Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
  • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
• • 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
  • C07D405/02—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 two hetero rings
  • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• This disclosure is directed to small molecule agonists of the chemokine receptor CXCR3, and product containing the same, as well as to methods related to the use of such small molecule agonists.
• the chemokine receptor CXCR3 is a member of the seven transmembrane- spanning G protein-coupled receptor (GPCR) superfamily. CXCR3 is primarily expressed on activated T lymphocytes and NK cells. CXCL9/Mig, CXCL10/IP-10 and CXCL11/I-TAC, the natural chemokine ligands for CXCR3, are involved in directing activated T cells and other cells, such as NK cells, to sites of inflammation.
• GPCR G protein-coupled receptor
• CXCR3 has been implicated in Th1 cell-mediated inflammation, and upregulation of CXCR3 has been shown in a number of diseases involving T cells, such as inflammatory bowel disease ⁇ (IBD), multiple sclerosis (MS), rheumatoid arthritis (RA) and diabetes, to name a few.
• IBD inflammatory bowel disease
• MS multiple sclerosis
• RA rheumatoid arthritis
• diabetes to name a few.
• CXCR3 receptor agonists inhibit migration of activated T lymphocytes and NK cells.
• O'Boyle et al (“Chemokine receptor CXCR3 agonist prevents human T-cell migration in a humanized model of arthritic inflammation," PNAS, 109(12):4598-4603, 2012)
• generalized chemokine receptor desensitization can be induced by specific stimulation of a CXCR3 receptor on the surface of activated T cells, resulting in the inhibition of the inflammatory response that is normally produced.
• CXCR3 receptor agonists may act as functional antagonists through chemokine receptor desensitization.
• the present disclosure is generally directed to compounds which serve as agonists of the chemokine receptor CXCR3, as well as to composition containing the same, and to methods of their preparation and use.
• R, R 1 , R 2 , R 3a and R 3b are as defined below.
• a pharmaceutical composition comprising a compound of Formula I together with at least one pharmaceutically acceptable carrier, diluent or excipient is provided.
• a method of use of a compound of Formula I comprising preparation of a medicament is provided.
• a method of agonism of the CXCR3 receptor comprising contacting the receptor with a compound of Formula I, or a pharmaceutical composition comprising the same.
• a method for treatment of a disease or condition in a subject for which agonism of the CXCR3 receptor is medically indicated comprising administering to the subject a compound of Formula I, or a pharmaceutical composition comprising the same.
• a method for treating rheumatoid arthritis, multiple sclerosis, or inflammatory bowel disease in a subject in need thereof comprising administering to the subject a compound of Formula I, or a pharmaceutical composition comprising the same.
• R 1 is aryl or heteroaryl and substituted with 0–4 R 4 groups
• R 2 is aryl or heteroaryl and substituted with 0–3 R 5 groups, or R 2 is–NR 8 R 9 ;
• R 3a is hydrogen or alkyl and R 3b is a nitrogen- or amine-containing moiety of carbon, at least one nitrogen atom and hydrogen,
• R 6 and R 7 are, at each occurrence, hydrogen or alkyl; and R 8 is hydrogen or alkyl and R 9 is alkyl or aryl substituted with 0–4 R 4 groups,
• “alkyl” groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons (C 1 –C 12 alkyl), or, in some embodiments, from 1 to 8 carbon atoms (C 1 –C 8 alkyl), or, in some embodiments, from 1 to 4 carbon atoms (C 1 –C 4 alkyl).
• cycloalkyl groups such groups have from 3–20 carbon atoms as more specifically defined below.
• straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n- octyl groups.
• branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
• alkenyl groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.
• alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms.
• alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to ⁇ C ⁇ CH, ⁇ C ⁇ C(CH 3 ), ⁇ C ⁇ C(CH 2 CH 3 ), ⁇ CH 2 C ⁇ CH, ⁇ CH 2 C ⁇ C(CH 3 ), and ⁇ CH 2 C ⁇ C(CH 2 CH 3 ), among others.
• Cycloalkyl groups are alkyl groups forming a ring structure, which can be substituted or unsubstituted, wherein the ring is either completely saturated, partially unsaturated, or fully unsaturated, wherein if there is unsaturation, the conjugation of the pi-electrons in the ring do not give rise to aromaticity.
• Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
• the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7.
• Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like.
• (Cycloalkyl)alkyl groups, also referred to as“cycloalkylalkyl”, are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.
• cycloalkenyl alone or in combination denotes a cyclic alkenyl group wherein at least one double bond is present in the ring structure.
• Cycloalkenyl groups include cycloalkyl groups having at least one double bond between two adjacent carbon atoms.
• cycloalkenyl groups include but are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienyl groups, as well as polycyclic and/or bridging ring systems such as adamantine.
• “(Cycloalkenyl)alkyl” groups also referred to as“cycloalkylalkyl”, are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above.
• Carbocyclic and “carbocyclyl” denote a ring structure wherein the atoms of the ring are carbon. In some embodiments, the carbocyclyl has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7. Carbocyclyl includes, for example, cycloalkyl and cycloalkenyl.
• (Carbocyclyl)alkyl groups, also referred to as“carbocyclylalkyls”, are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a carbocyclyl as defined above.
• A“nonaromatic carbocyclyl” or a“nonaromatic carbocyclylalkyl” is a group in which the carbocyclic ring of the carbocyclyl or carbocyclylalkyl is a completely saturated, a partially unsaturated, or a fully unsaturated carbocyclyl, wherein if there is unsaturation, the conjugation of the pi-electrons of the carbocyclic ring do not give rise to aromaticity.
• Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
• aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.
• aryl groups contain 6–14 carbons in the ring portions of the groups.
• the phrase“aryl groups” includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).
• “Aralkyl” groups are alkyl, alkenyl or alkynyl groups as defined above in which a hydrogen atom of an alkyl, alkenyl or alkynyl group is replaced with an aryl group as defined above.
• Aralky groups can be substituted on the aryl moiety, the alkyl, alkenyl or alkynyl moiety, or both.
• Heterocyclyl or“heterocyclic” groups include aromatic and non-aromatic ring moieties containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, S, or P.
• heterocyclyl groups include 3 to 20 ring members, whereas other such groups have 3 to 15 ring members, including for example single ring systems containing 5, 6 or 7 ring members. At least one ring contains a heteroatom, but every ring in a polycyclic system need not contain a heteroatom.
• a dioxolanyl ring and a benzdioxolanyl ring system are both heterocyclyl groups within the meaning herein.
• a heterocyclyl group designated as a C 2 -heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6- ring with two carbon atoms and four heteroatoms, and so forth.
• a C 4 - heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
• heterocyclyl includes fused ring species including those having fused aromatic and non-aromatic groups.
• the phrase also includes polycyclic and/or bridging ring systems containing a heteroatom such as, but not limited to, quinuclidyl and 7-azabicyclo[2.2.1]heptane.
• a heterocyclyl group as defined herein can be a heteroaryl group or a partially or completely saturated cyclic group including at least one ring heteroatom.
• Heterocyclyl groups include, but are not limited to, pyrazinyl, pyrimidinyl, pyridazinyl, thiadiazolyl, oxadiazolyl, imidazolinyl, hexahydropyrimidinyl, diazepanyl, triazinyl, imidazolyl, pyrrolidinyl, furanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaind
• Heteroaryl groups are aromatic ring moieties containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
• a heteroaryl group designated as a C 2 -heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
• a C 4 -heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
• Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, pyrazinyl, pyrimidinyl, thiadiazolyl, imidazolyl, oxadiazolyl, thienyl, triazolyl, tetrazolyl, triazinyl, thiazolyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xant
• heteroaryl and “heteroaryl groups” include fused ring compounds such as wherein at least one ring, but not necessarily all rings, are aromatic, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl and 2,3- dihydro indolyl.
• aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2- anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3- furyl), indolyl, oxadiazolyl (1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl),isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acriterionazolin
• Heterocyclylalkyl groups are alkyl, alkenyl or alkynyl groups as defined above in which a hydrogen or carbon bond of an alkyl, alkenyl or alkynyl group is replaced with a bond to a heterocyclyl group as defined above.
• heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3- yl methyl, pyridine-2-yl methyl ( ⁇ -picolyl), pyridine-3-yl methyl ( ⁇ -picolyl), pyridine-4-yl methyl ( ⁇ -picolyl), tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
• Heterocyclylalkyl groups can be substituted on the heterocyclyl moiety, the alkyl, alkenyl or alkynyl moiety, or both.
• Heteroarylalkyl groups are alkyl, alkenyl or alkynyl groups as defined above in which a hydrogen or carbon bond of an alkyl, alkenyl or alkynyl group is replaced with a bond to a heteroaryl group as defined above. Heteroarylalkyl groups can be substituted on the heteroaryl moiety, the alkyl, alkenyl or alkynyl moiety, or both.
• ring system as the term is used herein is meant a moiety comprising one, two, three or more rings, which can be substituted with non-ring groups or with other ring systems, or both, which can be fully saturated, partially unsaturated, fully unsaturated, or aromatic, and when the ring system includes more than a single ring, the rings can be fused, bridging, or spirocyclic.
• spirocyclic is meant the class of structures wherein two rings are fused at a single tetrahedral carbon atom, as is well known in the art.
• a "monocyclic, bicyclic or polycyclic, aromatic or partially aromatic ring” as the term is used herein refers to a ring system including an unsaturated ring possessing 4n+2 pi electrons, or a partially reduced (hydrogenated) form thereof.
• the aromatic or partially aromatic ring can include additional fused, bridged, or spiro rings that are not themselves aromatic or partially aromatic.
• naphthalene and tetrahydronaphthalene are both a "monocyclic, bicyclic or polycyclic, aromatic or partially aromatic ring" within the meaning herein.
• a benzo-[2.2.2]-bicyclooctane is also a "monocyclic, bicyclic or polycyclic, aromatic or partially aromatic ring" within the meaning herein, containing a phenyl ring fused to a bridged bicyclic system.
• a fully saturated ring has no double bonds therein, and is carbocyclic or heterocyclic depending on the presence of heteroatoms within the meaning herein.
• two“R” groups are said to be joined together or taken together to form a ring, it is meant that together with the carbon atom or a non-carbon atom (e.g., nitrogen atom), to which they are bonded, they may form a ring system.
• cyclopentyl cyclohexyl, cycloheptyl, piperidinyl, piperazinyl, pyrolidinyl, pyrrolyl, pyridinyl.
• alkoxy refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined above.
• linear alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, n-butoxy, n- pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy n-nonyloxy, and the like.
• branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert- butoxy, isopentyloxy, isohexyloxy, and the like.
• cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
• aryloxy and“arylalkoxy” refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moiety. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
• acyl group refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
• the carbonyl carbon atom is also bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like.
• the group is a“formyl” group, an acyl group as the term is defined herein.
• An acyl group can include 0 to about 12–20 additional carbon atoms bonded to the carbonyl group.
• An acyl group can include double or triple bonds within the meaning herein.
• An acryloyl group is an example of an acyl group.
• An acyl group can also include heteroatoms within the meaning here.
• a nicotinoyl group (pyridyl-3-carbonyl) group is an example of an acyl group within the meaning herein.
• Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like.
• the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a“haloacyl” group.
• An example is a trifluoroacetyl group.
• amine includes primary, secondary, and tertiary amines having, e.g., the formula N(group) 3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like.
• Amines include but are not limited to R ⁇ NH 2 , for example, alkylamines, arylamines, alkylarylamines; R 2 NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R 3 N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like.
• the term "amine” also includes ammonium ions as used herein.
• amino is a substituent of the form ⁇ NH 2 , ⁇ NHR, ⁇ NR 2 , ⁇ NR +
• any compound substituted with an amino group can be viewed as an amine.
• An "ammonium" ion includes the unsubstituted ammonium ion NH +
• trimethylammonium hydrochloride and tetramethylammonium chloride are both ammonium ions, and amines, within the meaning herein.
• amide includes C- and N-amide groups, i.e., ⁇ C(O)NR 2 , and–NRC(O)R groups, respectively.
• Amide groups therefore include but are not limited to carbamoyl groups ( ⁇ C(O)NH 2 ) and formamide groups ( ⁇ NHC(O)H).
• a "carboxamido” group is a group of the formula C(O)NR 2 , wherein R can be H, alkyl, aryl, etc.
• hydroxyalkyl refers to an ⁇ alkyl ⁇ OH group.
• Halo include fluorine, chlorine, bromine and iodine.
• perhaloalkyl refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms. Perhaloalkyl groups include, but are not limited to, ⁇ CF 3 and–C(CF 3 ) 3 .
• haloalkyl refers to an alkyl group where some but not necessarily all of the hydrogen atoms are replaced by halogen atoms. Haloalkyl groups include but are not limited to–CHF 2 and–CH 2 F.
• perhaloalkoxy refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.
• Perhaloalkoxy groups include, but are not limited to, ⁇ OCF 3 and–OC(CF 3 ) 3 .
• haloalkoxy refers to an alkoxy group where some but not necessarily all of the hydrogen atoms are replaced by halogen atoms.
• Haloalkoxy groups include but are not limited to–OCHF 2 and–OCH 2 F.
• the compounds disclosed herein may be in the form of a neutral compound, or in the form of the free acid or free base. Alternatively, the compounds disclosed herein may be associated with a counter ion, and be in the form a salt. In one embodiment, the compound is in the form of a“pharmaceutically acceptable” salt, which refers to a salt possessing toxicity profiles within a range that affords utility in pharmaceutical applications.
• a "hydrate” is a compound that exists in a composition with water molecules.
• the composition can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
• a "hydrate” refers to a solid form (i.e., a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein).
• a “solvate” is a similar composition except that a solvent other that water replaces the water.
• a solvent other that water replaces the water.
• methanol or ethanol can form an “alcoholate”, which can again be stoichiometric or non-stoichiometric.
• a “solvate” refers to a solid form (i.e., a compound in solution in a solvent, while it may be solvated, is not a solvate as the term is used herein).
• a prodrug is a substance that can be administered to a patient where the substance is converted in vivo by the action of biochemicals within the patient’s body, such as enzymes, to the active pharmaceutical ingredient.
• prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases as are found in the bloodstream of humans and other mammals.
• substances are provided that can be administered to a patient where the substance is converted in vivo by the action of biochemical within the patient's body, such as enzymes, to a compound having the structure of any one of Formulas (I)-(IV).
• isotope refers to atoms with the same number of protons but a different number of neutrons
• an isotope of a compound of Formula (I) includes any such compound wherein one or more atoms are replaced by an isotope of that atom.
• carbon 12 the most common form of carbon, has six protons and six neutrons, whereas carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons.
• Hydrogen has two stable isotopes, deuterium (one proton and one neutron) and tritium (one proton and two neutrons). While fluorine has a number of isotopes, fluorine 19 is longest-lived.
• an isotope of a compound having the structure of Formula (I) includes, but not limited to, compounds of Formula (I) wherein one or more carbon 12 atoms are replaced by carbon 13 and/or 14 atoms, wherein one or more hydrogen atoms are replaced with deuterium and/or tritium, and/or wherein one or more fluorine atoms are replaced by fluorine 19.
• isolated optical isomer means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula.
• the isolated isomer is at least about 80% pure by weight, or at least 80% pure by weight, or at least 85% pure by weight. In other embodiments, the isolated isomer is at least 90% pure by weight, or at least 98% pure by weight, or at least 99% pure by weight.
• substantially enantiomerically or diastereomerically pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer with respect to the other enantiomer or diastereomer of at least 80%, and in other embodiments means in excess of 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.
• Enantiomers are sometimes called optical isomers because a pure enantiomer rotates plane-polarized light in a particular direction. If the light rotates clockwise, then that enantiomer is labeled“(+)” or“d” for dextrorotatory, its counterpart will rotate the light counterclockwise and is labeled“(-)” or“l” for levorotatory.
• racemate and “racemic mixture” are frequently used interchangeably.
• a racemate is an equal mixture of two enantiomers.
• a racemate is labeled“( ⁇ )” because it is not optically active (i.e., will not rotate plane-polarized light in either direction since its constituent enantiomers cancel each other out).
• phrases such as“under conditions suitable to provide” or“under conditions sufficient to yield” or the like, in the context of methods of synthesis, as used herein refers to reaction conditions, such as time, temperature, solvent, reactant concentrations, and the like, that are within ordinary skill for an experimenter to vary, that provide a useful quantity or yield of a reaction product. It is not necessary that the desired reaction product be the only reaction product or that the starting materials be entirely consumed, provided the desired reaction product can be isolated or otherwise further used.
• heteroatoms refers to non-carbon and non-hydrogen atoms, capable of forming covalent bonds with carbon, and is not otherwise limited. Typical heteroatoms are N, O, and S.
• sulfur (S) When sulfur (S) is referred to, it is understood that the sulfur can be in any of the oxidation states in which it is found, thus including sulfoxides (R ⁇ S(O) ⁇ R') and sulfones (R ⁇ S(O) 2 ⁇ R'), unless the oxidation state is specified; thus, the term “sulfone” encompasses only the sulfone form of sulfur; the term “sulfide” encompasses only the sulfide (R ⁇ S ⁇ R') form of sulfur.
• compounds are provided having the structure of the following Formula II, including stereoisomers, hydrates, solvates, isotopes or pharmaceutically acceptable salts thereof:
• R, R 3a , R 3b , R 4 , and R 5 are as defined above.
• R, R 3b , R 4 and R 5 are as defined above.
• compounds are provided having the structure of the following Formula IV, including stereoisomers, hydrates, solvates, isotopes or pharmaceutically acceptable salts thereof: IV wherein R, R 3b and R 4 are as defined above.
• compounds are provided having the structure of the following Formula V, including stereoisomers, hydrates, solvates, isotopes or pharmaceutically acceptable salts thereof:
• R, R 1 , R 3a , R 3b , R 8 and R 9 are as defined above.
• compounds are provided having the structure of the following Formula VII, including stereoisomers, hydrates, solvates, isotopes or pharmaceutically acceptable salts thereof:
• R, R 1 , R 3a , R 3b and R 4 are as defined above.
• compounds are provided having the structure of the following Formula VIII, including stereoisomers, hydrates, solvates, isotopes or pharmaceutically acceptable salts thereof:
• R, R 1 , R 3a , R 3b and R 4 are as defined above.
• compounds are provided having the structure of the following Formula IX, including stereoisomers, hydrates, solvates, isotopes or pharmaceutically acceptable salts thereof:
• R, R 1 , R 3a , R 3b and R 4 are as defined above.
• R 14 is H or R 4 and R, R 1 , R 3a , R 3b and R 4 are as defined above.
• the various“R” groups are set forth in more detail with respect to the compounds of each of Formulas I through V, as applicable to the R group being further defined.
• R 1 is intended to further limit the compounds of Formulas I, V and VI, but not Formulas II, III and IV (since R 1 has already been further limited in those structures).
• R 3b would be applicable to each of Formulas I through VI since such structures list R 3a as a variable group.
• R 1 is aryl
• R 1 is aryl substituted with 1–4 R 4 groups.
• R 1 is aryl substituted with 0 R 4 groups.
• R 1 is heteroaryl
• R 1 is heteroaryl substituted with 1–4 R 4 groups.
• R 1 is heteroaryl substituted with 0 R 4 groups.
• R 1 is substituted with at least one R 4 group. In another embodiment, R 1 is substituted with at least two R 4 groups. In another embodiment, R 1 is substituted with at least three R 4 groups.
• R 4 is selected from halo and alkyl. In one embodiment, R 4 is halo. In another embodiment, R 4 is alkyl.
• R 1 is substituted with at least three R 4 groups selected from halo and alkyl.
• R 2 is aryl
• R 2 is heteroaryl
• R 2 is substituted with zero R 5 groups. In another embodiment, R 2 is substituted with at least one R 5 groups. In another embodiment, R 2 is substituted with at least two R 5 groups. In another embodiment, R 2 is substituted with three R 5 groups.
• R 3a is hydrogen
• R 3a is alkyl.
• R 3a is hydrogen and R 3b is a nitrogen or amine-containing moiety of carbon with at least one nitrogen atom and hydrogen.
• R 10 , R 11 , R 12 and R 13 are independently hydrogen, alkyl or haloalkyl.
• R 3a is hydrogen and R 3b is alkyl substituted with ⁇ NR 10 R 11 or ⁇ N + R 10 R 11 R 12 .
• R 3a is hydrogen and R 3b is–(CH 2 ) 2–4 NH 2 .
• R 3a is hydrogen and R 3b is:
• R 3a is hydrogen and R 3b is:
• R 3a is hydrogen and R 3b is:
• R 3a is hydrogen and R 3b is a nitrogen-containing heterocyclyl substituted with 0–4 R 4 groups.
• R 3a is hydrogen and R 3b is:
• R 3a is hydrogen and R 3b is alkyl substituted with a nitrogen- containing heterocyclyl substituted with 0–4 R 4 groups.
• R 3a is hydrogen and R 3b is: ,
• R 3a is hydrogen and R 3b is heteroaryl substituted with 0–4 R 4 groups.
• R 3a is hydrogen and R 3b is alkyl substituted with heteroaryl substituted with 0–4 R 4 groups.
• R 3a is hydrogen and R 3b is: ,
• R 3a and R 3b are taken together with the carbon atom to which they are attached to form a cyclic nitrogen- or amine-containing moiety of carbon, at least one nitrogen atom and hydrogen.
• R 3a and R 3b are taken together with the carbon atom to which they are attached to form a nitrogen-containing heterocyclyl substituted with 0–4 R 4 groups.
• R 3a and R 3b are taken together with the carbon atom to which they are attached to form:
• R 2 is ⁇ NR 8 R 9 , wherein R 8 is hydrogen or alkyl and R 9 is alkyl or aryl substituted with 0–4 R 4 groups.
• ⁇ NR 8 R 9 is:
• ⁇ NR 8 R 9 is:
• R, R 1 , R 2 and R 3b are as defined above.
• R, R 1 and R 2 are as defined above;
• R 3a and R 3b taken together with the carbon to which they are attached form a cyclic nitrogen- or amine-containing moiety of carbon.
• compounds are provided having the structure of the following Formula I, including stereoisomers, hydrates, solvates, isotopes or pharmaceutically acceptable salts thereof:
• “individual” (as in the subject or patient of the treatment) means both mammals and non-mammals. Mammals include, for example, humans; non-human primates, e.g., apes and monkeys; cattle; horses; sheep; and goats. Non-mammals include, for example, fish and birds.
• a "receptor”, as is well known in the art, is a biomolecular entity usually comprising a protein that specifically binds a structural class of ligands or a single native ligand in a living organism, the binding of which causes the receptor to transduce the binding signal into another kind of biological action, such as signaling a cell that a binding event has occurred, which causes the cell to alter its function in some manner.
• CXCR3 compound or “CXCR3 agonist” or “CXCR3 activator” or “CXCR3 modulator” or “CXCR3 antagonist” or “CXCR3 potentiator” or “CXCR3 modulator” as the terms are used herein refer to compounds that interact in some way with the CXCR3 receptor. They can be agonists, potentiators, or activators, or they can be antagonists or inhibitors, and can be selective for action of the CXCR3 receptor family.
• disease or “disorder” or “malcondition” are used interchangeably, and are used to refer to diseases or conditions wherein a CXCR3 receptor plays a role in the biochemical mechanisms involved in the disease or malcondition or symptom(s) thereof such that a therapeutically beneficial effect can be achieved by acting on a CXCR3 receptor.
• substantially as the term is used herein means completely or almost completely; for example, a composition that is "substantially free” of a component either has none of the component or contains such a trace amount that any relevant functional property of the composition is unaffected by the presence of the trace amount, or a compound is "substantially pure” is there are only negligible traces of impurities present.
• Treating” or “treatment” within the meaning herein refers to an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder.
• the expression“effective amount”, when used to describe use of a compound of the invention in providing therapy to a patient suffering from a disorder or malcondition mediated by a CXCR3 receptor refers to the amount of a compound of the invention that is effective to bind to as an agonist or as an antagonist a CXCR3 receptor in the individual's tissues, wherein the CXCR3 is implicated in the disorder, wherein such binding occurs to an extent sufficient to produce a beneficial therapeutic effect on the patient.
• an“effective amount” or a“therapeutically effective amount” of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition.
• a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result by acting as an agonist of CXCR3 activity.
• a therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects.
• a therapeutically effective amount of a CXCR3 receptor antagonist of the invention is an amount sufficient to control the malcondition, to mitigate the progress of the malcondition, or to relieve the symptoms of the malcondition.
• a pharmaceutical composition comprising a compound of Formula I together with at least one pharmaceutically acceptable carrier, diluent or excipient.
• a method for activating, potentiating, or agonizing (i.e., to have an agonic effect, to act as an agonist) a CXCR3 receptor, with a compound of Formula I.
• the method involves contacting the receptor with a suitable concentration of a compound of Formula I to bring about activation of the receptor.
• the contacting can take place in vitro, for example in carrying out an assay to determine the CXCR3 receptor activation activity of a compound undergoing experimentation related to a submission for regulatory approval.
• the method for activating a CXCR3 receptor can be carried out in vivo; that is, within the living body of a mammal, such as a human patient or a test animal.
• the compound of Formula I can be supplied to the living organism via a suitable route (e.g., orally), or can be provided locally within the body tissues.
• a method is provided for treatment of a disease or condition in a subject or patient for which activation of a CXCR3 receptor is medically indicated, wherein the subject or patient is administered a therapeutically effective amount of a compound of Formula I.
• a method for treating or preventing a disease or condition comprising administering a pharmaceutical composition comprising a compound of Formula I together with at least one pharmaceutically acceptable carrier, diluent or excipient to a subject or patient in need thereof.
• the subject or patient is afflicted with, or at risk of developing, rheumatoid arthritis, multiple sclerosis, or inflammatory bowel disease.
• use of a compound of Formula I is provided for preparation of a medicament.
• System 2 Agilent 1100/6110 HPLC system equipped with a Agilent Poroshell 120 EC-C8, 2.7 ⁇ (50 x 3 mm) column using water with 5 mM ammonium acetate as the mobile phase C, and acetonitrile with 5 mM ammonium acetate as the mobile phase D with a flow rate of 1 mL/min.
• Method 3 5% D (95% C) to 95% D over 12 min then held at 95% D for 2.8 min and then to 5% D over 0.2 min.
• ammonia (NH 3 ), tetrahydrofuran (THF), hydrochloric acid (HCl), sodium bicarbonate (NaHCO 3 ), dichloroethane (DCE), trifluoroacetic acid (TFA), magnesium sulfate (MgSO 4 ), hydrogen (H 2 ), tetrabutylammonium fluoride (TBAF), diazabicycloundecene (DBU), methyl tert-butyl ether (MTBE), nitric acid (HNO 3 ), ethyl acetate (EA), 1-methy-2-pyrrolidinone (NMP), triethylamine (TEA), 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), N-hydroxybenzotriazole (HOBt), 1-ethyl-3-(
• Step 1A Ethyl (S)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3- carboxylate (Intermediate 1A).
• Step 1C Methyl N 6 -(tert-butoxycarbonyl)-N 2 -((S)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4- tetrahydroisoquinoline-3-carbonyl)-L-lysinate (Intermediate 1C).
• Step 1E Tert-butyl ((S)-6-((3,4-dichlorophenyl)amino)-6-oxo-5-((S)-2-(4-oxo-4- phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)hexyl)carbamate (Intermediate 1E).
• Step 1F (S)-N-((S)-6-amino-1-((3,4-dichlorophenyl)amino)-1-oxohexan-2-yl)-2-(4- oxo-4-phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (Compound 1-1)
• Step 2A 2,5-dioxopyrrolidin-1-yl (S)-2- (4-oxo-4-phenylbutanoyl)-1,2,3,4-tetra hydro isoquinoline -3-carboxylate (Intermediate 2A).
• Step 2C tert-butyl ((S)-4-((3,4-dichlorophenyl)amino)-4-oxo-3-((S)-2-(4-oxo-4- phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)butyl)carbamate (Intermediate 2C).
• Step 2D (S)-N-((S)-4-amino-1-((3,4-dichlorophenyl)amino)-1-oxobutan-2-yl)-2-(4- oxo-4-phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (Compound 2-1).
• Step 3A Synthesis of tert-butyl (S)-(1-((3,4-dichlorophenyl)amino)-1-oxo-5- ureidopentan-2-yl)carbamate (Intermediate 3A).
• Step 3C Synthesis of (S)-N-((S)-1-((3,4-dichlorophenyl)amino)-1-oxo-5-ureidopentan- 2-yl)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (Compound 3-1).
• Step 4A Synthesis of (9H-fluoren-9-yl)methyl tert-butyl (6-((4-chloro-3- methylphenyl)amino)-6-oxohexane-1,5-diyl)(S)-dicarbamate (Intermediate 4A).
• Step 4B Synthesis of tert-butyl (S)-(5-amino-6-((4-chloro-3-methylphenyl)amino)-6- oxohexyl)carbamate (Intermediate 4B).
• Step 4C Synthesis of tert-butyl ((S)-6-((4-chloro-3-methylphenyl)amino)-6-oxo-5- ((S)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido) hexyl) carbamate. (Intermediate 4C).
• Step 4D Synthesis of (S)-N-((S)-6-amino-1-((4-chloro-3-methylphenyl)amino)-1- oxohexan-2-yl)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamide (Compound 4-2).
• Step 5A Synthesis of (9H-fluoren-9-yl)methyl (S)-(1-((3,4-dichlorophenyl)amino)-5- (3,3-dimethylguanidino)-1-oxopentan-2-yl)carbamate (Intermediate 5A).
• Step 7A Synthesis of 2-(4-(4-fluorophenyl) -4-oxobutanoyl)- 1,2,3,4- tetrahydroisoquinoline -3-carboxylic acid (Intermediate 7A).
• Step 7C Synthesis of (9H-fluoren-9-yl)methyl tert-butyl (6-((4-chloro-3-methylphenyl )amino)-6-oxohexane-1,5-diyl)(S)-dicarbamate (Intermediate 7C).
• Step 7E Synthesis of tert-butyl ((5S)-6-((4-chloro-3-methylphenyl)amino)-5-(2-(4-(4- fluorophenyl) -4-oxobutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)-6- oxohexyl) carbamate (Intermediate 7E).
• Step 7F Synthesis of N-((S)-6-amino-1-((4-chloro-3-methylphenyl)amino)-1-oxohexan -2-yl) -2-(4-(4-fluorophenyl)-4-oxobutanoyl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamide (Compound 7-1).
• Step 8A Synthesis of (S)-N-((S)-1-((4-chloro-3-methylphenyl)amino)-4- (isobutylamino) -1-oxobutan-2-yl)-2- (4-oxo-4-phenylbutanoyl)- 1,2,3,4- tetrahydroisoquinoline -3-carboxamide (Compound 8-1).
• Step 9A Synthesis of (2S)-3-guanidino-2-(2-(4-oxo-4-phenylbutanoyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamido)propanoic acid (Intermediate 9A)
• Step 10A Synthesis of (9H-fluoren-9-yl)methyl (S)-3-(((S)-4-((tert- butoxycarbonyl)amino)-1-((4-chloro-3-methylphenyl)amino)-1-oxobutan-2- yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Intermediate 10A).
• Step 10B Synthesis of tert-butyl ((S)-4-((4-chloro-3-methylphenyl)amino)-4-oxo-3- ((S)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)butyl)carbamate (Intermediate 10B).
• Step 10C Synthesis of tert-butyl ((S)-4-((4-chloro-3-methylphenyl)amino)-4-oxo-3- ((S)-2-(4-oxo-4-(piperidin-1-yl)butanoyl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamido) butyl) carbamate (Intermediate 10C).
• Step 11A Synthesis of tert-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4- ((2-chloro-3-methylphenyl)carbamoyl)piperidine-1-carboxylate (Intermediate 11A).
• Step 11E Synthesis of tert-butyl (S)-4-((2-chloro-3-methylphenyl)carbamoyl)-4-(2-(4- oxo-4-phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)piperidine-1- carboxylate (Intermediate 11E).
• Step 11F Synthesis of (S)-N-(4-((2-chloro-3-methylphenyl)carbamoyl)piperidin-4-yl)- 2-(4-oxo-4-phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (Compound 11-1)
• Step 12B Synthesis of tert-butyl ((S)-4-((4-chloro-3-methylphenyl)amino)-3-((S)-2-(4- ((2R,6S)-2,6-dimethylmorpholino)-4-oxobutanoyl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamido)-4-oxobutyl)carbamate (Intermediate 12B).
• Step 13A Synthesis of 1-(tert-butyl) 4-methyl (S)-4-(2-(((9H-fluoren-9- yl)methoxy)carbonyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxamido) piperidine-1,4- dicarboxylate (Intermediate 13A).
• Step 13C Synthesis of (S)-1-tert-butyl 4-methyl 4-(2-(4-oxo-4-phenylbutanoyl)- 1,2,3,4-tetrahydroisoquinoline-3-carboxamido)piperidine-1,4-dicarboxylate
• Step 13D Synthesis of (S)-1-(tert-butoxycarbonyl)-4-(2- (4-oxo-4-phenylbutanoyl)- 1,2,3,4- tetra hydro isoquinoline -3- carboxamido) piperidine-4- carboxylic acid (Intermediate 13D).
• Step 13E Synthesis of tert-butyl (S)-4-((2,3-dihydro-1H-inden-5-yl)carbamoyl)-4-(2- (4-oxo-4-phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)piperidine-1- carboxylate (Intermediate 13E).
• Step 13F Synthesis of ((S)-N-(4-((2,3-dihydro-1H-inden-5-yl)carbamoyl) piperidin-4- yl)- 2-(4-oxo-4-phenylbutanoyl)- 1,2,3,4- tetrahydroisoquinoline-3-carboxamide (Compound 13-1).
• Step 14A Synthesis of (9H-fluoren-9-yl) methyl (S)-(4-azido-1-((2-chloro-5-fluoro phenyl) amino)-1-oxo butan-2-yl)carbamate (Intermediate 14A).
• Step 14D Synthesis of (S)-N-((S)-4-amino- 1-((2-chloro-5-fluorophenyl) amino)-1- oxobutan-2-yl)-2- (4-oxo-4-phenylbutanoyl)-1,2,3,4- tetrahydroisoquinoline-3- carboxamide (Compound 14-1)
• Step 15A Synthesis of tert-butyl (S)-3-(((S)-4-azido-1-((3,4-dichloro-2-fluorophenyl) amino)-1-oxobutan-2-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Intermediate 15A).
• Step 15D Synthesis of (S)-N-((S)-4-azido-1-((3,4-dichloro-2-fluorophenyl)amino)-1- oxobutan-2-yl)-2-(4-(4,4-dimethylpiperidin-1-yl)-4-oxobutanoyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide (Intermediate 15D).
• Step 15E Synthesis of (S)-N-((S)-4-amino-1-((3,4-dichloro-2-fluorophenyl)amino)-1- oxobutan-2-yl)-2-(4-(4,4-dimethylpiperidin-1-yl)-4-oxobutanoyl)-1,2,3,4-tetrahydro iso quinoline-3-carboxamide (Compound 15-1).
• Step 16A Synthesis of tert-butyl (S)-(4-(benzyloxy)- 1-((4-chloro-3-methylphenyl) amino) -1-oxobutan-2-yl) carbamate (Intermediate 16A).
• Oxalyl dichloride (199 ⁇ L, 2.35 mmol) was added dropwise to a solution of DMSO (332 ⁇ L, 4.67 mmol) in DCM (6 mL) at -78 o C. After 15 min, a solution of Intermediate 16B (450 mg, 1.313 mmol) in DCM (4 mL) was added slowly. After 45 min at -78 oC, NEt 3 (951 ⁇ L, 6.83 mmol) was added dropwise. After 1 h, the mixture was warmed to 0 oC then quenched with NaHCO 3 (20 mL), split through a hydrophobic frit, and washed with DCM.
• Step 16D Synthesis of tert-butyl (S)-(1-((4-chloro-3-methylphenyl)amino)-4- (cyclopropylamino)-1-oxobutan-2-yl)carbamate (Intermediate 16D).
• Step 16F Synthesis of (S)-N-((S)-1-((4-chloro-3-methylphenyl)amino)-4- (cyclopropylamino)-1-oxobutan-2-yl)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide (Compound 16-1)
• Step 17A Synthesis of tert-butyl (S)-3-((((9H-fluoren-9-yl)methoxy) carbonyl)amino) - 4-((4-chloro-3-methylphenyl)amino)-4-oxobutanoate (Compound 17A)
• Step 17C Synthesis of (9H-fluoren-9-yl)methyl (S)-3-(((S)-4- (tert-butoxy)- 1-((4- chloro- 3-methylphenyl) amino) -1,4-dioxobutan-2-yl) carbamoyl) -3,4- dihydroisoquinoline -2(1H)-carboxylate (Compound 17C)
• Step 17D Synthesis of (S)-3-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamido)-4-((4-chloro-3-methylphenyl)amino)-4- oxobutanoic acid (Compound 17D)
• Step 17E Synthesis of (9H-fluoren-9-yl)methyl (S)-3-(((S)-1-((4-chloro-3- methylphenyl)amino)-4-hydroxy-1-oxobutan-2-yl)carbamoyl)-3,4-dihydroisoquinoline- 2(1H)-carboxylate (Compound 17E)
• Step 17F Synthesis of (9H-fluoren-9-yl)methyl (S)-3-(((S)-1-((4-chloro-3- methylphenyl)amino)-4-hydroxy-1-oxobutan-2-yl)carbamoyl)-3,4-dihydroisoquinoline- 2(1H)-carboxylate (Compound 17F)
• Step 17G Synthesis of (9H-fluoren-9-yl)methyl (S)-3-(((S)-1-((4-chloro-3- methylphenyl)amino)-4-(4-hydroxypiperidin-1-yl)-1-oxobutan-2-yl)carbamoyl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (Compound 17G)
• Step 17H Synthesis of (9H-fluoren-9-yl)methyl (S)-3-(((S)-1-((4-chloro-3- methylphenyl)amino)-4-(4-hydroxypiperidin-1-yl)-1-oxobutan-2-yl)carbamoyl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (Compound 17H)
• Step 17I Synthesis of (S)-N-((S)-1-((4-chloro-3-methylphenyl)amino)-4-(4- hydroxypiperidin-1-yl)-1-oxobutan-2-yl)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide (Compound 17-1)
• Step 18A Synthesis of (S)-4-(3-(tert-butoxycarbonyl)-3,4-dihydroisoquinolin-2(1H)- yl)-4-oxobutanoic acid (Compound 18A)
• Step 18B Synthesis of tert-butyl (S)-2-(4-(2,2-dimethylpiperidin-1-yl)-4-oxobutanoyl)- 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Compound 18B)
• Step 18C Synthesis of (S)-2-(4-(2,2-dimethylpiperidin-1-yl)-4-oxobutanoyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid (Compound 18C)
• Step 18D Synthesis of (S)-N-((S)-4-azido-1-((4-chloro-2-iodo-5-methylphenyl) amino)-1-oxobutan-2-yl)-2-(4-(2,2-dimethylpiperidin-1-yl)-4-oxobutanoyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide (Compound 18D)
• Step 18F Synthesis of (S)-N-((S)-4-amino- 1-((4-chloro-2- cyano-5-methyl phenyl) amino)-1-oxobutan-2-yl) -2-(4-(2,2-dimethyl piperidin-1-yl)-4-oxobutanoyl)- 1,2,3,4- tetrahydroisoquinoline -3-carboxamide (Compound 18-1)
• Step 19A Synthesis of (S)-4-(3-(tert-butoxycarbonyl)-3,4-dihydroisoquinolin-2(1H)- yl)-4-oxobutanoic acid (Compound 19-1)
• Step 20A Synthesis of (S)-N-(1-(2-((tert- butyldimethylsilyl)oxy)ethyl)-4- ((4-chloro- 3-methyl phenyl) carbamoyl)piperidin-4-yl)- 2-(4-oxo-4-phenylbutanoyl) -1,2,3,4- tetrahydro isoquinoline-3-carboxamide (Compound 20A)
• Step 20B Synthesis of (S)-N-(4-((4-chloro-3-methyl phenyl) carbamoyl)-1-(2- hydroxyethyl) piperidin- 4-yl)-2-(4-oxo-4-phenylbutanoyl) -1,2,3,4-tetrahydro isoquinoline - 3-carboxamide (Compound 20-1)
• Step 21A Synthesis of methyl (E)-2-((tert-butoxycarbonyl)amino)-4-(3- (dimethylamino)oxetan-3-yl)but-2-enoate (Intermediate 21A)
• Step 21D Synthesis of tert-butyl (1-((4-chloro-3-methylphenyl)amino)-4-(3- (dimethylamino)oxetan-3-yl)-1-oxobutan-2-yl)carbamate (Intermediate 21D)
• Step 21F Synthesis of (3S)-N-(1-((4-chloro-3-methylphenyl)amino)-4-(3- (dimethylamino)oxetan-3-yl)-1-oxobutan-2-yl)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide (Compound 21-1)
• Step 22A Synthesis of (E)-methyl 2-(((benzyloxy)carbonyl)amino)-3-(3-((tert- butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)acrylate (Intermediate 22A)
• Step 22C Synthesis of (3-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)-2- ((S)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamido)propanoic acid (Intermediate 22C)
• Step 22D Synthesis of 3-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)-2- ((S)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido) propanoic acid (Intermediate 22D)
• Step 22E Synthesis of tert-butyl (3-(3-((4-chloro-3-methylphenyl)amino)-3-oxo-2-((S)- 2-(4-oxo-4-phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamido)propyl)bicyclo[1.1.1]pentan-1-yl)carbamate (Intermediate 22E)
• Step 22F Synthesis of (S)-N-((S)-3-(3-aminobicyclo[1.1.1]pentan-1-yl)-1-((4-chloro-3- methylphenyl)amino)-1-oxopropan-2-yl)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide (Compound 22-1) and (S)-N-((R)-3-(3- aminobicyclo[1.1.1]pentan-1-yl)-1-((4-chloro-3-methylphenyl)amino)-1-oxopropan-2- yl)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
• Step 23A Synthesis of tert-butyl (((9H-fluoren-9-yl)methoxy)carbonyl)-L- homoserinate (Intermediate 23A)
• Step 23B Synthesis of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)- 4-oxobutanoate (Intermediate 23B)
• Step 23C Synthesis of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)- 4-(4-fluoropiperidin-1-yl)butanoate (Intermediate 23C)
• Step 23D Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(4- fluoropiperidin-1-yl)butanoic acid (Intermediate 23D)
• Step 23F Synthesis of (S)-2-amino-N-(2,3-dihydro-1H-inden-5-yl)-4-(4- fluoropiperidin-1-yl)butanamide (Intermediate 23F)
• Step 23G Synthesis of N-(1-((2,3-dihydro-1H-inden-5-yl)amino)-4-(4-fluoropiperidin- 1-yl)-1-oxobutan-2-yl)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamide (Compound 23-1)
• Step 24A Synthesis of (9H-fluoren-9-yl)methyl (S)-3-(((S)-1-((4-chloro-3- methylphenyl)amino)-4-iodo-1-oxobutan-2-yl)carbamoyl)-3,4-dihydroisoquinoline- 2(1H)-carboxylate (Intermediate 24A)
• Step 24C Synthesis of (S)-N-((S)-1-((4-chloro-3-methylphenyl)amino)-4-(4- methoxypiperidin-1-yl)-1-oxobutan-2-yl)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide (Intermediate 24-1)
• Step 25A Synthesis of (9H-fluoren-9-yl)methyl (3S)-3-((1-(tert-butoxy)-4-(4- hydroxypiperidin-1-yl)-1-oxobutan-2-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)- carboxylate (Intermediate 25A)
• Step 25B Synthesis of (9H-fluoren-9-yl)methyl (3S)-3-((4-(4-acetoxypiperidin-1-yl)-1- (tert-butoxy)-1-oxobutan-2-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Intermediate 25B)
• Step 25C Synthesis of tert-butyl 4-(4-acetoxypiperidin-1-yl)-2-((S)-2-(4-oxo-4- phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)butanoate (Intermediate 25C)
• the crude material was purified chromatography (MeOH/DCM / Hexanes) to provide
• Step 25E Synthesis of 1-(4-((2,4-dichloro-3-methylphenyl)amino)-4-oxo-3-((S)-2-(4- oxo-4-phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)butyl)piperidin- 4-yl acetate (Compound 25-E)
• Step 25F Synthesis of (3S)-N-(1-((2,4-dichloro-3-methylphenyl)amino)-4-(4- hydroxypiperidin-1-yl)-1-oxobutan-2-yl)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide (Compound 25-1)
• Step 26A Synthesis of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)- 4-(4-acetoxypiperidin-1-yl)butanoate (Intermediate 26A)
• Step 26C Synthesis of (S)-1-(3-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((3,4- dichloro-2-fluorophenyl)amino)-4-oxobutyl)piperidin-4-yl acetate (Intermediate 26C)
• Step 26D Synthesis of (S)-1-(3-amino-4-((3,4-dichloro-2-fluorophenyl)amino)-4- oxobutyl)piperidin-4-yl acetate (Intermediate 26D)
• Step 26E Synthesis of (9H-fluoren-9-yl)methyl (S)-3-(((S)-4-(4-acetoxypiperidin-1-yl)- 1-((3,4-dichloro-2-fluorophenyl)amino)-1-oxobutan-2-yl)carbamoyl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (Intermediate 26E)
• Step 26F Synthesis of 1-((S)-4-((3,4-dichloro-2-fluorophenyl)amino)-4-oxo-3-((S)- 1,2,3,4-tetrahydroisoquinoline-3-carboxamido)butyl)piperidin-4-yl acetate (Intermediate 26F)
• Step 26G Synthesis of 4-((S)-3-(((S)-4-(4-acetoxypiperidin-1-yl)-1-((3,4-dichloro-2- fluorophenyl)amino)-1-oxobutan-2-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-4- oxobutanoic acid (Intermediate 26G)
• Step 26H Synthesis of 1-((S)-4-((3,4-dichloro-2-fluorophenyl)amino)-3-((S)-2-(4-(2,2- dimethylpiperidin-1-yl)-4-oxobutanoyl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamido)-4-oxobutyl)piperidin-4-yl acetate (Intermediate 26H)
• Step 26I Synthesis of (S)-N-((S)-1-((3,4-dichloro-2-fluorophenyl)amino)-4-(4- hydroxypiperidin-1-yl)-1-oxobutan-2-yl)-2-(4-(2,2-dimethylpiperidin-1-yl)-4- oxobutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (Compound 26-1)
• Step 27A Synthesis of tert-butyl ((S)-4-((4-chloro-5-methylpyridin-2-yl)amino)-4-oxo- 3-((S)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamido)butyl)carbamate (Intermediate 27A)
• Step 27B Synthesis of (S)-N-((S)-4-amino-1-((4-chloro-5-methylpyridin-2-yl)amino)- 1-oxobutan-2-yl)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamide (Compound 27-1)
• Step 28A Synthesis of tert-butyl (S)-4-(4-hydroxypiperidin-1-yl)-2-((S)-2-(4-oxo-4- phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)butanoate (Intermediate 28A)
• Step 28C Synthesis of (S)-N-((S)-1-((2,3-dihydro-1H-inden-5-yl)amino)-4-(4- hydroxypiperidin-1-yl)-1-oxobutan-2-yl)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide (Compound 28-1)
• Step 29A Synthesis of (S)-3-(((S)-4-((tert-butoxycarbonyl)amino)-1-((3,4-dichloro-2- fluorophenyl)amino)-1-oxobutan-2-yl)carbamoyl)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4- tetrahydroisoquinolin-7-yl methanesulfonate (Intermediate 29A)
• Step 29B Synthesis of (S)-3-(((S)-4-amino-1-((3,4-dichloro-2-fluorophenyl)amino)-1- oxobutan-2-yl)carbamoyl)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4-tetrahydroisoquinolin-7- yl methanesulfonate (Compound 29-1)
• Step 30A Synthesis of tert-butyl ((S)-4-((3,4-dichloro-2-fluorophenyl)amino)-4-oxo-3- ((S)-2- (4-oxo-4-phenylbutanoyl)-7- ((trifluoromethyl)sulfonyl)-1,2,3,4-tetra hydro isoquinoline -3-carboxamido)butyl)carbamate (Intermediate 30A)
• Step 30B Synthesis of tert-butyl ((S)-3-((S)-7-cyano-2-(4-oxo-4-phenylbutanoyl)- 1,2,3,4-tetrahydroisoquinoline-3-carboxamido)-4-((3,4-dichloro-2-fluorophenyl) amino) -4-oxobutyl)carbamate (Intermediate 30B)
• Step 30C Synthesis of (S)-N-((S)-4-amino-1-((3,4-dichloro-2-fluorophenyl)amino)-1- oxobutan-2-yl)-7-cyano-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamide (Compound 30-1)
• Step 31A Synthesis of tert-butyl (2-(((S)-4-((4-chloro-3-methylphenyl)amino)-4- oxo- 3-((S)-2- (4-oxo-4-(piperidin-1-yl) butanoyl)- 1,2,3,4 tetrahydroisoquinoline-3- carboxamido) butyl )amino)-2-oxoethyl)carbamate (Intermediate 31A)
• Step 31B Synthesis of (S)-N-((S)-4-(2-aminoacetamido)-1-((4-chloro-3- methylphenyl) amino) -1-oxobutan- 2-yl)-2- (4-oxo-4- (piperidin -1-yl) butanoyl) -1,2,3,4-tetra hydroisoquinoline -3-carboxamide (Compound 31-1)
• Step 32A Synthesis of (S)-N-((S)-1-((3,4-dichloro-2-fluorophenyl)amino)-4- (methylsulfonamido)-1-oxobutan-2-yl)-2-(4-oxo-4-(piperidin-1-yl)butanoyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide (Compound 32-1)
• Step 33A Synthesis of methyl 3-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1] pentan- 1-yl)-2-((S) -2-(4-(2,2-dimethylpiperidin-1-yl) -4-oxobutanoyl)-1,2,3,4-tetra hydro isoquinoline -3-carboxamido) propanoate (Intermediate 33A)
• Step 33B Synthesis of 3-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)-2- ((S)-2-(4-(2,2-dimethylpiperidin-1-yl)-4-oxobutanoyl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamido)propanoic acid (Intermediate 33-B)
• Step 33C Synthesis of tert-butyl (3-(3-((3,4-dichloro-2-fluorophenyl)amino)-2-((S)-2- (4-(2,2-dimethylpiperidin-1-yl)-4-oxobutanoyl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamido)-3-oxopropyl)bicyclo[1.1.1]pentan-1-yl)carbamate (Intermediate 33-C)
• Step 33D Synthesis of (3S)-N-(3-(3-aminobicyclo[1.1.1]pentan-1-yl)-1-((3,4-dichloro- 2-fluorophenyl)amino)-1-oxopropan-2-yl)-2-(4-(2,2-dimethylpiperidin-1-yl)-4- oxobutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (Compound 33-1)
• Step 34A Synthesis of (S)-6-fluoro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Intermediate 34A) [300] Into a suspension of (S)-2-amino-3-(3-fluorophenyl)propanoic acid, HCl (250 mg, 1.14 mmol) in conc HCl (2500 ⁇ l, 82 mmol) was added formaldehyde in water (1000 ⁇ l, 13.4 mmol). The mixture was heated at 90 °C for 1 h, then was left to stand at rt for 2 d.
• Step 34C Synthesis of (9H-fluoren-9-yl)methyl (S)-3-(((S)-4-((tert- butoxycarbonyl)amino)-1-((3,4-dichloro-2-fluorophenyl)amino)-1-oxobutan-2- yl)carbamoyl)-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (Intermediate 34C)
• Step 34D Synthesis of tert-butyl ((S)-4-((3,4-dichloro-2-fluorophenyl)amino)-3-((S)-6- fluoro-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)-4-oxobutyl)carbamate
• Step 34E Synthesis of 4-((S)-3-(((S)-4-((tert-butoxycarbonyl)amino)-1-((3,4-dichloro- 2-fluorophenyl)amino)-1-oxobutan-2-yl)carbamoyl)-6-fluoro-3,4-dihydroisoquinolin- 2(1H)-yl)-4-oxobutanoic acid (Intermediate 34E)
• Step 34F Synthesis of tert-butyl ((S)-4-((3,4-dichloro-2-fluorophenyl)amino)-3-((S)-2- (4-(2,2-dimethylpiperidin-1-yl)-4-oxobutanoyl)-6-fluoro-1,2,3,4- tetrahydroisoquinoline-3-carboxamido)-4-oxobutyl)carbamate (Intermediate 34F)
• Step 35A Synthesis of tert-butyl ((S)-4-((4-cyano-2,3-dihydro-1H-inden-5-yl)amino)- 4-oxo-3-((S)-2-(4-oxo-4-phenylbutanoyl)- 1,2,3,4-tetrahydroisoquinoline-3- carboxamido) butyl)carbamate (Intermediate 35A)
• Step 35B Synthesis of (S)-N-((S)-4-amino-1-((4-cyano-2,3-dihydro-1H-inden-5- yl)amino)-1-oxobutan-2-yl)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide (Compound 35-1)
• Step 36B Synthesis of 7-bromo-5-nitro-2,3-dihydro-1H-inden-4-ol (Intermediate 36B) [311]
• Intermediate 36A (1.64g, 7.7 mmol) was dissolved in AcOH (2.3 mL) and H 2 O (0.46 mL). After cooling at 5 o C, fuming HNO 3 (0.13 mL) in AcOH (0.9 mL) of was added dropwise. The mixture was stirred 15 min at 5 o C, diluted with H 2 O, extracted with DCM, washed with water, dried (Na 2 SO 4 ), concentrated and purified by chromatography (EA/hexane) to provide 400 mg (20%) of Intermediate 36B.
• Step 36D Synthesis of 4-methoxy-2,3-dihydro-1H-inden-5-amine (Intermediate 36-1) [313]
• Intermediate 36B 200 mg, 0.74 mmol
• MeOH MeOH
• THF THF
• 10% Pd/C 200 mg
• the reaction mixture was purged with H 2 and stirred under H 2 for 24 h.
• LCMS [m/z] calculated for C 10 H 13 NO: 163.1; found 164 [M+H] + , t R 2.45 min (Method 4).
• Step 37A Synthesis of 2,3-dimethylphenol (Intermediate 37A)
• Step 37B Synthesis of 1-bromo-4-methoxy-2,3-dimethylbenzene (Intermediate 37B)
• Step 37D Synthesis of 2-methoxy-3,4-dimethylaniline (Intermediate 37-1)
• Step 38A Synthesis of 5-methoxy-1,2,3,4-tetrahydronaphthalene (Intermediate 38A)
• Step 38B Synthesis of 5-bromo-8-methoxy-1,2,3,4-tetrahydronaphthalene (Intermediate 38B)
• Step 39A Synthesis of 1-fluoro-4-methoxy-2-methyl-5-nitrobenzene (Intermediate 39A)
• Step 40A Synthesis of 1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (Intermediate 40- 1)
• Step 41A Synthesis of 2,2-dimethyl-2,3-dihydro-1H-inden-5-amine (Intermediate 41A)
• Step 42A Synthesis of 2-methoxy-1-nitro-3-vinylbenzene (Intermediate 42A)
• Step 42B Synthesis of 3-ethyl-2-methoxyaniline (Intermediate 42-1) [329] To a flask containing Intermediate 42A (500 mg, 2.8 mmol) was added Pd/C (10%, 500 mg, 0.28 mmol), and MeOH (8 mL). The flask was placed under vacuum for 1 min, then a H 2 balloon was attached and the reaction was stirred at rt overnight.
• Step 43A Synthesis of tert-butyl (3,4-dichloro-2-hydroxyphenyl)carbamate (Intermediate 43A)
• Step 43B Synthesis of tert-butyl (3,4-dichloro-2-methoxyphenyl)carbamate (Intermediate 43B) [331] To a stirring solution of Intermediate 43A (173 mg, 0.62 mmol) in DMF (5 mL) was added K 2 CO 3 (129 mg, 0.93 mmol). MeI (58 ⁇ L, 0.93 mmol) was added after 5 min. The reaction mixture was stirred at rt for 16 h under an atmosphere of N 2 .
• Step 44A Synthesis of 5-methyl-2-(trifluoromethoxy)aniline (Intermediate 44A)
• Step 44B Synthesis of 4-bromo-5-methyl-2-(trifluoromethoxy)aniline (Intermediate 44B)
• Step 45A Synthesis of 5-fluoro-6-nitro-2,3-dihydro-1H-inden-1-one (Intermediate 45A) [336] Fuming HNO 3 (31.3 mmol) was added dropwise to 5-fluoro-2,3-dihydro-1H- inden-1-one (4.7 g, 31.3 mmol) at 0 o C. The reaction mixture was stirred for 1.5 h. The reaction mixture was quenched with the addition of H 2 O (50 mL). The precipitated solid was collected by filtration and washed with H 2 O. The resulting crude residue (2 g, 33%) was dried under high vac and used without further purification.
• Step 45B Synthesis of 6-fluoro-2,3-dihydro-1H-inden-5-amine (Intermediate 45-1) [337] To a solution of Intermedaite 45A (1.3 g, 6.7 mmol) in MeOH (20 mL) and THF (10 mL) was added MeSO 3 H (0.83 g, 8.66 mmol) followed by Pd/C (10%, 650 mg). The reaction mixture was evacuated and filled with H 2 . The mixture was stirred overnight under an atmosphere of H 2 .
• Step 46A Synthesis of 4,6-dibromo-2,3-dihydro-1H-inden-5-amine (Intermediate 46A)
• Step 46C Synthesis of 4-chloro-2,3-dihydro-1H-inden-5-amine (Intermediate 46-1)
• Step 47A Synthesis of 1-bromo-4-methoxy-5-nitro-2-(trifluoromethyl)benzene (Intermediate 47A)
• the cAMP HunterTM CHOK1 CXCR3 Gi cell line was purchased from DiscoveRx. Cells were seeded into a 96-well white assay plate at 50,000 cells/well/94 ⁇ l assay buffer (Hank’s Buffered Saline Solution, 10 mM HEPES, 0.1% fatty acid-free BSA, pH 7.4) and immediately assayed in suspension. Forskolin was added to 20 ⁇ M (5 ⁇ l of 400 ⁇ M stock) simultaneously with a 12- point dose response curve of compound at 0–10 ⁇ M (1 ⁇ l of 100x stock in 100% DMSO), and cells were incubated for 30 minutes. A cAMP standard curve is run as an assay control.
• CXCL11 dose response was included to determine maximum efficacy.
• Direct detection of cAMP was carried out using the DiscoveRx HitHunter cAMP kit according to manufacturer’s instructions, and luminescence was read using a SpectraMax M5 plate reader.
• the column used was a Phenomenex Luna C8 30x2 mm 5 ⁇ m with a security guard. Mass detection was performed by an Applied Biosystems 4000 Qtrap in MRM mode and ionization was achieved by positive electrospray with a source temperature of 500 ⁇ C. The ion transitions, depolarizing potential and collision energies were dependent on the specific analyte.

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