WO2023081661A1 - Dérivés bicycliques utilisés en tant que modulateurs de ccr2 - Google Patents

Dérivés bicycliques utilisés en tant que modulateurs de ccr2 Download PDF

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Publication number
WO2023081661A1
WO2023081661A1 PCT/US2022/079088 US2022079088W WO2023081661A1 WO 2023081661 A1 WO2023081661 A1 WO 2023081661A1 US 2022079088 W US2022079088 W US 2022079088W WO 2023081661 A1 WO2023081661 A1 WO 2023081661A1
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heteroaryl
heterocyclyl
aryl
cycloalkyl
compound
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PCT/US2022/079088
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English (en)
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Anjali Pandey
Biswajit Kalita
Athisayamani Jeyaraj DURAISWAMY
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Aria Pharmaceuticals, Inc.
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Publication of WO2023081661A1 publication Critical patent/WO2023081661A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • Chemotactic cytokines also known as chemokines, intercrines, and SIS cytokines, are a group of inflammatory/immunomodulatory polypeptide factors released at disease sites (e.g., inflammatory sites) by cells including, for example, macrophages, monocytes, fibroblasts, vascular endothelial cells, eosinophils, neutrophiles, smooth muscle cells, and mast cells.
  • MCP-1/CCL2 Monocyte chemoattractant protein-1
  • MCP-1 monocyte/macrophage and/or T cells
  • diseases include, but are not limited to, psoriasis, uveitis, rheumatoid arthritis, multiple sclerosis, restenosis, asthma, obesity, chronic obstructive pulmonary disease, pulmonary fibrosis, atherosclerosis, myocarditis, ulcerative colitis, nephritis (nephropathy), lupus, systemic lupus erythematosus, hepatitis, pancreatitis, sarcoidosis, organ transplantation, Crohn’s disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, experimental autoimmune encephalomyelitis, and sepsis in which tissue infiltration of blood leukocytes, such as monocytes and lymphocytes, play a
  • CCR2 is a chemokine receptor, a member of the super family of seven-transmembrane G-protein coupled receptor, and is predominantly expressed on monocytes.
  • the CCR2 receptor a type of receptor for the CC family chemokines, is the primary receptor to MCP-1 . Therefore, by modulating (e.g.. antagonizing, such as using antagonists or inhibitors) the activity of CCR2 receptors, certain medical benefit may be realized.
  • the “CC” family of chemokine contains two amino terminal cysteine residues (C) that are immediately adjacent (as opposed to be separated by one amino acid, known as the “CXC” family), and shows sequence similarities between 25 to 60% within the family. Thus, there remains a strong need to develop CCR2 inhibitors for treatment of several diseases.
  • the compounds modulate the regulation of CCR2 receptor. In some aspects the compounds act via antagonism of the CCR2 receptor.
  • the compounds modulate the interaction between CCR2 receptor and ligands to the CCR2 receptor.
  • the compounds modulate the interaction between CCR2 receptor and chemokines.
  • the compounds modulate the interaction between CCR2 receptor and MCP-1.
  • a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable carrier.
  • a method for treating a disease or condition mediated, at least in part, by CCR2 receptor comprising administering an effective amount of the pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof.
  • a method for treating a disease or condition, at least in part, by regulation of CCR2 receptor comprising administering an effective amount of the pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable carrier, to a subject in need thereof.
  • a method for treating a disease or condition, at least in part, by a CCR2 antagonist comprising administering an effective amount of the pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable carrier, to a subject in need thereof.
  • a method for treating a disease or condition, at least in part, by inhibiting CCR2 receptor comprising administering an effective amount of the pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable carrier, to a subject in need thereof.
  • 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, at least in part, by CCR2 receptor.
  • 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 CCR2 receptor, such as lupus, atherosclerosis, fibrosis, cancer, metabolic, and autoimmune diseases.
  • a dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -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.
  • 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.
  • Reference 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.
  • 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 12 carbon atoms (i.e., C 1-12 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, e.g., 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.
  • butyl includes n-butyl (i.e., -(CH 2 ) 3 CH 3 ), sec-butyl (i.e., -CH(CH 3 )CH 2 CH 3 ), isobutyl (i.e., -CH 2 CH(CH 3 ) 2 ) and tert-butyl (i.e., -C(CH 3 ) 3 ); and “propyl” includes n-propyl (i.e., -(CH 2 ) 2 CH 3 ), and isopropyl (i.e., -CH(CH 3 ) 2 ).
  • 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 or aralkyl, 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, e.g., ethenyl, propenyl, and 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-”.
  • alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
  • Alkoxyalkyl refers to the group “alkyl-O-alkyl”.
  • Alkylthio refers to the group “alkyl-S-”.
  • Alkylsulfinyl refers to the group “alkyl-S(O)-”.
  • Alkylsulfonyl refers to the group “alkyl-S(O) 2 -”.
  • Alkylsulfonylalkyl refers to -alkyl-S(O) 2 -alkyl.
  • “Acyl” refers to a group -C(O)R y , wherein R y 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, e.g., formyl, acetyl, cyclohexylcarbonyl, 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, or R y and R z are taken together to form a cycloalkyl or heterocyclyl; 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.
  • Aminoalkyl refers to the group “-alkyl-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.
  • “Amidino” refers to -C(NR y )(NR z 2), 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).
  • aryl groups include, e.g., 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.
  • Arylalkyl or “Aralkyl” refers to the group “aryl-alkyl-”.
  • 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 or “ester” refer to both -OC(O)R x and -C(O)OR x , wherein R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein [0036] “Cyanoalkyl” refers to refers to an alkyl group as defined above, wherein one or more (e.g., one to three) hydrogen atoms are replaced by a cyano (-CN) group.
  • 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) and carbocyclic fused ring systems having at least one sp 3 carbon atom (i.e., at least one non-aromatic ring).
  • 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).
  • Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic groups include, for example, bicyclo[2.2. l]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbomyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • 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.
  • cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.
  • Cycloalkoxy refers to “-O-cycloalkyl.”
  • Cycloalkylalkyl refers to the group “cycloalkyl-alkyl-”.
  • Cycloalkylalkoxy refers to “-O-alkyl-cycloalkyl.”
  • Hydrazino refers to -NHNH2.
  • Imino refers to a group -C(NR y )R z , wherein R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • “Imido” refers to a group -C(O)NR y C(O)R z , wherein R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Halogen refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.
  • Haloalkyl refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., one to five or one to three) hydrogen atoms are replaced by a halogen.
  • 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.
  • haloalkyl examples include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • Haloalkoxy refers to an alkoxy group as defined above, wherein one or more (e.g., one to five or one to three) hydrogen atoms are replaced by a halogen.
  • Hydroxyalkyl refers to an alkyl group as defined above, wherein one or more (e.g., one to five or one to three) hydrogen atoms are replaced by a hydroxy group.
  • “Heteroalkyl” refers to an alkyl group in which one or more (e.g., one to five or one to three) of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group, provided the point of attachment to the remainder of the molecule is through a carbon atom.
  • heteroalkyl includes unbranched or branched saturated chain having carbon and heteroatoms.
  • 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 y -, -O-, -S-, -S(O)-, -S(O) 2 -, and the like, wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • heteroalkyl groups include, e.g., ethers (e.g., -CH 2 OCH 3 , -CH(CH 3 )OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , etc.), thioethers (e.g., -CH 2 SCH 3 , -CH(CH 3 )SCH 3 , -CH 2 CH 2 SCH 3 , -CH 2 CH 2 SCH 2 CH 2 SCH 3 , etc.), sulfones (e.g., -CH 2 S(O) 2 CH 3 , -CH(CH 3 )S(O) 2 CH 3 , -CH 2 CH 2 S(O) 2 CH 3 , -CH 2 CH 2 S(O) 2 CH 2 CH 2 OCH 3 , etc.), and amines (e.g., -CH 2 NR y CH 3 , -CH(CH 3 )NR y CH 3 ,
  • 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.
  • “Heteroalkylene” refers to a divalent alkyl group (i.e., alkylene) in which one or more (e.g., one to five or one to three) of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group.
  • “Heteroalkylene” groups must have at least one carbon and at least one heteroatomic group within the chain.
  • the term “heteroalkylene” includes unbranched or branched saturated chain having carbon and heteroatoms.
  • 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 y -, -O-, -S-, -S(O)-, -S(O) 2 -, and the like, wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
  • heteroalkylene groups include, e.g., -CH 2 OCH 2 -, -CH(CH 3 )OCH 2 -, -CH 2 CH 2 OCH 2 -, -CH 2 CH 2 OCH 2 CH 2 OCH 2 -, -CH 2 SCH 2 -, -CH(CH 3 )SCH 2 -, -CH 2 CH 2 SCH 2 -, -CH 2 CH 2 SCH 2 CH 2 SCH 2 -, -CH 2 S(O) 2 CH 2 -, -CH(CH 3 )S(O) 2 CH 2 -, -CH 2 CH 2 S(O) 2 CH 2 -, -CH 2 CH 2 S(O) 2 CH 2 CH 2 OCH 2 -, -CH 2 NR y CH 2 -, -CH(CH 3 )NR y CH 2 -, -CH 2 CH 2 NR y CH 2 -, -CH 2 CH 2 NR y CH 2 CH 2 NR y CH 2 -,
  • heteroalkylene 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.
  • heteroalkylene does not include groups such as amides or other functional groups having an oxo present on one or more carbon atoms.
  • 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 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, oxygen and sulfur.
  • heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring 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, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxid
  • fused-heteroaryl rings include, but are not limited to, benzo [d]thiazolyl, quinolinyl, isoquinolinyl, benzo [b]thiophenyl, indazolyl, benzo [d] imidazolyl, pyrazolo[l,5-a]pyridinyl, and imidazo[l,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.
  • Heteroarylalkyl refers to the group “heteroaryl-alkyl-”.
  • Heterocyclyl refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • 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.
  • Any non-aromatic ring or fused ring system containing at least one heteroatom and one non-aromatic ring 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 a cycloalkyl, an aryl, or heteroaryl ring, regardless of the attachment to the remainder of the molecule.
  • 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., 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.
  • heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][l,4]dioxepinyl, 1,4- benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-
  • heterocyclyl also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom.
  • spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl and 6-oxa-l- 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.
  • Heterocyclylalkyl refers to the group “heterocyclyl -alkyl-”.
  • “Sulfonyl” refers to the group -S(O)2R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
  • R y 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 y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
  • R y 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.
  • “Sulfonamido” refers to the groups -SO 2 NR y R z and -NR y SO 2 R z , where R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • 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.
  • R y and R z as used herein are optionally substituted. In certain embodiments, R y and R z as used herein are unsubstituted.
  • substituted means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and/or heteroalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroaryl
  • R g and R h are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl.
  • substituted also means any of the above groups in which one or more (e.g., one to five or one to three) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl, or two of R g and R h and R 1 are taken together with the atoms to which they are attached to form a heterocyclyl ring optionally substituted with oxo, halo or alkyl optionally substituted with oxo, halo, amino, hydroxyl, or alkoxy.
  • 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.
  • substituted may describe other chemical groups defined herein.
  • the phrase “one or more” refers to one to five. In certain embodiments, as used herein, the phrase “one or more” refers to one to three.
  • any compound or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. These forms of compounds may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have structures depicted herein, except that one or more (e.g., one to five or one to three) atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine, such as 2 H, 3 H, “C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 0, 18 O, 31 P, 32 P, 35 S, 18 F, 36 C1, 123 I, and 125 I, respectively.
  • isotopically labeled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H and 14 C 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 singlephoton emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT singlephoton emission computed tomography
  • isotopically enriched analogs includes “deuterated analogs” of compounds described herein in which one or more (e.g., one to five or one to three) hydrogens is/are replaced by deuterium, such as a hydrogen on a carbon atom.
  • deuterium such as a hydrogen on a carbon atom.
  • Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound 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 (e.g., one to five or one to three) 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 a compound described herein.
  • 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.
  • 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.
  • 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, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic 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, aluminum, 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., NH2(substituted alkyl)
  • di(substituted alkyl) amines i.e., HN(substituted alkyl) 2 ).
  • 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 ⁇
  • 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)
  • 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 described herein 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.
  • the compounds of the disclosure, or their pharmaceutically acceptable salts include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (.S')- or, as (D)- or (L)- for amino acids.
  • the present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), (R)- and (.S')-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
  • “Diastereomers” 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 a structure described herein in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound described herein are prepared by modifying functional groups present in the compound described herein 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 described herein wherein a hydroxy, amino, carboxyl, or sulfhydryl group in a compound described herein is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, 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 described herein and the like. Preparation, selection and use of prodrugs is discussed in T. Higuchi and V.
  • a compound of Formula I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: L is a -NR 4 CH 2 -, -NR 4 -, -4 to 10-membered cycloalkyl-, a -NR 4 -4 to 10-membered cycloalkyl-, -4 to 10-membered heterocyclyl-, or a -4 to 10 membered heterocyclyl-NR 4 -, a -C(O)-4 to 10 membered heteroaryl-, -5 to 10-membered heteroaryl-; wherein bond a - is attached to ring A; and further wherein the cycloalkyl, heterocyclyl, or heteroaryl is independently optionally substituted with one to five R 5 ; m is 0, 1, or 2; t is 0, 1, 2, 3, 4, 5, or 6; ring A is aryl or heteroaryl
  • a compound of Formula I I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: L is a -NR 4 CH 2 -, -NR 4 -, -4 to 10-membered cycloalkyl-, a -NR 4 -4 to 10-membered cycloalkyl-, -4 to 10-membered heterocyclyl-, or a -4 to 10 membered heterocyclyl-NR 4 -, a -C(O)-4 to 10 membered heteroaryl-, -5 to 10-membered heteroaryl-; wherein bond a - is attached to ring A; and further wherein the cycloalkyl, heterocyclyl, or heteroaryl is independently optionally substituted with one to five R 5 ; m is 0, 1, or 2; t is 0, 1, 2, 3, 4, 5, or 6; ring A is aryl or heteroaryl
  • L is a -NR 4 CH 2 -, -NR 4 -, -4 to 10-membered cycloalkyl-, a -NR 4 -4 to 10- membered cycloalkyl-, -4 to 10-membered heterocyclyl-, a -4 to 10 membered heterocyclyl-NR 4 -, a -C(O)-4 to 10 membered heteroaryl-, or -5 to 10-membered heteroaryl-; wherein bond a - is attached to ring A; m is 0, 1, or 2; t is 0, 1, 2, 3, 4, 5, or 6; ring A is aryl or heteroaryl; wherein the aryl or heteroaryl is independently optionally substituted with C 1-6 alkyl; R 1 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, ary
  • each R 11 is independently hydrogen, C 1-6 alkyl, C2-g alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; and each R 13 is independently hydrogen, C 1-6 alkyl, C2-g alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl,
  • R 4 is hydrogen
  • L is a -NR 4 CH2-, a -NR 4 -4 to 10-membered cycloalkyl-, -4 to 10-membered heterocyclyl-, a -4 to 10 membered heterocyclyl-NR 4 -, a -C(O)-4 to 10 membered heteroaryl-, or -5 to 10- membered heteroaryl-; wherein bond a - is attached to ring A; and further wherein the cycloalkyl, heterocyclyl, or heteroaryl is independently optionally substituted with one to five R 5 .
  • L is a -NR 4 CH2-, a -NR 4 -4 to 10-membered cycloalkyl-, -4 to 10-membered heterocyclyl-, a -4 to 10 membered heterocyclyl-NR 4 -, a -C(O)-4 to 10 membered heteroaryl-, or -5 to 10-membered heteroaryl-; wherein bond a - is attached to ring A.
  • L is a -NR 4 CH2-; wherein bond a - is attached to ring A.
  • L is a -NR 4 -4 to 10-membered cycloalkyl-; wherein bond a - is attached to ring A.
  • L is -4 to 10-membered heterocyclyl-.
  • L is a -4 to 10 membered heterocyclyl-NR 4 -; wherein bond a - is attached to ring A.
  • L is a -C(O)-4 to 10 membered heteroaryl-; wherein bond a - is attached to ring A.
  • L is -5 to 10- membered heteroaryl-; wherein bond a - is attached to ring A.
  • L is a -NHCH2-; wherein bond a - is attached to ring A.
  • L is a -NH-.
  • L is a 4 to 10-membered monocyclic or bridged bicyclic heterocyclyl optionally substituted with one to five R 5 .
  • L is a -4 to 10 membered monocyclic or bridged heterocyclyl-NR 4 - optionally substituted with one to five R 5 .
  • L is , , wherein q is 0, 1, 2, 3, 4, or 5, and bond a - is attached to ring A.
  • L is a 5 to 6-membered heteroaryl optionally substituted with one to five R 5 .
  • L is a 5-membered heteroaryl optionally substituted with one to five R 5 .
  • L is a 5-membered heteroaryl.
  • L is a -C(O)-4 to 10 membered heteroaryl- optionally substituted with one to five R 5 .
  • L is imidazolyl or oxazolyl.
  • L is a 4 to 10-membered cycloalkyl optionally substituted with one to five R 5 .
  • L is cyclobutyl or bicyclo[1.1.1]pentyl.
  • L is a -NR 4 -4 to 10-membered cycloalkyl- optionally substituted with one to five R 5 .
  • L is a -NR 4 -cyclobutyl or a -NR 4 -bicyclo[1.1.1]pentyl. In certain embodiments, L is a -NH-cyclobutyl or a -NH-bicyclo[1.1.1]pentyl.
  • each R 5 is independently halo or C 1-6 alkyl. [0100] In certain embodiments, each R 5 is independently fluoro or methyl. [0101] In certain embodiments, q is 0, 1 or 2. In certain embodiments, q is 0. [0102] In certain embodiments, L is a -NHCH 2 - atached to ring A.
  • a compound of Formula IA wherein R 1 , R 2 , R 3 , t, m, and ring A are each independently as defined herein, and ring B is a 4 to 10- membered monocyclic or bridged heterocyclyl optionally substituted with one to five R 5 .
  • m is 0.
  • m is 1.
  • m is 2.
  • a compound of Formula IIA, IIB, IIC, or IID wherein R 1 , R 2 , R 3 , L, t, and ring A are each independently as defined herein.
  • ring A is aryl or heteroaryl; wherein the aryl or heteroaryl is independently optionally substituted with C 1-6 alkyl.
  • ring A is aryl optionally substituted with one to five Z 1 . In certain embodiments, ring A is aryl optionally substituted with Ci-6 alkyl. In certain embodiments, ring A is aryl. [0112] In certain embodiments, ring A is phenyl.
  • ring A is heteroaryl optionally substituted with one to five Z ’ . In certain embodiments, ring A is heteroaryl optionally substituted with C 1-6 alkyl. In certain embodiments, ring A is heteroaryl.
  • ring A is quinazolinyl, benzo[d]isoxazole, or indazolyl, wherein each is optionally substituted with one to five Z 1 . In certain embodiments, ring A is benzo[d]isoxazole.
  • R 1 is C 1-6 haloalkyl.
  • ring A is aryl or heteroaryl; wherein the aryl or heteroaryl is independently optionally substituted with Ci-g alkyl, and R 1 is Ci-ghaloalkyl.
  • ring A is aryl optionally substituted with Ci-g alkyl, and R 1 is Ci-g haloalkyl.
  • ring A is aryl, and R 1 is C 1-6 haloalkyl.
  • ring A is heteroaryl optionally substituted with Ci-g alkyl, and R 1 is C 1-6 haloalkyl.
  • L is a -NR 4 CH2-, a -NR 4 -4 to 10-membered cycloalkyl-, -4 to 10-membered heterocyclyl-, a -4 to 10 membered heterocyclyl-NR 4 -, a -C(O)-4 to 10 membered heteroaryl-, or -5 to 10- membered heteroaryl-; wherein bond a - is attached to ring A; ring A is aryl or heteroaryl; wherein the aryl or heteroaryl is independently optionally substituted with Ci-6 alkyl; and R 1 is Ci-g haloalkyl. [0118] In certain embodiments, R 1 is trifluoromethyl.
  • each R 3 is independently halo or hydroxy.
  • t is 0 or 1.
  • t is 0 or 1; and each R 3 is independently halo or -OR 13 . In certain embodiments, t is 0 or 1; and each R 3 is independently fluoro or -OH. In certain embodiments, t is 0 or 1; and R 3 is -OH.
  • t is 1; and R 3 is hydroxy.
  • a compound of Formula IV wherein R 1 , R 2 , R 3 , L, and ring A are each independently as defined herein.
  • R 3 is hydroxy. wherein R 1 , R 2 , R 3 , and ring A are each independently as defined herein.
  • R 2 is aryl or heteroaryl; wherein each aryl or heteroaryl is optionally substituted with one to five Z 1 .
  • R 2 is aryl optionally substituted with one to five Z 1 .
  • R 2 is phenyl optionally substituted with one to five Z 1 .
  • R 2 is heteroaryl optionally substituted with one to five Z 1 .
  • R 2 is pyridyl optionally substituted with one to five Z 1 .
  • R 2 is optionally substituted with one to five heteroaryl or -OR 10 .
  • R 2 is optionally substituted with pyrimidyl or methoxy.
  • L is a -NR 4 CH2-, a -NR 4 -4 to 10-membered cycloalkyl-, -4 to 10-membered heterocyclyl-, a -4 to 10 membered heterocyclyl-NR 4 -, a -C(O)-4 to 10 membered heteroaryl-, or -5 to 10- membered heteroaryl-; wherein bond a - is attached to ring A; ring A is aryl or heteroaryl; wherein the aryl or heteroaryl is independently optionally substituted with C 1-6 alkyl; R 1 is C 1-6 haloalkyl; and R 2 is Cg aryl, 5 or 6-membered heteroaryl, -O-aryl, or -O-heteroaryl; wherein each aryl or heteroaryl is optionally substituted with one to five Z 1
  • L is a -NR 4 CH2-, a -NR 4 -4 to 10-membered cycloalkyl-, -4 to 10-membered heterocyclyl-, a -4 to 10 membered heterocyclyl-NR 4 -, a -C(O)-4 to 10 membered heteroaryl-, or -5 to 10- membered heteroaryl-; wherein bond a - is attached to ring A; ring A is aryl or heteroaryl; wherein the aryl or heteroaryl is independently optionally substituted with Ci-g alkyl; R 1 is Ci-ghaloalkyl; R 2 is C 6 aryl, 5 or 6- membered heteroaryl, -O-aryl, or -O-heteroaryl; wherein each aryl or heteroaryl is optionally substituted with one to five Z 1 ; t is 0 or 1; R 3 is halo or -OH; and R 4 is hydrogen.
  • L is a -NR 4 CH2-, a -NR 4 -4 to 10-membered cycloalkyl-, -4 to 10-membered heterocyclyl-, or a -4 to 10 membered heterocyclyl-NR 4 -, a -C(O)-4 to 10 membered heteroaryl-, -5 to 10- membered heteroaryl-; wherein bond a - is attached to ring A; m is 2; t is 0 or 1; ring A is aryl or heteroaryl; wherein the aryl or heteroaryl is independently optionally substituted with Ci-g alkyl;
  • R 1 is Ci-ghaloalkyl
  • R 2 is heteroaryl substituted with heteroaryl
  • R 3 is -OH
  • R 4 is hydrogen
  • a compound selected from Table 1 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.
  • a compound selected from Table 2 or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof:
  • 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,
  • treating does not encompass preventing.
  • 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. In some embodiments, the subject is a mammal. In certain embodiments, the subject is a human.
  • terapéuticaally effective amount or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug 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 of 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.
  • 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.
  • the compounds disclosed herein can be used to treat or lessen a disease or condition mediated, at least in part, by CCR2, for example, by administering an effective amount of the compound disclosed herein to a subject in need thereof.
  • the compounds disclosed herein can be used to treat psoriasis, uveitis, rheumatoid arthritis, multiple sclerosis, restenosis, asthma, obesity, chronic obstructive pulmonary disease, pulmonary fibrosis, atherosclerosis, myocarditis, ulcerative colitis, nephritis (nephropathy), lupus, systemic lupus erythematosus, hepatitis, pancreatitis, sarcoidosis, organ transplantation, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, experimental autoimmune encephalomyelitis, and sepsis in which tissue infiltration of blood leukocytes, such as monocytes and lymphocytes, play a major role in the initiation, progression or maintenance of the disease.
  • tissue infiltration of blood leukocytes such as monocytes and lymphocytes
  • the compounds disclosed herein can be used to treat autoimmune diseases.
  • the compounds disclosed herein can be used to treat multiple sclerosis, rheumatoid arthritis, lupus erythematosus, Guillain-Barre syndrome, retinal damage, among others.
  • the compounds disclosed herein can be used to treat an allergy.
  • the compounds disclosed herein can be used to treat metabolic syndrome and cardiovascular disease.
  • the compounds disclosed herein can be used to treat obesity and atherosclerosis.
  • the compounds disclosed herein can be used to treat inflammatory disorders.
  • the compounds disclosed herein can be used to treat cancers. It is contemplated that the compounds described herein can be used to treat any type of cancer, including, but not limited to, carcinomas, sarcomas, lymphomas, leukemias and germ cell tumors.
  • Exemplary cancers include, but are not limited to, adrenocortical carcinoma, anal cancer, appendix cancer, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, osteosarcoma or malignant fibrous histiocytoma, brain cancer (e.g., brain stem glioma, astrocytoma (e.g., cerebellar, cerebral, etc.), atypical teratoid/rhabdoid tumor, central nervous system embryonal tumors, malignant glioma, craniopharyngioma, ependymoblastoma, ependymoma, medulloblastoma, medulloepithelioma, pineal parenchymal tumors of intermediate differentiation, supratentorial primitive neuroectodermal tumors and/or pineoblastorn a, visual pathway and/or hy pothalamic glioma, brain and spinal cord tumors, etc.), breast
  • noncancerous cellular proliferative disorders include, but are not limited to, fibroadenoma, adenoma, intraductal papilloma, nipple adenoma, adenosis, fibrocystic disease or changes of breast, plasma cell proliferative disorder (PCPD), restenosis, atherosclerosis, rheumatoid arthritis, myofibromatosis, fibrous hamartoma, granular lymphocyte proliferative disorders, benign hyperplasia of prostate, heavy chain diseases (HCDs), lymphoproliferative disorders, psoriasis, idiopathic pulmonary fibrosis, scleroderma, cirrhosis of the liver, IgA nephropathy, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, hemangiomas, vascular and non-vascular intraocular proliferative
  • the compounds disclosed herein can be used to treat solid tumors.
  • the compounds disclosed herein can be used to treat prostate cancer, breast cancer, and colorectal cancer.
  • the compounds disclosed herein can be used to treat pancreatic cancer, gastric cancer, bladder cancer, chondrosarcoma, and skin cancer.
  • the compounds disclosed herein can be used to inhibit metastasis formation.
  • the compounds disclosed herein can be used to treat metastatic resistant prostate cancer.
  • the compounds disclosed herein can be used to treat bone metastasis.
  • the compounds disclosed herein can be used to treat diseases of the nervous system. For example, Ischemia, Stroke, Neurodegeneration, Excitotoxic and mechanical injury'. Neurological complications of HIV infections.
  • the compounds disclosed herein are capable of inhibiting neuronal cell death, such as in prion disease.
  • the method includes administering a therapeutically effective amount of a compound or composition as described herein, to a patient in need of.
  • the disorder is a neurodegenerative disease.
  • the term “neurodegenerative disease” refers to a disease or condition in which the function of a subject's nervous system becomes impaired.
  • neurodegenerative diseases include, e.g., Alexander’s disease, Alper’s disease, Alzheimer’s disease, Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt- Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe’s disease, kuru, Lewy body dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple sclerosis, Multiple System Atrophy, Narcolepsy, Neuroborreliosis, Parkinson’s disease, Pelizaeus-Merzbacher Disease, Pick's disease, Primary lateral sclerosis, Prion diseases,
  • the compounds disclosed herein can be used to treat or lessen the severity of cancer, Alzheimer's disease, stroke, Type 1 diabetes, Parkinson disease, Huntington's disease, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, atherosclerosis, arrhythmias, or age-related macular degeneration.
  • the compounds disclosed herein can be used to treat or lessen inflammation, rheumatoid arthritis, atherosclerosis, neuropathic pain, lupus, lupus nephritis, systemic lupus erythematosus, restenosis, immune disorders, transplant rejection, neuroinflammation, acute brain injury, solid tumors, or cancer, for example, by administering an effective amount of the compound disclosed herein to a subject in need thereof.
  • the compounds disclosed herein can be used to treat or lessen systemic lupus erythematosus or lupus nephritis, for example, by administering an effective amount of the compound disclosed herein to a subject in need thereof.
  • the disease or condition is inflammation, rheumatoid arthritis, atherosclerosis, neuropathic pain, lupus, systemic lupus erythematosus, lupus nephritis, fibrosis, immune disorders, transplant rejection, neuroinflammation, acute brain injury, solid tumors, metabolic disease, or cancer.
  • provided herein are compounds or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in therapy.
  • provided herein are compounds or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in treating systemic lupus erythematosus or lupus nephritis.
  • kits that include a compound of the disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and suitable packaging.
  • a kit further includes instructions for use.
  • a kit includes a compound of the disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug 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, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug 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 a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug 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 fdlers, 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.
  • 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, com 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.
  • 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.
  • 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, semisolid, 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, e.g., 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, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug 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.
  • 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. 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, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug 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, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug 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.
  • a dosage of from about 0.0001 to about 100 mg per kg of body weight per day, from about 0.001 to about 50 mg of compound per kg of body weight, or from about 0.01 to about 10 mg of compound per kg of body weight may be appropriate.
  • body weight 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 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 and starting materials may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers.
  • 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, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Uouis, Missouri, USA).
  • a method of preparing a compound of Formula I comprising coupling a compound of Formula 1-4: with a compound of Formula 1-5: under conditions suitable to provide a compound of Formula I, wherein L, ring A, R 1 , R 2 , R 3 , m, and t are as defined herein.
  • compound 1-3 can be provided by contacting 1-1 with compound 1-2 under amide coupling conditions. Deprotection of compound 1-3 provides compound 1-4, or a salt thereof. Coupling of compound 1-4 with compound 1-5 under reductive amination conditions provides Formula I.
  • Appropriate starting materials and reagents can be purchased or prepared by methods known to one of skill in the art. For any compound shown in Scheme I, it should be understood that various derivatives can be provided by functional group interconversion at any step. In some embodiments, the various substituents of Formula 1-1, 1-2, 1-3, 1-4, or 1-5 are as defined herein.
  • 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. It should be appreciated that various isomers of Formula I can be separated as well. EXAMPLES
  • NMR Spectroscopy All NMR data was collected on Bruker 400 MHz instruments using the deuterated solvent as mentioned in the procedures described below. The peak frequencies are expressed in 5 ppm.
  • Reaction mixture was purged with N2 for 10 minutes, after that dicyclohexyl[2',4',6'-tris(propan-2-yl)-[l, l'-biphenyl]-2- yl]phosphane (212 mg, 0.444 mmol) and tris(l,5-diphenylpenta-l,4-dien-3-one) dipalladium (203 mg, 0.222mmol) were added, and the reaction mixture was stirred at 100 °C for 1 h in microwave.
  • reaction mixture was stirred at rt for 2 hours. Progress of the reaction mixture was checked by TLC monitoring. After completion of the reaction, the reaction mixture was poured into cold water (30 mL), extracted with ethyl acetate (2x100 mL), and concentrated in vacuo to give the crude product. The crude was purified by flash column chromatography, eluted on 40% EtOAc - Heptane as eluent, to afford tert-butyl 7- ⁇ 1-[3-(trifluoromethyl)phenyl]piperidine-4-carbonyl ⁇ -2,7- diazaspiro[4.4]nonane-2-carboxylate. LC-MS (ESI) m/z: 482.3 [M+H] + .
  • the reaction mixture was stirred at rt for 0.5 h and then cooled to 0 °C, and sodium bis(acetyloxy)boranuidyl acetate (0.2 g, 1.05 mmol, 2 eq) was added and stirred at room temperature for 1 h. Progress of the reaction mixture was checked by TLC monitoring. After completion of the reaction, the reaction mixture was evaporated under reduced pressure, extracted with DCM (2 x 50 mL), and the combined organic layers were dried with anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the crude product, which was loaded on a preparative TLC plate. The preparative TLC plate was developed with 4% MeOH.NH 3 in DCM.
  • Non-polar and polar bands of compound were separated and isolated to afford non-polar isomer (Example 1) and polar isomer (Example 2).
  • Non-Polar Isomer (Example 1) LC-MS (ESI) m/z: 635.49 [M+H] + .
  • reaction mixture was stirred at rt for 0.5 h and then cooled to 0 °C.
  • Sodium bis(acetyloxy)boranuidyl acetate (137 mg, 0.65 mmol) was added and stirred at room temperature for 3 h. Progress of the reaction was checked by TLC monitoring.
  • the ability of compounds to inhibit the activation of CCR2 receptor was measured using PathHunter ⁇ -Arrestin engineered cell lines (DiscoverX; 93-0192C1) and Chemiluminescence method, by detecting p- Arrestin recruitment.
  • the assay procedure is as follows: 5000 cells in 20pL of plating medium (DiscoverX; 93-0563R7A) were seeded into a white Opaque 384-well microplate (Perkin Elmer Cat# 6007680) and incubated overnight at 37°C and 5% CO2. Next, 5pL of diluted compounds (6X) in assay buffer (HBSS; 20mM HEPES) was added to the 384 well plate and incubated at 37°C and 5% CO2 for 30min.
  • HBSS assay buffer
  • the ability of compounds to inhibit the activation of CCR2 receptor was measured in THP-1 cells (ATCC; TIB-202) using a fluorescence method by detecting intracellular calcium flux.
  • the assay procedure is as follows: 20000 cells in 20 pL of assay buffer (HBSS; 20 mM HEPES) were seeded into an optically clear bottom 384-well microplate (Perkin Elmer Cat# 6007550) and incubated for 1 h at 37°C and 5% CO2. Then cells were loaded with calcium 6 dye (Molecular devices; R8191) following 1 h incubation at 37°C and 5% CO2.

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Abstract

La présente invention concerne de manière générale des modulateurs à petites molécules de cytokines chimiotactiques (chimiokine), récepteurs CCR2, ou un sel pharmaceutiquement acceptable, un stéréoisomère, un mélange de stéréoisomères ou un promédicament de ceux-ci, et des procédés de fabrication et d'utilisation de ceux-ci.
PCT/US2022/079088 2021-11-02 2022-11-01 Dérivés bicycliques utilisés en tant que modulateurs de ccr2 WO2023081661A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004050024A2 (fr) * 2002-11-27 2004-06-17 Incyte Corporation Derives de la 3-aminopyrrolidine modulateurs des recepteurs de la chemoquine
WO2012125661A1 (fr) * 2011-03-17 2012-09-20 Merck Sharp & Dohme Corp. Dérivés de 3-azabicyclo[3.1.0]hexane substitués utiles en tant qu'antagonistes de ccr2
WO2017127306A1 (fr) * 2016-01-18 2017-07-27 Arisan Therapeutics Dérivés d'adamatane pour le traitement d'une infection à filovirus

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Publication number Priority date Publication date Assignee Title
WO2004050024A2 (fr) * 2002-11-27 2004-06-17 Incyte Corporation Derives de la 3-aminopyrrolidine modulateurs des recepteurs de la chemoquine
WO2012125661A1 (fr) * 2011-03-17 2012-09-20 Merck Sharp & Dohme Corp. Dérivés de 3-azabicyclo[3.1.0]hexane substitués utiles en tant qu'antagonistes de ccr2
WO2017127306A1 (fr) * 2016-01-18 2017-07-27 Arisan Therapeutics Dérivés d'adamatane pour le traitement d'une infection à filovirus

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"Larock's Comprehensive Organic Transformations", vol. 1-5, 1989, ELSEVIER SCIENCE PUBLISHERS
"March's Advanced Organic Chemistry", 2001, JOHN WILEY, AND SONS
"Remington's Pharmaceutical Sciences", 1985, MACE PUBLISHING CO.
FIESERFIESER'S: "Reagents for Organic Synthesis", vol. 1-40, 1991, JOHN WILEY, AND SONS
FOSTER: "Deuterium Isotope Effects in Studies of Drug Metabolism", TRENDS PHARMACOL. SCI., vol. 5, no. 12, 1984, pages 524 - 527, XP025943358, DOI: 10.1016/0165-6147(84)90534-0
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