line indicates the point of attachment to L and the dashed line represents the point of attachment to ring A.
  • In certain embodiments, ring A is:
  • Figure US20190119236A1-20190425-C00031
  • In certain embodiments, ring A is:
  • Figure US20190119236A1-20190425-C00032
  • In certain embodiments, ring A is:
  • Figure US20190119236A1-20190425-C00033
  • In certain embodiments, m is 0 or 1.
  • In certain embodiments, R4 is hydrogen, —C(O)NH2, or —C(NH)NH2. In certain embodiments, R4 is hydrogen.
  • In certain embodiments, R1 is —NHC(O)NH2, —NHS(O)2CH3, or —NHC(O)CH3. In certain embodiments, R1 is —NHS(O)2CH3, or —NHC(O)CH3.
  • In certain embodiments, R2 is hydrogen, C1-6 alkyl, —CO2H or —C(O)NH2. In certain embodiments, R2 is —CO2H or —C(O)NH2. In certain embodiments, R2 is hydrogen. In certain embodiments, R2 is hydrogen or methyl.
  • In certain embodiments, R4 is hydrogen, —C(O)NH2, or —C(NH)NH2. In certain embodiments, R4 is hydrogen.
  • In certain embodiments, L is a bond, —CH2—, —O—, —C(O)—, —S(O)2—, —S(O)2NH—, or —NH—. In certain embodiments, L is —CH2—, —O—, —C(O)—, —S(O)2—, —S(O)2NH—, or —NH—. In certain embodiments, L is —CH2—, —O—, —C(O)—, —S(O)2—, or —NH—. In certain embodiments, L is a bond.
  • In certain embodiments, R3 is hydrogen, amino, halo, C1-6alkyl, aryl, or C3-10 heterocyclyl, wherein C1-6alkyl, aryl, or C3-10 heterocyclyl is optionally substituted with one or more halo. In certain embodiments, R3 is hydrogen, C1-6alkyl, or C3-10 heterocyclyl, wherein C1-6alkyl or C3-10 heterocyclyl is optionally substituted with one or more halo. In certain embodiments, R3 is hydrogen. In certain embodiments, R3 is CH3. In certain embodiments, R3 is CF3. In certain embodiments, R3 is F. In certain embodiments, R3 is Cl. In certain embodiments, R3 is NH2. In certain embodiments, R3 is cyclohexyl. In certain embodiments, R3 is aryl. In one embodiment, R3 is C3-10 heterocyclyl.
  • In certain embodiments, L is a bond and R3 is hydrogen, C1-6alkyl, haloalkyl, halo, C3-10 cycloalkyl, heterocyclyl, or aryl. In certain embodiments, L is a bond and R3 is hydrogen. In certain embodiments, L is a bond and R3 is CH3. In certain embodiments, L is a bond and R3 is CF3. In certain embodiments, L is a bond and R3 is F. In certain embodiments, L is a bond and R3 is Cl. In certain embodiments, L is a bond and R3 is cyclohexyl. In certain embodiments, L is a bond, and R3 is phenyl.
  • In certain embodiments, R3 is:
  • Figure US20190119236A1-20190425-C00034
  • wherein:
  • Y is —O—, —N(Re)—, —CH((CH2)f OH), or —N((CH2)f OH);
  • each Re is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 alkyl where the C2-6 alkyl is substituted with a hydroxy; and
  • f is 0, 1, 2, 3, or 4.
  • In certain embodiments, Y is —N(Re)—.
  • In certain embodiments, provided is a compound of Formula (Ib):
  • Figure US20190119236A1-20190425-C00035
  • wherein:
  • m is 0, 1, or 2;
  • n is 0, 1, or 2;
  • X1, X2, X3, and X4 are each independently CH, C(O), N, NH, S, SO2, or O; or
  • X1 is absent and X2, X3, and X4 are each independently CH, C(O), N, NH, S, SO2, or O;
  • and the dotted line can represent one or more double bonds;
  • X5 and X6 are either CH or N;
  • ring A is selected from:
  • Figure US20190119236A1-20190425-C00036
  • where the wavy line in ring A indicates the point of attachment to
  • Figure US20190119236A1-20190425-C00037
  • R1 in each instance is independently, halo, cyano, C1-6 alkyl optionally substituted with halo or hydroxy, C3-6 cycloalkyl, —NRbC(O)NRbRb, —NRbS(O)2Rb, —N(Rb)2, or —NRbC(O)Rb;
      • where each Rb is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl;
  • R2 in each instance is independently, halo, C1-6 alkyl optionally substituted with halo or hydroxy, C3-6 cycloalkyl, C2-6 hydroxyalkyl, cyano, —C(O)ORc, or —C(O)NRcRc;
      • where each Rc is independently, hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl;
  • R4 in each instance is independently, hydrogen, C1-6 alkyl, —C(O)NRdRd, —C(NRd)NRdRd, —C(O)Rd, or —S(O)2NRdRd;
      • where each Rd is independently, hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl; and
  • L-R3 is
  • Figure US20190119236A1-20190425-C00038
  • wherein:
  • i) J is selected from the group consisting of —O—, —CO—, —CH2—, —CF2—, —SO2—;
  • ii) if J is —CH2 or —CF2 then M is nothing, if J is —O— then M is nothing or —CH2, if J is —CO or SO2 then M is —NH—;
  • iii) Ring C is a 5 or 6 membered saturated or unsaturated aryl, heteroaryl, carbocyclic or heterocyclic ring. And ring C may be fused via R11, R12 to form a 5-6 membered aryl, heteroaryl, carbocyclic or heterocyclic ring;
  • iv) E1, E2, and E3 are independently selected from C or N;
  • v) if M is nothing or —CH2— then R11 and R12 are independently selected from the group consisting of lower alkyl, halo, hydroxy, amino, aminoalkyl, hydroxylalkyl, haloalkyl, carboxy, —C(O)NH2, nitrile, —S-alkyl, —O-alkyl, acyl, and oxo; and
  • vi) if M is —NH— then R10, R11, and R12 are independently selected from the group consisting of lower alkyl, halo, hydroxy, amino, aminoalkyl, hydroxylalky, haloalkyl, carboxy, —C(O)NH2, —C(O)N-alkyl, nitrile, —S-alkyl, —O-alkyl, acyl, oxo; and R10 and R11 may be joined to form a 5-6 membered fused saturated or unsaturated ring D containing 0-3 heteroatoms where Ring D may further be substituted at positions at least two atoms away from the juncture with Ring C,
  • or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof.
  • In one embodiment, a compound may be selected from those compounds in Table 1 or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof.
  • TABLE 1
    No. Name Structure
    1 1-(4- (trifluoromethyl) naphthalen- 1-yl)piperazine
    Figure US20190119236A1-20190425-C00039
    2 4-(4- (trifluoromethyl) naphthalen- 1-yl)piperidine
    Figure US20190119236A1-20190425-C00040
    3 1-(4-(trifluoromethyl)- 5,6,7,8- tetrahydronaphthalen-1- yl)piperazine
    Figure US20190119236A1-20190425-C00041
    4 1-(4-(piperidin-4- yloxy)naphthalen-1- yl)piperazine
    Figure US20190119236A1-20190425-C00042
    5 N-(4-(piperazin-1- yl)naphthalen-1-yl) piperidin-4-amine
    Figure US20190119236A1-20190425-C00043
    6 1-(4-(piperidin-4- ylmethyl)naphthalen-1- yl)piperazine
    Figure US20190119236A1-20190425-C00044
    7 1-(4-(piperidin-4- ylsulfonyl)naphthalen- 1-yl)piperazine
    Figure US20190119236A1-20190425-C00045
    8 piperazin-1-yl(4- (piperazin- 1-yl)naphthalen-1- yl)methanone
    Figure US20190119236A1-20190425-C00046
    9 5-(piperazin-1-yl)-8- (piperidin-4- yloxy)isoquinoline
    Figure US20190119236A1-20190425-C00047
    10 4-(naphthalen-1- yl)piperazine-1- carboximidamide
    Figure US20190119236A1-20190425-C00048
    11 4-(naphthalen-1- yl)piperazine-1- carboxamide
    Figure US20190119236A1-20190425-C00049
    12 4-(piperazin-1-yl)-7- (piperidin-4-yloxy) indolin-2-one
    Figure US20190119236A1-20190425-C00050
    13 4-(piperazin-1-yl)-7- (piperidin-4- yloxy)isoindolin-1-one
    Figure US20190119236A1-20190425-C00051
    14 5-(piperazin-1-yl)-8- (piperidin-4- yloxy)isoquinoline-3- carboxylic acid
    Figure US20190119236A1-20190425-C00052
    15 5-(3-oxopiperazin-1- yl)-8-(piperidin-4- yloxy)isoquinoline-3- carboxamide
    Figure US20190119236A1-20190425-C00053
    16 4-(8-(piperidin-4- yloxy)isoquinolin-5- yl)piperazin-2-one
    Figure US20190119236A1-20190425-C00054
    17 N-(1-(naphthalen-1- yl)piperidin-4- yl)methanesulfonamide
    Figure US20190119236A1-20190425-C00055
    18 N-(1-(naphthalen-1- yl)piperidin-4-yl) acetamide
    Figure US20190119236A1-20190425-C00056
    19 1-(1-(naphthalen-1- yl)piperidin-4-yl)urea
    Figure US20190119236A1-20190425-C00057
    20 4-(piperidin-4-yl)-1H- benzo[d]imidazole
    Figure US20190119236A1-20190425-C00058
    21 4-(piperidin-4- yl)benzo[d]thiazole
    Figure US20190119236A1-20190425-C00059
    22 4-((4-(piperidin-4- yl)naphthalen-1- yl)methyl)piperidine
    Figure US20190119236A1-20190425-C00060
    23 4-((4-(piperidin-4- yl)naphthalen-1- yl)sulfonyl)piperidine
    Figure US20190119236A1-20190425-C00061
    24 4-(piperidin-4-yl)-7- (piperidin-4-yloxy) indolin-2-one
    Figure US20190119236A1-20190425-C00062
    25 5-(piperidin-4-yl)-8- (piperidin-4- yloxy)isoquinoline-3- carboxylic acid
    Figure US20190119236A1-20190425-C00063
    26 5-(2-oxopiperidin-4- yl)-8-(piperidin-4- yloxy)isoquinoline-3- carboxamide
    Figure US20190119236A1-20190425-C00064
    27 4-(8-(piperidin-4- yloxy)isoquinolin-5- yl)piperidin-2-one
    Figure US20190119236A1-20190425-C00065
    28 5-(piperazin-1-yl)-8- (piperidin-4-yloxy) quinoline- 3-carboxylic acid
    Figure US20190119236A1-20190425-C00066
    29 8-(piperazin-1-yl)-5- (piperidin-4-yloxy) quinazoline-2- carboxylic acid
    Figure US20190119236A1-20190425-C00067
    30 8-(piperazin-1-yl)-5- (piperidin-4-yloxy) quinoline-2-carboxylic acid
    Figure US20190119236A1-20190425-C00068
    31 4-(piperazin-1-yl)-7- (piperidin-4- yloxy)benzo[d]thiazole
    Figure US20190119236A1-20190425-C00069
    32 7-(piperazin-1-yl)-4- (piperidin-4- yloxy)benzo[d]thiazole
    Figure US20190119236A1-20190425-C00070
    33 8-(piperazin-1-yl)-5- (piperidin-4-yloxy) isoquinoline-3- carboxylic acid
    Figure US20190119236A1-20190425-C00071
    34 4-(piperazin-1-yl)-7- (piperidin-4-yloxy)-1H- benzo[d][1,2,3]triazole
    Figure US20190119236A1-20190425-C00072
    35 1-(7-(piperidin-4- yloxy)-2,3-dihydro-1H- inden-4-yl)piperazine
    Figure US20190119236A1-20190425-C00073
    36 5-(piperazin-1-yl)-8- (piperidin-4-yloxy) quinoline
    Figure US20190119236A1-20190425-C00074
    37 3-methyl-5-(piperidin- 4-yl)- 8-(piperidin-4- yloxy)cinnoline
    Figure US20190119236A1-20190425-C00075
    38 4-((7-(piperidin-4- yl)benzo[d][1,3]dioxol- 4-yl)oxy)piperidine
    Figure US20190119236A1-20190425-C00076
    39 1-(7-(piperidin-4- yloxy)benzo[b] thiophen-4-yl) piperazine
    Figure US20190119236A1-20190425-C00077
    40 4-(piperazin-1-yl)-1H- benzo[d]imidazole
    Figure US20190119236A1-20190425-C00078
    41 4-(piperazin-1- yl)benzo[d]thiazole
    Figure US20190119236A1-20190425-C00079
    42 7-(piperazin-1- yl)benzo[d]thiazole
    Figure US20190119236A1-20190425-C00080
    43 4-(4-methylnaphthalen- 1-yl)piperidine
    Figure US20190119236A1-20190425-C00081
    44 4-(4-methoxy- naphthalen- 1-yl)piperidine
    Figure US20190119236A1-20190425-C00082
    45 4-(piperidin-4- yl)isoquinoline
    Figure US20190119236A1-20190425-C00083
    46 1-(piperidin-4- yl)isoquinoline
    Figure US20190119236A1-20190425-C00084
    47 4-(piperidin-4-yl) naphthalen-1-ol
    Figure US20190119236A1-20190425-C00085
    48 4-(piperidin-4-yl) quinazoline
    Figure US20190119236A1-20190425-C00086
    49 4-(4-fluoronaphthalen- 1-yl)piperidine
    Figure US20190119236A1-20190425-C00087
    50 4-(piperidin-4-yl) quinoline
    Figure US20190119236A1-20190425-C00088
    51 8-fluoro-5-(piperidin-4- yl)quinoline
    Figure US20190119236A1-20190425-C00089
    52 8-fluoro-5-(piperidin-4- yl)isoquinoline
    Figure US20190119236A1-20190425-C00090
    53 4-(5-methylnaphthalen- 1-yl)piperidine
    Figure US20190119236A1-20190425-C00091
    54 (5-(piperidin-4- yl)naphthalen-1-yl) methanol
    Figure US20190119236A1-20190425-C00092
    55 4-(6-methylnaphthalen- 1-yl)piperidine
    Figure US20190119236A1-20190425-C00093
    56 4-(piperidin-4-yl) naphthalen-1-amine
    Figure US20190119236A1-20190425-C00094
    57 8-(piperidin-4-yl) quinoline
    Figure US20190119236A1-20190425-C00095
    58 5-fluoro-8-(piperidin-4- yl)quinoline
    Figure US20190119236A1-20190425-C00096
    59 4-(4-chloronaphthalen- 1-yl)piperidine
    Figure US20190119236A1-20190425-C00097
    60 4-(4-cyclohexyl- naphthalen- 1-yl)piperidine
    Figure US20190119236A1-20190425-C00098
    61 4-(piperidin-4-yl)-N- (5,6,7,8- tetrahydronaphthalen-2- yl)naphthalene-1- sulfonamide
    Figure US20190119236A1-20190425-C00099
    62 N-phenyl-4-(piperidin- 4-yl)naphthalene-1- sulfonamide
    Figure US20190119236A1-20190425-C00100
    63 4-(piperidin-4- yl)naphthalene-1- sulfonamide
    Figure US20190119236A1-20190425-C00101
    64 8-(piperidin-4-yl)-5- (trifluoromethyl) quinoline
    Figure US20190119236A1-20190425-C00102
    65 5-(piperidin-4-yl)-8- (trifluoromethyl) quinoline
    Figure US20190119236A1-20190425-C00103
    66 5-(piperidin-4-yl)-2- naphthamide
    Figure US20190119236A1-20190425-C00104
    67 5-(piperidin-4-yl)-1- naphthamide
    Figure US20190119236A1-20190425-C00105
    68 4-(piperidin-4-yl)-1- naphthamide
    Figure US20190119236A1-20190425-C00106
    69 8-(naphthalen-1-yl)-1,3- diazaspiro[4.5]decan-2- one
    Figure US20190119236A1-20190425-C00107
    70 N-(4-(piperidin-4- yl)naphthalen-1- yl)tetrahydro-2H-pyran- 4-amine
    Figure US20190119236A1-20190425-C00108
    71 4-(4-((tetrahydro-2H- pyran-4-yl)oxy) naphthalen-1- yl)piperidine
    Figure US20190119236A1-20190425-C00109
    72 4-(piperazin-1-yl)-N- (5,6,7,8- tetrahydronaphthalen-1- yl)naphthalene-1- sulfonamide
    Figure US20190119236A1-20190425-C00110
    73 N-phenyl-4-(piperazin- 1-yl)naphthalene-1- sulfonamide
    Figure US20190119236A1-20190425-C00111
    74 4-(piperazin-1- yl)naphthalene-1- sulfonamide
    Figure US20190119236A1-20190425-C00112
    75 8-methoxy-5-(piperidin- 4-yl)isoquinoline-3- carboxylic acid
    Figure US20190119236A1-20190425-C00113
    76 8-methoxy-5-(piperidin- 4-yl)isoquinoline-3- carboxamide
    Figure US20190119236A1-20190425-C00114
    77 8-(naphthalen-1-yl)-2- azaspiro[4.5]decan-3- one
    Figure US20190119236A1-20190425-C00115
    78 8-(naphthalen-1-yl)-2- azaspiro[4.5]decan-1- one
    Figure US20190119236A1-20190425-C00116
    79 5-fluoro-8-(piperidin-4- yl)isoquinoline
    Figure US20190119236A1-20190425-C00117
    80 4-fluoro-1-(piperidin-4- yl)isoquinoline
    Figure US20190119236A1-20190425-C00118
    81 4-(piperidin-4-yl)-1- (trifluoromethyl) isoquinoline
    Figure US20190119236A1-20190425-C00119
    82 1-(piperidin-4-yl)-4- (trifluoromethyl) isoquinoline
    Figure US20190119236A1-20190425-C00120
    83 8-(piperidin-4-yl)-5- (trifluoromethyl) isoquinoline
    Figure US20190119236A1-20190425-C00121
    84 5-(piperidin-4-yl)-8- (trifluoromethyl) isoquinoline
    Figure US20190119236A1-20190425-C00122
    85 4-chloro-1-(piperidin-4- yl)isoquinoline
    Figure US20190119236A1-20190425-C00123
    86 5-chloro-8-(piperidin-4- yl)quinoline
    Figure US20190119236A1-20190425-C00124
    87 5-chloro-8-(piperidin-4- yl)isoquinoline
    Figure US20190119236A1-20190425-C00125
    88 8-chloro-5-(piperidin-4- yl)isoquinoline
    Figure US20190119236A1-20190425-C00126
    89 8-chloro-5-(piperidin-4- yl)quinoline
    Figure US20190119236A1-20190425-C00127
    90 4-(4-phenoxy- naphthalen- 1-yl)piperidine
    Figure US20190119236A1-20190425-C00128
    91 8-(piperidin-4-yl)-2- naphthamide
    Figure US20190119236A1-20190425-C00129
    92 4-(piperidin-4-yl)-2- naphthamide
    Figure US20190119236A1-20190425-C00130
    93 4-(5- (trifluoromethyl) naphthalen- 1-yl)piperidine
    Figure US20190119236A1-20190425-C00131
    94 4-(6- (trifluoromethyl) naphthalen- 1-yl)piperidine
    Figure US20190119236A1-20190425-C00132
    95 4-(4-phenylnaphthalen- 1-yl)piperidine
    Figure US20190119236A1-20190425-C00133
    96 4-(4-(4- fluorobenzyl) naphthalen- 1-yl)piperidine
    Figure US20190119236A1-20190425-C00134
    97 3-(naphthalen-1-yl)-6- azabicyclo[3.1.1] heptane
    Figure US20190119236A1-20190425-C00135
    98 3-(4- (trifluoromethyl) naphthalen-1-yl)-6- azabicyclo[3.1.1] heptane
    Figure US20190119236A1-20190425-C00136
    99 3-(4-chloronaphthalen- 1-yl)-6-azabicyclo [3.1.1]heptane
    Figure US20190119236A1-20190425-C00137
    100 3-(4-methylnaphthalen- 1-yl)-6-azabicyclo [3.1.1]heptane
    Figure US20190119236A1-20190425-C00138
    101 4-(piperidin-4-yl)-2- (trifluoromethyl) quinazoline
    Figure US20190119236A1-20190425-C00139
    102 5-(naphthalen-1-yl)-2- azabicyclo[2.1.1]hexane
    Figure US20190119236A1-20190425-C00140
    103 5-(4- (trifluoromethyl) naphthalen-1-yl)-2- azabicyclo[2.1.1]hexane
    Figure US20190119236A1-20190425-C00141
    104 5-(4-chloronaphthalen- 1-yl)-2-azabicyclo [2.1.1]hexane
    Figure US20190119236A1-20190425-C00142
    105 5-(2-oxopiperidin-4-yl)- 8-(piperidin-4- yloxy)isoquinoline-3- carboxylic acid
    Figure US20190119236A1-20190425-C00143
    106 5-(4-methylnaphthalen- 1-yl)-2-azabicyclo [2.1.1]hexane
    Figure US20190119236A1-20190425-C00144
  • In one embodiment, a compound may be selected from those compounds in Table 2 or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof.
  • TABLE 2
    No. Name Structure
    107 1-(naphthalen-1- yl)piperazine
    Figure US20190119236A1-20190425-C00145
    108 4-(naphthalen-1- yl)piperidine
    Figure US20190119236A1-20190425-C00146
    109 5-(piperidin-4- yl)isoquinoline
    Figure US20190119236A1-20190425-C00147
    110 8-(piperidin-4- yl)isoquinoline
    Figure US20190119236A1-20190425-C00148
    111 5-(piperidin-4-yl)quinoline
    Figure US20190119236A1-20190425-C00149
  • As discussed herein, the compounds provided herein, such as those provided in Table 1 and Table 2, are useful for binding to PCSK9 and modulating PCSK9 proprotein convertase enzyme activity.
    • 4. Treatment Methods and Uses
  • “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
  • “Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
  • “Subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.
  • The term “therapeutically effective amount” or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition of as described herein. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one or ordinary skill in the art.
  • The methods described herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to determine the optimal schedule and/or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suited are described below or will become apparent to those skilled in the art. The selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.
  • Compounds of Formula (I), Formula (Ia), Formula (Ib), or additional Formulas or compounds described throughout, are contemplated to be useful in treating diseases or conditions meadiated, at least in part by, PCSK9. Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is an enzyme that in humans is encoded by the PCSK9 gene. Seidah et al., “The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation,” Proc. Natl. Acad. Sci. U.S.A. 100 (3): 928-933 (2003). Similar genes (orthologs) are found across many species. Many enzymes, including PCSK9, are inactive when they are first synthesized, because they have a section of peptide chains that blocks their activity; proprotein convertases remove that section to activate the enzyme.
  • The PCSK9 gene encodes a proprotein convertase belonging to the proteinase K subfamily of the secretory subtilase family. The encoded protein is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum. The protein may function as a proprotein convertase. For example, a human PCSK9 amino acid sequence is:
  • 001 mgtvssrrsw wplpllllll lllgpagara qededgdyee lvlalrseed glaeapehgt
  • 061 tatfhrcakd pwrlpgtyvv vlkeethlsq sertarrlqa qaarrgyltk ilhvfhgllp
  • 121 gflvkmsgdl lelalklphv dyieedssvf aqsipwnler itppryrade yqppdggslv
  • 181 evylldtsiq sdhreiegrv mvtdfenvpe edgtrfhrqa skcdshgthl agvvsgrdag
  • 241 vakgasmrsl rvlncqgkgt vsgtliglef irksqlvqpv gplvvllpla ggysrvlnaa
  • 301 cqrlaragvv lvtaagnfrd daclyspasa pevitvgatn aqdqpvtlgt lgtnfgrcvd
  • 361 lfapgediig assdcstcfv sqsgtsqaaa hvagiaamml saepeltlae lrqrlihfsa
  • 421 kdvineawfp edqrvltpnl vaalppsthg agwqlfcrtv wsahsgptrm atavarcapd
  • 481 eellscssfs rsgkrrgerm eaqggklvcr ahnafggegv yaiarccllp qancsvhtap
  • 541 paeasmgtrv hchqqghvlt gcsshweved lgthkppvlr prgqpnqcvg hreasihasc
  • 601 chapgleckv kehgipapqe qvtvaceegw tltgcsalpg tshvlgayav dntcvvrsrd
  • 661 vsttgstseg avtavaiccr srhlaqasqe lq (Accession No. NP_777596).
  • PCSK9 is believed to play a regulatory role in cholesterol homeostasis. For example, PCSK9 can bind to the epidermal growth factor-like repeat A (EGF-A) domain of the low-density lipoprotein receptor (LDL-R) resulting in LDL-R internalization and degradation. Clearly, it would be expected that reduced LDL-R levels result in decreased metabolism of LDL-C, which could lead to hypercholesterolemia.
  • As it is estimated that approximately nine million Americans have a high or very high risk for heart-related problems that could benefit from PCSK9 inhibitors (especially when in combination with statins). PCSK9 inhibitors could result in such widespread usage having the potential to replace statins in certain conditions. PCSK9 has medical significance because it acts in cholesterol homeostasis. Drugs that block PCSK9 biological actions are believed to lower circulating low-density lipoprotein cholesterol (LDL-C) levels (e.g., by increasing the availability of LDL-Rs and, consequently, LDL-C clearance). Some such drugs, such as Evolocumab (trade name Repatha™ from Amgen, Inc.) and Alirocumab (tradename Praluent™ from Sanofi U.S., LLC and Regeneron Pharmaceuticals, Inc.) have been FDA approved, but are still in clinical trials to determine if they can improve outcomes in heart disease.
  • Variants of PCSK9 can reduce or increase circulating cholesterol. Abifadel et al., “Mutations in PCSK9 cause autosomal dominant hypercholesterolemia” Nat. Genet. 34 (2): 154-156 (2003). LDL-C is normally removed from the blood when it binds to an LDL-R on the surface of liver cells, and is internalized within the hepatocyte as a receptor-ligand complex. However, when PCSK9 binds to an LDL-R, the LDL-R is concomitantly degraded along with the complexed LDL particle. However, if a PCSK9 is not bound to an LDL-R, the LDL-R is recycled after internalization thereby returning to the surface of the cell for removal of more cholesterol.
  • Disclosed herein are compounds contemplated to have a modulation effect on PCSK9's ability to form an LDL-R/PCSK9 complex. In some embodiments, the compounds may bind to a PCSK9 protein and modulate the protein's biological activity. In some embodiments, compounds decrease LDL-R/PCSK9 complex formation and are thereby useful to treat various diseases involving lipid dysregulation. In some embodiments, compounds increase LDL-R/PCSK9 complex formation and are thereby useful in research and development of therapies relevant to LDL dysregulation.
  • Without being bound by any particular theory, it is believed that “gain-of-function” (GOF) PCSK9 mutants may result in conditions including, but not limited to, hypercholesterolemia. For example, compounds that bind to a PCSK9 and increase the affinity of PCSK9's low density lipoprotein receptor for a low density lipoprotein receptor on the surface of a cell (e.g., a hepatocyte) would be expected to increase the symptoms of hypercholesterolemia by increasing low density lipoprotein receptor internalization and degradation.
  • Further, and without being bound by any particular theory, it is believed that “loss-of-function” (LOF) PCSK9 mutants may result in conditions comprising reduced low density lipoproteins and would be expected to result in hypocholesterolemia thereby reducing the risk of cardiovascular diseases, including but not limited to, coronary heart disease. For example, compounds that bind to a PCSK9 that decrease the affinity of PCSK9's low density lipoprotein receptor binding site for a low density lipoprotein receptor on the surface of a cell (e.g., a hepatocyte) would be expected to reduce the symptoms of hypercholesterolemia by promoting low density lipoprotein internalization and clearance due to concomitant recycling of the low density lipoprotein receptor.
  • The compounds of the present disclosure are therefore useful for treating diseases and conditions mediated, at least in part by, PCSK9, including but not limited to cardiovascular diseases (e.g., a coronary disease) and metabolic diseases. For example, the compounds of the present disclosure are useful for treating diseases and conditions including, but not limited to hypercholesterolemia, atherosclerosis, and hypertension. Further, the compounds of the present disclosure are useful for reducing symptoms including, but not limited to elevated low density lipoprotein receptor density, reduced low density lipoprotein receptor density, symptoms of liver disease.
  • Without being bound by any particular theory, it is believed that the administration of a compound of the present disclosure, induces a conformational shift of the PCSK9 protein such that the affinity of the low density lipoprotein binding site for a low density lipoprotein receptor is decreased, wherein PCSK9/LDL-R complex formation is decreased. The decrease in PCSK9/LDL-R complex formation results in an increase in the bioavailability of LDL-R receptors for binding to circulating LDL, thereby increasing the internalization and clearance of LDL by LDL-R. It is further believed that administration of the compound may result in increased bioavailability of hepatocyte cell LDL-Rs.
  • Further, and also without being bound by any particular theory, it is believed that the administration of a compound of the present disclosure, induces a conformational shift of the PCSK9 protein such that the affinity of the low density lipoprotein binding site for a low density lipoprotein receptor is increased, wherein PCSK9/LDL-R complex formation is increased or stabilized. The increase or stabilization in PCSK9/LDL-R complex formation results in a decrease in the bioavailability of LDL-R receptors for binding to circulating LDL, thereby decreasing the internalization and clearance of LDL by LDL-R. It is further believed that a PCSK9 allosteric activator compound may result in decreased bioavailability of hepatocyte cell LDL-Rs.
  • In certain embodiments, provided herein is a method of treating a disease or condition mediated, at least in part, by PCSK9, the method comprising administering to a patient in need thereof a compound of Formula (I):
  • Figure US20190119236A1-20190425-C00150
  • or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof; wherein:
  • m is 0, 1, or 2;
  • X1 is absent, CR2, CR2R2, C(O), N, NR2, S, SO2, or O;
  • X2, X3, and X4 are each independently CR2, CR2R2, C(O), N, NR2, S, SO2, or O;
  • ring B is a five- or six-membered ring comprising one or more double bonds;
  • X5 and X6 are either CR2 or N;
  • X7 is C or N;
  • ring A is selected from:
  • Figure US20190119236A1-20190425-C00151
  • where the wavy line in ring A indicates the point of attachment to
  • Figure US20190119236A1-20190425-C00152
  • L is a bond, C1-6-alkylene, —O—, —C(O)—, —N(Ra)—, —N(Ra)SO2—, or —SO2N(Ra)-where Ra is hydrogen, C1-6 alkyl, or C1-6 heteroalkyl, wherein the C1-6 alkyl or C1-6 heteroalkyl are optionally substituted with 1 to 3 substituents independently selected from halo, oxo, hydroxy, C1-6 alkyl, or C1-6 heteroalkyl;
  • R1 in each instance is independently halo, cyano, C1-6 alkyl optionally substituted with halo or hydroxy, C3-6 cycloalkyl, —NRbC(O)NRbRb, or —NRbS(O)2Rb;
      • wherein each Rb is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl;
  • R2 in each instance is independently hydrogen, halo, C1-6 alkyl optionally substituted with halo or hydroxy, C3-6 cycloalkyl, C2-6 hydroxyalkyl, cyano, —C(O)ORc, or —C(O)NRcRc;
      • wherein each Rc is independently, hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl;
  • R3 is hydrogen, halo, cyano, amino, C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl, or heteroaryl;
      • wherein each C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl and heteroaryl of R3 is optionally substituted with 1 to 3 substituents independently selected from halo, hydroxy, cyano, C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, C1-6 alkoxy, acyl, C3-10 cycloalkyl, heteroalkyl, heteroaryl, heterocyclyl, aryl, oxo, —N3, —NO2, —N(Rf)2, —C(O)N(Rf)2, —C(NRf)(N(Rf)2), —NRfC(O)ORf, —C(O)N(Rf)2, —CO2H, —CO2Rf, —NRfC(NRf)(N(Rf)2), haloalkyl, haloalkoxy, —N(Rf)N(Rf)2, —C(NRf)Rf, —S(O)Rf, —SO2H, —S(O)2Rf, —SCN, —SH, or (═S), and where each Rf is independently H or C1-6 alkyl;
  • or when X7 is N, then L-R3 is absent;
  • R4 in each instance is independently hydrogen, C1-6 alkyl, —C(O)NRdRd, —C(NRd)NRdRd, —C(O)Rd, or —S(O)2NRdRd;
      • wherein each Rd is independently, hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl.
  • In certain embodiments, provided herein is a method of treating a disease or condition mediated, at least in part, by PCSK9, the method comprising administering to a patient in need thereof a compound of Formula (I), as defined herein, with the following provisos:
  • 1) when m is zero then both R4 and L-R3 cannot be hydrogen;
  • 2) when m is 0, R4 is hydrogen, X1, X2, X3, X4 are all CH, then either L-R3 is not CF3 or n is not 0;
  • 3) when X5 and X6 are both nitrogen, then L-R3 is not hydrogen, —CH2-aryl, or —CH2-heteroaryl;
  • 4) when X1, X2, X3, and X4 are all CH or X1 is nitrogen and X2, X3, and X4 are all CH, then L-R3 is not —SO2-aryl, wherein the aryl is optionally substituted;
  • 5) when A is attached via a carbon atom to the remainder of the molecule, R1 is not appended to the same carbon;
  • 6) the compound is not 3-bromo-8-(4-methylpiperidin-1-yl)quinoline or 4-methyl-1-(naphthalen-1-yl)piperidine; and
  • 7) when L-R3 is hydrogen and A is piperidinyl, then R4 is not C(O)NH2.
  • In certain embodiments, provided herein is a method of treating a disease or condition mediated, at least in part, by PCSK9, the method comprising administering to a patient in need thereof a compound selected from Table 1 or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof. In certain embodiments, provided herein is a method of treating a disease or condition mediated, at least in part, by PCSK9, the method comprising administering to a patient in need thereof a compound selected from Table 2 or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof.
  • In certain embodiments, provided is a compound of Formula (I), as defined herein, for use in the treatment of a disease or condition mediated, at least in part, by PCSK9. In one embodiment, provided is a compound for use in the treatment of a disease or condition mediated, at least in part, by PCSK9, wherein the compound is of Formula (I), as defined herein, with the following provisos:
  • 1) when m is zero then both R4 and L-R3 cannot be hydrogen;
  • 2) when m is 0, R4 is hydrogen, X1, X2, X3, X4 are all CH, then either L-R3 is not CF3 or n is not 0;
  • 3) when X5 and X6 are both nitrogen, then L-R3 is not hydrogen, —CH2-aryl, or —CH2-heteroaryl;
  • 4) when X1, X2, X3, and X4 are all CH or X1 is nitrogen and X2, X3, and X4 are all CH, then L-R3 is not —SO2-aryl, wherein the aryl is optionally substituted;
  • 5) when A is attached via a carbon atom to the remainder of the molecule, R1 is not appended to the same carbon;
  • 6) the compound is not 3-bromo-8-(4-methylpiperidin-1-yl)quinoline or 4-methyl-1-(naphthalen-1-yl)piperidine; and
  • 7) when L-R3 is hydrogen and A is piperidinyl, then R4 is not C(O)NH2.
  • In certain embodiments, provided is a compound of Formula (Ia), Formula (Ib), or any other Formula, as defined herein, for use in the treatment of a disease or condition mediated, at least in part, by PCSK9.
  • In certain embodiments, provided is use of a compound of Formula (I), as defined herein, for the treatment of a disease or condition mediated, at least in part, by PCSK9. In one embodiment, provided is a use of a compound for the treatment of a disease or condition mediated, at least in part, by PCSK9, wherein the compound is of Formula (I), as defined herein, with the following provisos:
  • 1) when m is zero then both R4 and L-R3 cannot be hydrogen;
  • 2) when m is 0, R4 is hydrogen, X1, X2, X3, X4 are all CH, then either L-R3 is not CF3 or n is not 0;
  • 3) when X5 and X6 are both nitrogen, then L-R3 is not hydrogen, —CH2-aryl, or —CH2-heteroaryl;
  • 4) when X1, X2, X3, and X4 are all CH or X1 is nitrogen and X2, X3, and X4 are all CH, then L-R3 is not —SO2-aryl, wherein the aryl is optionally substituted;
  • 5) when A is attached via a carbon atom to the remainder of the molecule, R1 is not appended to the same carbon;
  • 6) the compound is not 3-bromo-8-(4-methylpiperidin-1-yl)quinoline or 4-methyl-1-(naphthalen-1-yl)piperidine; and
  • 7) when L-R3 is hydrogen and A is piperidinyl, then R4 is not C(O)NH2.
  • In certain embodiments, provided is use of a compound of Formula (Ia), (Ib) or any other Formula, as defined herein, for the treatment of a disease or condition mediated, at least in part, by PCSK9.
  • In certain embodiments, provided is use of a compound of Formula (I), as defined herein, for the manufacture of a medicament for treating a disease or condition mediated, at least in part, by PCSK9. In one embodiment, provided is a use of a compound for the manufacture of a medicament for treating a disease or condition mediated, at least in part, by PCSK9, wherein the compound is of Formula (I), as defined herein, with the following provisos:
  • 1) when m is zero then both R4 and L-R3 cannot be hydrogen;
  • 2) when m is 0, R4 is hydrogen, X1, X2, X3, X4 are all CH, then either L-R3 is not CF3 or n is not 0;
  • 3) when X5 and X6 are both nitrogen, then L-R3 is not hydrogen, —CH2-aryl, or —CH2-heteroaryl;
  • 4) when X1, X2, X3, and X4 are all CH or X1 is nitrogen and X2, X3, and X4 are all CH, then L-R3 is not —SO2-aryl, wherein the aryl is optionally substituted;
  • 5) when A is attached via a carbon atom to the remainder of the molecule, R1 is not appended to the same carbon;
  • 6) the compound is not 3-bromo-8-(4-methylpiperidin-1-yl)quinoline or 4-methyl-1-(naphthalen-1-yl)piperidine; and
  • 7) when L-R3 is hydrogen and A is piperidinyl, then R4 is not C(O)NH2.
  • In certain embodiments, provided is use of a compound of Formula (Ia), (Ib) or any other Formula, as defined herein, for the manufacture of a medicament for treating a disease or condition mediated, at least in part, by PCSK9.
  • In certain embodiments, provided is a method of inhibiting the activity of PCSK9, where the method comprising binding a compound of Formula (I), as defined herein, to PCSK9, thereby inhibiting the activity of PCSK9. In certain embodiments, provided herein is a method of inhibiting the activity of PCSK9, where the method comprising binding a compound to PCSK9, thereby inhibiting the activity of PCSK9, where the compound is of Formula (I), as defined herein, with the following provisos:
  • 1) when m is zero then both R4 and L-R3 cannot be hydrogen;
  • 2) when m is 0, R4 is hydrogen, X1, X2, X3, X4 are all CH, then either L-R3 is not CF3 or n is not 0;
  • 3) when X5 and X6 are both nitrogen, then L-R3 is not hydrogen, —CH2-aryl, or —CH2-heteroaryl;
  • 4) when X1, X2, X3, and X4 are all CH or X1 is nitrogen and X2, X3, and X4 are all CH, then L-R3 is not —SO2-aryl, wherein the aryl is optionally substituted;
  • 5) when A is attached via a carbon atom to the remainder of the molecule, R1 is not appended to the same carbon;
  • 6) the compound is not 3-bromo-8-(4-methylpiperidin-1-yl)quinoline or 4-methyl-1-(naphthalen-1-yl)piperidine; and
  • 7) when L-R3 is hydrogen and A is piperidinyl, then R4 is not C(O)NH2.
  • In certain embodiments, provided is a method of inhibiting the activity of PCSK9, where the method comprising binding a compound of Formula (Ia), (Ib) or any other Formula, as defined herein, to PCSK9, thereby inhibiting the activity of PCSK9.
  • In certain embodiments, provided is a method of inhibiting the activity of PCSK9, where the method comprising binding a compound, as described in Table 1 or Table 2, to PCSK9, thereby inhibiting the activity of PCSK9.
    • Hypercholesterolemia
  • Hypercholesterolemia (also spelled hypercholesterolaemia) is the presence of high levels of cholesterol in the blood. It is a form of “hyperlipidemia” (elevated levels of lipids in the blood) and “hyperlipoproteinemia” (elevated levels of lipoproteins in the blood). Durrington, P “Dyslipidaemia” The Lancet 2003; 362(9385):717-731. Hypercholesterolemia is typically due to a combination of environmental and genetic factors. Environmental factors include obesity and dietary choices. Genetic contributions are usually due to the additive effects of multiple genes, though occasionally may be due to a single gene defect such as in the case of familial hypercholesterolaemia. A number of secondary causes exist including: diabetes mellitus type 2, obesity, alcohol, monoclonal gammopathy, dialysis, nephrotic syndrome, obstructive jaundice, hypothyroidism, Cushing's syndrome, anorexia nervosa, medications (thiazide diuretics, ciclosporin, glucocorticoids, beta blockers, retinoic acid). Bhatnagar et al., (2008) “Hypercholesterolaemia and its management” BMJ 337: a993. Genetic abnormalities are in some cases completely responsible for hypercholesterolemia, such as in familial hypercholesterolemia where there is one or more genetic mutations in the autosomal dominant APOB gene, the autosomal recessive LDLRAP1 gene, autosomal dominant familial hypercholesterolemia (HCHOLA3) variant of the PCSK9 gene, or the LDL receptor gene. “Hypercholesterolemia” Genetics Home Reference U.S. National Institutes of Health, ghr.nlm.nih.gov/condition=hypercholesterolemia. Even when there is no single mutation responsible for hypercholesterolemia, genetic predisposition still plays a major role in combination with sedentary lifestyle, obesity, or an atherogenic diet. Citkowitz et al., (2010) “Polygenic Hypercholesterolemia”. eMedicine Medscape, emedicine.medscape.com/article/121424-overview.
  • Cholesterol is a sterol. It is one of three major classes of lipids which all animal cells utilize to construct their membranes and is thus manufactured by all animal cells. Plant cells do not manufacture cholesterol. It is also the precursor of the steroid hormones, bile acids and vitamin D. Since cholesterol is insoluble in water, it is transported in the blood plasma within protein particles (lipoproteins). Lipoproteins are classified by their density: very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL). Biggerstaff et al., (2004). “Understanding lipoproteins as transporters of cholesterol and other lipids” Adv Physiol Educ 28 (1-4): 105-6. All the lipoproteins carry cholesterol, but elevated levels of the lipoproteins other than HDL (termed non-HDL cholesterol), particularly LDL-cholesterol are associated with an increased risk of atherosclerosis and coronary heart disease. Carmena et al., (2004) “Atherogenic lipoprotein particles in atherosclerosis” Circulation 109(23 Suppl 1): III 2-7. In contrast, higher levels of HDL cholesterol are protective. Kontush et al., (2006) “Antiatherogenic small, dense HDL-guardian angel of the arterial wall?” Nat Clin Pract Cardiovasc Med 3(3):144-153. Elevated levels of non-HDL cholesterol and LDL in the blood may be a consequence of diet, obesity, inherited (genetic) diseases (such as LDL receptor mutations in familial hypercholesterolemia), or the presence of other diseases such as diabetes and an underactive thyroid. Total cholesterol is the amount of all of the fats in your blood. These fats are called lipids. There are different types of lipid that make up your total cholesterol. The two most important types are: low density lipoprotein (LDL)—“bad” cholesterol and high density lipoprotein (HDL)—“good” cholesterol. High cholesterol, especially “bad” cholesterol (LDL), can clog your arteries. This may reduce blood flow to your heart. It can lead to heart disease, stroke, or heart attack. Cholesterol is measured in milligrams per deciliter (mg/dL). In conditions such as heart disease or diabetes, LDL cholesterol should stay below 100 mg/dL. If there is a risk for heart disease, LDL cholesterol should be lower than 130 mg/dL. In general, LDL cholesterol should be lower than 160-190 mg/dL. Alternative, HDL “good” cholesterol should be high. For example, HDL levels in men should be above 40 mg/dL, while HDL levels should be above 50 mg/dL for women.
  • One symptom of hypercholesterolemia comprises a longstanding elevation of serum cholesterol that can lead to atherosclerosis. Bhatnagar et al., (2008) “Hypercholesterolaemia and its management” BMJ 337: a993. Over a period of decades, chronically elevated serum cholesterol contributes to formation of atheromatous plaques in the arteries. This can lead to progressive stenosis (narrowing) or even complete occlusion (blockage) of the involved arteries. Alternatively smaller plaques may rupture and cause a clot to form and obstruct blood flow. Finn A V, Nakano M, Narula J, Kolodgie F D, Virmani R (July 2010). “Concept of vulnerable/unstable plaque” Arterioscler. Thromb. Vasc. Biol. 30(7): 1282-1292. A sudden occlusion of a coronary artery results in a myocardial infarction or heart attack. An occlusion of an artery supplying the brain can cause a stroke. If the development of the stenosis or occlusion is gradual blood supply to the tissues and organs slowly diminishes until organ function becomes impaired. At this point that tissue ischemia (restriction in blood supply) may manifest as specific symptoms including, but not limited to, temporary ischemia of the brain (commonly referred to as a transient ischemic attack) may manifest as temporary loss of vision, dizziness and impairment of balance, aphasia (difficulty speaking), paresis (weakness) and paresthesia (numbness or tingling), usually on one side of the body. Insufficient blood supply to the heart may manifest as chest pain, and ischemia of the eye may manifest as transient visual loss in one eye. Insufficient blood supply to the legs may manifest as calf pain when walking, while in the intestines it may present as abdominal pain after eating a meal. Grundy et al., (1998) “Primary prevention of coronary heart disease: guidance from Framingham: a statement for healthcare professionals from the AHA Task Force on Risk Reduction. American Heart Association” Circulation 97(18):1876-1887.
    • Hypocholesterolemia
  • Hypocholesterolemia is the presence of abnormally low (hypo-) levels of cholesterol in the blood (-emia). Although the presence of high total cholesterol (hyper-cholesterolemia) correlates with cardiovascular disease, a defect in the body's production of cholesterol can lead to adverse consequences as well. Cholesterol is an essential component of mammalian cell membranes and is required to establish proper membrane permeability and fluidity. It is not clear if a lower than average cholesterol level is directly harmful; it is often encountered in particular illnesses.
  • Possible causes of low cholesterol include, but are not limited to, statins, hyperthyroidism, or an overactive thyroid gland, adrenal insufficiency, liver disease, malabsorption (inadequate absorption of nutrients from the intestines), such as in celiac disease, malnutrition, abetalipoproteinemia (a genetic disease that causes cholesterol readings below 50 mg/dl), hypobetalipoproteinemia (a genetic disease that causes cholesterol readings below 50 mg/dl, manganese deficiency, Smith-Lemli-Opitz syndrome, Marfan syndrome, leukemias and other hematological diseases.
  • Demographic studies suggest that low cholesterol is associated with increased mortality, mainly due to depression, cancer, hemorrhagic stroke, aortic dissection and respiratory diseases. Jacobs et al., (1992). “Report of the Conference on Low Blood Cholesterol: Mortality Associations” Circulation 86 (3): 1046-1060; and Suarez E. C., (1999) “Relations of trait depression and anxiety to low lipid and lipoprotein concentrations in healthy young adult women”. Psychosom Med 61(3): 273-279. It is also possible that whatever causes the low cholesterol level also causes mortality, and that the low cholesterol is simply a marker of poor health.
    • Diabetes
  • Diabetes affects more than 20 million Americans. Over 40 million Americans have pre-diabetes (which often develops before type 2 diabetes). Diabetes is usually a lifelong (chronic) disease in which there is a high level of sugar in the blood. Insulin is a hormone produced by the pancreas to control blood sugar. Diabetes can be caused by too little insulin, resistance to insulin, or both. To understand diabetes, it is important to first understand the normal process by which food is broken down and used by the body for energy.
  • Several things happen when food is digested. A sugar called glucose enters the bloodstream. Glucose is a source of fuel for the body. An organ called the pancreas makes insulin. The role of insulin is to move glucose from the bloodstream into muscle, fat, and liver cells, where it can be used as fuel.
  • People with diabetes have high blood sugar because their body cannot move sugar into fat, liver, and muscle cells to be stored for energy. This is because either their pancreas does not make enough insulin or their cells do not respond to insulin normally.
  • There are two major types of diabetes. The causes and risk factors are different for each type. Type 1 diabetes can occur at any age, but it is most often diagnosed in children, teens, or young adults. In this disease, the body makes little or no insulin. Daily injections of insulin are needed. The exact cause is unknown. Type 2 diabetes makes up most diabetes cases. It most often occurs in adulthood. But because of high obesity rates, teens and young adults are now being diagnosed with it. Many people with type 2 diabetes do not know they have it.
  • Gestational diabetes is high blood sugar that develops at any time during pregnancy in a woman who does not have diabetes.
  • Diabetes symptoms may result from high blood sugar level and include, but are not limited to, blurry vision, excess thirst, fatigue, hunger, urinating often and weight loss.
    • Combination Therapy
  • Patients being treated by administration of the compounds of the disclosure often exhibit diseases or conditions that benefit from treatment with other therapeutic agents. These diseases or conditions can be of cardiovascular nature or can be related to pulmonary disorders, metabolic disorders, gastrointestinal disorders and the like.
    • Cardiovascular Agent Combination Therapy
  • Cardiovascular related diseases or conditions that can benefit from a combination treatment of the compounds of the disclosure with other therapeutic agents include, without limitation, angina including stable angina, unstable angina (UA), exercised-induced angina, variant angina, arrhythmias, intermittent claudication, myocardial infarction including non-STE myocardial infarction (NSTEMI), pulmonary hypertension including pulmonary arterial hypertension, heart failure including congestive (or chronic) heart failure and diastolic heart failure and heart failure with preserved ejection fraction (diastolic dysfunction), acute heart failure, or recurrent ischemia.
  • Therapeutic agents suitable for treating cardiovascular related diseases or conditions include anti-anginals, heart failure agents, antithrombotic agents, antiarrhythmic agents, antihypertensive agents, and lipid lowering agents.
  • The co-administration of the compounds of the disclosure with therapeutic agents suitable for treating cardiovascular related conditions allows enhancement in the standard of care therapy the patient is currently receiving. In some embodiments, the compounds of the disclosure are co-administered with ranolazine (RANEXA®).
    • Anti-Anginals
  • Anti-anginals include beta-blockers, calcium channel blockers, and nitrates. Beta blockers reduce the heart's need for oxygen by reducing its workload resulting in a decreased heart rate and less vigorous heart contraction. Examples of beta-blockers include acebutolol (Sectral®), atenolol (Tenormin®), betaxolol (Kerlone®), bisoprolol/hydrochlorothiazide (Ziac®), bisoprolol (Zebeta®), carteolol (Cartrol®), esmolol (Brevibloc®), labetalol (Normodyne®, Trandate®), metoprolol (Lopressor®, Toprol® XL), nadolol (Corgard®), propranolol (Inderal®), sotalol (Betapace®), and timolol (Blocadren®).
  • Nitrates dilate the arteries and veins thereby increasing coronary blood flow and decreasing blood pressure. Examples of nitrates include nitroglycerin, nitrate patches, isosorbide dinitrate, and isosorbide-5-mononitrate.
  • Calcium channel blockers prevent the normal flow of calcium into the cells of the heart and blood vessels causing the blood vessels to relax thereby increasing the supply of blood and oxygen to the heart. Examples of calcium channel blockers include amlodipine (Norvasc®, Lotrel®), bepridil (Vascor®), diltiazem (Cardizem®, Tiazac®), felodipine (Plendil®), nifedipine (Adalat®, Procardia®), nimodipine (Nimotop®), nisoldipine (Sular®), verapamil (Calan®, Isoptin®, Verelan®), and nicardipine.
    • Heart Failure Agents
  • Agents used to treat heart failure include diuretics, ACE inhibitors, vasodilators, and cardiac glycosides. Diuretics eliminate excess fluids in the tissues and circulation thereby relieving many of the symptoms of heart failure. Examples of diuretics include hydrochlorothiazide, metolazone (Zaroxolyn®), furosemide (Lasix®), bumetanide (Bumex®), spironolactone (Aldactone®), and eplerenone (Inspra®).
  • Angiotensin converting enzyme (ACE) inhibitors reduce the workload on the heart by expanding the blood vessels and decreasing resistance to blood flow. Examples of ACE inhibitors include benazepril (Lotensin®), captopril (Capoten®), enalapril (Vasotec®), fosinopril (Monopril®), lisinopril (Prinivil®, Zestril®), moexipril (Univasc®), perindopril (Aceon®), quinapril (Accupril®), ramipril (Altace®), and trandolapril (Mavik®).
  • Vasodilators reduce pressure on the blood vessels by making them relax and expand. Examples of vasodilators include hydralazine, diazoxide, prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassium channel activators, and calcium channel blockers also act as vasodilators.
  • Cardiac glycosides are compounds that increase the force of the heart's contractions. These compounds strengthen the pumping capacity of the heart and improve irregular heartbeat activity. Examples of cardiac glycosides include digitalis, digoxin, and digitoxin.
    • Antithrombotic Agents
  • Antithrombotics inhibit the clotting ability of the blood. There are three main types of antithrombotics—platelet inhibitors, anticoagulants, and thrombolytic agents.
  • Platelet inhibitors inhibit the clotting activity of platelets, thereby reducing clotting in the arteries. Examples of platelet inhibitors include acetylsalicylic acid (aspirin), ticlopidine, clopidogrel (Plavix®), prasugrel (Effient®), dipyridamole, cilostazol, persantine sulfinpyrazone, dipyridamole, indomethacin, and glycoprotein llb/llla inhibitors, such as abciximab, tirofiban, and eptifibatide (Integrelin®). Beta blockers and calcium channel blockers also have a platelet-inhibiting effect.
  • Anticoagulants prevent blood clots from growing larger and prevent the formation of new clots. Examples of anticoagulants include bivalirudin (Angiomax®), warfarin (Coumadin®), unfractionated heparin, low molecular weight heparin, danaparoid, lepirudin, and argatroban.
  • Thrombolytic agents act to break down an existing blood clot. Examples of thrombolytic agents include streptokinase, urokinase, and tenecteplase (TNK), and tissue plasminogen activator (t-PA).
    • Antiarrhythmic Agents
  • Antiarrhythmic agents are used to treat disorders of the heart rate and rhythm. Examples of antiarrhythmic agents include amiodarone, dronedarone, quinidine, procainamide, lidocaine, and propafenone. Cardiac glycosides and beta blockers are also used as antiarrhythmic agents.
  • Combinations with amiodarone and dronedarone are of particular interest (see U.S. Patent Application Publication No. 2010/0056536 and U.S. Patent Application Publication No. 2011/0183990, the entirety of which are incorporated herein).
    • Antihypertensive Agents
  • Antihypertensive agents are used to treat hypertension, a condition in which the blood pressure is consistently higher than normal. Hypertension is associated with many aspects of cardiovascular disease, including congestive heart failure, atherosclerosis, and clot formation. Examples of antihypertensive agents include alpha-1-adrenergic antagonists, such as prazosin (Minipress®), doxazosin mesylate (Cardura®), prazosin hydrochloride (Minipress®), prazosin, polythiazide (Minizide®), and terazosin hydrochloride (Hytrin®); beta-adrenergic antagonists, such as propranolol (Inderal®), nadolol (Corgard®), timolol (Blocadren®), metoprolol (Lopressor®), and pindolol (Visken®); central alpha-adrenoceptor agonists, such as clonidine hydrochloride (Catapres®), clonidine hydrochloride and chlorthalidone (Clorpres®, Combipres®), guanabenz Acetate (Wytensin®), guanfacine hydrochloride (Tenex®), methyldopa (Aldomet®), methyldopa and chlorothiazide (Aldoclor®), methyldopa and hydrochlorothiazide (Aldoril®); combined alpha/beta-adrenergic antagonists, such as labetalol (Normodyne®, Trandate®), carvedilol (Coreg®); adrenergic neuron blocking agents, such as guanethidine (Ismelin®), reserpine (Serpasil®); central nervous system-acting antihypertensives, such as clonidine (Catapres®), methyldopa (Aldomet®), guanabenz (Wytensin®); anti-angiotensin II agents; ACE inhibitors, such as perindopril (Aceon®) captopril (Capoten®), enalapril (Vasotec®), lisinopril (Prinivil®, Zestril®); angiotensin-II receptor antagonists, such as candesartan (Atacand®), eprosartan (Teveten®), irbesartan (Avapro®), losartan (Cozaar®), telmisartan (Micardis®), valsartan (Diovan®); calcium channel blockers, such as verapamil (Calan®, Isoptin®), diltiazem (Cardizem®), nifedipine (Adalat®, Procardia®); diuretics; direct vasodilators, such as nitroprusside (Nipride®), diazoxide (Hyperstat® IV), hydralazine (Apresoline®), minoxidil (Loniten®), verapamil; and potassium channel activators, such as aprikalim, bimakalim, cromakalim, emakalim, nicorandil, and pinacidil.
    • Lipid Lowering Agents
  • Lipid lowering agents are used to lower the amounts of cholesterol or fatty sugars present in the blood. Examples of lipid lowering agents include bezafibrate (Bezalip®), ciprofibrate (Modalim®), and statins, such as atorvastatin (Lipitor®), fluvastatin (Lescol®), lovastatin (Mevacor®, Altocor®), mevastatin, pitavastatin (Livalo®, Pitava®) pravastatin (Lipostat®), rosuvastatin (Crestor®), and simvastatin (Zocor®).
    • PCSK9 Inhibitors
  • Drugs that block PCSK9 biological actions are believed to lower circulating low-density lipoprotein cholesterol (LDL-C) levels (e.g., by increasing the availability of LDL-Rs and, consequently, LDL-C clearance). Examples include FDA approved Evolocumab (trade name Repatha™ from Amgen, Inc.) and FDA approved Alirocumab (tradename Praluent™ from Sanofi U.S., LLC and Regeneron Pharmaceuticals, Inc.).
    • Additional Combination Therapies
  • A patient presenting with an acute coronary disease event often suffers from secondary medical conditions such as one or more of a metabolic disorder, a pulmonary disorder, or a peripheral vascular disorder. Such patients can benefit from treatment of a combination therapy comprising administering to the patient a compound of the disclosure in combination with at least one therapeutic agent.
    • Pulmonary Disorders Combination Therapy
  • Pulmonary disorder refers to any disease or condition related to the lungs. Examples of pulmonary disorders include, without limitation, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and emphysema.
  • Examples of therapeutics agents used to treat pulmonary disorders include bronchodilators including beta2 agonists and anticholinergics, corticosteroids, and electrolyte supplements. Specific examples of therapeutic agents used to treat pulmonary disorders include epinephrine, terbutaline (Brethaire®, Bricanyl®), albuterol (Proventil®), salmeterol (Serevent®, Serevent Diskus®), theophylline, ipratropium bromide (Atrovent®), tiotropium (Spiriva®), methylprednisolone (Solu-Medrol®, Medrol®), magnesium, and potassium.
    • Metabolic Disorders Combination Therapy
  • Examples of metabolic disorders include, without limitation, diabetes, including type I and type II diabetes, metabolic syndrome, dyslipidemia, obesity, glucose intolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.
  • Examples of therapeutic agents used to treat metabolic disorders include antihypertensive agents and lipid lowering agents, as described in the section “Cardiovascular Agent Combination Therapy” above. Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretin mimetics.
    • Peripheral Vascular Disorders Combination Therapy
  • Peripheral vascular disorders are disorders related to the blood vessels (arteries and veins) located outside the heart and brain, including, for example peripheral arterial disease (PAD), a condition that develops when the arteries that supply blood to the internal organs, arms, and legs become completely or partially blocked as a result of atherosclerosis.
  • Accordingly, one aspect of the disclosure provides for a composition comprising the compounds of the disclosure and at least one therapeutic agent. In an alternative embodiment, the composition comprises the compounds of the disclosure and at least two therapeutic agents. In further alternative embodiments, the composition comprises the compounds of the disclosure and at least three therapeutic agents, the compounds of the disclosure and at least four therapeutic agents, or the compounds of the disclosure and at least five therapeutic agents.
  • The methods of combination therapy include co-administration of a single formulation containing the compounds of the disclosure and therapeutic agent or agents, essentially contemporaneous administration of more than one formulation comprising the compounds of the disclosure and therapeutic agent or agents, and consecutive administration of a compound of the disclosure and therapeutic agent or agents, in any order, wherein preferably there is a time period where the compounds of the disclosure and therapeutic agent or agents simultaneously exert their therapeutic effect.
  • These and other embodiments of the present disclosure will readily occur to those of ordinary skill in the art in view of the disclosure herein and are specifically contemplated.
    • 5. Kits
  • Provided herein are also kits that include a compound of the disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and suitable packaging. In one embodiment, a kit further includes instructions for use. In one aspect, a kit includes a compound of the disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.
  • Provided herein are also articles of manufacture that include a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag.
    • 6. Pharmaceutical Compositions and Modes of Administration
  • Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that contain one or more of the compounds described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.).
  • The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
  • Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • The compositions that include at least one compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
    • 7. Dosing
  • The specific dose level of a compound of the present application for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject's body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate. Normalizing according to the subject's body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.
  • The daily dosage may also be described as a total amount of a compound described herein administered per dose or per day. Daily dosage of a compound of Formula I may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 10 to 500 mg/day, between about 20 to 500 mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day, or between about 15 to 150 mg/day.
  • When administered orally, the total daily dosage for a human subject may be between 1 mg and 1,000 mg, between about 1,000-2,000 mg/day, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day.
  • The compounds of the present application or the compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known in cancer chemotherapy, and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous.
  • In a particular embodiment, the method comprises administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week.
    • 8. Synthesis of the Compounds
  • The compounds may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers.
  • The compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006). Greene's protective groups in organic synthesis. Hoboken, N.J., Wiley-Interscience, and references cited therein.
  • Furthermore, the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.
  • The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce or Sigma (St. Louis, Mo., USA). Others may be prepared by procedures or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), Heterocyclic Chemistry (Blackwell Publishing, 4th Edition, 2002), Vogel's Textbook of Practical Organic Chemistry (Prentice Hall, 5th Edition, 1996).
  • The terms “solvent,” “inert organic solvent” or “inert solvent” refer to a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like).
  • Scheme 1 shows exemplary synthetic routes (Route A and Route B) for preparing compounds of Formula I, wherein ring A, X1, X2, X3, X4, X5, X6, R1, R2, R3, m, n, and L are as defined herein and Z1, Z2, Z3, and Z4 are functional groups suitable for coupling reactions (e.g., halogen, hydroxyl, etc.).
  • Figure US20190119236A1-20190425-C00153
  • In Scheme 1, Route A, compound 1-b can be provided by contacting compound 1-a with compound 1-e under reaction conditions suitable for coupling, where Z3 and Z4 are functional groups that are complementary with respect to a particular coupling reaction. Compounds of formula I can then be provided from compound 1-b by contacting compound 1-b with compound 1-d under reaction conditions suitable for coupling, where Z1 and Z2 are functional groups that are complementary with respect to a particular coupling reaction. For example, the coupling can be a cross coupling reaction, such as a Heck reaction, Negishi coupling, Stille coupling, Suzuki reaction, Kumada coupling, and the like.
  • In Scheme 1, Route B, compound 1-c can be provided by contacting compound 1-a with compound 1-d under reaction conditions suitable for coupling, where Z1 and Z2 are functional groups that are complementary with respect to a particular coupling reaction. For example, the coupling can be a cross coupling reaction, such as a Heck reaction, Negishi coupling, Stille coupling, Suzuki reaction, Kumada coupling, and the like. Compounds of formula I can then be provided from compound 1-c by contacting compound 1-e with compound 1-e under reaction conditions suitable for coupling, where Z3 and Z4 are functional groups that are complementary with respect to a particular coupling reaction.
  • Alternatively, compounds of formula I where L is a bond and R3 is a heterocyclic ring bound to the core via nitrogen can be prepared according to Scheme 2, where the aminated core is reacted with compound 1-f under alkylation reaction conditions. In Scheme 2, X1, X2, X3, X4, X5, X6, R2, and n are as defined herein, each Z5 is a leaving group (e.g., chloro, bromo, iodo, or any other suitable leaving group) and R13 is an alkylene or heteroalkylene.
  • Figure US20190119236A1-20190425-C00154
  • It will be appreciated that any one of compounds 1-a, 1-b, 1-c, 1-d, 1-e, or 1-f may be purchased from commercial sources or prepared according to literature methods available to the skilled artisan, and may be optionally further functionalized (e.g., with one or more R2 moieties) for use in Scheme 1 or Scheme 2.
    • EXAMPLES
  • The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.
  • Unless otherwise stated all temperatures are in degrees Celsius (° C.).
  • As indicated in certain example below, certain synthetic processes were monitored by at least one of the following LCMS methods.
      • Method 1 employed an Acquity BEH C-18 (2.1×100 mm, 1.7 um) column eluting with 5 mM ammonium acetate in water (solvent A) and acetonitrile (solvent B) using the following elution gradient: 0-1.0 min 10% B, 1.0-2.0 min 15% B, 2.0-4.5 min 55% B, 4.5-6.0 min 90% B, 6.0-8.0 min 90B, 8.0-9.0 min 10% B, 9.0-10.0 min 10% B at a flow rate of 0.3 ml/min and a column temperature of 30° C.
      • Method 2 employedan Acquity BEH C-18 (2.1×100 mm, 1.7 um) column eluting with 5 mM ammonium acetate in water (solvent A) and acetonitrile (solvent B) using the following elution gradient: 0-2.0 min 2% B, 2.0-6.0 min 50% B, 6.0-7.0 min 80% B, 7.0-8.5 min 2% B, 8.5-10.0 min 2% B at a flow rate of 0.3 ml/min and a column temperature of 30° C.
      • Method 3 employed a Kinetex C-18 (2.1×100 mm, 1.7 um) column eluting with 0.01% TFA in water (solvent A) and acetonitrile (solvent B) using the following elution gradient: 0-10 min 5% B-90% B, 10.0-15.0 min 90% B, at a flow rate of 0.5 ml/min and a column temperature of 30° C.
    Example 1 1-(4-(Trifluoromethyl)naphthalen-1-yl)piperazine (1) a) 1-bromo-4-(trifluoromethyl)naphthalene
  • Figure US20190119236A1-20190425-C00155
  • Place 4-bromonaphthalen-1-amine (1 mmol), 5-(trifluoromethyl)dibenzothiophenium tetrafluoroborate (1.5 mmol), and copper powder (3.0 mmol) in a Schlenk tube. Evacuate and backfill the Schlenk tube with argon three times and then cool to 0° C. Add acetonitrile and isoamyl nitrite (3.0 mmol) to the resulting mixture and stir for 8 h. Purify the mixture by flash chromatography to prepare the title compound.
    • b) tert-butyl 4-(4-(trifluoromethyl)naphthalen-1-yl)piperazine-1-carboxylate
  • Figure US20190119236A1-20190425-C00156
  • Dissolve 1-bromo-4-(trifluoromethyl)naphthalene (1.00 mmol), tert-butyl piperazine-1-carboxylate (1.20 mmol), Pd2(dba)3 (0.05 mmol), BINAP (0.15 mmol), and NaOtBu (1.40 mmol) in toluene and degas the resulting solution under a stream of argon. Heat the reaction mixture to 80° C. for 8 h and subsequently cool to room temperature. Dilute the solution with ethyl acetate and wash with brine. Separate the organic phase, dry over sodium sulfate, filter, and concentrate the filtrate under vacuum. Purify the resulting by flash chromatography to prepare the title compound.
    • c) 1-(4-(trifluoromethyl)naphthalen-1-yl)piperazine
  • Figure US20190119236A1-20190425-C00157
  • Dissolve tert-butyl 4-(4-(trifluoromethyl)naphthalen-1-yl)piperazine-1-carboxylate (1.00 mmol) in HCl/dioxane (4 N) and stir the resulting solution at room temperature for 2 h. Concentrate the mixture under vacuum and purify the residue by reverse phase chromatography to prepare the title compound.
  • 1-(4-(Trifluoromethyl)naphthalen-1-yl)piperazine (1) can also be prepared via the following alternative synthesis.
    • a) 1-bromo-4-(trifluoromethyl)naphthalene
  • Figure US20190119236A1-20190425-C00158
  • To a stirred solution of 4-bromonaphthalen-1-amine (500 mg, 2.252 mmol) dissolved in a mixture of EtOH (1 ml) and 50% aq. HBF4 (0.28 mL, 4.504 mmol) was added tert-butyl nitrite (0.53 mL, 4.5 mmol) drop wise at 0° C. The resulting reaction mixture was stirred at RT for 1 h. After completion of the reaction the reaction mixture was diluted and triturated with diethyl ether (15 mL) to give a precipitate. The precipitate was filtered to give the diazonium tetra fluoro borate intermediate, which was used in the next step.
  • To a stirred solution of CuSCN (164 mg, 3.37 mmol) and Cs2CO3 (1.1 gr, 3.78 mmol) in acetonitrile (5 mL) was added drop wise TMSCF3 (0.5 mL, 3.37 mmol) under an inert atmosphere. The resulting reaction mixture was stirred at RT for 10 min. A solution of the diazonium tetra fluoro borate intermediate (610 mg, 2.24 mmol) in acetonitrile (5 mL) was added drop wise to the reaction mixture at 0° C. The resulting reaction mixture was cooled to 0-15° C. and stirred for 5 h. The reaction was monitored by TLC and LCMS. The reaction mixture was filtered through a celite pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography using 2% EtOAc in hexane to furnish 1-bromo-4-(trifluoromethyl)naphthalene. 1H-NMR (400 MHz, DMSO-d6): δ 8.41(d, 1H), 8.30 (d, 1H), 7.85-7.65 (m, 4H).
    • b) 1-(4-(trifluoromethyl)naphthalen-1-yl)piperazine
  • Figure US20190119236A1-20190425-C00159
  • An oven dried Schlenk flask was evacuated and back filled with inert gas. The flask was charged with BINAP (181 mg, 0.2909 mmol) and Pd2(dba)3 (133 mg, 0.1454 mmol) in toluene (5 mL) at room temperature under an inert atmosphere. The resultant reaction mixture was evacuated on stirring for 5 min and then reaction mixture was heated to 115° C. for 1-2 min to give a catalyst, to which 1-bromo-4-(trifluoromethyl)naphthalene (400 mg, 1.4545 mmol)), piperazine (1.25 g, 14.54 mmol), tBuONa (280 mg, 2.909 mmol) and 15 mL of toluene were added. The resulting reaction mixture was heated to 120° C. for 4 h. The reaction was monitored by TLC and LCMS. The reaction mixture was filtered through a celite pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC to furnish 1-(4-(trifluoromethyl)naphthalen-1-yl)piperazine product. LCMS purity: 97.892%, RT=5.279 min, m/z=281.2 [M+H]+, (Method 3). 1H-NMR (400 MHz, DMSO-d6): δ 9.05 (brs, 1H), 8.30 (d, 1H), 8.11 (d, 1H), 7.95 (d, 1H), 7.80-7.65 (m, 2H), 7.25 (d, 1H), 3.51-3.41 (m, 4H), 3.31-3.20 (m, 4H).
    • Example 2 4-(4-(Trifluoromethyl)naphthalen-1-yl)piperidine (2) a) tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate
  • Figure US20190119236A1-20190425-C00160
  • Dissolve tert-butyl 4-oxopiperidine-1-carboxylate (1.00 mmol), bis(pinacolato)diboron (1.10 mmol), NaOtBu (0.05 mmol), and (ICy)CuCl (0.03 mmol) in toluene and heat the resulting solution to 50° C. After 24 h, cool the reaction mixture to room temperature and filter through celite. Add p-toluenesulfonic acid (2.00 mmol) and methylene chloride to the crude product and heat the resulting mixture to 50° C. After 24 h, concentrate the reaction under vacuum and purify the residue by flash chromatography to prepare the title compound.
    • b) tert-butyl 4-(4-(trifluoromethyl)naphthalen-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate
  • Figure US20190119236A1-20190425-C00161
  • Prepare a suspension of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.00 mmol), 1-bromo-4-(trifluoromethyl)naphthalene (1.00 mmol), Pd(PPh3)4 (0.1 mmol), and K2CO3 (2.00 mmol) dioxane/water (2/1, v/v) and degas the resulting solution under a stream of argon. Heat the reaction mixture to 90° C. for 8 h, and subsequently cool to room temperature. Dilute the solution with ethyl acetate and wash with brine. Separate the organic phase, dry over sodium sulfate, filter, and concentrate the filtrate under vacuum. Purify the residue by flash chromatography to prepare the title compound.
    • c) 4-(4-(trifluoromethyl)naphthalen-1-yl)piperidine
  • Figure US20190119236A1-20190425-C00162
  • Prepare a suspension of tert-butyl 4-(4-(trifluoromethyl)naphthalen-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.00 mmol) and Pd/C (10%) in ethyl acetate and stir the resulting solution under an atmosphere of hydrogen (1 atm) for 8 h. Filter the resulting suspension was filtered through celite and concentrate the filtrate under vacuum. Dissolve the residue in HCl/dioxane (4 N) and stir the resulting solution at room temperature for 2 h. Concentrate the mixture under vacuum and purify the residue by reverse phase chromatography to prepare the title compound.
    • Example 3 1-(4-(Trifluoromethyl)-5,6,7,8-tetrahydronaphthalen-1-yl)piperazine (3)
  • Figure US20190119236A1-20190425-C00163
  • The title compound may be synthesized using methods similar to Example 1 using 4-bromo-5,6,7,8-tetrahydronaphthalen-1-amine as the starting material.
    • Example 4 1-(4-(Piperidin-4-yloxy)naphthalen-1-yl)piperazine (4) a) tert-butyl 4-(4-bromonaphthalen-1-yl)piperazine-1-carboxylate
  • Figure US20190119236A1-20190425-C00164
  • Dissolve tert-butyl bis(2-chloroethyl)carbamate (1.00 mmol), 4-bromonaphthalen-1-amine (1.00 mmol), and potassium carbonate in DMF and stir the resulting suspension at 90° C. for 18 h. Dilute the solution with ethyl acetate and wash with brine. Separate the organic phase, dry over sodium sulfate, filter and concentrate the filtrate under vacuum. Purify the residue by flash chromatography to prepare the title compound.
    • b) tert-butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)naphthalen-1-yl)piperazine-1-carboxylate
  • Figure US20190119236A1-20190425-C00165
  • Prepare a suspension of tert-butyl 4-(4-bromonaphthalen-1-yl)piperazine-1-carboxylate (1.00 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (1.50 mmol), Pd(OAc)2 (0.10 mmol), [1,1′-binaphthalen]-2-yldi-tert-butylphosphine (0.15 mmol), and Cs2CO3 (2.50 mmol) in toluene and degas under a stream of argon. Heat the reaction mixture to 80° C. for 24 h. Dilute the solution with ethyl acetate and wash with brine. Separate the organic phase, dry over sodium sulfate, filter, and concentrate the filtrate was under vacuum. Purify the residue was purified by flash chromatography to prepare the title compound.
    • c) 1-(4-(piperidin-4-yloxy)naphthalen-1-yl)piperazine
  • Figure US20190119236A1-20190425-C00166
  • Dissolve tert-butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)naphthalen-1-yl)piperazine-1-carboxylate in HCl/dioxane (4 N) and stir the resulting solution at room temperature for 2 h. Concentrate the mixture under vacuum and purify the residue by reverse phase chromatography to prepare the title compound.
  • 1-(4-(piperidin-4-yloxy)naphthalen-1-yl)piperazine (4) can also be prepared by the following alternative synthesis.
    • a) tert-butyl piperazine-1-carboxylate
  • Figure US20190119236A1-20190425-C00167
  • To a stirred solution of piperazine (5.0 g, 0.0580 mol) was added slowly acetic acid (50 mL) at 0° C. under a N2 atmosphere for 20 min and the resulting solution was stirred at RT for a further 20 min. (Boc)2O (13.3 mL dissolved in 40 mL acetic acid) was added drop wise to the reaction mixture at 0° C. for 30 min and stirring was continued for 2 h at RT. The reaction mixture was poured onto ice cold water and basified with saturated aqueous KOH. The material that was formed was separated by filtration and dried under vacuum to give tert-butyl piperazine-1-carboxylate.
    • b) tert-butyl 4-(naphthalen-1-yl)piperazine-1-carboxylate
  • Figure US20190119236A1-20190425-C00168
  • To a stirred solution of 1-bromonapthalene (4.3 g, 0.0207 mol) and tert-butyl piperazine-1-carboxylate (5.0 g, 0.0269 mol) in 1,4-dioxane (86 mL) was added BINAP, Pd(OAc)2 and Cs2CO3 under a N2 atmosphere. The reaction mixture was purged with N2 for 30 min and the temperature was slowly raised to 80° C. for 18 h. The reaction was reaction cooled to RT, filtered through small pad of celite, and washed with EtOAc (2×20 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by silica gel (60-120 mesh) using 1-2% EtOAc/hexanes to give tert-butyl 4-(naphthalen-1-yl)piperazine-1-carboxylate. LCMS: 92.4%.
    • c) tert-butyl 4-(4-bromonaphthalen-1-yl) piperazine-1-carboxylate
  • Figure US20190119236A1-20190425-C00169
  • To a stirred solution of tert-butyl 4-(naphthalen-1-yl)piperazine-1-carboxylate (0.5 g, 0.001597 mol) in CH3CN (13 mL) was added portion wise NBS (0.25 g, 0.001437 mol) and FeCl3 (0.1 g, 0.001592 mol) at RT under N2 atmosphere. The reaction was slowly heated to 50° C. and stirring continued for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude mixture was diluted with water (20 mL) and subsequently extracted with EtOAc (3×20 mL). The combined organic layers were dried, filtered and concentrated under reduced pressure. The crude product was purified by basic Al2O3 column chromatography [elution: 2-3% EtOAc/hexanes] to give tert-butyl 4-(4-bromonaphthalen-1-yl)piperazine-1-carboxylate. LCMS: 95.49%.
    • d) tert-butyl 4-(4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)naphthalen-1-yl)piperazine-1-carboxylate
  • Figure US20190119236A1-20190425-C00170
  • To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.23 g, 0.001147 mol) in dry toluene (6 mL) was added NaH (0.07 g, 0.00153 mol) at 0° C. under N2 atmosphere. The reaction mixture was slowly raised to 70° C. and stirred for 1 h. tert-Butyl 4-(4-bromonaphthalen-1-yl)piperazine-1-carboxylate (0.3 g, 0.000765 mol), Pd2(dba)3 and BINAP were added to the reaction at rt under N2 atmosphere and the resulting solution was slowly raised to 80° C. and stirred for 18 h. Ice cold water was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried filtered and concentrated under reduced pressure. The crude product was purified by basic Al2O3 column chromatography using 10% EtOAc/hexanes to give tert-butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)naphthalen-1-yl)piperazine-1-carboxylate. LCMS: 91.9%.
    • e) 1-(4-(piperidin-4-yloxy)naphthalen-1-yl)piperazine
  • Figure US20190119236A1-20190425-C00171
  • To stirred solution of tert-butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)naphthalen-1-yl)piperazine-1-carboxylate (0.120 g, 0.234 mol) in dry DCM (2.4 mL) was added HCl in diethyl ether (2.4 mL) at RT under a N2 atmosphere. The reaction was stirred at RT for 3 h and monitored by TLC. After completion of the reaction, solvents were decanted and the resulting material was washed with diethyl ether (3×5 mL). The resulting material was dried under high vacuum to give 1-(4-(piperidin-4-yloxy)naphthalen-1-yl)piperazine. LCMS: 92.58%. RT=2.806 min, m/z=312.3 [M+H]+, (method 3). 1H-NMR (300 MHz, DMSO-d6): δ 9.34 (1H, s), 9.12 (1H, d), 8.23-8.20 (1H, m), 8.17-8.14(1H, m), 7.60-7.52 (2H, m), 7.11 (1H, d), 7.03 (1H, d), 4.84 (1H, m), 4.38-4.21 (8H, m), 3.39-3.16 (6H, m), 2.18 (2H, brs), 2.06-1.92 (2H, m).
    • Example 5 N-(4-(Piperazin-1-yl)naphthalen-1-yl)piperidin-4-amine (5)
  • Figure US20190119236A1-20190425-C00172
  • The title compound may be synthesized using methods similar to Example 1, except using tert-butyl 4-(4-bromonaphthalen-1-yl)piperazine-1-carboxylate and tert-butyl 4-aminopiperidine-1-carboxylate as the starting materials.
  • N-(4-(Piperazin-1-yl)naphthalen-1-yl)piperidin-4-amine (5) can also be prepared using the following alternative synthesis.
    • a) tert-butyl 4-(4-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)naphthalen-1-yl)piperazine-1-carboxylate
  • Figure US20190119236A1-20190425-C00173
  • To stirred solution of tert-butyl 4-(4-bromonaphthalen-1-yl)piperazine-1-carboxylate (0.3 g, 0.000765 mol) and tert-butyl 4-aminopiperidine-1-carboxylate (0.306 g, 0.00153 mol) in 1,4 dioxane (12 mL) were added BINAP and Cs2CO3 at RT under N2 atmosphere. The reaction mixture was purged with N2 for 30 min and Pd(OAc)2 (34 mg, 0.000153 mol) was added. The temperature was slowly raised to 70° C. and the resulting solution stirred for 18 h. The reaction was monitored by TLC, and after completion, filtered through a small pad of celite and washed with EtOAc (3×5 mL). The combined filtrate was concentrated under reduced pressure. The crude was purified by silica gel (60-120 mesh) column chromatography using 10% EtOAc/Hexanes to give tert-butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)naphthalen-1-yl)piperazine-1-carboxylate. LCMS: 93.7%.
    • b) N-(4-(piperazin-1-yl)naphthalen-1-yl)piperidin-4-amine
  • Figure US20190119236A1-20190425-C00174
  • To stirred solution of tert-butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)naphthalen-1-yl)piperazine-1-carboxylate (0.120 g, 0.000234 mol) in dry DCM (2.4 mL) was added HCl in diethyl ether (2.4 mL) at RT under a N2 atmosphere and the reaction was stirred at RT for 4 h. The reaction was monitored by TLC, and after completion, solvents were decanted and washed with diethyl ether (3×5 mL). The reaction mixture was dried under high vacuum and the resulting material was washed with hexanes (3×10 mL) to give N-(4-(piperazin-1-yl)naphthalen-1-yl)piperidin-4-amine. LCMS: 97.65%. RT=2.405 min, m/z=311.3 [M+H]+, (method 3) 1H-NMR (300 MHz, DMSO-d6): δ 8.29-8.26(1H, m), δ 7.81(1H, d), δ 7.52-7.46(2H, m), δ 6.99(1H, d), δ 6.60-6.58(1H, m), δ 4.08-4.06(4H, m), δ 3.64-3.53(1H, m), δ 3.01(4H, t), δ 2.13(2H, d), δ 1.62-1.55(4H, m), δ 1.54(1H, bs), δ 1.48-1.45(4H, m).
    • Example 6 1-(4-(Piperidin-4-ylmethyl)naphthalen-1-yl)piperazine (6) a) 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1-naphthoic acid
  • Figure US20190119236A1-20190425-C00175
  • To a solution of tert-butyl 4-(4-bromonaphthalen-1-yl)piperazine-1-carboxylate (1.00 mmol) in THF at 0° C., add a solution of iPrMgCl:LiCl in THF (1.50 mmol). Stir the resulting at 0° C. for 0.5 h, then warm to room temperature and stir the resulting mixture for 3 h. Cool the mixture to −10° C. and bubble CO2 gas through the solution for 1 h. Add 1 N aqueous HCl and extract the resulting solution with ethyl acetate to prepare the title compound.
    • b) tert-Butyl 4-(4-(hydroxymethyl)naphthalen-1-yl)piperazine-1-carboxylate
  • Figure US20190119236A1-20190425-C00176
  • Dissolve 4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-1-naphthoic acid (1.00 mmol) in THF and add a solution of borane in THF (2.00 mmol). Stir the resulting solution at room temperature for 24 h. Add aqueous HCl and stir the resulting solution for 1 h. Dilute the solution with ethyl acetate and wash with brine. Separate the organic phase, dry over sodium sulfate, filter, and concentrate the filtrate under vacuum. Purify the residue by flash chromatography to prepare the title compound.
    • c) tert-butyl 4-(4-formylnaphthalen-1-yl)piperazine-1-carboxylate
  • Figure US20190119236A1-20190425-C00177
  • Dissolve tert-Butyl 4-(4-(hydroxymethyl)naphthalen-1-yl)piperazine-1-carboxylate (1.00 mmol) in methylene chloride and add PCC (2.00 mmol) and SiO2. Stir the resulting suspension at room temperature for 2 h and subsequently filter through celite to give tert-butyl 4-(4-formylnaphthalen-1-yl)piperazine-1-carboxylate to prepare the title compound.
    • d) (1-(tert-butoxycarbonyl)piperidin-4-yl)triphenylphosphonium bromide
  • Figure US20190119236A1-20190425-C00178
  • Dissolve tert-Butyl 4-bromopiperidine-1-carboxylate (1.00 mmol) and triphenylphosphine (1.50 mmol) in toluene and stir the resulting solution at 80° C. for 12 h. Cool the solution to room temperature and filter to remove the precipitate. Concentrate the filtrate to prepare the title compound.
    • e) tert-butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-ylidene)methyl)naphthalen-1-yl)piperazine-1-carboxylate
  • Figure US20190119236A1-20190425-C00179
  • Slowly add n-BuLi (1.20 mmol) to a solution of (1-(tert-butoxycarbonyl)piperidin-4-yl)triphenylphosphonium bromide (1.00 mmol) in THF at −20° C. Stir the resulting suspension was stirred at room temperature for 2 h. To the suspension, add a solution of tert-butyl 4-(4-formylnaphthalen-1-yl)piperazine-1-carboxylate (1.00 mmol) in THF and stir the resulting solution at room temperature for 4 h. Filter the suspension through celite and concentrate the filtrate under vacuum. Purify the residue was purified by flash chromatography to prepare the title compound.
    • f) 1-(4-(piperidin-4-ylmethyl)naphthalen-1-yl)piperazine
  • Figure US20190119236A1-20190425-C00180
  • Prepare a suspension of tert-Butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-ylidene) methyl)naphthalen-1-yl)piperazine-1-carboxylate (1.00 mmol) and Pd/C (10%) in ethyl acetate and stir the resulting solution under an atmosphere of hydrogen (1 atm) for 8 h. Filter the resulting suspension through celite and concentrate the filtrate under vacuum. Dissolve the residue in HCl/dioxane (4 N) and stir the resulting solution at room temperature for 2 h. Concentrate the mixture under vacuum and purify the residue by reverse phase chromatography to prepare the title compound.
    • Example 7 1-(4-(Piperidin-4-ylsulfonyl)naphthalen-1-yl)piperazine (7) a) tert-butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)sulfonyl)naphthalen-1-yl)piperazine-1-carboxylate
  • Figure US20190119236A1-20190425-C00181
  • Add n-BuLi (1.10 mmol) to a solution of tert-butyl 4-(4-bromonaphthalen-1-yl)piperazine-1-carboxylate (1.00 mmol) in THF at −78° C. and stir the resulting solution at −78° C. for 1 h. To the reaction mixture, add a solution of tert-butyl 4-(chlorosulfonyl)piperidine-1-carboxylate (1.00 mmol) in THF and allow the resulting solution to warm to room temperature. Add aqueous HCl followed by ethyl acetate. Separate the organic phase was separated, dry over sodium sulfate, filter, and concentrate the filtrate under vacuum. Purify the residue by flash chromatography to prepare the title compound.
    • b) 1-(4-(piperidin-4-ylsulfonyl)naphthalen-1-yl)piperazine
  • Figure US20190119236A1-20190425-C00182
  • Dissolve tert-Butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)sulfonyl)naphthalen-1-yl)piperazine-1-carboxylate in HCl/dioxane (4 N) and stir the resulting solution at room temperature for 2 h. Concentrate the mixture under vacuum and purify the residue by reverse phase chromatography to prepare the title compound.
  • 1-(4-(Piperidin-4-ylsulfonyl)naphthalen-1-yl)piperazine (7) can also be prepared by the following alternative synthesis.
    • a) Synthesis of tert-butyl 4-(4-(1-(tert-butoxycarbonyl)piperidin-4-ylthio)naphthalen-1-yl)piperazine-1-carboxylate
  • Figure US20190119236A1-20190425-C00183
  • To a stirred solution of tert-butyl 4-(4-bromonaphthalen-1-yl)piperazine-1-carboxylate (1.36 g, 0.00347 mol) and tert-butyl 4-(acetylthio)piperidine-1-carboxylate (0.9 g, 0.00344 mol) in 1,4-dioxane (30 mL) was added Pd(dba)2 (0.099 g, 0.008175 mol), dppf (0.135 g, 0.000243 mol) and K3PO4 (0.879 g, 0.004169 mol) at RT under N2 atmosphere. The reaction mixture was purged with N2 for 30 min and slowly raised to 120° C. for 2 days. After completion of the reaction the solution was cooled to RT, and the solvents were evaporated under reduced pressure. The crude product was purified by silica gel (60-120 mesh) column chromatography using 2-8% EtOAc/Hexanes to give tert-butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)thio)naphthalen-1-yl)piperazine-1-carboxylate. LCMS: 52.1%.
    • b) tert-butyl 4-(4-(1-(tert-butoxycarbonyl)piperidin-4-ylsulfonyl)naphthalen-1-yl)piperazine-1-carboxylate
  • Figure US20190119236A1-20190425-C00184
  • To a stirred solution of tert-butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)thio)naphthalen-1-yl)piperazine-1-carboxylate (0.34 g, 0.0006584 mol) in dry DCM (7 mL) was added m-CPBA (0.332 g, 0.3393 mol) at 0° C. under N2 atmosphere. The reaction was stirred at RT overnight. After completion of the reaction, the mixture was quenched with sat. NaHCO3 solution (10 mL) and extracted with DCM (3×20 mL). The combined organic layers were dried and concentrated under reduced pressure. The crude material was purified by neutral Al2O3 using 10-30% EtOAc/Hexanes to give tert-butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)sulfonyl)naphthalen-1-yl)piperazine-1-carboxylate. LCMS: 81.76%.
    • c) 1-(4-(piperidin-4-ylsulfonyl)naphthalen-1-yl)piperazine
  • Figure US20190119236A1-20190425-C00185
  • To stirred solution of compound tert-butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)sulfonyl)naphthalen-1-yl)piperazine-1-carboxylate (0.2 g, 0.0003577 mol) in dry DCM (3.3 mL) was added HCl in diethyl ether (3.3 mL). The reaction was stirred at RT for 4 h under an atmosphere of nitrogen. The reaction was monitored by TLC, and after completion, solvents were decanted and washed with diethyl ether (3×5 mL). The reaction mixture was dried under high vacuum and the resulting material was washed with hexanes (3×10 mL) to give 1-(4-(piperidin-4-ylsulfonyl)naphthalen-1-yl)piperazine. LCMS: 94.36%. RT=2.670 min, m/z=360.3 [M+H]+, (method 3). 1H-NMR (300 MHz, DMSO-d6): δ 9.66 (2H, s), δ 9.39 (1H, d), δ 8.93 (1H, d), δ 8.63 (1H, d), δ 8.27 (1H, d), δ 8.11(1H, d), δ 7.79-7.67 (2H, m), δ 7.34 (1H, d), δ 3.72 (1H, bs), δ 3.37 (8H, m), δ 3.26 (2H, d), δ 2.83 (2H, d), δ 1.89(4H, s).
    • Example 8 Piperazin-1-yl(4-(piperazin-1-yl)naphthalen-1-yl)methanone (8) a) tert-butyl 4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1-naphthoyl)piperazine-1-carboxylate
  • Figure US20190119236A1-20190425-C00186
  • Dissolve 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1-naphthoic acid (1.00 mmol), tert-butyl piperazine-1-carboxylate (1.00 mmol), HATU (1.20 mmol) and DIPEA (2.00 mmol) in DMF and stir the resulting solution at room temperature for 4 h. Dilute the solution with ethyl acetate and wash with brine. Separate the organic phase, dry over sodium sulfate, filter, and concentrate the filtrate under vacuum. Purify the residue by flash chromatography to prepare the title compound.
    • b) piperazin-1-yl(4-(piperazin-1-yl)naphthalen-1-yl)methanone
  • Figure US20190119236A1-20190425-C00187
  • Dissolve tert-Butyl 4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1-naphthoyl)piperazine-1-carboxylate in HCl/dioxane (4 N) and stir the resulting solution at room temperature for 2 h. Concentrate the mixture under vacuum and purify the residue by reverse phase chromatography to prepare the title compound.
  • Piperazin-1-yl(4-(piperazin-1-yl)naphthalen-1-yl)methanone (8) can also be prepared by the following alternative synthesis.
    • a) tert-butyl 4-(4-(ethoxycarbonyl)naphthalen-1-yl)piperazine-1-carboxylate
  • Figure US20190119236A1-20190425-C00188
  • tert-Butyl 4-(4-bromonaphthalen-1-yl)piperazine-1-carboxylate (0.3 g, 0.000765 mol) was dissolved in EtOH (30 mL) in a pressure vessel and NaOAc (0.125 g, 0.00153 mol) and Pd(dppf)Cl2 (0.0279 g, 0.000038 mol) were added. The reaction was degassed with N2 and the vessel was pressurized with CO gas (2 BAR). The temperature was slowly raised to 110° C. and the resulting solution was stirred overnight. After completion of the reaction the solution was filtered through a small pad of celite and washed with EtOH (3×50 mL). The solvents were evaporated under reduced pressure and the crude tert-butyl 4-(4-(ethoxycarbonyl)naphthalen-1-yl)piperazine-1-carboxylate (0.180 g, 61.4%) was used without further purification. LCMS: 98.65%.
    • b) 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1-naphthoic acid
  • Figure US20190119236A1-20190425-C00189
  • To a stirred solution of tert-butyl 4-(4-(ethoxycarbonyl)naphthalen-1-yl)piperazine-1-carboxylate (0.5 g, 0.00130 mol) in MeOH/H2O (2:1, 15 mL) was added LiOH.H2O (0.059 g, 0.001432 mol) at RT. After stirring overnight the solvent was evaporated under reduced pressure. The residue was acidified with saturated citric acid solution and extracted with DCM (3×5 mL). The combined organic layers were dried, filtered and concentrated under reduced pressure to give 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1-naphthoic. LCMS: 91.95%.
    • c) tert-butyl 4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1-naphthoyl)piperazine-1-carboxylate
  • Figure US20190119236A1-20190425-C00190
  • To a stirred solution of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1-naphthoic acid (0.15 g, 0.4216 mmol) in dry DCM (4 mL) at 0° C. was added EDC.HCl (0.097 g, 0.5056 mmol), HOBt (11.3 mg, 0.064 mmol), DMAP (10.2 mg, 0.064 mmol), DIPEA (0.5 mL, 0.82 mmol) and tert-butyl piperazine-1-carboxylate (0.086 g, 0.463 mmol). The resulting solution was stirred at RT overnight. After completion of the reaction ice cold water was added and the resulting solution was extracted with DCM (3×10 mL). The combined organic layers were dried concentrated under reduced pressure. The crude material was purified by silica gel (60-120 mesh) column chromatography using 10-30% EtOAc/hexanes to give tert-butyl 4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1-naphthoyl)piperazine-1-carboxylate. LCMS: 98.72%.
    • d) piperazin-1-yl(4-(piperazin-1-yl)naphthalen-1-yl)methanone
  • Figure US20190119236A1-20190425-C00191
  • To stirred solution of tert-butyl 4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1-naphthoyl)piperazine-1-carboxylate (0.07 g, 0.000133 mol) in dry DCM (1.4 mL) was added HCl in diethyl ether (1.4 mL). The reaction was stirred at RT for 4 h under an atmosphere of nitrogen. The reaction was monitored by TLC, and after completion, solvents were decanted and washed with diethyl ether (3×5 mL). The reaction mixture was dried under high vacuum and the resulting material was washed with hexanes (3×10 mL) to give piperazin-1-yl(4-(piperazin-1-yl)naphthalen-1-yl)methanone. LCMS: 98.8%. RT=1.945 min, m/z=325.3 [M+H]+, (method 3). 1H-NMR (300 MHz, DMSO-d6): δ 9.69(2H, d), δ 8.22-8.19 (1H, m), δ 7.82-7.79 (1H, m), δ 7.61-7.57 (2H, m), δ 7.49 (1H, d), δ 7.19 (1H, d), δ 5.22-5.00 (8H, m), δ 3.99 (2H, s), δ 3.43-3.33 (6H, m), δ 2.92 (2H, d).
    • Example 9 5-(Piperazin-1-yl)-8-(piperidin-4-yloxy)isoquinoline (9)
  • Figure US20190119236A1-20190425-C00192
  • The title compound may be synthesized using the same methods similar to of Example 11, except using 8-bromoisoquinolin-5-amine as the starting material.
  • 5-(Piperazin-1-yl)-8-(piperidin-4-yloxy)isoquinoline (9) can also be prepared using the following alternative synthesis.
    • a) tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00193
  • To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (10 g, 0.053 mol) in MeOH (150 mL) was added NaBH4 (4 g, 0.107 mol) at 0° C. and the resulting reaction mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and concentrated to give tert-butyl 4-hydroxypiperidine-1-carboxylate. To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate in DCM (150 ml) were added TEA (22.3 mL, 0.172 mol) and DMAP (316 mg, 0.0032 mol) and the resulting solution was stirred for 10 min at 0° C. followed by the addition of methyl sulfonyl chloride (4.5 ml, 0.0645 mol). The resulting reaction mixture was stirred for 1 h at RT after which water was added and the solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate.
    • b) tert-butyl 4-(5-bromoisoquinolin-8-yloxy)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00194
  • To a solution of 4-bromonaphthalen-1-ol (500 mg, 2.232 mmol) in DMF (6 mL) was added tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (809 mg, 2.901 mmol) and Cs2CO3 (2.18 g, 6.696 mmol) and the resulting mixture was heated to 80° C. for 4 h. The reaction mixture was poured into ice water and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by basic alumina column chromatography using 30% ethyl acetate in hexane to yield compound tert-butyl 4-((5-bromoisoquinolin-8-yl)oxy)piperidine-1-carboxylate. LCMS Purity: 93.416%.
    • c) tert-butyl 4-(5-(piperazin-1-yl)isoquinolin-8-yloxy)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00195
  • To a stirred solution of compound tert-butyl 4-((5-bromoisoquinolin-8-yl)oxy)piperidine-1-carboxylate (500 mg, 0.0012 mol) and in toluene (12 mL) was added piperazine (530 mg, 0.0061 mol), Pd2(dba)3 (113 mg, 0.00012 mol), BINAP (15.3 mg, 0.000246 mol) and NaOtBu (355 mg, 0.0037 mol). The resulting reaction mixture was degassed and then heated to 110° C. for 5 h. The reaction was cooled to room temperature and filtered through a celite pad. The collected filtrate was concentrated under reduced pressure and purified by basic alumina column chromatography using 10% methanol in DCM give tert-butyl 4-((5-(piperazin-1-yl)isoquinolin-8-yl)oxy)piperidine-1-carboxylate. LCMS Purity: 81.262%.
    • d) 5-(piperazin-1-yl)-8-(piperidin-4-yloxy)isoquinoline
  • Figure US20190119236A1-20190425-C00196
  • To a stirred solution of tert-butyl 4-(5-(piperazin-1-yl)isoquinolin-8-yloxy)piperidine-1-carboxylate (300 mg, 0.72 mmol) in DCM (10 mL) was added TFA (2 ml) and the resulting reaction mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated under vacuum and the crude product was purified by preparative HPLC to yield 5-(piperazin-1-yl)-8-(piperidin-4-yloxy)isoquinoline. LCMS Purity: 97.340%, RT=0.879 min, m/z=313.3 (M+H)+ (Method 3). 1H-NMR (400 MHz, DMSO-d6): δ 9.72 (1H, s), 9.08 (1H, brs), 8.78 (1H, brs), 8.62 (1H, d), 8.18(1H, d), 7.50 (1H, d), 7.26 (1H, d), 4.98 (1H, brs), 3.58-3.02 (12H, m), 2.25-1.92 (1H, m).
    • Example 10 4-(8-(Piperidin-4-yloxy)isoquinolin-5-yl)piperazin-2-one (16) 4-(8-(Piperidin-4-yloxy)isoquinolin-5-yl)piperidin-2-one (27)
  • Figure US20190119236A1-20190425-C00197
    Figure US20190119236A1-20190425-C00198
  • The known 5-nitroisoquinolin-8-ol is reacted with triphenylphosphine/DEAD/THF (Johansson, G. et al WO 2004000828) and combined with 1-BOC-4-hydroxypiperidine, giving N-BOC-5-nitro-8-(piperidin-4-yloxy)isoquinoline.
  • The nitro group is reduced to the amine; the amine is converted the diazonium salt using sodium nitrite and, subsequently, to the iodide (Knochel, P. et al Synthesis, 2007, 81-84).
  • The iodide may be coupled using palladium catalysts with either 2-ketopiperazine (Ford, D. et al WO 2013096051) or (2-methoxypyridin-4-yl)boronic acid (Marsilje, T. H. et al J. Med. Chem. 2013, 56, 5675-90) to afford, after deprotection, either 4-(8-(piperidin-4-yloxy)isoquinolin-5-yl)piperazin-2-one (16) or 4-(8-(piperidin-4-yloxy)isoquinolin-5-yl)piperidin-2-one (27).
  • 4-(8-(piperidin-4-yloxy)isoquinolin-5-yl)piperazin-2-one can also be prepared by the following alternative synthesis (16).
    • a) tert-butyl4-(5-(3-oxopiperazin-1-yl)isoquinolin-8-yloxy)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00199
  • To a stirred solution of tert-butyl 4-((5-bromoisoquinolin-8-yl)oxy)piperidine-1-carboxylate (400 mg, 0.98 mmol) and in 1,4 dioxane (10 mL) was added piperazin-2-one (296 mg, 2.96 mmol), Pd2(OAc)2 (22 mg, 0.0987 mmol), BINAP (122 mg, 0.197 mmol), and Cs2CO3 (965 mg, 2.962 mmol). The resulting reaction mixture was degassed and then heated to 110° C. for 36 h. The reaction was cooled to room temperature and filtered through a celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC to give tert-butyl 4-((5-(3-oxopiperazin-1-yl)isoquinolin-8-yl)oxy)piperidine-1-carboxylate.
    • b) 4-(8-(piperidin-4-yloxy)isoquinolin-5-yl)piperazin-2-one
  • Figure US20190119236A1-20190425-C00200
  • To a stirred solution of tert-butyl 4-((5-(3-oxopiperazin-1-yl)isoquinolin-8-yl)oxy)piperidine-1-carboxylate (35 mg, 0.0825 mmol) in DCM (10 mL) was added TFA (2 ml) and the resulting reaction mixture was stirred for 1 h at room temperature. The solvents were removed under reduced pressure and the crude product was recrystallized by using diethyl ether to yield 4-(8-(piperidin-4-yloxy)isoquinolin-5-yl)piperazin-2-one. LCMS Purity: 97.42%, RT=2.242 min, m/z=327.3(M+H)+, (Method 3). 1H-NMR (400 MHz, DMSO-d6): δ 8.8-8.5 (3H, m), 8.05 (1H, s), 7.45 (1H, d), 7.23 (1H, d), 4.96 (1H, s), 3.52-3.26 (6H, m), 3.25-3.08 (4H, m), 2.23-1.94 (4H, m).
    • Example 11 4-Bromonaphthalene-1-thiolen-1-yl)sulfonyl)piperidine (23)
  • Figure US20190119236A1-20190425-C00201
  • Using the Newman-Kwart reaction, 4-bromonaphthalen-1-ol, is converted to a dimethyaminoisothiourea intermediate, which rearranges on vigorous heating to give, on hydrolysis, 4-bromonaphthalene-1-thiol. The thiol is reacted with N-BOC-piperidine-4-Br and the sulfur oxidized to the corresponding sulfone. The aryl bromide is coupled to a second piperidine subunit. Reduction/deprotection leads to the desired 4-bromonaphthalene-1-thiolen-1-yl)sulfonyl)piperidine (23).
    • Example 12 5-(Piperazin-1-yl)-8-(piperidin-4-yloxy)isoquinoline-3-carboxylic acid (14) 5-(3-Oxopiperazin-1-yl)-8-(piperidin-4-yloxy)isoquinoline-3-carboxamide (15) 5-(2-Oxopiperidin-4-yl)-8-(piperidin-4-yloxy)isoquinoline-3-carboxamide (26) 5-(Piperidin-4-yl)-8-(piperidin-4-yloxy)isoquinoline-3-carboxylic acid (25)
  • Figure US20190119236A1-20190425-C00202
  • The commercial 8-methoxyisoquinoline is N-oxidized (Dirnberger, D. et al Archiv der Pharmazie 1990, 323, 323) and treated with TMS-CN (Norrby, T. et al Acta Chemica Scand. 1998, 52, 77), affording 8-methoxyisoquinoline-3-carbonitrile.
  • The carbonitrile is brominated. The key bromide, 5-bromo-8-methoxyisoquinoline-3-carbonitrile, may be coupled using palladium reagents and subsequently modified and deprotected to give piperazine (5-(piperazin-1-yl)-8-(piperidin-4-yloxy)isoquinoline-3-carboxylic acid (22)), piperazone (5-(3-oxopiperazin-1-yl)-8-(piperidin-4-yloxy)isoquinoline-3-carboxamide (15)), piperidone (5-(2-oxopiperidin-4-yl)-8-(piperidin-4-yloxy)isoquinoline-3-carboxylic acid (110)), and piperidine (5-(piperidin-4-yl)-8-(piperidin-4-yloxy)isoquinoline-3-carboxylic acid (25)) analogs.
    • Example 13 1-(4-(Piperidin-4-ylmethyl)naphthalen-1-yl)piperazine (22)
  • Figure US20190119236A1-20190425-C00203
  • tert-Butyl 4-(4-bromonaphthalen-1-yl)piperazine-1-carboxylate is lithiated and reacted with the carboxaldehyde derived from N-BOC-isonipecotic acid. The carbinol is cleaved by catalytic reduction, and deprotection affords 1-(4-(piperidin-4-ylmethyl)naphthalen-1-yl)piperazine (22).
    • Example 14 4-(Piperazin-1-yl)-7-(piperidin-4-yloxy)indolin-2-one (12) 4-(Piperidin-4-yl)-7-(piperidin-4-yloxy)indolin-2-one (24)
  • Figure US20190119236A1-20190425-C00204
    Figure US20190119236A1-20190425-C00205
  • 4-Bromo-2-nitrophenol is combined with N-BOC-4-hydroxypiperidine, employing Mitsonubo conditions. Vinyl magnesium bromide at low temperature installs an indole ring via the Bartoli reaction.
  • The ultimate indolines, 4-(piperidin-4-yl)-7-(piperidin-4-yloxy)indolin-2-one (24) or 4-(piperazin-1-yl)-7-(piperidin-4-yloxy)indolin-2-one (12), can be targeted by oxidizing the indole rings to indolines using, for example, NBS, and performing the appropriate palladium couplings and deprotections according to the scheme.
    • Example 15 4-(Piperazin-1-yl)-7-(piperidin-4-yloxy)isoindolin-1-one (13)
  • Figure US20190119236A1-20190425-C00206
    Figure US20190119236A1-20190425-C00207
  • 3-Chloroacrolein is condensed with 1-BOC-piperidin-ol by means of a Michael reaction, giving N-BOC-(E)-3-(piperidin-4-yloxy)acrylaldehyde. The aldehyde can dibromoolefinated using CBr4/PPh3, giving a diene which can undergo a thermal or Lewis acid catalyzed Diels-Alder cyclization, followed by aromatization with loss of HBr.
  • The aryl bromide may be coupled to BOC-piperazine. Reduction of the nitrile induces cyclization to the indicated lactam affording, on deprotection, the isoindolone, 4-(piperazin-1-yl)-7-(piperidin-4-yloxy)isoindolin-1-one (13).
    • Example 16 4-(Naphthalen-1-yl)piperazine-1-carboximidamide (10) a) 1-(naphthalen-1-yl)piperazine
  • Figure US20190119236A1-20190425-C00208
  • An oven dried Schlenk flask was evacuated and back filled with inert gas. Then to the flask was charged with BINAP (1.2 g, 1.93 mmol) and palladium (II)-acetate (216 mg, 0.96 mmol) in dioxane (5 mL) at room temperature under an inert atmosphere. The resultant reaction mixture was evacuated on stirring for 5 min and then the reaction mixture was heated to 115° C. for 1-2 min to give a catalyst, to which 1-bromo naphthalene (2 g, 9.65 mmol), piperazine (4.1 g, 48.2 mmol), Cs2CO3 (6.2 g, 19.31 mmol) and also 20 mL of dioxane were added. The resulting reaction mixture was heated to 110° C. for 4 h. The reaction was monitored by TLC and LCMS. The reaction mixture was filtered through a celite pad and was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified on basic alumina with a gradient elution of 3% MeOH in DCM to furnish 1-(naphthalen-1-yl)piperazine. LCMS purity: 93.356%, m/z=213.3 [M+H]+.
    • b) 4-(naphthalen-1-yl)piperazine-1-carboximidamide
  • Figure US20190119236A1-20190425-C00209
  • To a stirred solution of 1-(naphthalen-1-yl)piperazine (300 mg, 1.41 mmol) and 2H-1,2,3-triazole-2-carboximidamide hydrochloride (207 mg, 1.41 mmol) in DMF (2.5 mL) was added DIPEA (0.26 mL, 0.00141 mol) and the resulting mixture was heated to 80° C. for 10 h. The reaction mixture was monitored by TLC. After completion of the reaction the mixture was concentrated under reduced pressure the crude product was purified by column chromatography on basic alumina with a gradient elution of 20% MeOH in DCM to furnish 4-(naphthalen-1-yl)piperazine-1-carboximidamide. LCMS purity: 97.938%, RT=5.067 min, m/z=255.3 (M+H)+ (Method 3). 1H-NMR (400 MHz, DMSO-d6): δ 8.20 (d, 1H), 7.91 (d, 1H), 7.75-7.60 (m, 4H), 7.55-7.41 (brs, 2H), 7.20 (d, 1H), 3.79-3.60 (m, 4H), 3.09-2.91 (m, 4H).
    • Example 17 4-(Naphthalen-1-yl)piperazine-1-carboxamide (11)
  • Figure US20190119236A1-20190425-C00210
  • To a stirred solution of 1-(naphthalen-1-yl)piperazine (200 mg, 0.942 mmol) and TEA (0.16 mL, 1.88 mmol) in DCM (8 mL) was added TMSNCO (0.16 mL, 1.22 mmol) and the resulting solution was stirred at room temperature for 2 h. The reaction mixture was monitored by TLC. After completion of the reaction the mixture was concentrated under reduced pressure and the residue was purified by column chromatography on basic alumina with a gradient elution of 2% MeOH in DCM to furnish 4-(naphthalen-1-yl)piperazine-1-carboxamide. LCMS purity: 90.785%, RT=5.712 min, m/z=256.3 (M+H)+ (Method 3). 1H-NMR (400 MHz, DMSO-d6): δ 8.20 (d, 1H), 7.91 (d, 1H), 7.70-7.39 (m, 4H), 7.1 (d, 1H), 6.1 (brs, 2H), 3.80-3.61(m, 4H), 3.11-2.90 (m, 4H).
    • Example 18 4-(4-Methylnaphthalen-1-yl)piperidine (43) a) tert-butyl 4-(4-methylnaphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Figure US20190119236A1-20190425-C00211
  • A mixture of 1-bromo-4-methylnaphthalene (1.0 g, 4.52 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.1 g, 6.78 mmol, 1.5 eq) and Na2CO3 (1.43 g, 13.56 mmol, 3.0 eq) in a mixture of 1,2-DME (15 mL) and water (5 mL) was purged with nitrogen for 15 min. Pd(dppf)Cl2.DCM (0.36 g, 0.45 mmol, 0.1 eq) was added to the reaction mixture and was stirred under nitrogen atmosphere, at 80° C. for 2 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(4-methylnaphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate. LCMS: Purity 82.42%. MS calculated for [M]323.44 and found [M+H]+324.20.
    • b) tert-butyl 4-(4-methylnaphthalen-1-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00212
  • Pd—C (10% w/w, 50% moisture, 0.5 g) was added to the solution of tert-butyl 4-(4-methylnaphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.5 g, 1.54 mmol, 1.0 eq) in MeOH (10 mL) and reaction was allowed to stir at room temperature under hydrogen atmosphere (balloon pressure) for 2 h. Pd—C was filtered off (through celite) and solvent was evaporated from the filtrate under reduced pressure to afford tert-butyl 4-(4-methylnaphthalen-1-yl)piperidine-1-carboxylate. LCMS: Purity 86.18%. MS calculated for [M]325.45 and found [M+H]+326.32.
    • c) -(4-methylnaphthalen-1-yl)piperidine hydrochloride
  • Figure US20190119236A1-20190425-C00213
  • 4M HCl in 1,4-dioxane (2 mL) was added drop-wise to a solution of tert-butyl 4-(4-methylnaphthalen-1-yl)piperidine-1-carboxylate (0.18 g, 0.553 mmol, 1.0 eq) in dichloromethane (4 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. Solvents evaporated under reduced pressure, the residue was triturated with diethyl ether and dried under vacuum to afford 4-(4-methylnaphthalen-1-yl)piperidine hydrochloride. LCMS: Purity 99.39%. RT=4.66 min (Method 1). MS calculated for [M] 225.34 and found [M+H]−226.17. 1H-NMR (400 MHz, DMSO-d6) δ 8.89 (bs, 2H), 8.25-8.23 (m, 1H), 8.06-8.03 (m, 1H), 7.59-7.56 (m, 2H), 7.35 (d, J=7.08 Hz, 1H), 7.25 (d, J=7.32 Hz,1H),3.72-3.66 (m, 1H), 3.40 (d, J=12.6 Hz, 1H), 3.22-3.16 (m, 2H), 2.62 (s, 3H), 1.98-1.90 (m, 4 H).
    • Example 19 4-(Piperidin-4-yl)-1H-benzo[d]imidazole (20)
  • Figure US20190119236A1-20190425-C00214
  • 4-(piperidin-4-yl)-1H-benzo[d]imidazole (20) may be prepared by methods similar to those described in Example 18, using 4-bromo-1H-benzo[d]imidazole as the aryl halide starting material. LCMS RT=4.97 min, m/z=202.34 [M+H]+ (Method 1).
    • Example 20 4-(Piperidin-4-yl)benzo[d]thiazole (21)
  • Figure US20190119236A1-20190425-C00215
  • 4-(Piperidin-4-yl)benzo[d]thiazole (21) may be prepared by methods similar to those described in Example 18, using 4-bromobenzo[d]thiazole as the aryl halide starting material. LCMS RT=3.61 min, m/z=219.30 [M+H]+ (Method 1).
    • Example 21 5-(Piperidin-4-yl)isoquinoline (109)
  • Figure US20190119236A1-20190425-C00216
  • 5-(piperidin-4-yl)isoquinoline (109) may be prepared by methods similar to those described in Example 18, using 5-bromoisoquinoline as the aryl halide starting material. LCMS RT=5.21 min, m/z=213.12 [M+H]+ (Method 1).
    • Example 22 4-(4-Methoxynaphthalen-1-yl)piperidine (44)
  • Figure US20190119236A1-20190425-C00217
  • 4-(4-methoxynaphthalen-1-yl)piperidine (47) may be prepared using similar methods as described in Example 18, except using 1-bromo-4-methoxynaphthalene as the aryl halide starting material. LCMS RT=5.21 min, m/z=213.12 [M+H]+ (Method 1).
    • Example 23 8-(Piperidin-4-yl)isoquinoline (110)
  • Figure US20190119236A1-20190425-C00218
  • 8-(Piperidin-4-yl)isoquinoline (110) may be prepared by methods similar to those described in Example 18, using 8-bromoisoquinoline as the aryl halide starting material. LCMS RT=3.42 min, m/z=213.12 [M+H]+ (Method 1).
    • Example 24 4-(Piperidin-4-yl)isoquinoline (45)
  • Figure US20190119236A1-20190425-C00219
  • 4-(piperidin-4-yl)isoquinoline (45) may be prepared by methods similar to those described in Example 18, using 4-bromoisoquinoline as the aryl halide starting material. LCMS RT=3.33 min, m/z=213.14 [M+H]+ (Method 1).
    • Example 25 1-(Piperidin-4-yl)isoquinoline (46)
  • Figure US20190119236A1-20190425-C00220
  • 1-(piperidin-4-yl)isoquinoline (46) may be prepared by methods similar to those described in Example 18, using 1-bromoisoquinoline as the aryl halide starting material. LCMS RT=3.82 min, m/z=213.12 [M+H]+ (Method 1).
    • Example 26 4-(Piperidin-4-yl)naphthalen-1-ol (47)
  • Figure US20190119236A1-20190425-C00221
  • 4-(piperidin-4-yl)naphthalen-1-ol (47) may be prepared by methods similar to those described in Example 18, using 4-bromonaphthalen-1-ol as the aryl halide starting material. LCMS RT=3.82 min, m/z=228.12 [M+H]+ (Method 1).
    • Example 27 4-(Piperidin-4-yl)quinazoline (48)
  • Figure US20190119236A1-20190425-C00222
  • 4-(piperidin-4-yl)quinazoline (48) may be prepared by methods similar to those described in Example 18, using 4-chloroquinazoline as the aryl halide starting material. LCMS m/z=214.2 [M+H]+ (Method 1).
    • Example 28 4-(4-Fluoronaphthalen-1-yl)piperidine (49)
  • Figure US20190119236A1-20190425-C00223
  • 4-(4-fluoronaphthalen-1-yl)piperidine (49) may be prepared by methods similar to those described in Example 18, using 1-bromo-4-fluoronaphthalene as aryl halide starting material. LCMS RT=4.56 min, m/z=230.28 [M+H]+ (Method 1).
    • Example 29 5-(Piperidin-4-yl)quinoline (111)
  • Figure US20190119236A1-20190425-C00224
  • 5-(piperidin-4-yl)quinoline (111) may be prepared by methods similar to those described in Example 18, using 5-bromoquinoline as the aryl halide starting material. LCMS RT=4.48 min, m/z=213.15 [M+H]+ (Method 2).
    • Example 30 4-(Piperidin-4-yl)quinoline (50)
  • Figure US20190119236A1-20190425-C00225
  • 4-(piperidin-4-yl)quinoline (50) may be prepared by methods similar to those described in Example 18, using 4-bromoquinoline as the aryl halide starting material. LCMS RT=4.28 min, m/z=212.97 [M+H]+ (Method 2).
    • Example 31 8-Fluoro-5-(piperidin-4-yl)quinoline (51)
  • Figure US20190119236A1-20190425-C00226
  • 8-fluoro-5-(piperidin-4-yl)quinoline (51) may be prepared by methods similar to those described in Example 18, using 5-bromo-8-fluoroquinoline as the aryl halide starting material. LCMS RT=4.22 min, m/z=231.12 [M+H]+ (Method 2).
    • Example 32 8-Fluoro-5-(piperidin-4-yl)isoquinoline (52)
  • Figure US20190119236A1-20190425-C00227
  • 8-fluoro-5-(piperidin-4-yl)isoquinoline (52) may be prepared by methods similar to those described in Example 18, using 5-bromo-8-fluoroisoquinoline as the aryl halide starting material. LCMS RT=3.30 min, m/z=231.04 [M+H]+ (Method 1).
    • Example 33 4-(5-Methylnaphthalen-1-yl)piperidine (53) a) (5-bromonaphthalen-1-yl)methanol
  • Figure US20190119236A1-20190425-C00228
  • Borane dimethylsulfide (1.51 g, 19.9 mmol, 2.5 eq) was added to the solution of 5-bromo-1-naphthoic acid (2.0 g, 7.96 mmol, 1.0 eq) in THF (50 mL) under nitrogen atmosphere at 0° C. and the solution was stirred at ambient temperature for 16 h. After complete consumption of starting material, the reaction mixture was quenched with drop-wise addition of MeOH at 0° C., diluted with water and extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to afford (5-bromonaphthalen-1-yl)methanol.
    • b) 1-bromo-5-(bromomethyl)naphthalene
  • Figure US20190119236A1-20190425-C00229
  • Phosphorus tribromide (0.89 g, 3.3 mmol, 1.2 eq) was added to the solution of (5-bromonaphthalen-1-yl) methanol (0.65 g, 2.75 mmol, 1.0 eq) in CHCl3 (20 mL) under nitrogen atmosphere at 0° C. and the solution was stirred at ambient temperature for 2 h. After complete consumption of starting material, the reaction mixture was diluted with dichloromethane and washed with water, saturated aqueous sodium bicarbonate and brine. The organic extract was then dried over anhydrous sodium sulfate, filtered, and solvent evaporated from the filtrate under reduced pressure to afford 1-bromo-5-(bromomethyl)naphthalene.
    • c) 1-bromo-5-methylnaphthalene
  • Figure US20190119236A1-20190425-C00230
  • Sodium borohydride (0.56 g, 14.8 mmol, 8.0 eq) was added to the solution of 1-bromo-5-(bromomethyl)naphthalene (0.55 g, 1.85 mmol, 1.0 eq) in DMSO (5 mL) under nitrogen atmosphere at 0° C. and the solution was stirred at ambient temperature for 2 h. After complete consumption of starting material, the reaction mixture was poured into chilled water. The precipitate was filtered and dried under vacuum to afford 1-bromo-5-methylnaphthalene.
    • d) tert-butyl 4-(5-methylnaphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Figure US20190119236A1-20190425-C00231
  • A mixture of 1-bromo-5-methylnaphthalene (0.28 g, 1.24 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.422 g, 1.36 mmol, 1.1 eq) and Na2CO3 (0.395 g, 3.73 mmol, 3.0 eq) in a mixture of 1,2-DME (8 mL) and water (2 mL) was purged with nitrogen for 15 min. Pd(dppf)Cl2.DCM (0.101 g, 0.124 mmol, 0.1 eq) was added to the reaction mixture and was stirred under nitrogen atmosphere, at 80° C. for 2 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(5-methylnaphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate.
    • e) tert-butyl 4-(5-methylnaphthalen-1-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00232
  • Pd—C (10% w/w, 50% moisture, 0.08 g) was added to the solution of tert-butyl 4-(5-methylnaphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.28 g, 0.866 mmol, 1.0 eq) in MeOH (5 mL) and reaction was allowed to stir at room temperature under hydrogen atmosphere (balloon pressure) for 1 h. Pd—C was filtered off (through celite) and solvent was evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(5-methylnaphthalen-1-yl)piperidine-1-carboxylate. LCMS: Purity 97.77%. MS calculated for [M] 325.45 and found [M+H]+326.42.
    • f) 4-(5-methylnaphthalen-1-yl)piperidine hydrochloride
  • Figure US20190119236A1-20190425-C00233
  • 4M HCl in 1,4-dioxane (1 mL) was added dropwise to a solution of tert-butyl 4-(5-methylnaphthalen-1-yl)piperidine-1-carboxylate (0.12 g, 0.36 mmol, 1.0 eq) in dichloromethane (2 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. Solvents evaporated under reduced pressure, the residue was triturated with diethyl ether and dried under vacuum to afford 4-(5-methylnaphthalen-1-yl)piperidine hydrochloride. LCMS: Purity 99.25%. RT=5.02 min (Method 1). MS calculated for [M] 225.34 and found [M+H]+226.09. 1H-NMR (400 MHz, DMSO-d6) δ 8.88 (bs, 2H), 8.10 (d, J=8.56 Hz,1H), 7.93 (d, J=8.36 Hz,1H), 7.54 (t, J=7.48 Hz,1H), 7.46 (t, J=7.04 Hz,1H), 7.39 (d, J=6.88 Hz, 2H), 3.76-3.70 (m,1H), 3.42-3.39 (m, 2H), 3.22-3.16 (m, 2H), 2.65 (s, 3H), 2.00-1.92 (m, 4 H).
    • Example 34 (5-(Piperidin-4-yl)naphthalen-1-yl)methanol (54) a) methyl 5-bromo-1-naphthoate
  • Figure US20190119236A1-20190425-C00234
  • Sulfuric acid (0.3 mL) was added to the solution of 5-bromo-1-naphthoic acid (1.5 g, 5.97 mmol, 1.0 eq) in MeOH (50 mL) at room temperature and the solution was stirred under nitrogen atmosphere, at 80° C. for 16 h. After complete consumption of starting material, the reaction mixture was evaporated under reduced pressure, dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to afford methyl 5-bromo-1-naphthoate. LCMS: Purity 93.15%. MS calculated for [M] 263.98 and found [M+H]+265.05.
    • b) tert-butyl 4-(5-(methoxycarbonyl)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Figure US20190119236A1-20190425-C00235
  • A mixture of methyl 5-bromo-1-naphthoate (1.3 g, 4.92 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.67 g, 5.41 mmol, 1.1 eq) and Na2CO3 (1.56 g, 14.77 mmol, 3.0 eq) in a mixture of 1,2-DME (16 mL) and water (4 mL) was purged with nitrogen for 15 min. Pd(dppf)Cl2.DCM (0.4 g, 0.49 mmol, 0.1 eq) was added to the reaction mixture and was stirred under nitrogen atmosphere, at 80° C. for 2 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(5-(methoxycarbonyl)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate. LCMS: Purity 99.35%. MS calculated for [M] 367.45 and found [M+H]+368.26.
    • c) tert-butyl 4-(5-(methoxycarbonyl)naphthalen-1-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00236
  • Pd—C (10% w/w, 50% moisture, 0.8 g) was added to the solution of tert-butyl 4-(5-(methoxycarbonyl)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.3 g, 3.54 mmol, 1.0 eq) in MeOH (50 mL) and reaction was allowed to stir at room temperature under hydrogen atmosphere (balloon pressure) for 4 h. Pd—C was filtered off (through celite) and solvent was evaporated from the filtrate under reduced pressure to obtain tert-butyl 4-(5-(methoxycarbonyl)naphthalen-1-yl)piperidine-1-carboxylate. LCMS: Purity 97.77%.
    • d) tert-butyl 4-(5-(hydroxymethyl)naphthalen-1-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00237
  • Lithium borohydride (0.89 g, 4.12 mmol, 5.0 eq) was added to the solution of tert-butyl 4-(5-(methoxycarbonyl)naphthalen-1-yl)piperidine-1-carboxylate (0.3 g, 0.82 mmol, 1.0 eq) in THF (10 mL) under nitrogen atmosphere at 0° C. and the reaction mixture was stirred under nitrogen atmosphere, at 60° C. for 4 h. After complete consumption of starting material, saturated aqueous ammonium chloride was added drop-wise at 0° C., the mixture was diluted with water and extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to afford tert-butyl 4-(5-(hydroxymethyl)naphthalen-1-yl)piperidine-1-carboxylate. LCMS: Purity 99.54%. MS calculated for [M] 341.20 and found [M+H]+342.17.
    • e) (5-(piperidin-4-yl)naphthalen-1-yl)methanol hydrochloride
  • Figure US20190119236A1-20190425-C00238
  • 4M HCl in 1,4-dioxane (2 mL) was added dropwise to a solution of tert-butyl 4-(5-(hydroxymethyl)naphthalen-1-yl)piperidine-1-carboxylate (0.1 g, 0.29 mmol, 1.0 eq) in dichloromethane (2 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h. Solvents evaporated under reduced pressure, the residue was triturated with diethyl ether and dried under vacuum to afford (5-(piperidin-4-yl)naphthalen-1-yl)methanol hydrochloride. LCMS: Purity 97.08%. RT=3.94 min (Method 1). MS calculated for [M] 241.33 and found [M+H]+242.13. 1H-NMR (400 MHz, DMSO-d6) δ 8.90 (bs, 1H), 8.75 (bs, 1H), 8.16 (d, J=8.2 Hz,1H), 7.98 (d, J=8.48 Hz,1H), 7.59-7.51 (m, 3H), 7.38 (d, J=7.12 Hz,1H), 5.32 (bs,1H), 4.96 (s, 2H),), 3.77-3.71 (m,1H), 3.42-3.39 (m, 2H), 3.24-3.16 (m, 2H), 2.03-1.91 (m, 4 H).
    • Example 35 4-(6-Methylnaphthalen-1-yl)piperidine (55) a) (5-bromonaphthalen-2-yl)methanol
  • Figure US20190119236A1-20190425-C00239
  • Borane dimethylsulfide (1.51 g, 19.9 mmol, 2.5 eq) was added to the solution of 5-bromo-2-naphthoic acid (2.0 g, 7.96 mmol, 1.0 eq) in THF (20 mL) under nitrogen atmosphere at 0° C. and the solution was stirred at ambient temperature for 16 h. After complete consumption of starting material, the reaction mixture was quenched by drop-wise addition of MeOH at 0° C., diluted with water and extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to afford (5-bromonaphthalen-2-yl)methanol.
    • b) 1-bromo-6-(bromomethyl)naphthalene
  • Figure US20190119236A1-20190425-C00240
  • Phosphorus tribromide (2.4 g, 8.89 mmol, 1.2 eq) was added to the solution of (5-bromonaphthalen-2-yl)methanol (1.75 g, 7.4 mmol, 1.0 eq) in CHCl3 (20 mL) under nitrogen atmosphere at 0° C. and the solution was stirred at ambient temperature for 2 h. After complete consumption of starting material, the reaction mixture was diluted with dichloromethane and washed with water followed by saturated aqueous sodium bicarbonate and brine. The organic extract was then dried over anhydrous sodium sulfate, filtered, and solvent evaporated from the filtrated under reduced pressure to afford 1-bromo-6-(bromomethyl)naphthalene. MS calculated for [M] 299.99.
    • c) 1-bromo-6-methylnaphthalene
  • Figure US20190119236A1-20190425-C00241
  • Sodium borohydride (1.2 g, 31.8 mmol, 8.0 eq) was added to the solution of 1-bromo-6-(bromomethyl)naphthalene (1.89 g, 6.36 mmol, 1.0 eq) in DMSO (15 mL) under nitrogen atmosphere at 0° C. and the solution was stirred at ambient temperature for 2 h. After complete consumption of starting material, the reaction mixture was partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to afford 1-bromo-6-methylnaphthalene.
    • d) tert-butyl 4-(6-methylnaphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Figure US20190119236A1-20190425-C00242
  • A mixture of 1-bromo-6-methylnaphthalene (0.9 g, 4.09 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.39 g, 4.49 mmol, 1.1 eq) and Na2CO3 (1.3 g, 12.27 mmol, 3.0 eq) in a mixture of 1,2-DME (16 mL) and water (4 mL) was purged with nitrogen for 15 min. Pd(dppf)Cl2.DCM (0.33 g, 0.409 mmol, 0.1 eq) was added to the reaction mixture and was stirred under nitrogen atmosphere, at 80° C. for 2 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(6-methylnaphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate. LCMS: Purity 91.97%. MS calculated for [M]323.44 and found [M+H]+324.28.
    • e) tert-butyl 4-(6-methylnaphthalen-1-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00243
  • Pd—C (10% w/w, 50% moisture, 0.9 g) was added to the solution of tert-butyl 4-(6-methylnaphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.81 g, 2.5 mmol, 1.0 eq) in MeOH (100 mL) and reaction was allowed to stir at room temperature under hydrogen atmosphere (balloon pressure) for 24 h. Pd—C was filtered off (through celite) and solvent was evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(6-methylnaphthalen-1-yl)piperidine-1-carboxylate. LCMS: Purity 99.81%. MS calculated for [M] 325.45 and found [M−56]+270.25.
    • f) 4-(6-methylnaphthalen-1-yl)piperidine hydrochloride
  • Figure US20190119236A1-20190425-C00244
  • 4M HCl in 1,4-dioxane (2 mL) was added dropwise to a solution of tert-butyl 4-(6-methylnaphthalen-1-yl)piperidine-1-carboxylate (0.08 g, 0.24 mmol, 1.0 eq) in dichloromethane (2 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h. Solvents evaporated under reduced pressure, the residue was triturated with diethyl ether and dried under vacuum to afford 4-(6-methylnaphthalen-1-yl)piperidine hydrochloride. LCMS: Purity 99.43%. RT=5.05 min (Method 1) MS calculated for [M] 225.34 and found [M+H]+226.14. 1H-NMR (400 MHz, DMSO-d6) δ 8.98 (bs, 1H), 8.84 (bs, 1H), 8.13 (d, J=8.76 Hz,1H), 7.72-7.20 (m, 2H), 7.47-7.40 (m, 2H), 7.29 (d, J=7.04 Hz,1H), 3.71-3.66 (m,1H), 3.41-3.38 (m, 2H), 3.20-3.18 (m, 2H), 1.98-1.91 (m, 4H).
    • Example 36 4-(Piperidin-4-yl)naphthalen-1-amine (56) a) di-boc protected 4-bromonaphthalen-1-amine
  • Figure US20190119236A1-20190425-C00245
  • Boc anhydride(1.5 g, 6.75 mmol, 1.0 eq) was added to the solution of 4-bromonaphthalen-1-amine (1.0 g, 4.5 mmol, 1.1 eq), Et3N (0.68 g, 6.75 mmol, 1.5 eq), DMAP (0.1 g) in dichloromethane (20 mL) under nitrogen atmosphere at 0° C. and the solution was stirred at ambient temperature for 12 h. After complete consumption of starting material, the reaction mixture was diluted with dichloromethane and washed with water followed by brine. The organic extract was then dried over anhydrous sodium sulfate, filtered, and solvent evaporated from the filtrated under reduced pressure to afford diboc protected 4-bromonaphthalen-1-amine. LCMS: Purity 48.07%.
    • b) diboc protected tert-butyl 4-(4-aminonaphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Figure US20190119236A1-20190425-C00246
  • A mixture of diboc protected 4-bromonaphthalen-1-amine (0.5 g, 1.18 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.4 g, 1.3 mmol, 1.1 eq) and Na2CO3 (0.376 g, 3.55 mmol, 3.0 eq) in a mixture of 1,2-DME (15 mL) and water (5 mL) was purged with nitrogen for 15 min. Pd(dppf)Cl2.DCM (0.96 g, 0.118 mmol, 0.1 eq) was added to the reaction mixture and was stirred under nitrogen atmosphere, at 80° C. for 2 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain diboc protected tert-butyl 4-(4-aminonaphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate. LCMS: Purity 72.43%. MS calculated for [M] 524.66 and found [M+H]+525.38.
    • c) diboc protected tert-butyl 4-(4-aminonaphthalen-1-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00247
  • Pd—C (10% w/w, 50% moisture, 0.3 g) was added to the solution of diboc protected tert-butyl 4-(4-aminonaphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.3 g, 0.572 mmol, 1.0 eq) in MeOH (10 mL) and reaction was allowed to stir at room temperature under hydrogen atmosphere (balloon pressure) for 2 h. Pd—C was filtered off (through celite) and solvent was evaporated from the filtrate under reduced pressure to afford diboc protected tert-butyl 4-(4-aminonaphthalen-1-yl)piperidine-1-carboxylate. LCMS: Purity 88.43%. MS calculated for [M] 526.56 and found [M−200]+326.29.
    • d) 4-(piperidin-4-yl)naphthalen-1-amine dihydrochloride
  • Figure US20190119236A1-20190425-C00248
  • 4M HCl in 1,4-dioxane (2 mL) was added dropwise to a solution of diboc protected tert-butyl 4-(4-aminonaphthalen-1-yl)piperidine-1-carboxylate (0.2 g, 0.38 mmol, 1.0 eq) in dichloromethane (4 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 1 h. Solvents evaporated under reduced pressure, the residue was triturated with diethyl ether and dried under vacuum to afford 4-(piperidin-4-yl)naphthalen-1-amine dihydrochloride. LCMS: Purity 98.72%. RT=5.17 min (Method 2). MS calculated for [M] 226.32 and found [M+H]+227.15. 1H-NMR (400 MHz, DMSO-d6) δ 9.02 (bs, 1H), 8.91-8.89 (m, 2H), 8.30-8.28 (m,1H), 8.10-8.08 (m,1H), 7.66-7.64 (m, 2H),7.44 (m,1H), 7.35 (d, J=7.68 Hz, 1H), 3.77-3.67 (bs,1H), 3.40 (d, J=12 Hz, 2H), 3.20-3.17 (m, 2H), 1.97-1.91(m, 4 H).
    • Example 37 8-(Piperidin-4-yl)quinoline (57) a) tert-butyl 4-(quinolin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Figure US20190119236A1-20190425-C00249
  • A mixture of 8-bromoquinoline (0.5 g, 2.4 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.96 g, 3.12 mmol, 1.3 eq) and Na2CO3 (0.76 g, 7.2 mmol, 3.0 eq) in a mixture of 1,2-DME (5 mL) and water (2 mL) was purged with nitrogen for 20 min. Pd(dppf)Cl2.DCM (0.19 g, 0.24 mmol, 0.1 eq) was added to the reaction mixture and nitrogen was bubbled into it for an additional 5 min. The reaction mixture was stirred under nitrogen atmosphere, at 80° C. for 2 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(quinolin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate. LCMS: Purity 91.94%. MS calculated for [M] 310.40 and found [M+H]+311.21.
    • b) tert-butyl 4-(1,2,3,4-tetrahydroquinolin-8-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00250
  • Pd—C (10% w/w, 50% moisture, 0.5 g) was added to the solution of tert-butyl 4-(quinolin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.5 g, 1.61 mmol, 1.0 eq) in MeOH (5 mL) and reaction was allowed to stir at room temperature under hydrogen atmosphere (balloon pressure) for 2 h. Pd—C was filtered off (through celite) and solvent was evaporated from the filtrate under reduced pressure to afford tert-butyl 4-(1,2,3,4-tetrahydroquinolin-8-yl)piperidine-1-carboxylate. LCMS: Purity 80.48%. MS calculated for [M] 316.45 and found [M+H]+317.30.
    • c) tert-butyl 4-(quinolin-8-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00251
  • Pd—C (10% w/w, 50% moisture, 0.2 g) was added to the solution of tert-butyl 4-(1,2,3,4-tetrahydroquinolin-8-yl)piperidine-1-carboxylate (0.2 g, 0.63 mmol, 1.0 eq) in MeOH (10 mL) and reaction was allowed to stir at room temperature under oxygen atmosphere (balloon pressure) for 16 h. Pd—C was filtered off (through celite) and solvent was evaporated from the filtrate under reduced pressure to afford tert-butyl 4-(quinolin-8-yl)piperidine-1-carboxylate. MS calculated for [M] 312.41 and found [M+H]+313.27.
    • d) 8-(piperidin-4-yl)quinoline dihydrochloride
  • Figure US20190119236A1-20190425-C00252
  • 2M HCl in diethyl ether (2 mL) was added dropwise to a solution of tert-butyl 4-(quinolin-8-yl)piperidine-1-carboxylate (0.1 g, 0.32 mmol, 1.0 eq) in dichloromethane (3 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 4 h. Solvents evaporated under reduced pressure, the residue was triturated with pentane and dried under vacuum to afford 8-(piperidin-4-yl)quinoline dihydrochloride. LCMS: Purity 98.92%. RT=3.74 min (Method 1). MS calculated for [M] 212.30 and found [M+H]+213.12. 1H-NMR (400 MHz, DMSO-d6) δ 9.08-8.98 (m, 3H), 8.59 (d, J=7.28 Hz, 1H),7.99-7.96 (m, 1H), 7.72-7.69 (m, 3H), 4.35-4.15 (m, 1H), 3.43-3.40 (m, 2H),3.20-3.14 (m, 2H), 2.05-1.99 (m, 4 H).
    • Example 38 5-Fluoro-8-(piperidin-4-yl)quinoline (58) a) tert-butyl 4-(5-fluoroquinolin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Figure US20190119236A1-20190425-C00253
  • A mixture of 8-bromo-5-fluoroquinoline (0.7 g, 3.09 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.4 g, 4.64 mmol, 1.5 eq) and Na2CO3 (0.98 g, 9.29 mmol, 3.0 eq) in a mixture of 1,2-DME (7 mL) and water (3 mL) was purged with nitrogen for 15 min. Pd(dppf)Cl2.DCM (0.25 g, 0.309 mmol, 0.1 eq) was added to the reaction mixture and was stirred under nitrogen atmosphere, at 85° C. for 4 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(5-fluoroquinolin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate. LCMS: Purity 96.19%. MS calculated for [M] 328.39 and found [M+H]+329.26.
    • b) tert-butyl 4-(5-fluoro-1,2,3,4-tetrahydroquinolin-8-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00254
  • Pd—C (10% w/w, 50% moisture, 0.5 g) was added to the solution of tert-butyl 4-(5-fluoroquinolin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.85 g, 2.59 mmol, 1.0 eq) in mixture of EtOH (1 mL) and THF (3 mL).The reaction was allowed to stir at room temperature under hydrogen atmosphere (balloon pressure) for 12 h. Pd—C was filtered off (through celite) and solvent was evaporated from the filtrate under reduced pressure to afford tert-butyl 4-(5-fluoro-1,2,3,4-tetrahydroquinolin-8-yl)piperidine-1-carboxylate. LCMS: Purity 78.70%. MS calculated for [M] 334.44 and found [M+H]+335.25.
    • c) tert-butyl 4-(5-fluoroquinolin-8-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00255
  • DDQ (1.63 g, 7.18 mmol, 3.0 eq) was added to the solution of tert-butyl 4-(5-fluoro-1,2,3,4-tetrahydroquinolin-8-yl)piperidine-1-carboxylate (0.8 g, 2.39 mmol, 1.0 eq) in toluene (10 mL). The reaction mixture was heated at 110° C. for 12 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(5-fluoroquinolin-8-yl) piperidine-1-carboxylate. LCMS: Purity 99.09%. MS calculated for [M]330.40 and found [M+H]+331.16.
    • d) 5-fluoro-8-(piperidin-4-yl)quinoline hydrochloride
  • Figure US20190119236A1-20190425-C00256
  • 4M HCl in 1,4-dioxane (2.5 mL) was added dropwise to a solution of tert-butyl 4-(5-fluoroquinolin-8-yl)piperidine-1-carboxylate (0.05 g, 0.156 mmol, 1.0 eq) in dichloromethane (5 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. Solvents evaporated under reduced pressure, the residue was triturated with diethyl ether followed by pentane and dried under vacuum to afford 5-fluoro-8-(piperidin-4-yl)quinoline hydrochloride. LCMS: Purity 97.11%. RT=3.91 (Method 1). MS calculated for [M] 230.29 and found [M+H]+231.12. 1H-NMR (400 MHz, DMSO-d6) δ 9.04-9.03 (m, 3H), 8.52 (d, J=8.36 Hz, 1H),7.71-7.67 (m, 1H), 7.59 (t, J=8.0 Hz, 1H), 7.46 (t, J=9.72 Hz, 1H), 4.15-4.09 (m, 1H), 3.41-3.38(m, 2H), 3.18-3.08 (m, 2H), 2.03-2.01 (m, 4 H).
    • Example 39 4-(4-Chloronaphthalen-1-yl)piperidine (59) a) tert-butyl 4-(2-tosylhydrazono)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00257
  • To a solution of tosylhydrazine (0.93 g, 5.01 mmol, 1.0 eq) in MeOH (5 mL), a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.0 g, 5.01 mmol, 1.0 eq) in MeOH (5 mL) was added drop-wise under nitrogen atmosphere and the solution was stirred at ambient temperature for 3 h. After complete consumption of starting material, the reaction mixture was evaporated under reduced pressure to afford tert-butyl 4-(2-tosylhydrazono)piperidine-1-carboxylate. LCMS: Purity 96.84%. MS calculated for [M]367.46 and found [M+H]+368.30.
    • b) 4-chloronaphthalen-1-yl trifluoromethanesulfonate
  • Figure US20190119236A1-20190425-C00258
  • Triflic anhydride (6.63 g, 23.59 mmol, 1.4 eq) was added dropwise to the solution of 4-chloronaphthalen-1-ol (3.0 g, 16.85 mmol, 1.0 eq) and Et3N (6.8 g, 64.41 mmol, 4.0 eq) in dichloromethane (30 mL) under nitrogen atmosphere at 0° C. and the solution was stirred at ambient temperature for 2 h. After complete consumption of starting material, the reaction mixture was diluted with dichloromethane and washed with water and brine. The organic extract was then dried over anhydrous sodium sulfate, filtered, and solvent evaporated under reduced pressure to afford 4-chloronaphthalen-1-yl trifluoromethanesulfonate. LCMS: Purity 80.81%.
    • c) 2-(4-chloronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
  • Figure US20190119236A1-20190425-C00259
  • A mixture of 4-chloronaphthalen-1-yl trifluoromethanesulfonate (3.3 g, 10.61 mmol, 1.0 eq), bis(pinacolato)diboron (5.3 g, 21.29 mmol, 2.0 eq) and KOAc (1.45 g, 14.86 mmol, 1.4 eq) in 1,4-dioxane (30 mL) was purged with nitrogen for 15 min. Pd(dppf)Cl2.DCM (0.86 g, 1.06 mmol, 0.1 eq) was added to the reaction mixture and was stirred under nitrogen atmosphere, at 100° C. for 12 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain 2-(4-chloronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMS: Purity 98.76%. MS calculated for [M]288.11 and found [M+H]+288.99.
    • d) tert-butyl 4-(4-chloronaphthalen-1-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00260
  • Cesium carbonate (1.69 g, 5.2 mmol, 1.5 eq) was added to a mixture of 2-(4-chloronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.0 g, 3.47 mmol, 1.0 eq) and tert-butyl 4-(2-tosylhydrazono)piperidine-1-carboxylate (1.5 g, 4.16 mmol, 1.2 eq) in 1,4-dioxane (10 mL). The reaction mixture was heated at 110° C. for 12 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain tert-butyl 4-(4-chloronaphthalen-1-yl)piperidine-1-carboxylate. LCMS: Purity 97.73%. MS calculated for [M]345.87 and found [M+H]+346.17.
    • e) 4-(4-chloronaphthalen-1-yl)piperidine hydrochloride
  • Figure US20190119236A1-20190425-C00261
  • 4M HCl in 1,4-dioxane (4 mL) was added dropwise to a solution of tert-butyl 4-(4-chloronaphthalen-1-yl)piperidine-1-carboxylate (0.25 g, 0.724 mmol, 1.0 eq) in dichloromethane (5 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. Solvents evaporated under reduced pressure, the residue was triturated with diethyl ether and pentane, dried under vacuum to afford 4-(4-chloronaphthalen-1-yl)piperidine hydrochloride. LCMS: Purity 98.99%. RT=4.98 min (Method 1). MS calculated for [M]245.75 and found [M+H]+246.08. 1H-NMR (400 MHz, DMSO-d6) δ 8.92 (bs, 2H), 8.35 (d, J=8.64 Hz, 1H), 8.25 (d, J=9.16 Hz, 1H), 7.74-7.69 (m, 3H), 7.36 (d, J=7.8 Hz, 1H), 3.77-3.72 (m, 1H), 3.42-3.39 (m, 2H), 3.22-3.16 (m, 2H), 2.00-1.91 (m, 4 H).
    • Example 40 4-(4-Cyclohexylnaphthalen-1-yl)piperidine (60) a) 4-(cyclohex-1-en-1-yl) naphthalen-1-ol
  • Figure US20190119236A1-20190425-C00262
  • A mixture of 4-bromonaphthalen-1-ol (2.0 g, 8.96 mmol, 1.0 eq), cyclohex-1-en-1-ylboronic acid (2.42 g, 11.65 mmol, 1.3 eq) and Na2CO3 (2.85 g, 26.9 mmol, 3.0 eq) in a mixture of 1,2-DME (36 mL) and water (4 mL) was purged with nitrogen for 15 min. Pd(dppf)Cl2.DCM (2.92 g, 3.58 mmol, 0.4 eq) was added to the reaction mixture and was stirred under nitrogen atmosphere, at 100° C. for 16 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain 4-(cyclohex-1-en-1-yl)naphthalen-1-ol. LCMS: Purity 92.23%. MS calculated for [M] 224.30 and found [M−H]+223.09.
    • b) 4-(cyclohex-1-en-1-yl)naphthalen-1-yl trifluoromethanesulfonate
  • Figure US20190119236A1-20190425-C00263
  • Triflic anhydride (1.76 g, 6.25 mmol, 2.0 eq) was added dropwise to the solution of 4-(cyclohex-1-en-1-yl)naphthalen-1-ol (0.7 g, 3.12 mmol, 1.0 eq) in pyridine (5 mL) at 0° C. The reaction mixture was stirred under nitrogen atmosphere, at room temperature for 2 h. After complete consumption of starting material, 1N HCl was added to the reaction mixture, diluted with water and extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to afford 4-(cyclohex-1-en-1-yl)naphthalen-1-yl trifluoromethanesulfonate. LCMS: Purity 88.36%. MS calculated for [M] 356.36 and found [M+H]+357.07.
    • c) tert-butyl 4-(4-(cyclohex-1-en-1-yl)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Figure US20190119236A1-20190425-C00264
  • A mixture of 4-(cyclohex-1-en-1-yl)naphthalen-1-yl trifluoromethanesulfonate (0.61 g, 1.7 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.63 g, 2.05 mmol, 1.2 eq) and Na2CO3 (0.54 g, 5.12 mmol, 3.0 eq) in a mixture of 1,2-DME (16 mL) and water (4 mL) was purged with nitrogen for 15 min. Pd(dppf)Cl2.DCM (0.278 g, 0.34 mmol, 0.2 eq) was added to the reaction mixture and was stirred under nitrogen atmosphere, at 80° C. for 2 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(4-(cyclohex-1-en-1-yl)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate. LCMS: Purity 91.18%. MS calculated for [M] 389.54 and found [M+H]+390.23.
    • d) tert-butyl 4-(4-cyclohexylnaphthalen-1-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00265
  • Pd—C (10% w/w, 50% moisture, 0.6 g) was added to the solution of tert-butyl 4-(4-(cyclohex-1-en-1-yl)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.6 g, 1.54 mmol, 1.0 eq) in MeOH (50 mL) and reaction was allowed to stir at room temperature under hydrogen atmosphere (balloon pressure) for 4 h. Pd—C was filtered off (through celite) and solvent was evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(4-cyclohexylnaphthalen-1-yl)piperidine-1-carboxylate. LCMS: Purity 98.99%. MS calculated for [M] 393.57 and found [M−56]+338.24.
    • e) 4-(4-cyclohexylnaphthalen-1-yl)piperidine hydrochloride
  • Figure US20190119236A1-20190425-C00266
  • 4M HCl in 1,4-dioxane (2 mL) was added drop-wise to a solution of tert-butyl 4-(4-cyclohexylnaphthalen-1-yl)piperidine-1-carboxylate (0.15 g, 0.38 mmol, 1.0 eq) in dichloromethane (2 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 4 h. Solvents evaporated under reduced pressure, the residue was triturated with diethyl ether and dried under vacuum to afford 4-(4-cyclohexylnaphthalen-1-yl)piperidine hydrochloride. LCMS: Purity 98.38%. RT=6.17 min (Method 1). MS calculated for [M] 293.45 and found [M+H]+294.21. 1H-NMR (400 MHz, DMSO-d6) δ 8.77 (bs, 2H), 8.26-8.23 (m,1H), 8.20-8.18 (m,1H), 7.58-7.55 (m, 2H), 7.40 (d, J=7.6 Hz,1H), 7.32 (d, J=7.6 Hz,1H), 3.68-3.66 (m,1H), 3.42-4.39 (m,1H), 3.22-3.16 (m, 1H), 2.02-1.77 (m, 10 H), 1.61-1.28 (m, 5 H).
    • Example 41 4-(Piperazin-1-yl)-1H-benzo[d]imidazole (40) a) 4-bromo-1-trityl-1H-benzo[d]imidazole
  • Figure US20190119236A1-20190425-C00267
  • To a stirred solution of 4-bromo-1H-benzo[d]imidazole (150 mg, 0.761 mmol) in THF (5 mL) was added NaH (36 mg, 0.91 mmol) at 0° C. and the resulting mixture was stirred at rt for 30 min. Trityl chloride (275 mg, 0.98 mmol) and a catalytic amount of TBAI were added and the resulting reaction mixture was heated to reflux for 5 h. The reaction mixture was cooled and quenched with ice water and subsequently extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to obtain 4-bromo-1-trityl-1H-benzo[d]imidazole. LCMS Purity: 92.612%, m/z=441.2 [M+H]+.
    • b) 4-(piperazin-1-yl)-1-trityl-1H-benzo[d]imidazole
  • Figure US20190119236A1-20190425-C00268
  • To a stirred solution of 4-bromo-1-trityl-1H-benzo[d]imidazole (200 mg, 0.4552 mmol) in toluene (5 mL) was added piperazine (195 mg, 2.27 mmol), Pd2(dba)3 (41 mg, 0.04 mmol), BINAP (56 mg, 0.09 mmol), and NaOtBu (131 mg, 1.365 mmol). The resulting reaction mixture was degassed and heated to 110° C. for 12 h. After completion, the reaction was cooled to room temperature and filtered through a celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by basic alumina column chromatography using 10% methanol in DCM to furnish 4-(piperazin-1-yl)-1-trityl-1H-benzo[d]imidazole. LCMS Purity: 91.821%, m/z=445.4(M+H)+.
    • c) 4-(piperazin-1-yl)-1H-benzo[d]imidazole
  • Figure US20190119236A1-20190425-C00269
  • To a stirred solution of compound 4-(piperazin-1-yl)-1-trityl-1H-benzo[d]imidazole (40 mg) in THF (0.5 mL) were added AcOH (0.5 mL) and water (0.5 mL) at room temperature and the reaction mixture was heated to 60° C. for 4 h. The reaction was concentrated under reduced pressure and then basified with sat. aq. Na2CO3 and extracted with DCM (2×5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative HPLC to give 4-(piperazin-1-yl)-1H-benzo[d]imidazole. LCMS Purity: 91.821%, RT=1.126, m/z=203.3 [M+H]+ (Method 3). 1H-NMR (400 MHz, DMSO-d6): δ 9.15 (1H, s), 9.01 (2H, s), 7.42-7.37 (2H, m), 6.97 (1H, d), 3.55-3.21 (8H, m).
    • Example 42 4-(Piperazin-1-yl)benzo[d]thiazole (41)
  • Figure US20190119236A1-20190425-C00270
  • 4-(piperazin-1-yl)benzo[d]thiazole (41) may be prepared by methods similar to those described in Example 41, using 4-bromobenzo[d]thiazole as the aryl halide starting material. LCMS RT=3.508 min, m/z=220.2 [M+H]+ (Method 3).
    • Example 43 7-(Piperazin-1-yl)benzo[d]thiazole (42)
  • Figure US20190119236A1-20190425-C00271
  • 7-(piperazin-1-yl)benzo[d]thiazole (42) may be prepared methods similar to those described in Example 41, using 7-bromobenzo[d]thiazole as the aryl halide starting material. LCMS RT=3.072 min, m/z=220.2 [M+H]+ (Method 3).
    • Example 44 4-(Piperidin-4-yl)-N-(5,6,7,8-tetrahydronaphthalen-2-yl)naphthalene-1-sulfonamide (61) a) 4-bromonaphthalene-1-sulfonyl chloride
  • Figure US20190119236A1-20190425-C00272
  • Thionyl chloride (1.56 g, 13.11 mmol, 1.5 eq) was added dropwise to the solution of 4-bromonaphthalene-1-sulfonic acid (2.5 g, 8.74 mmol, 1.0 eq) in a mixture of toluene (20 mL) and DMF (2 mL) under nitrogen atmosphere, at room temperature and the solution was at heated at 110° C. for 4 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and evaporated under reduced pressure to afford 4-bromonaphthalene-1-sulfonyl chloride, which was used in the next step without purification.
    • b) 4-bromo-N-(5,6,7,8-tetrahydronaphthalen-2-yl)naphthalene-1-sulfonamide
  • Figure US20190119236A1-20190425-C00273
  • A solution of 5,6,7,8-tetrahydronaphthalen-2-amine (1.24 g, 4.07 mmol, 1.2 eq) in dichloromethane (5 mL) was added drop-wise to solution of 4-bromonaphthalene-1-sulfonyl chloride (0.5 g, 3.39 mmol, 1.0 eq) and DIPEA (1.31 g, 10.2 mmol, 3.0 eq) in dichloromethane (15 mL) under nitrogen atmosphere at 0° C. and the solution was stirred at ambient temperature for 2 h. After complete consumption of starting material, the reaction mixture was diluted with dichloromethane and washed with water and brine. The organic extract was then dried over anhydrous sodium sulfate, filtered, and solvent evaporated from the filtrated under reduced pressure to afford 4-bromo-N-(5,6,7,8-tetrahydronaphthalen-2-yl)naphthalene-1-sulfonamide. LCMS: Purity 92.04%. MS calculated for [M] 415.02 and found [M−H]+414.13.
    • c) tert-butyl 4-(4-(N-(5,6,7,8-tetrahydronaphthalen-2-yl)sulfamoyl)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Figure US20190119236A1-20190425-C00274
  • A mixture of 4-bromo-N-(5,6,7,8-tetrahydronaphthalen-2-yl)naphthalene-1-sulfonamide (0.2 g, 0.48 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.222 g, 0.72 mmol, 1.5 eq) and Na2CO3 (0.152 g, 1.44 mmol, 3.0 eq) in a mixture of 1,4-Dioxane (3.2 mL) and H2O (0.8 mL) was purged with nitrogen for 15 min. Pd(dppf)Cl2.DCM (0.039 g, 0.048 mmol, 0.1 eq) was added to the reaction mixture and was stirred under nitrogen atmosphere, at 90° C. for 1 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(4-((tetrahydro-2H-pyran-4-yl)amino)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate. LCMS: Purity 95.72%. MS calculated for [M] 518.67 and found [M−H]+517.36.
    • d) tert-butyl 4-(4-(N-(5,6,7,8-tetrahydronaphthalen-2-yl)sulfamoyl)naphthalen-1-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00275
  • Pd—C (10% w/w, 50% moisture, 0.1 g) was added to the solution of tert-butyl 4-(4-(N-(5,6,7,8-tetrahydronaphthalen-2-yl)sulfamoyl)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.2 g, 0.386 mmol, 1.0 eq) in a mixture of EtOH (5 mL) and THF (10 mL). The reaction was allowed to stir at room temperature under hydrogen atmosphere (balloon pressure) for 16 h. Pd—C was filtered off (through celite) and solvent was evaporated from the filtrate under reduced pressure to afford tert-butyl 4-(4-(N-(5,6,7,8-tetrahydronaphthalen-2-yl)sulfamoyl)naphthalen-1-yl)piperidine-1-carboxylate. LCMS: Purity 90.20%. MS calculated for [M] 520.69 and found [M−H]+519.33.
    • e) 4-(piperidin-4-yl)-N-(5,6,7,8-tetrahydronaphthalen-2-yl)naphthalene-1-sulfonamide hydrochloride
  • Figure US20190119236A1-20190425-C00276
  • 4M HCl in 1,4-dioxane (2 mL) was added to a solution of tert-butyl 4-(4-(N-(5,6,7,8-tetrahydronaphthalen-2-yl)sulfamoyl)naphthalen-1-yl)piperidine-1-carboxylate (0.2 g, 0.384 mmol, 1.0 eq) in dichloromethane (2 mL) at 0° C. and the mixture was stirred for 2 h at room temperature. Solvents evaporated under reduced pressure, the residue was triturated with diethyl ether, followed by pentane, and dried under vacuum to afford 4-(piperidin-4-yl)-N-(5,6,7,8-tetrahydronaphthalen-2-yl)naphthalene-1-sulfonamide hydrochloride. LCMS: Purity 93.27%. RT=5.24 min (Method 1). MS calculated for [M] 420.57 and found [M+H]+421.03. 1H-NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.85 (bs, 1H), 8.78 (d, J=8.6 Hz,1H), 8.68-8.65 (m,1H), 8.38 (d, J=8.44 Hz,1H), 8.19 (d, J=7.84 Hz,1H), 7.76-7.70 (m, 2H), 7.49 (d, J=7.88 Hz,1H), 6.80 (d, J=8.24 Hz, 1H), 6.75 (d, J=8.48 Hz,1H), 6.69 (s,1H), 3.79-3.76 (m,1H), 3.42-3.39 (m, 2H), 3.23-3.17 (m, 2H), 2.02-1.88 (m, 4H), 4.18 (s, 4H).
    • Example 45 N-phenyl-4-(piperidin-4-yl)naphthalene-1-sulfonamide (62)
  • Figure US20190119236A1-20190425-C00277
  • N-phenyl-4-(piperidin-4-yl)naphthalene-1-sulfonamide may be prepared by methods similar to those described in Example 44, using aniline as the arylamine in step 2. LCMS RT=4.76 min, m/z=367.17 [M+H]− (Method 1).
    • Example 46 4-(Piperidin-4-yl)naphthalene-1-sulfonamide (63) a) 4-bromonaphthalene-1-sulfonyl chloride
  • Figure US20190119236A1-20190425-C00278
  • Chlorosulphonic acid (5.63 g, 48.3 mmol, 2.0 eq) was added drop-wise to the solution of 1-bromonaphthalene (5.0 g, 24.1 mmol, 1.0 eq) in chloroform (50 mL) under nitrogen atmosphere at 0° C. and the solution was stirred at ambient temperature for 1 h. After complete consumption of starting material, the reaction mixture was poured into chilled water and extracted with dichloromethane. The organic extract was separated and the aqueous extract was again extracted with dichloromethane. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain 4-bromonaphthalene-1-sulfonyl chloride, which was used in the next step without purification.
    • b) 4-bromonaphthalene-1-sulfonamide
  • Figure US20190119236A1-20190425-C00279
  • Ammonia gas was purged to a solution of 4-bromonaphthalene-1-sulfonyl chloride (1.0 g, 3.29 mmol, 1.0 eq) in dichloromethane (10 mL) and the solution was stirred at ambient temperature for 2 h. After complete consumption of starting material, the reaction mixture was evaporated under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 234-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain 4-bromonaphthalene-1-sulfonamide. LCMS: Purity 85.83%. MS calculated for [M] 286.14 and found [M−H]+285.97.
    • c) tert-butyl 4-(4-sulfamoylnaphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Figure US20190119236A1-20190425-C00280
  • A mixture of 4-bromonaphthalene-1-sulfonamide (0.825 g, 2.89 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.25 g, 7.23 mmol, 2.5 eq) and K3PO4 (1.84 g, 8.68 mmol, 3.0 eq) in 1,4-Dioxane (10 mL) was purged with nitrogen for 15 min. Pd(PPh3)2Cl2 (0.203 g, 0.289 mmol, 0.1 eq) was added to the reaction mixture and was stirred under nitrogen atmosphere, at 100° C. for 16 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 100-200 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(4-sulfamoylnaphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate. LCMS: Purity 96.79%. MS calculated for [M] 388.48 and found [M−H]+387.25.
    • d) tert-butyl 4-(4-sulfamoylnaphthalen-1-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00281
  • Pd—C (10% w/w, 50% moisture, 0.25 g) was added to the solution of tert-butyl 4-(4-sulfamoylnaphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.25 g, 0.644 mmol, 1.0 eq) in MeOH (5 mL). The reaction was allowed to stir at room temperature under hydrogen atmosphere (balloon pressure) for 2 h. Pd—C was filtered off (through celite) and solvent was evaporated from the filtrate under reduced pressure to afford tert-butyl 4-(4-sulfamoylnaphthalen-1-yl)piperidine-1-carboxylate. LCMS: Purity 99.07%. MS calculated for [M] 390.50 and found [M−H]+389.26.
    • e) 4-(piperidin-4-yl)naphthalene-1-sulfonamide hydrochloride
  • Figure US20190119236A1-20190425-C00282
  • 4M HCl in 1,4-dioxane (2 mL) was added dropwise to a solution of tert-butyl 4-(4-sulfamoylnaphthalen-1-yl)piperidine-1-carboxylate (0.2 g, 0.512 mmol, 1.0 eq) in dichloromethane (4 mL) and the mixture was stirred for 1 h at room temperature. Solvents evaporated under reduced pressure, the residue was triturated with diethyl ether followed by pentane and dried under vacuum to afford 4-(piperidin-4-yl)naphthalene-1-sulfonamide hydrochloride. LCMS: Purity 97.61%. RT=3.84 min (Method 1). MS calculated for [M] 290.38 and found [M+H]+291.07. 1H-NMR (400 MHz, DMSO-d6) δ 8.98 (bs, 1H), 8.80-8.78 (m,1H), 8.71-8.68 (m,1H), 8.41-8.12 (m,1H), 8.13 (d, J=7.68 Hz,1H), 7.72-7.70 (m,1H),7.63 (s, 2H),7.50 (d, J=6.92 Hz,1H), 3.82-3.80 (m,1H), 3.43-3.20 (m, 4H), 2.02-1.93 (m, 4H).
    • Example 47 8-(Piperidin-4-yl)-5-(trifluoromethyl)quinoline (64) a) 8-bromo-5-(trifluoromethyl)quinoline
  • Figure US20190119236A1-20190425-C00283
  • 70% Sulfuric acid (18 mL) was added drop-wise to the solution of 2-bromo-5-(trifluoromethyl)aniline (5.0 g, 21.0 mmol, 1.0 eq), propane-1,2,3-triol (3.8 g, 42.0 mmol, 2.0 eq) and sodium m-Nitrobenzene sulfonate (7.3 g, 32.55 mmol, 1.55 eq) at 0° C. and the mixture was stirred under nitrogen atmosphere, at 150° C. for 4 h. After complete consumption of starting material, the mixture was cooled to ambient temperature, poured into chilled water and filtered through a celite bed. The filtrate was neutralized with 2N aqueous NaOH, which led to a precipitate, which was filtered and dried under vacuum to obtain 8-bromo-5-(trifluoromethyl)quinoline. LCMS: Purity 95.13%. MS calculated for [M] 274.96 and found [M+H]+276.04.
    • b) tert-butyl 4-(5-(trifluoromethyl)quinolin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Figure US20190119236A1-20190425-C00284
  • A mixture of 8-bromo-5-(trifluoromethyl)quinoline (1.3 g, 4.71 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.9 g, 9.42 mmol, 2.0 eq) and K3PO4 (2.99 g, 14.13 mmol, 3.0 eq) in 1,4-Dioxane (15 mL) was purged with nitrogen for 15 min. Pd(PPh3)2Cl2 (0.33 g, 0.471 mmol, 0.1 eq) was added to the reaction mixture and was stirred under nitrogen atmosphere, at 85° C. for 16 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(5-(trifluoromethyl)quinolin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate. LCMS: Purity 61.96%. MS calculated for [M] 378.40 and found [M+H]−379.31.
    • c) tert-butyl 4-(5-(trifluoromethyl)quinolin-8-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00285
  • Pd—C (10% w/w, 50% moisture, 0.25 g) was added to the solution of tert-butyl 4-(5-(trifluoromethyl)quinolin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.5 g, 1.29 mmol, 1.0 eq) in MeOH (7 mL). The reaction was allowed to stir at room temperature under hydrogen atmosphere (balloon pressure) for 1 h. Pd—C was filtered off (through celite) and solvent was evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(5-(trifluoromethyl)quinolin-8-yl)piperidine-1-carboxylate. LCMS: Purity 97.53%. MS calculated for [M] 380.41 and found [M−100+H+]−281.15.
    • d) 8-(piperidin-4-yl)-5-(trifluoromethyl)quinoline dihydrochloride
  • Figure US20190119236A1-20190425-C00286
  • 4M HCl in 1,4-dioxane (1.0 mL) was added drop-wise to a solution of tert-butyl 4-(5-(trifluoromethyl)quinolin-8-yl)piperidine-1-carboxylate (0.1 g, 0.262 mmol, 1.0 eq) in dichloromethane (2 mL) and the reaction mixture was stirred at ambient temperature for 2 h. Solvents evaporated under reduced pressure, the residue was triturated with diethyl ether and dried under vacuum to afford 8-(piperidin-4-yl)-5-(trifluoromethyl)quinoline dihydrochloride. LCMS: Purity 98.23%. RT=4.48 min (Method 1). MS calculated for [M] 280.29 and found [M+H]+281.29. 1H-NMR (400 MHz, DMSO-d6) δ 9.11-9.10 (m, 1H), 9.00 (bs,1H), 8.51 (d, J=8.56 Hz, 1H), 8.11 (d, J=7.52 Hz, 1H), 7.81-7.78 (m, 1H), 7.74 (d, J=7.44 Hz, 1H), 4.45-4.18 (m, 1H), 3.49-3.43 (m, 2H), 3.25-3.10 (m, 2H), 2.05-2.04 (m, 4 H).
    • Example 48 5-(Piperidin-4-yl)-8-(trifluoromethyl)quinoline (65)
  • Figure US20190119236A1-20190425-C00287
  • 5-(piperidin-4-yl)-8-(trifluoromethyl)quinoline may be prepared by methods similar to those described in Example 47, using 5-bromo-2-(trifluoromethyl)aniline as the arylamine starting material in step 1. LCMS RT=3.87 min, m/z=281.29 [M+H]+ (Method 1).
    • Example 49 5-(Piperidin-4-yl)-2-naphthamide (66) a) methyl 5-bromo-2-naphthoate
  • Figure US20190119236A1-20190425-C00288
  • Sulfuric acid (0.2 mL) was added to the solution of 5-bromo-2-naphthoic acid (1.0 g, 3.98 mmol, 1.0 eq) in MeOH (10 mL) at room temperature and the solution was stirred under nitrogen atmosphere, at 80° C. for 16 h. After complete consumption of starting material, the reaction mixture was evaporated under reduced pressure, diluted ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to afford methyl 5-bromo-2-naphthoate.
    • b) tert-butyl 4-(6-(methoxycarbonyl)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Figure US20190119236A1-20190425-C00289
  • A mixture of methyl 5-bromo-2-naphthoate (0.5 g, 1.88 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.64 g, 2.07 mmol, 1.1 eq) and Na2CO3 (0.57 g, 5.4 mmol, 3.0 eq) in a mixture of 1,2-DME (5 mL) and water (1 mL) was purged with nitrogen for 15 min. Pd(dppf)Cl2.DCM (0.14 g, 0.188 mmol, 0.1 eq) was added to the reaction mixture and the mixture was stirred under nitrogen atmosphere, at 80° C. for 5 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(6-(methoxycarbonyl)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate. LCMS: Purity 99.14%. MS calculated for [M] 367.45 and found [M+H]+368.28.
    • c) tert-butyl 4-(6-(methoxycarbonyl)naphthalen-1-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00290
  • Pd—C (10% w/w, 50% moisture, 0.25 g) was added to the solution of tert-butyl 4-(6-(methoxycarbonyl)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.5 g, 1.36 mmol, 1.0 eq) in MeOH (5 mL) and reaction was allowed to stir at room temperature under hydrogen atmosphere (balloon pressure) for 10 h. Pd—C was filtered off (through celite) and solvent was evaporated from the filtrate under reduced pressure to obtain tert-butyl 4-(6-(methoxycarbonyl)naphthalen-1-yl)piperidine-1-carboxylate. LCMS: Purity 96.12%. MS calculated for [M] 369.46 and found [M+H]+370.35.
    • d) 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-naphthoic acid
  • Figure US20190119236A1-20190425-C00291
  • Lithium hydroxide (0.085 g, 2.02 mmol, 1.5 eq) was added to the solution of tert-butyl 4-(6-(methoxycarbonyl)naphthalen-1-yl)piperidine-1-carboxylate (0.3 g, 1.35 mmol, 1.0 eq) in a mixture of THF (2 mL), MeOH (2 mL) and water (2 mL) and the reaction mixture was stirred at room temperature for 4 h. After complete consumption of starting material, the reaction mixture was evaporated under reduced pressure, the residue was dissolved in water, acidified with 10% aqueous citric acid and extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to afford 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-naphthoic acid. LCMS: Purity 96.88%. MS calculated for [M]355.43 and found [M−H]+354.34.
    • e) tert-butyl 4-(6-carbamoylnaphthalen-1-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00292
  • HATU (0.32 g, 0.84 mmol, 1.5 eq) was added to a solution of 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-naphthoic acid (0.2 g, 0.56 mmol, 1.0 eq) and DIPEA (0.32 g, 0.84 mmol, 1.5 eq) in DMF (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min. Ammonium chloride (0.29 g, 5.6 mmol, 10.0 eq) was added and the reaction mixture was stirred at room temperature for 4 h. After complete consumption of starting material, the reaction mixture was poured into chilled water. The precipitate was filtered, washed with water, pentane and dried under vacuum to afford tert-butyl 4-(6-carbamoylnaphthalen-1-yl)piperidine-1-carboxylate. MS calculated for [M] 354.19 and found [M+H]−355.35.
    • f) (5-(piperidin-4-yl)-2-naphthamide hydrochloride
  • Figure US20190119236A1-20190425-C00293
  • 4M HCl in 1,4-dioxane (0.4 mL) was added drop-wise to a solution of tert-butyl 4-(6-carbamoylnaphthalen-1-yl)piperidine-1-carboxylate (0.1 g, 0.28 mmol, 1.0 eq) in dichloromethane (5 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 4 h. Solvents evaporated under reduced pressure, the residue was triturated with diethyl ether, pentane and dried under vacuum to afford 5-(piperidin-4-yl)-2-naphthamide hydrochloride. LCMS: Purity 95.49%. RT=3.74 min (Method 1). MS calculated for [M] 254.33 and found [M+H]+255.11. 1H-NMR (400 MHz, DMSO-d6) δ 9.03-8.98 (m, 1H), 8.93-8.84 (m, 1H), 8.51 (s, 1H), 8.29 (d, J=9.0 Hz,1H), 8.17 (bs, 1H), 8.00 (d, J=8.88 Hz,1H), 7.90 (d, J=8.04 Hz,1H), 7.57 (t, J=7.6 Hz,1H), 7.47 (t, J=8.76 Hz,1H), 3.78-3.71 (m,1H), 3.40 (d, J=11.76 Hz, 2H), 3.25-3.16 (m, 2H), 2.04-1.95 (m, 4 H).
    • Example 50 5-(Piperidin-4-yl)-1-naphthamide (67)
  • Figure US20190119236A1-20190425-C00294
    Figure US20190119236A1-20190425-C00295
  • 5-(piperidin-4-yl)-1-naphthamide may be prepared by methods similar to those described in Example 49, using 5-bromo-1-naphthoic acid as the starting material. LCMS RT=4.61 min, m/z=255.11 [M+H]− (Method 2).
    • Example 51 4-(Piperidin-4-yl)-1-naphthamide (68)
  • Figure US20190119236A1-20190425-C00296
    Figure US20190119236A1-20190425-C00297
  • 4-(piperidin-4-yl)-1-naphthamide may be prepared by methods similar to those described in Example 49, using 4-bromo-1-naphthoic acid as the starting material. LCMS RT=3.41 min, m/z=255.11 [M+H]− (Method 1).
    • Example 52 8-(Naphthalen-1-yl)-1,3-diazaspiro[4.5]decan-2-one (69) a) [8-(naphthalen-1-yl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20190119236A1-20190425-C00298
  • To a stirred solution of ammonium carbonate (3.07 g, 32.00 mmol, 8.0 equiv) and sodium cyanide (784 mg, 16.000 mol, 4.0 equiv) in a solvent mixture of water (10.44 mL, 11.6 vol.) and EtOH (1.04 mL, 1.6 vol.) was added portion wise 4-(naphthalen-1-yl)cyclohexanone (0.9 g, 4.00 mmol, 1.0 eq) at RT. The reaction mixture was slowly heated to 40-50° C. for 3 h and then refluxed for 5 days. The reaction mixture was concentrated under reduced pressure and water was added to the residue to generate a precipitate. The precipitate was isolated by filtration, washed with water (1 mL), and dried under vacuum to give 8-(naphthalen-1-yl)-1,3-diazaspiro[4.5]decane-2,4-dione.
    • b) [8-(naphthalen-1-yl)-1,3-diazaspiro[4.5]decan-2-one]
  • Figure US20190119236A1-20190425-C00299
  • To a solution of 8-(naphthalen-1-yl)-1,3-diazaspiro[4.5]decane-2,4-dione (145 mg, 0.492 mmol, 1.0 equiv) in THF was added portion wise LiAlH4 (55 mg, 1.478 mmol, 3.0 equiv) and then (5×55 mg for a 24 h period) at RT under a N2 atmosphere. The reaction mixture was slowly heated to reflux for 6 days. The reaction mixture was cooled to RT, quenched with a 10% citric acid solution and extracted with DCM (2×10 mL). The aqueous fraction was basified with aq. NH4OH, and subsequently extracted with DCM (2×5 mL). The combined organic layers were washed with water and brine, and concentrated under reduced pressure. The residue was purified by preparative HPLC to yield 8-(naphthalen-1-yl)-1,3-diazaspiro[4.5]decan-2-one. LCMS: 86.105%, m/z=281.3 [M+H]+ (Method 3). 1H-NMR (400 MHz, DMSO-d6): δ 8.11(1H, d), 7.91 (1H, d), 7.74 (1H, d), 7.60-7.41 (4H, m), 5.58 (1H, brs), 4.70 (1H, brs), 3.35 (2H, s), 2.21-2.20 (3H, m), 1.85-1.51 (6H, m).
    • Example 53 N-(4-(piperidin-4-yl)naphthalen-1-yl)tetrahydro-2H-pyran-4-amine (70) a) N-(4-bromonaphthalen-1-yl)tetrahydro-2H-pyran-4-amine
  • Figure US20190119236A1-20190425-C00300
  • Tetrahydro-4H-pyran-4-one (0.677 g, 6.75 mmol, 1.5 eq) was added to a mixture of 4-bromonaphthalen-1-amine (1.0 g, 4.5 mmol, 1.0 eq) in 1,2-dichloroethane (10 mL). The reaction mixture was stirred at room temperature for 5 min. Acetic acid (0.1 mL) was added to the reaction mixture and was stirred under nitrogen atmosphere, at room temperature for 1 h. A solution of sodium triacetoxyborohydride (1.43 g, 6.75 mmol, 1.5 eq) in 1,2-dichloroethane (10 mL) and was added drop-wise to the above mixture and stirring continued at room temperature for 16 h. After complete consumption of starting material, the mixture was partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain N-(4-bromonaphthalen-1-yl) tetrahydro-2H-pyran-4-amine. LCMS: Purity 61.71%. MS calculated for [M] 305.04 and found [M−H−]304.05.
    • b) tert-butyl 4-(4-((tetrahydro-2H-pyran-4-yl)amino)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Figure US20190119236A1-20190425-C00301
  • A mixture of N-(4-bromonaphthalen-1-yl)tetrahydro-2H-pyran-4-amine (0.5 g, 1.63 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.5 g, 1.63 mmol, 1.0 eq) and K3PO4 (1.03 g, 4.9 mmol, 3.0 eq) in a mixture of 1,2-dichloroethane (5 mL) and water (2 mL) was purged with nitrogen for 15 min. Pd(dppf)Cl2 (0.133 g, 0.16 mmol, 0.1 eq) was added to the reaction mixture and was stirred under nitrogen atmosphere, at 80° C. for 8 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(4-((tetrahydro-2H-pyran-4-yl)amino)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate.
    • c) tert-butyl 4-(4-((tetrahydro-2H-pyran-4-yl)amino)naphthalen-1-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00302
  • Pd—C (10% w/w, 50% moisture, 0.1 g) was added to the solution of tert-butyl 4-(4-((tetrahydro-2H-pyran-4-yl)amino)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.2 g, 0.489 mmol, 1.0 eq) in MeOH (5 mL) and reaction was allowed to stir at room temperature under hydrogen atmosphere (balloon pressure) for 4 h. Pd—C was filtered off (through celite) and solvent was evaporated from the filtrate under reduced pressure to afford tert-butyl 4-(4-((tetrahydro-2H-pyran-4-yl)amino)naphthalen-1-yl)piperidine-1-carboxylate. LCMS: Purity 98.35%. MS calculated for [M] 410.56 and found [M+H]+411.30.
    • d) N-(4-(piperidin-4-yl)naphthalen-1-yl)tetrahydro-2H-pyran-4-amine dihydrochloride
  • Figure US20190119236A1-20190425-C00303
  • 4M HCl in 1,4-dioxane (3 mL) was added dropwise to a solution of tert-butyl 4-(4-((tetrahydro-2H-pyran-4-yl)amino)naphthalen-1-yl)piperidine-1-carboxylate (0.1 g, 0.243 mmol, 1.0 eq) in dichloromethane (5 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 4 h. Solvents evaporated under reduced pressure, the residue was triturated with diethyl ether followed by pentane and dried under vacuum to afford N-(4-(piperidin-4-yl)naphthalen-1-yl)tetrahydro-2H-pyran-4-amine dihydrochloride. LCMS: Purity 99.64%. RT=3.72 min (Method 1). MS calculated for [M] 310.44 and found [M+H]+311.16. 1H-NMR (400 MHz, DMSO-d6) δ 8.94 (bs, 1H), 8.80-8.78 (m, 1H), 8.26 (d, J=8.24 Hz, 1H), 8.18 (bs,1H),7.58-7.57 (m, 2H), 7.31 (bs,1H), 7.00 (bs, 1H), 3.91-3.60 (m, 6H), 3.41-3.38 (m, 4H), 3.21-3.15 (m, 2H), 1.96-1.91 (m, 6H), 1.71 (bs, 2 H).
    • Example 54 4-(4-((Tetrahydro-2H-pyran-4-yl)oxy)naphthalen-1-yl)piperidine (71) a) tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate
  • Figure US20190119236A1-20190425-C00304
  • A solution of tosyl chloride (1.4 g, 7.34 mmol, 1.5 eq) in pyridine (5 mL) was added to a solution of tetrahydro-2H-pyran-4-ol (0.5 g, 4.9 mmol, and 1.0 eq) in pyridine (5 mL) at 0° C. The reaction mixture was stirred under nitrogen atmosphere, at room temperature for 4 h. After complete consumption of starting material, 1N aqueous HCl was added, diluted with water and extracted with ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate.
    • b) 4-((4-bromonaphthalen-1-yl)oxy)tetrahydro-2H-pyran
  • Figure US20190119236A1-20190425-C00305
  • Tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate (1.19 g, 4.66 mmol, 1.3 eq) was added to a mixture of 4-bromonaphthalen-1-ol (0.8 g, 3.5 mmol, 1.0 eq) and K2CO3 (0.64 g, 4.6 mmol, 1.3 eq) in DMF (10 mL) at ambient temperature and the mixture was stirred under nitrogen atmosphere, at 80° C. for 16 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain 4-((4-bromonaphthalen-1-yl)oxy)tetrahydro-2H-pyran. LCMS: Purity 90.19%.
    • c) tert-butyl 4-(4-((tetrahydro-2H-pyran-4-yl)oxy)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Figure US20190119236A1-20190425-C00306
  • A mixture of 4-((4-bromonaphthalen-1-yl)oxy)tetrahydro-2H-pyran (0.27 g, 0.88 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.27 g, 0.88 mmol, 1.0 eq) and Na2CO3 (0.267 g, 2.6 mmol, 3.0 eq) in a mixture of 1,2-DME (5 mL) and water (1 mL) was purged with nitrogen for 15 min. Pd(dppf)Cl2.DCM (0.071 g, 0.08 mmol, 0.1 eq) was added to the reaction mixture and was stirred under nitrogen atmosphere, at 80° C. for 8 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(4-((tetrahydro-2H-pyran-4-yl)oxy)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate. LCMS: Purity 96.36%. MS calculated for [M] 409.53 and found [M+H]+410.34.
    • d) tert-butyl 4-(4-((tetrahydro-2H-pyran-4-yl)oxy)naphthalen-1-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00307
  • Pd—C (10% w/w, 50% moisture, 0.02 g) was added to the solution of tert-butyl 4-(4-((tetrahydro-2H-pyran-4-yl)oxy)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.06 g, 0.146 mmol, 1.0 eq) in MeOH (5 mL) and reaction was allowed to stir at room temperature under hydrogen atmosphere (balloon pressure) for 2 h. Pd—C was filtered off (through celite) and solvent was evaporated from the filtrate under reduced pressure to afford tert-butyl 4-(4-((tetrahydro-2H-pyran-4-yl)oxy)naphthalen-1-yl)piperidine-1-carboxylate, which was utilized in the next step without purification.
    • e) 4-(4-((tetrahydro-2H-pyran-4-yl)oxy)naphthalen-1-yl)piperidine hydrochloride
  • Figure US20190119236A1-20190425-C00308
  • 4M HCl in 1,4-dioxane (0.2 mL) was added dropwise to a solution of tert-butyl 4-(4-((tetrahydro-2H-pyran-4-yl)oxy)naphthalen-1-yl)piperidine-1-carboxylate (0.038 g, 0.092 mmol, 1.0 eq) in dichloromethane (5 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 4 h. Solvents evaporated under reduced pressure, the residue was triturated with diethyl ether and pentane, dried under vacuum to afford 4-(4-((tetrahydro-2H-pyran-4-yl)oxy)naphthalen-1-yl)piperidine hydrochloride. LCMS: Purity 99.88%. RT=4.67 min (Method 1). MS calculated for [M] 311.43 and found [M+H]−312.20. 1H-NMR (400 MHz, DMSO-d6) δ 8.68 (bs, 1H), 8.34 (bs, 1H), 8.27 (d, J=8.16 Hz, 1H), 8.16 (d, J=8.4 Hz, 1H), 7.60-7.51 (m, 2H), 7.24 (d, J=8.16 Hz, 1H), 7.05 (d, J=8.08 Hz, 1H), 4.80-4.77 (m, 1H), 3.91-3.88 (m, 2H), 3.63-3.53 (m, 3H), 3.41-3.18 (m, 4H), 2.06-1.86 (m, 6H), 1.76-1.72 (m, 2H).
    • Example 55 (4-(Piperazin-1-yl)-N-(5,6,7,8-tetrahydronaphthalen-1-yl)naphthalene-1-sulfonamide) (72) a) 4-fluoronaphthalene-1-sulfonyl chloride
  • Figure US20190119236A1-20190425-C00309
  • To a stirred solution of 1-fluoronaphthalene (500 mg, 0.342 mmol) was added TFA (2.43 mL) drop wise at 0° C. under an inert atmosphere. The solution was stirred for 10 min. after which HSO3Cl (0.5 ml) was added drop wise to the reaction mixture. The reaction was stirred at 0° C. for 0.5 h and subsequently warmed to room temperature 2 h. The reaction mixture was quenched with ice cold water and the resulting material was isolated by filtration. The hygroscopic solid was dried in a vacuum desiccator containing P2O5 to provide intermediate 4-fluoronaphthalene-1-sulfonyl chloride. LCMS purity: 90.7%
    • b) 4-fluoro-N-(5,6,7,8-tetrahydronaphthalen-1-yl)naphthalene-1-sulfonamide
  • Figure US20190119236A1-20190425-C00310
  • To a stirred solution of 5,6,7,8-tetrahydronaphthalen-1-amine (100 mg, 0.6802 mmol) in pyridine (0.2 ml) was added drop wise a solution of 4-fluoronaphthalene-1-sulfonyl chloride (2) (140 mg, 0.566 mmol) in DCM (3 mL). The resulting mixture was stirred for 1 h after which the reaction mixture was diluted with ethyl acetate and the organic phase was washed with 1M HCl. The collected organic phase was dried over Na2SO4 and was concentrated to obtain 4-fluoro-N-(5,6,7,8-tetrahydronaphthalen-1-yl)naphthalene-1-sulfonamide. LCMS purity: 94.71%.
    • c) 4-(piperazin-1-yl)-N-(5,6,7,8-tetrahydronaphthalen-1-yl) naphthalene-1-sulfonamide (75)
  • Figure US20190119236A1-20190425-C00311
  • To a stirred solution of 4-fluoro-N-(5,6,7,8-tetrahydronaphthalen-1-yl)naphthalene-1-sulfonamide 3 (150 mg, 0.421 mmol) in DMSO (0.5 mL) was added piperazine (36 mg, 0.421 mmol) at room temperature under an inert atmosphere. The resulting reaction mixture was heated to 100° C. and stirred for 3 h. The reaction mixture was diluted with diethyl ether and the solidified product was isolated by filtration. The solid was washed with a sat. NaHCO3 solution and then dissolved in 10% MeOH in DCM. The solution was dried over Na2SO4, concentrated under vacuum and the crude product was purified by column chromatography (elution of product: 5% MeOH in DCM) to furnish 4-(piperazin-1-yl)-N-(5,6,7,8-tetrahydronaphthalen-1-yl)naphthalene-1-sulfonamide. LCMS purity: 88.2%, RT=5.919 min, m/z=422.3 [M+H]+. 1H-NMR (DMSO-d6): δ 8.65(1H, d), 8.20(1H, d), 7.92 (1H, d), 7.92 (1H, d), 7.40-7.72 (4H, m), 7.13 (1H, t), 6.88 (1H, d), 6.80 (1H, d), 6.67(1H, d), 3.20-2.22 (10H, m), 1.58-1.96 (6H, m).
    • Example 56 (N-phenyl-4-(piperazin-1-yl)naphthalene-1-sulfonamide) (73) a) 4-fluoro-N-phenylnaphthalene-1-sulfonamide
  • Figure US20190119236A1-20190425-C00312
  • To a stirred solution of 4-fluoronaphthalene-1-sulfonyl chloride (100 mg, 0.409 mol) in DCM (2 mL) were added drop wise pyridine (0.1 mL) and aniline (0.04 mL) under an inert atmosphere. The resulting solution was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (10 mL) and then the organic phase was washed with a 1M aqueous HCl solution. The organic fraction was separation, dried over Na2SO4, filtered and concentrated under vacuum to obtain intermediate 4-fluoro-N-phenylnaphthalene-1-sulfonamide. LCMS purity: 69.7%.
    • b) N-phenyl-4-(piperazin-1-yl)naphthalene-1-sulfonamide (73)
  • Figure US20190119236A1-20190425-C00313
  • To a stirred solution of 4-fluoro-N-phenylnaphthalene-1-sulfonamide (80 mg, 0.264 mmol) in DMSO (0.5 mL) was added piperazine (113 mg, 1.324 mmol) under an inert atmosphere. The resulting reaction mixture was heated to 100° C. and stirring continued for 3 h. After completion of the reaction the reaction mixture was diluted with diethyl ether and the solidified product was filtered, and washed with a Na2CO3 solution. The solid was washed with a sat. NaHCO3 solution and then dissolved in 10% MeOH in DCM. The solution was dried over Na2SO4, concentrated under vacuum and the crude product was purified by column chromatography to furnish N-phenyl-4-(piperazin-1-yl)naphthalene-1-sulfonamide. LCMS purity: 94.6%, RT=5.050 min, m/z=368.3 [M+H]+. 1H-NMR (400 MHz, DMSO-d6): δ 8.71(1H, d), 8.20-8.01(2H, m), 7.75-7.50 (2H, m), 718-6.76 (7H, m), 3.12-2.80(8H, m).
    • Example 57 (4-(Piperazin-1-yl)naphthalene-1-sulfonamide) (74) a) 4-fluoronaphthalene-1-sulfonamide
  • Figure US20190119236A1-20190425-C00314
  • To a stirred solution of 4-fluoronaphthalene-1-sulfonyl chloride (250 mg, 1.024 mmol) in NH4OH solution (5 mL) was added Na2CO3 (543 mg, 5.122 mmol) at room temperature under an inert atmosphere. The resulting reaction mixture was heated to 100° C. and stirring continued for 3 h. The reaction mixture was diluted with water and extracted with EtOAc (2×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain intermediate 4-fluoronaphthalene-1-sulfonamide. LCMS purity: 91.98%.
    • b) 4-(piperazin-1-yl)naphthalene-1-sulfonamide (74)
  • Figure US20190119236A1-20190425-C00315
  • To a stirred solution of 4-fluoronaphthalene-1-sulfonamide (200 mg, 0.888 mmol) in DMSO (0.5 mL) was added piperazine (76 mg, 0.888 mmol) at room temperature under an inert atmosphere. The resulting reaction mixture was heated to 100° C. and stirring was continued for 12 h. The reaction mixture was diluted with diethyl ether and the solidified product mass was filtered, which washed with sat. NaHCO3 solution. The solid was washed with a sat. NaHCO3 solution and then dissolved in 10% MeOH in DCM. The solution was dried over Na2SO4, concentrated under vacuum and the crude product was purified by column chromatography to furnish 4-(piperazin-1-yl)naphthalene-1-sulfonamide. LCMS purity: 94.7%, RT=3.354 min, m/z=292.2 [M+H]+. 1H-NMR [DMSO-d6]: δ 8.61(1H, d), 8.22 (1H, d), 8.05 (1H, d), 7.70-7.58 (2H, m), 7.50 (2H, s), 7.15 (1H, d), 3.12-2.90 (8H, m).
    • Example 58 N-(1-(naphthalen-1-yl)piperidin-4-yl)methanesulfonamide (17) a) tert-butyl 1-(naphthalen-1-yl)piperidin-4-ylcarbamate
  • Figure US20190119236A1-20190425-C00316
  • An oven dried Schlenk flask was evacuated and back filled with inert gas. The flask was charged with BINAP (1.2 g, 1.93 mmol) and palladium (II)-acetate (216 mg, 0.96 mmol) in dioxane (10 mL) at room temperature under an inert atmosphere. The resultant reaction mixture was evacuated with stirring for 5 min and then the reaction mixture was heated to 110° C. for 1-2 min to generate a red colored catalyst. 1-Bromonaphthalene (2 g, 9.65 mmol), tert-butyl piperidin-4-ylcarbamate (2.12 g, 10.6 mmol), Cs2CO3 (9.44 g, 28.9 mmol) and 30 mL of dioxane were added and the resulting reaction mixture was heated to 110° C. for 12 h. The reaction mixture was filtered through a celite pad and washed with ethyl acetate. The filtrate, was concentrated under reduced pressure and the residue was purified by basic alumina [elution: ethyl acetate/hexane (10:90)] to furnish tert-butyl 1-(naphthalen-1-yl)piperidin-4-ylcarbamate. LCMS purity: 98.363%. 1H-NMR (400 MHz, DMSO-d6): δ 8.1 (d, 1H), 7.85 (d, 1H), 7.6-7.35 (m, 4H), 7.1 (d, 1H), 6.9(d, 1H), 3.5-3.4 (m, 1H), 3.25 (d, 2H), 2.8-2.7 (t, 2H), 2.0-1.85 (d, 2H), 1.8-1.65 (m, 2H),1.4 (s, 9H).
    • b) 1-(naphthalen-1-yl)piperidin-4-amine
  • Figure US20190119236A1-20190425-C00317
  • To a stirred solution of tert-butyl 1-(naphthalen-1-yl)piperidin-4-ylcarbamate (2.4 g) in MeOH (10 mL) was added methanolic HCl (10 mL) at 0° C. and the resulting solution was stirred at RT for 1 h under an inert atmosphere. The reaction was concentrated under vacuum and the crude residue was diluted with EtOAc (25 mL) and basified with aq. Na2CO3 to pH=8. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by basic alumina column chromatography on gradient elution of 3% MeOH in DCM to give 1-(naphthalen-1-yl)piperidin-4-amine. LCMS purity: 96.137%. 1H-NMR (400 MHz, DMSO-d6): δ 8.10 (d, 1H), 7.85 (d, 1H), 7.6-7.35 (m, 4H), 7.15 (d, 1H), 3.35-3.28 (m, 2H), 2.80-2.61 (m, 3H),1.95-1.81 (d, 2H), 1.6-1.45 (m, 2H).
    • c) N-(1-(naphthalen-1-yl)piperidin-4-yl)methanesulfonamide (17)
  • Figure US20190119236A1-20190425-C00318
  • To a solution of 1-(naphthalen-1-yl)piperidin-4-amine (200 mg, 0.884 mmol) and DIPEA (0.3 mL, 1.769 mmol) in DCM (8 mL) was added methane sulfonyl Chloride (0.1 mL, 1.1504 mmol) at 0° C. under an inert atmosphere and the resulting mixture was stirred at 0° C. for 2 h. After completion of the reaction H2O (10 mL) was added and the mixture was extracted with DCM (2×10 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by basic alumina column chromatography on gradient elution of using 50% EtoAc in hexane to give N-(1-(naphthalen-1-yl)piperidin-4-yl)methanesulfonamide. LCMS purity: 99.183%, RT=6.823 min, m/z=305.3 [M+H]+ (Method 3). 1H-NMR (400 MHz, DMSO-d6): δ 8.10 (d, 1H), 7.85 (d, 1H), 7.61-7.35 (m, 4H), 7.25 (d, 1H), 7.10 (d, 1H), 3.31-3.20 (m, 3H), 3.01 (s, 3H), 2.85-2.75 (t, 2H), 2.05-1.95 (m, 2H), 1.80-1.65 (m, 2H).
    • Example 59 N-(1-(naphthalen-1-yl)piperidin-4-yl)acetamide (18)
  • Figure US20190119236A1-20190425-C00319
  • To a stirred solution of 1-(naphthalen-1-yl)piperidin-4-amine (200 mg, 0.884 mmol) and TEA (0.24 mL, 1.7699 mmol) in DCM (8 mL) was added acetyl chloride (0.082 mL, 1.1504 mmol) at 0° C. under an inert atmosphere and the resulting mixture was stirred at 0° C. for 1 h. After completion of the reaction H2O (10 mL) was added and the mixture was extracted with DCM (2×10 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by basic alumina column chromatography of using 100% DCM to give N-(1-(naphthalen-1-yl)piperidin-4-yl)acetamide. LCMS purity: 97.330%, RT=5.884 min, m/z): 269.3 (M+H)+ (Method 3). 1H-NMR (400 MHz, DMSO-d6): δ 8.11 (d, 1H), 8.02-7.85 (m, 2H), 7.60-7.35 (m, 4H), 7.11 (d, 1H), 3.85-3.65 (brs, 1H), 3.30-3.21 (m, 2H), 2.85-2.75 (m, 2H), 2.05-1.9 (m, 2H), 1.8 (s, 3H), 1.80-1.61 (m, 2H).
    • Example 60 1-(1-(Naphthalen-1-yl)piperidin-4-yl)urea (19)
  • Figure US20190119236A1-20190425-C00320
  • To a stirred solution of 1-(naphthalen-1-yl)piperidin-4-amine (200 mg, 0.884 mmol), TEA (0.24 mL, 1.7699 mmol) in DCM (8 mL) was added TMSNCO (0.15 mL, 1.1504 mmol) at room temperature under an inert atmosphere and the resulting mixture was stirred at same temperature for 3 h. The reaction mixture was concentrated under reduced pressure the crude product was purified by flash column chromatography of basic alumina on gradient elution of 6% MeOH in DCM to furnish 1-(1-(naphthalen-1-yl)piperidin-4-yl)urea. LCMS purity: 99.330%, RT=5.351 min, m/z=270.3 [M+H]+ (Method 3). 1H-NMR (400 MHz, DMSO-d6): δ 8.10 (d, 1H),7.91 (d, 1H), 7.60-7.35 (m, 4H), 7.11 (d, 1H), 6.10 (d,1H), 5.40 (brs, 2H), 3.65-3.45 (brs, 1H), 3.25-3.21 (d, 2H), 2.85-2.71 (m, 2H), 2.01-1.90 (m, 2H), 1.75-1.55 (m, 2H).
    • Example 61 4-((4-(Piperidin-4-yl)naphthalen-1-yl)sulfonyl)piperidine (23) a) tert-butyl 4-((4-bromonaphthalen-1-yl)thio)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00321
  • Cs2CO3 (1.64 g, 5.0 mmol, 2.0 eq) was added to a solution of 4-bromonaphthalene-1-thiol (0.6 g, 2.50 mmol, 1.0 eq) and tert-butyl 4-bromopiperidine-1-carboxylate (0.795 g, 3.02 mmol, 1.2 eq) in DMSO (5 mL) under nitrogen atmosphere at room temperature. The mixture was stirred at 120° C. for 15 h. After complete consumption of starting material, the reaction mixture was diluted with ethyl acetate and washed with water. The organic extract was then dried over anhydrous sodium sulfate, filtered, and solvent evaporated from the filtrated under reduced pressure to afford tert-butyl 4-((4-bromonaphthalen-1-yl)thio)piperidine-1-carboxylate. LCMS: Purity 95.04%. MS calculated for [M] 421.07 and found [M+H]+421.99.
    • b) tert-butyl 4-((4-bromonaphthalen-1-yl)sulfonyl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00322
  • m-CPBA (0.572 g, 3.31 mmol, 2.0 eq) was added to a solution of tert-butyl 4-((4-bromonaphthalen-1-yl)thio)piperidine-1-carboxylate (0.7 g, 1.66 mmol, 1.0 eq) in DCM (7 mL) under nitrogen atmosphere at 0° C. The mixture was stirred at RT for 1 h. After complete consumption of starting material, the reaction mixture was diluted with DCM and washed with water. The organic extract was then dried over anhydrous sodium sulfate, filtered, and solvent evaporated from the filtrated under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-((4-bromonaphthalen-1-yl)sulfonyl)piperidine-1-carboxylate. LCMS: Purity 87.64%. MS calculated for [M] 453.06 and found [M+NH4 +] 471.07.
    • c) tert-butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)sulfonyl)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Figure US20190119236A1-20190425-C00323
  • A mixture of tert-butyl 4-((4-bromonaphthalen-1-yl)sulfonyl)piperidine-1-carboxylate (0.78 g, 1.72 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.638 g, 2.06 mmol, 1.2 eq) and Na2CO3 (0.545 g, 5.16 mmol, 3.0 eq) in DMF (8 mL) was purged with nitrogen for 15 min. Pd(PPh3)4 (0.198 g, 0.171 mmol, 0.1 eq) was added to the reaction mixture and the mixture was then stirred under nitrogen atmosphere, at 80° C. for 4 h. After complete consumption of starting material, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)sulfonyl)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate. LCMS: Purity 97.31%. MS calculated for [M] 556.26 and found [M+H]+557.27.
    • d) tert-butyl 4-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)naphthalen-1-yl)sulfonyl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00324
  • To a solution of tert-butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)sulfonyl)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.47 g, 0.84 mmol, 1.0 eq) in MeOH (20 mL) was added Pd—C (0.2 g, 10% w/w Pd on carbon, 50% moisture) at RT. The mixture was stirred at RT under H2 atmosphere (balloon pressure) for 16 h. The progress of reaction was monitored by TLC. The mixture was filtered through celite and washed with MeOH. Solvents evaporated from the mixture of filtrate and washings under reduced pressure to obtain tert-butyl 4-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)naphthalen-1-yl)sulfonyl)piperidine-1-carboxylate. LCMS: Purity 92.14%. MS calculated for [M] 558.28 and found [M+H]−559.34.
    • e) 4-((4-(piperidin-4-yl)naphthalen-1-yl)sulfonyl)piperidine dihydrochloride
  • Figure US20190119236A1-20190425-C00325
  • 4M HCl in Dioxane (2.0 mL) was added to a solution of tert-butyl 4-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)naphthalen-1-yl)sulfonyl)piperidine-1-carboxylate (0.45 g, 0.80 mmol, 1.0 eq) in DCM (40 mL) at RT and stirred for 2 h. After complete consumption of starting material, solvents evaporated from the mixture under reduced pressure, the residue was washed with diethyl ether and dried under vacuum to obtain 4-((4-(piperidin-4-yl)naphthalen-1-yl)sulfonyl)piperidine dihydrochloride. LCMS: Purity 91.25%. RT=3.32 min (Method 1). MS calculated for [M] 358.17 and found [M+H]+359.19. 1H-NMR (400 MHz, DMSO-d6) δ 9.27 (bs, 1H), 9.18 (bs, 2H), 8.79 (bs, 1H), 8.72 (d, J=8.0 Hz, 1H), 8.49 (d, J=8.0 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.82-7.78 (m, 2H), 7.64 (d, J=8.0 Hz, 1H), 3.95-3.85 (m, 1H), 3.85-3.75 (m, 1H), 3.43-3.40 (m, 2H), 3.28-3.16 (m, 4H), 2.91-2.79 (m, 2H), 2.11-2.00 (m, 4H), 1.98-1.87 (m, 4H).
    • Example 62 8-Methoxy-5-(piperidin-4-yl)isoquinoline-3-carboxylic acid (75) a) 2-amino-3-(2-bromo-5-hydroxyphenyl)propanoic acid
  • Figure US20190119236A1-20190425-C00326
  • A solution of bromine (13.26 g, 82.97 mmol, 1.02 eq) in AcOH (700 mL) was added to a solution of 2-amino-3-(3-hydroxyphenyl)propanoic acid (14.6 g, 0.08 mmol, 1.0 eq) in AcOH (700 mL) at RT and stirred for 16 h. The precipitate formed in reaction mixture was collected by filtration, washed with diethyl ether and dried under high vacuum to afford 2-amino-3-(2-bromo-5-hydroxyphenyl)propanoic acid. LCMS: Purity 79.11%. MS calculated for [M] 258.98 and found [M+H]+260.03.
    • b) 5-bromo-8-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
  • Figure US20190119236A1-20190425-C00327
  • To a solution of 2-amino-3-(2-bromo-5-hydroxyphenyl)propanoic acid (14.0 g, 53.82 mmol, 1.0 eq) in H2O (500 mL) was added 37% formaldehyde (72.5 mL, 807.19 mmol, 15.0 eq) and conc. HCl (44 mL). The mixture was stirred at RT for 1.5 h followed by at 60° C. for 1.5 h. Another lot of conc. HCl (40 mL) was added and stirred at RT for further 30 min. Then the reaction mixture was subjected to heating and stirred at 90° C. for additional 40 min. After complete consumption of starting material, solvent was evaporated to give 5-bromo-8-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. LCMS: Purity 79.02%. MS calculated for [M] 270.98 and found [M+H]+271.99.
    • c) methyl 5-bromo-8-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
  • Figure US20190119236A1-20190425-C00328
  • SOCl2 (0.234 g, 66.14 mmol, 2.0 eq) was added to a solution of 5-bromo-8-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (9.0 g, 33.07 mmol, 1.0 eq) in MeOH (90 mL) at 0° C. and the mixture was stirred at RT for 1 h. After complete consumption of starting material, solvent evaporated under reduced pressure. The residue was triturated in DCM and filtered to afford methyl 5-bromo-8-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate. LCMS: Purity 85.20%. MS calculated for [M] 285.00 and found [M−H]+283.99 [M+H]+286.01.
    • d) 2-(tert-butyl) 3-methyl 5-bromo-8-hydroxy-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate
  • Figure US20190119236A1-20190425-C00329
  • Boc anhydride (6.4 g, 29.3 mmol, 2.0 eq) was added to a solution of methyl 5-bromo-8-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (4.2 g, 14.6 mmol, 1.0 eq) and Na2CO3 (3.11 g, 29.37 mmol, 2.0 eq) in a mixture of 1,4-Dioxane (85 mL) and water (15 mL) at RT and stirred for 3 h. Reaction mixture was then diluted with ethyl acetate and washed with brine. Organic extract was dried over anhydrous Na2SO4, filtered and solvents was evaporated from the filtrate under reduced pressure to afford crude residue, which was subjected to purification by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain to 2-(tert-butyl) 3-methyl 5-bromo-8-hydroxy-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate. LCMS: Purity 81.83%. MS calculated for [M] 385.05 and found [M+H]+386.06.
    • e) 2-(tert-butyl) 3-methyl 5-bromo-8-methoxy-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate
  • Figure US20190119236A1-20190425-C00330
  • MeI (4.4 g, 31.06 mmol, 1.5 eq) was added to a solution of 2-(tert-butyl) 3-methyl 5-bromo-8-hydroxy-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (8.0 g, 20.71 mmol, 1.0 eq) and K2CO3 (4.2 g, 31.06 mmol, 1.5 eq) in DMF (85.0 mL) at RT and stirred at 90° C. for 6 h. The reaction mixture was then cooled to ambient temperature, diluted in ethyl acetate and washed with water followed by brine. The organic extract was dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to afford 2-(tert-butyl) 3-methyl 5-bromo-8-hydroxy-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate. LCMS: Purity 73.85%. MS calculated for [M] 399.07 and found [M+H]+400.12.
    • f) methyl 5-bromo-8-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride
  • Figure US20190119236A1-20190425-C00331
  • 4M HCl in dioxane (8.0 mL) was added to a solution of 2-(tert-butyl) 3-methyl 5-bromo-8-methoxy-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (8.0 g, 19.95 mmol, 1.0 eq) in DCM (80 mL) at RT and stirred for 6 h. After complete consumption of starting material, solvent was evaporated under reduced pressure, the residue was washed with diethyl ether and dried under vacuum to afford methyl 5-bromo-8-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride. LCMS: Purity 83.25%. MS calculated for [M] 299.02 and found [M+H]+300.04.
    • g) methyl 5-bromo-8-methoxyisoquinoline-3-carboxylate
  • Figure US20190119236A1-20190425-C00332
  • KMnO4 (13.2 g, 83.6 mmol, 1.0 eq) was added to a solution of methyl 5-bromo-8-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (5.0 g, 83.61 mmol, 1.0 eq) in THF (50 mL) at RT and stirred for 6 h. The reaction mixture was diluted in ethyl acetate and washed with water followed by brine. The organic extract was dried over anhydrous Na2SO4, filtered and solvents was evaporated from the filtrate under reduced pressure to afford a crude residue, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain methyl 5-bromo-8-methoxyisoquinoline-3-carboxylate. LCMS: Purity 99.16%. MS calculated for [M] 294.98 and found [M−H]+295.99.
    • h) methyl 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-8-methoxyisoquinoline-3-carboxylate
  • Figure US20190119236A1-20190425-C00333
  • A mixture of methyl 5-bromo-8-methoxyisoquinoline-3-carboxylate (0.32 g, 1.08 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.672 g, 2.16 mmol, 2.0 eq) and K3PO4 (0.687 g, 3.24 mmol, 3.0 eq) in 1,4-Dioxane (5 mL) was purged with nitrogen for 15 min. PdCl2(PPh3)2 (0.076 g, 0.108 mmol, 0.1 eq) was added to the reaction mixture and was stirred under nitrogen atmosphere, at 90° C. for 16 h. The mixture was then cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was subjected to purification by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain methyl 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-8-methoxyisoquinoline-3-carboxylate. LCMS: Purity 78.48%. MS calculated for [M] 398.18 and found [M+H]+399.28.
    • i) methyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-8-methoxyisoquinoline-3-carboxylate
  • Figure US20190119236A1-20190425-C00334
  • To a solution of methyl 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-8-methoxyisoquinoline-3-carboxylate (0.15 g, 0.376 mmol, 1.0 eq) in MeOH (15 mL) was added Pd—C (0.100 g, 10% w/w Pd on carbon, 50% moisture) at RT. The mixture was stirred at RT under H2 atmosphere (balloon pressure) for 3 h. The progress of reaction was monitored by TLC. The mixture was filtered through celite and washed with MeOH. Solvents evaporated from the mixture of filtrate and washings under reduced pressure to obtain methyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-8-methoxyisoquinoline-3-carboxylate. LCMS: Purity 89.91%. MS calculated for [M] 400.20 and found [M+H]+401.29.
    • j) 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-8-methoxyisoquinoline-3-carboxylic acid
  • Figure US20190119236A1-20190425-C00335
  • LiOH.H2O (0.034 g, 0.828 mmol, 3.0 eq) was added to a solution of methyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-8-methoxyisoquinoline-3-carboxylate (0.11 g, 0.276 mmol, 1.0 eq) in a mixture of MeOH:THF:H2O (1:1:1; 1.5 mL) at RT and stirred for 2 h. After complete consumption of starting material, the reaction mixture was acidified with saturated aq. citric acid (pH=6), diluted with water and extracted with a mixture of isopropanol:CHCl3 (1:9). The organic extract was dried over anhydrous Na2SO4, filtered and solvents was evaporated from the filtrate under reduced pressure to afford 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-8-methoxyisoquinoline-3-carboxylic acid. LCMS: Purity 95.78%. MS calculated for [M] 386.18 and found [M+H]+387.35
    • k) 8-methoxy-5-(piperidin-4-yl)isoquinoline-3-carboxylic acid hydrochloride
  • Figure US20190119236A1-20190425-C00336
  • 4M HCl in Dioxane (1.0 mL) was added to a solution of 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-8-methoxyisoquinoline-3-carboxylic acid (0.05 g, 0.129 mmol, 1.0 eq) in DCM (3 mL) at RT and stirred for 2 h. After complete consumption of starting material, solvent was evaporated under reduced pressure, the residue was washed with diethyl ether and dried under vacuum to afford 4-((4-(piperidin-4-yl)naphthalen-1-yl)methyl)piperidine dihydrochloride. LCMS: Purity 98.08%. RT=4.92 min (Method 2). MS calculated for [M] 286.13 and found [M+H]+287.31. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.57 (s, 1 H), 8.95 (s, 1 H), 8.84 (bs, 1 H), 8.75 (bs, 1 H), 7.70 (d, J=8.0 Hz, 1 H), 7.33 (d, J=8.0 Hz 1 H), 4.05 (s, 3 H), 3.76-3.71 (m, 1 H), 3.41-3.38 (m, 2 H), 3.24-3.22 (m, 2 H), 2.05-1.90 (m, 4 H).
    • Example 63 8-Methoxy-5-(piperidin-4-yl)isoquinoline-3-carboxamide (76) a) tert-butyl 4-(3-carbamoyl-8-methoxyisoquinolin-5-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00337
  • A solution of 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-8-methoxyisoquinoline-3-carboxylic acid (0.05 g, 0.129 mmol, 1.0 eq), EDC.HCl (0.037 g, 0.193 mmol, 1.5 eq), HOBt (0.026 g, 0.194 mmol, 1.5 eq) and Et3N (0.026 g, 0.259 mmol, 2.0 eq) in DCM (2 mL) was purged with ammonia (gas) at 0° C. and the mixture was stirred for 30 min. The progress of reaction was monitored by TLC. After consumption of starting material, the mixture was partitioned between water and DCM. The organic extract was separated and the aqueous extract was again extracted with DCM. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was purified by flash chromatography on silica gel, 230-400 mesh, using gradient of MeOH in DCM as eluent to obtain tert-butyl 4-(3-carbamoyl-8-methoxyisoquinolin-5-yl)piperidine-1-carboxylate. LCMS: Purity 91.81%. MS calculated for [M] 385.20 and found [M+H]+386.30.
    • b) 8-methoxy-5-(piperidin-4-yl)isoquinoline-3-carboxamide
  • Figure US20190119236A1-20190425-C00338
  • 4M HCl in Dioxane (1.0 mL) was added to a solution of tert-butyl 4-(3-carbamoyl-8-methoxyisoquinolin-5-yl)piperidine-1-carboxylate (0.016 g, 0.041 mmol, 1.0 eq) in DCM (1 mL) at RT and stirred for 2 h. After complete consumption of starting material, solvent was removed under reduced pressure, the residue was washed with diethyl ether and dried under vacuum to afford 8-methoxy-5-(piperidin-4-yl)isoquinoline-3-carboxamide hydrochloride. LCMS: Purity 90.89%. RT=3.69 min (Method 1). MS calculated for [M] 285.15 and found [M+H]+286.16. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.53 (s, 1 H), 8.83 (bs, 1 H), 8.70 (s, 1H), 8.69 (bs, 1 H), 8.35 (s, 1 H), 7.80 (s, 1 H), 7.64 (d, J=8.0 Hz, 1 H), 7.26 (d, J=8.0 Hz, 1 H), 4.03 (s, 3H), 3.662-3.61 (m, 1 H), 3.42-3.39 (m, 2 H), 3.25 (m, 2 H), 1.95-1.89 (m, 4 H).
    • Example 64 4-((4-(Piperidin-4-yl)naphthalen-1-yl)methyl)piperidine (22) a) 1-bromo-4-(bromomethyl)naphthalene
  • Figure US20190119236A1-20190425-C00339
  • Freshly crystalized NBS (13.84 g, 77.80 mmol, 1.2 eq) was added to the solution of 1-bromo-4-methylnaphthalene (15.0 g, 67.84 mmol, 1.0 eq) and AIBN (1.11 g, 6.78 mmol, 0.1 eq) in carbon tetrachloride (150 mL) and the mixture was stirred at 80° C. for 16 h under nitrogen atmosphere. After complete consumption of starting material, water was added to the reaction mixture and extracted with DCM. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulfate, filtered, and the solvent evaporated from the filtrated under reduced pressure to obtain 1-bromo-4-(bromomethyl)naphthalene. LCMS: Purity 96.83%.
    • b) tert-butyl 4-(4-((1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)methyl)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Figure US20190119236A1-20190425-C00340
  • A mixture of 1-bromo-4-(bromomethyl)naphthalene (1.0 g, 3.34 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.10 g, 10.03 mmol, 1.5 eq) and K2CO3 (2.78 g, 20.07 mmol, 3.0 eq) in 1,2-DME (10 mL) was purged with nitrogen for 15 min. Pd(dppf)Cl2.DCM (0.546 g, 0.669 mmol, 0.1 eq) was added to the reaction mixture and was stirred under nitrogen atmosphere, at 110° C. for 16 h. The mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic extract was separated and the aqueous extract was again extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and solvents evaporated from the filtrate under reduced pressure to obtain a crude product, which was subjected to purification by flash chromatography on silica gel, 230-400 mesh, using gradient of ethyl acetate in hexanes as eluent to obtain tert-butyl 4-(4-((1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)methyl)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate. LCMS: Purity 57.36%. MS calculated for [M] 504.30 and found [M+H]+505.31.
    • c) tert-butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)naphthalen-1-yl)piperidine-1-carboxylate
  • Figure US20190119236A1-20190425-C00341
  • To a solution of tert-butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-ylidene)methyl)naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.4 g, 0.792 mmol, 1.0 eq) in MeOH (20 mL) was added Pd—C (0.2 g, 10% w/w Pd on carbon, 50% moisture) at RT. The mixture was stirred at ambient temperature, under hydrogen atmosphere (balloon pressure) for 18 h. The progress of reaction was monitored by TLC. After complete consumption of starting material, the mixture was filtered through celite and washed with MeOH. The mixture of filtrate and washings was evaporated under reduced pressure to obtain tert-butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)naphthalen-1-yl)piperidine-1-carboxylate. LCMS: Purity 95.56%. MS calculated for [M] 508.33 and found [M−H]+509.32.
    • d) 4-((4-(piperidin-4-yl)naphthalen-1-yl)methyl)piperidine dihydrochloride
  • Figure US20190119236A1-20190425-C00342
  • 4M HCl in Dioxane (2.0 mL) was added to a solution of tert-butyl 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)naphthalen-1-yl)piperidine-1-carboxylate (0.17 g, 0.354 mmol, 1.0 eq) in DCM (20 mL) at RT and stirred for 2 h. The solvent was removed under reduced pressure, the residue was washed with diethyl ether and dried under vacuum to obtain 4-((4-(piperidin-4-yl)naphthalen-1-yl)methyl)piperidine dihydrochloride. LCMS: Purity 96.72%. RT=3.95 min (Method 1). MS calculated for [M] 308.23 and found [M+H]+309.24. 1H-NMR (400 MHz, DMSO-d6) δ 9.06 (bs, 2 H), 8.89 (bs, 1 H), 8.66 (bs, 1 H), 8.27-8.25 (m, 1 H), 8.13-8.11 (m, 1 H), 7.59-7.56 (m, 2 H), 7.33-7.12 (m, 2H), 3.71-3.66 (m, 1 H), 3.41-3.38 (m, 2 H), 3.21-3.18 (m, 4 H), 2.97-2.96 (m, 2 H), 2.78-2.70 (m, 2 H), 2.01-1.99 (m, 4 H), 1.95-1.85 (m, 1H), 1.75-1.72 (m, 2 H), 1.50-1.41 (m, 2 H).
    • Example 65
  • The compounds presented in Table 3 can be synthesized according to the Examples or general schemes described herein.
  • TABLE 3
    No. Structure
    10
    Figure US20190119236A1-20190425-C00343
    11
    Figure US20190119236A1-20190425-C00344
    17
    Figure US20190119236A1-20190425-C00345
    18
    Figure US20190119236A1-20190425-C00346
    19
    Figure US20190119236A1-20190425-C00347
    20
    Figure US20190119236A1-20190425-C00348
    21
    Figure US20190119236A1-20190425-C00349
    28
    Figure US20190119236A1-20190425-C00350
    29
    Figure US20190119236A1-20190425-C00351
    30
    Figure US20190119236A1-20190425-C00352
    31
    Figure US20190119236A1-20190425-C00353
    32
    Figure US20190119236A1-20190425-C00354
    33
    Figure US20190119236A1-20190425-C00355
    34
    Figure US20190119236A1-20190425-C00356
    35
    Figure US20190119236A1-20190425-C00357
    36
    Figure US20190119236A1-20190425-C00358
    37
    Figure US20190119236A1-20190425-C00359
    38
    Figure US20190119236A1-20190425-C00360
    39
    Figure US20190119236A1-20190425-C00361
    40
    Figure US20190119236A1-20190425-C00362
    41
    Figure US20190119236A1-20190425-C00363
    42
    Figure US20190119236A1-20190425-C00364
    82
    Figure US20190119236A1-20190425-C00365
    77
    Figure US20190119236A1-20190425-C00366
    78
    Figure US20190119236A1-20190425-C00367
    79
    Figure US20190119236A1-20190425-C00368
    80
    Figure US20190119236A1-20190425-C00369
    81
    Figure US20190119236A1-20190425-C00370
    82
    Figure US20190119236A1-20190425-C00371
    83
    Figure US20190119236A1-20190425-C00372
    84
    Figure US20190119236A1-20190425-C00373
    85
    Figure US20190119236A1-20190425-C00374
    86
    Figure US20190119236A1-20190425-C00375
    87
    Figure US20190119236A1-20190425-C00376
    88
    Figure US20190119236A1-20190425-C00377
    89
    Figure US20190119236A1-20190425-C00378
    90
    Figure US20190119236A1-20190425-C00379
    91
    Figure US20190119236A1-20190425-C00380
    92
    Figure US20190119236A1-20190425-C00381
    93
    Figure US20190119236A1-20190425-C00382
    94
    Figure US20190119236A1-20190425-C00383
    95
    Figure US20190119236A1-20190425-C00384
    96
    Figure US20190119236A1-20190425-C00385
    97
    Figure US20190119236A1-20190425-C00386
    98
    Figure US20190119236A1-20190425-C00387
    99
    Figure US20190119236A1-20190425-C00388
    100
    Figure US20190119236A1-20190425-C00389
    101
    Figure US20190119236A1-20190425-C00390
    102
    Figure US20190119236A1-20190425-C00391
    103
    Figure US20190119236A1-20190425-C00392
    104
    Figure US20190119236A1-20190425-C00393
    105
    Figure US20190119236A1-20190425-C00394
    107
    Figure US20190119236A1-20190425-C00395
    108
    Figure US20190119236A1-20190425-C00396
    • Biological Assays
  • The compounds of the present disclosure may be tested for binding to, inhibition of, and/or modulation of PCSK9 activity according to the following protocols.
    • Cell Culture
  • Cells, such as HepG2, HuH7, FL83B, or a cell line transfected with a short-hairpin PCSK9 knockdown sequence (e.g., HepG2/shPCSK9, HuH7/shPCSK9) can be cultured following routine procedures, such as those described by Benjannet et al., “Effects of the prosegment and pH on the activity of PCSK9: evidence for additional processing events” J Biol Chem. 285(52): 40965-40978 (2010), which is hereby incorporated by reference in its entirety.
    • LDLR Flow Cytometric Analysis
  • LDLR levels can be measured using flow cytometry or fluorescence activated cell sorting (FACS) using protocols adapted from Benjannet et al., “Effects of the prosegment and pH on the activity of PCSK9: evidence for additional processing events” J Biol Chem. 285(52): 40965-40978 (2010) and “Composition and Methods of Use of Small Molecules as Binding Ligands for the Modulation of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Protein Activity” (WO2016029037), which are incorporated by reference in their entirety.
  • Cells, such as HepG2, HuH7, FL83B, or a cell line transfected with a short-hairpin PCSK9 knockdown sequence such as HepG2/shPCSK9, HuH7/shPCSK9, or FL83B/shPCSK9 are cultured in media composed of complete, high glucose DMEM (Invitrogen) with 10% fetal bovine serum (Life Technologies), supplemented with penicillin-streptomycin (Life Technologies). Cells are plated in a 24-well plate, at 125 k cells/well, and cultured at 37° C. for 12-24 h. Culture media is removed and replaced with fresh culture media or culture media plus a predetermined amount of recombinant PCSK9 (final 5 ug/ml). Wells evaluating test compounds are dosed with concentrations ranging from 0 nM to 100 uM.
  • Following an incubation period of 4-6 hours at 37° C., the media is removed and the cells are rinsed by adding 0.5 ml of complete D-PBS (i.e., Dulbecco's phosphate buffered saline (D-PBS, Life Technologies) supplemented with 0.5% bovine serum albumin (BSA, Sigma) and 1 g/L glucose (Sigma)). The wash media is carefully aspirated, and cells are released from the plate using 200 uls of TrypLE Express (Life Technologies) by incubating for 5-10 minutes at 37° C. The TyrpLE-Cell suspension is inactivated by adding 100 uls of Fetal Bovine Serum, transferred to a v-bottom plate, and centrifuged at 250× gravity for 5 minutes. Following centrifugation, the supernatant is aspirated and the cell pellet is resuspended in 100 uL of complete D-PBS, and centrifuged at 250× gravity for 5 minutes. Following centrifugation, the supernatant is aspirated and the cell pellet is resuspended in 100 uls of antibody staining solution (600 uls of anti-LDLr-PE in complete D-PBS) and incubated on ice, protected from light, for 30 minutes. The cells are then pelleted by centrifugation, resuspended in 100 uL of 4′,6-Diamidino-2-phenylindole (DAPI, Cayman Chemical) or 7-aminoactinomycin D (7AAD, Life Technologies) staining solution to measure cell viability
  • Cells are analyzed for both cell viability marker (dead cells) and LDLR in live cells using a flow cytometer per the manufacturer's operating manual. Cells incubated with small molecule compounds that are inhibitors of PCSK9 will be expected to show increased amounts of LDLR, relative to control (no compound) specimens, and cells incubated with small molecule compounds that are activators of PCSK9 will be expected to show decreased amounts of LDLR relative to control (no compound) specimens.
    • Cellular DiI-LDL Uptake Analysis
  • Cellular DiI-LDL uptake can be measured using protocols adapted from Benjannet et al., “Effects of the prosegment and pH on the activity of PCSK9: evidence for additional processing events” J Biol Chem. 285(52): 40965-40978 (2010) and “Composition and Methods of Use of Small Molecules as Binding Ligands for the Modulation of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Protein Activity” (WO2016029037), which are incorporated by reference in their entirety.
  • Cells, such as HepG2, HuH7, FL83B, or a cell line transfected with a short-hairpin PCSK9 knockdown sequence such as HepG2/shPCSK9, HuH7/shPCSK9, or FL83B/shPCSK9 are plated and cultured at 37° C. for 12-24 h. Culture media is removed and replaced with fresh lipoprotein-depleted culture media supplemented with 5 ug/mL of DiI-LDL (Kalen Biomedical) or lipoprotein-depleted culture media supplemented with 5 ug/mL of DiI-LDL plus a predetermined concentration of recombinant PCSK9, for example a 10 nM final concentration of PCSK9. Lipoprotein-depleted culture media can be composed of DMEM (Invitrogen) with 10% lipoprotein-depleted fetal bovine serum (Kalen Biomedical) and supplemented with penicillin-streptomycin (Life Technologies). Cells are dosed with small molecule test compounds at doses ranging from 0 nM to 100 uM.
  • Following an incubation period of specified length, such as 16 hours, Hoechst 33342 (AnaSpec) stain is added to the cell media per manufacturer's instructions and incubated for a specified length (e.g., 30 minutes). The lipoprotein-depleted media is removed and cells rinsed three times with phosphate buffered saline. A final volume of phosphate buffered saline is added back to the wells. The DiI fluorescence is measured with a plate reader using an exciting wavelength of 550 nm and the resulting emission at 590 nm is measured. The Hoechst stain fluorescence is measured with a plate reader using an exciting wavelength of 355 nm and the resulting emission at 460 nm is measured.
  • Cells are analyzed by for both Hoechst stain (DNA content) and DiI-LDL fluorescence. Cells incubated with small molecule compounds that are inhibitors of PCSK9 will be expected to show increased amounts of DiI-LDL fluorescence, relative to control (no compound) specimens, and cells incubated with small molecule compounds that are activators of PCSK9 will be expected to show decreased amounts of DiI-LDL fluorescence relative to control (no compound) specimens.
  • Results of the LDLR and DiI-LDL uptake assay are set forth in Table 4. As described therein, the percentage recovery in the LDL-R assay at 20 uM concentration is provided as follows: +++=>30% recovery; ++=10-30% recovery; +=0-10% recovery. The percentage uptake of DiI-LDL over the control in the LDL-uptake assay at 20 uM concentration is provided as follows: +++=>150%; ++=100-150%; +=<100%.
  • TABLE 4
    Compound No. LDL-R % Recovered LDL-uptake % of control
    107 ++ +++
    108 +++ +++
    11 + +
    5 ++ +
    1 +++ +++
    23 + +++
    62 +++ +++
    43 ++ +++
    44 ++ +++
    73 + ++
    7 + +++
    8 + +++
    4 + +++
    46 + ++
    • LDL Uptake Cell-Based Assay Kit
  • LDL uptake and LDLR expression can also be measured in cells, such as HepG2 or HuH7 cells, using a commercial kit (Cayman Chemical Co., Catalog # 10011125) and the accompanying protocols provided by the manufacturer.
    • Fluorescent-LDL Uptake Analysis by Flow Cytometric Analysis
  • Cells, such as HuH7, FL83B, or a cell line transfected with a short-hairpin PCSK9 knockdown sequence such as HuH7/shPCSK9 or FL83B/shPCSK9 are plated and cultured at 37° C. for 12-24 h. Culture media is removed and replaced with fresh lipoprotein-depleted culture media supplemented with 5 ug/mL of fluorescently labeled LDL or lipoprotein-depleted culture media supplemented with 5 ug/mL of fluorescently labeled LDL plus 10 nM recombinant PCSK9. Examples of fluorescently labeled LDL include: DiI-LDL (Kalen Biomedical), or LDL conjugated to Dylight (e.g., LDL-Dylight 488, or LDL-Dylight 550 (Cayman Chemical, Cat. # 10011229)). Lipoprotein-depleted culture media can be composed of DMEM (Invitrogen) with 10% lipoprotein-depleted fetal bovine serum (Kalen Biomedical) and supplemented with penicillin-streptomycin (Life Technologies). Cells are dosed with small molecule test compounds at doses ranging from 0 nM to 100 uM, following a protocol adapted from Benjannet et al., “Effects of the prosegment and pH on the activity of PCSK9: evidence for additional processing events” J Biol Chem. 285(52): 40965-40978 (2010), which is incorporated by reference in its entirety.
  • Following an incubation period of specified length, such as 16 hours, the lipoprotein-depleted media is removed and cells rinsed three times with a rinse solution (Dulbecco's phosphate buffered saline (D-PBS, Life Technologies), supplemented with 0.5% bovine serum albumin (BSA, Sigma) and 1 g/L glucose (Sigma)). The fluid is then removed, and cells are released from the plate using TrypLE Express (Life Technologies) per manufacturer's recommended procedures, such as incubation for 5-10 minutes at 37° C. The TyrpLE-Cell suspension is then transferred to 15 mL conical tubes, volume is increased to 2 mL with D-PBS supplemented with 0.5% BSA, and 1 g/mL glucose, and the tubes are centrifuged at 250× gravity for 10 minutes. Following centrifugation, the supernatant is aspirated and the cell pellet is resuspended in 300 uL PBS and counterstained with 4′,6-diamidino-2-phenylindole (DAPI, Cayman Chemical) as a cell viability marker, other cell viability markers such as 7-aminoactinomycin D (7AAD, Life Technologies) have also been described in the art.
  • Cells are analyzed by for both 7AAD (dead cells) and fluorescent LDL in live cells using a flow cytometer per the manufacturer's operating manual. Cells incubated with small molecule compounds that are inhibitors of PCSK9 will be expected to show increased amounts of LDL fluorescence, relative to control (no compound) specimens, and cells incubated with small molecule compounds that are activators of PCSK9 will be expected to show decreased amounts of LDL fluorescence relative to control (no compound) specimens.
    • Back-Scattering Interferometry Direct Binding Measurement
  • Direct binding can be measured using Back-Scattering Interferometry (BSI), which has been previously described in “Interferometric detection system and method” (EP 1210581), “Free solution measurement of molecular interactions by backscattering interferometry” (WO 2009039466), “Temperature-stable interferometer” (WO 2009076372), and “Improved event detection for back-scattering interferometry” (WO 2013158300); each of which are hereby incorporated by reference in their entirety.
  • Thus, it should be understood that although the present disclosure has been specifically disclosed by exemplary embodiments and optional features, modification, improvement and variation of the disclosed embodiments may be implemented by those skilled in the art, and that such modifications, improvements and variations are considered to be within the scope of the present disclosure and claims. The materials, methods, and examples provided here are representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure nor as limitations on the scope of the appended claims.
  • All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control.
  • It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Claims (27)

1. A compound of Formula (I):
Figure US20190119236A1-20190425-C00397
or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof;
wherein:
m is 0, 1, or 2;
X1 is absent, CR2, CR2R2, C(O), N, NR2, S, SO2, or O;
X2, X3, and X4 are each independently CR2, CR2R2, C(O), N, NR2, S, SO2, or O;
ring B is a five- or six-membered ring optionally comprising one or more double bonds;
X5 and X6 are either CR2 or N;
X7 is C or N; provided that when X7 is N, then L-R3 is absent:
ring A is selected from:
Figure US20190119236A1-20190425-C00398
where the wavy line in ring A indicates the point of attachment to
Figure US20190119236A1-20190425-C00399
L is a bond, C1-6-alkylene, —O—, —C(O)—, —SO2—, —N(Ra)—, —N(Ra)SO2—, or —SO2N(Ra)— where Ra is hydrogen, C1-6 alkyl, or C1-6 heteroalkyl, wherein the C1-6 alkyl or C1-6 heteroalkyl are optionally substituted with 1 to 3 substituents independently selected from halo, oxo, hydroxy, C1-6 alkyl, or C1-6 heteroalkyl;
R1 in each instance is independently halo, cyano, C1-6 alkyl optionally substituted with halo or hydroxy, C3-6 cycloalkyl, —NRbC(O)NRbRb, or —NRbS(O)2Rb;
wherein each Rb is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl;
R2 in each instance is independently hydrogen, halo, C1-6 alkyl optionally substituted with halo or hydroxy, C3-6 cycloalkyl, C2-6 hydroxyalkyl, cyano, —C(O)ORc, or —C(O)NRcRc;
wherein each Rc is independently, hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl;
R3 is hydrogen, halo, cyano, amino, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl, or heteroaryl;
wherein each C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl and heteroaryl of R3 is optionally substituted with 1 to 3 substituents independently selected from halo, hydroxy, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, acyl, C3-10 cycloalkyl, heteroalkyl, heteroaryl, heterocyclyl, aryl, oxo, —N3, —NO2, —N(Rf)2, —C(O)N(Rf)2, —C(NRf)(N(Rf)2), —NRfC(O)ORf, —C(O)N(Rf)2, —CO2H, —CO2Rf, —NRfC(NRf)(N(Rf)2), haloalkyl, haloalkoxy, —N(Rf)N(Rf)2, —C(NRf)Rf, —S(O)Rf, —SO2H, —S(O)2Rf, —SCN, —SH, or (═S), and where each Rf is independently H or C1-6 alkyl;
R4 in each instance is independently hydrogen, C1-6 alkyl, —C(O)NRdRd, —C(NRd)NRdRd, —C(O)Rd, or —S(O)2NRdRd;
wherein each Rd is independently, hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl;
with the following provisos:
1) when m is 0, then both R4 and L-R3 cannot be hydrogen;
2) when m is 0, R4 is hydrogen, X1, X2, X3, X4 are all CH, then L-R3 is not CF3;
3) when X5 and X6 are both nitrogen, then L-R3 is not hydrogen, —CH2-aryl, or —CH2-heteroaryl;
4) when X1, X2, X3, and X4 are all CH or X1 is nitrogen and X2, X3, and X4 are all CH, then L-R3 is not —SO2-aryl, wherein the aryl is optionally substituted;
5) when A is attached via a carbon atom to the remainder of the molecule and m is other than 0, then R1 is not appended to the same carbon;
6) the compound is not 3-bromo-8-(4-methylpiperidin-1-yl)quinoline or 4-methyl-1-(naphthalen-1-yl)piperidine; and
7) when A is piperidinyl and L-R3 is hydrogen, then R4 is not C(O)NH2.
2. The compound of claim 1, wherein the moiety
Figure US20190119236A1-20190425-C00400
is:
Figure US20190119236A1-20190425-C00401
Figure US20190119236A1-20190425-C00402
Figure US20190119236A1-20190425-C00403
Figure US20190119236A1-20190425-C00404
wherein the wavy line indicates the point of attachment to L and the dashed line represents the point of attachment to ring A, and further wherein the bicyclic ring may be optionally substituted with 1 to 7 R2.
3. The compound of claim 1, wherein the moiety
Figure US20190119236A1-20190425-C00405
is:
Figure US20190119236A1-20190425-C00406
wherein the wavy line indicates the point of attachment to L and the dashed line represents the point of attachment to ring A, and further wherein the bicyclic ring may be optionally substituted with one or more R2.
4. The compound of claim 1, wherein the moiety
Figure US20190119236A1-20190425-C00407
is:
Figure US20190119236A1-20190425-C00408
wherein the wavy line indicates the point of attachment to L and the dashed line represents the point of attachment to ring A, and further wherein the bicyclic ring may be optionally substituted with one or more R2.
5. The compound of claim 1, wherein ring A is:
Figure US20190119236A1-20190425-C00409
6. The compound of claim 1, wherein ring A is:
Figure US20190119236A1-20190425-C00410
7. The compound of claim 1, wherein ring A is:
Figure US20190119236A1-20190425-C00411
8. The compound of claim 1, wherein m is 0 or 1.
9. The compound of claim 1, wherein R4 is hydrogen, —C(O)NH2, or —C(NH)NH2.
10. The compound of claim 1, wherein R1 is —NHS(O)2CH3 or —NHC(O)CH3.
11. The compound of claim 1, wherein R2 is hydrogen, C1-6 alkyl, —CO2H, or —C(O)NH2.
12. The compound of claim 1, wherein L is a bond, —CH2—, —O—, —C(O)—, —S(O)2—, —S(O)2NH—, or —NH—.
13. The compound of claim 1, wherein R3 is hydrogen, amino, halo, C1-6alkyl, aryl, or C3-10 heterocyclyl, wherein C1-6alkyl, aryl, or C3-10 heterocyclyl is optionally substituted with 1 to 3 halo.
14. The compound of claim 1, wherein L is a bond and R3 is hydrogen.
15. The compound of claim 1, wherein L is a bond, and R3 is CF3.
16. The compound of claim 1, wherein R3 is:
Figure US20190119236A1-20190425-C00412
wherein:
Y is —O—, —N(Re)—, —CH(CH2)f OH, or —N(CH2)f OH;
each Re is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl; and
f is 0, 1, 2, 3, or 4.
17. The compound of claim 16, wherein Y is —N(Re)—.
18. A compound selected from
Figure US20190119236A1-20190425-C00413
Figure US20190119236A1-20190425-C00414
Figure US20190119236A1-20190425-C00415
Figure US20190119236A1-20190425-C00416
Figure US20190119236A1-20190425-C00417
Figure US20190119236A1-20190425-C00418
Figure US20190119236A1-20190425-C00419
Figure US20190119236A1-20190425-C00420
Figure US20190119236A1-20190425-C00421
Figure US20190119236A1-20190425-C00422
Figure US20190119236A1-20190425-C00423
or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof.
19. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1.
20. A method of treating a disease or condition mediated, at least in part, by PCSK9, the method comprising administering to a patient in need thereof a compound of Formula (I):
Figure US20190119236A1-20190425-C00424
or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof;
wherein:
m is 0, 1, or 2;
X1 is absent, CR2, CR2R2, C(O), N, NR2, S, SO2, or O;
X2, X3, and X4 are each independently CR2, CR2R2, C(O), N, NR2, S, SO2, or O;
ring B is a five- or six-membered ring optionally comprising one or more double bonds;
X5 and X6 are either CR2 or N;
X7 is C or N; provided that when X7 is N, then L-R3 is absent:
ring A is selected from:
Figure US20190119236A1-20190425-C00425
where the wavy line in ring A indicates the point of attachment to
Figure US20190119236A1-20190425-C00426
L is a bond, C1-6-alkylene, —O—, —C(O)—, —SO2—, —N(Ra)—, —N(Ra)SO2—, or —SO2N(Ra)— where Ra is hydrogen, C1-6 alkyl, or C1-6 heteroalkyl, wherein the C1-6 alkyl or C1-6 heteroalkyl are optionally substituted with 1 to 3 substituents independently selected from halo, oxo, hydroxy, C1-6 alkyl, or C1-6 heteroalkyl;
R1 in each instance is independently halo, cyano, C1-6 alkyl optionally substituted with halo or hydroxy, C3-6 cycloalkyl, —NRbC(O)NRbRb, or —NRbS(O)2Rb;
wherein each Rb is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl;
R2 in each instance is independently hydrogen, halo, C1-6 alkyl optionally substituted with halo or hydroxy, C3-6 cycloalkyl, C2-6 hydroxyalkyl, cyano, —C(O)ORc, or —C(O)NRcRc;
wherein each Rc is independently, hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl;
R3 is hydrogen, halo, cyano, amino, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl, or heteroaryl;
wherein each C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl and heteroaryl of R3 is optionally substituted with 1 to 3 substituents independently selected from halo, hydroxy, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, acyl, C3-10 cycloalkyl, heteroalkyl, heteroaryl, heterocyclyl, aryl, oxo, —N3, —NO2, —N(Rf)2, —C(O)N(Rf)2, —C(NRf)(N(Rf)2), —NRfC(O)ORf, —C(O)N(Rf)2, —CO2H, —CO2Rf, —NRfC(NRf)(N(Rf)2), haloalkyl, haloalkoxy, —N(Rf)N(Rf)2, —C(NRf)Rf, —S(O)Rf, —SO2H, —S(O)2Rf, —SCN, —SH, or (═S), and where each Rf is independently H or C1-6 alkyl;
R4 in each instance is independently hydrogen, C1-6 alkyl, —C(O)NRdRd, —C(NRd)NRdRd, —C(O)Rd, or —S(O)2NRdRd;
wherein each Rd is independently, hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C2-6 hydroxyalkyl.
21. A method of treating a disease or condition mediated, at least in part, by PCSK9, the method comprising administering to a patient in need thereof a compound selected from
Figure US20190119236A1-20190425-C00427
Figure US20190119236A1-20190425-C00428
Figure US20190119236A1-20190425-C00429
Figure US20190119236A1-20190425-C00430
Figure US20190119236A1-20190425-C00431
Figure US20190119236A1-20190425-C00432
Figure US20190119236A1-20190425-C00433
Figure US20190119236A1-20190425-C00434
Figure US20190119236A1-20190425-C00435
Figure US20190119236A1-20190425-C00436
Figure US20190119236A1-20190425-C00437
Figure US20190119236A1-20190425-C00438
or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof.
22. The method of claim 20, wherein the disease or condition is a cardiovascular disease, a metabolic disease, or hypocholesterolemia.
23. The method of claim 21, wherein the cardiovascular disease is coronary disease, hypertension, hypercholesterolemia, or atherosclerosis.
24. The method of claim 21, the metabolic disease is diabetes.
25. The method of claim 20, wherein the patient has elevated plasma levels of low density lipoprotein cholesterol.
26. The method of claim 20, wherein the patient has depleted plasma levels of low density lipoprotein cholesterol.
27. A method of inhibiting the activity of PCSK9, the method comprising binding a compound of claim 1 to PCSK9, thereby inhibiting the activity of PCSK9.
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