[go: up one dir, main page]

WO2007076318A2 - Camphor-derived cxcr3 antagonists - Google Patents

Camphor-derived cxcr3 antagonists Download PDF

Info

Publication number
WO2007076318A2
WO2007076318A2 PCT/US2006/062222 US2006062222W WO2007076318A2 WO 2007076318 A2 WO2007076318 A2 WO 2007076318A2 US 2006062222 W US2006062222 W US 2006062222W WO 2007076318 A2 WO2007076318 A2 WO 2007076318A2
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
sulfonyl
piperazinyl
pyridinyl
heptan
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2006/062222
Other languages
French (fr)
Other versions
WO2007076318A3 (en
Inventor
Jakob Busch-Petersen
Jian Jin
Todd L. Graybill
Terence J. Kiesow
Ralph A. Rivero
Feng Wang
Yonghui Wang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of WO2007076318A2 publication Critical patent/WO2007076318A2/en
Publication of WO2007076318A3 publication Critical patent/WO2007076318A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • This invention relates to certain camphor derivatives and their use as inhibitors of a chemokine receptor knows as CXCR3 and its equivalent chemokine receptors including splice variants.
  • Chemokines are chemolaclic cytokines lhal are released by a variety of cells Lo attract macrophages, T cells, eoxinophils, basophils and neutrophils to sites of inflammation [see Schall, Cytokine, 3:165-183 (1991), Schall, ct al, Curr. Opin. Immunol., 6:865-873 (1994) and Murphy, Rev. Immun., 12:593-663 (1994)1.
  • chemokines In addition to stimulating chemotaxis other activities can be selectively induced by chemokines in responsive cells including changes in cell shape, transient rises in the concentration of intracellular free calcium ions, granule exocy losis, inlegrin upregulation, formation of bioactive lipids and respiratory bursts associated with leukocyte activation.
  • chemokines arc early triggers of the inflammatory response, causing inflammatory mediator release, chemotaxis and estravasation to the sites of infection or inflammation.
  • CXC CXC
  • C-X-C CXC 3 C
  • the Q-chemoMnes such as interleuken-8 (IL-8), melanoma growth stimulatory activity protein (MGSA), and stromal cell derived factor 1 (SDF-I) are chemo tactic primarily for neutrophils and lymphocytes, whereas D- chemokines, such as RANTES, MIP-ID, MIP-lD, monocyte chemotaclic protein -1 (MCP-I), MCP- 2, MCP-3 and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, et al. , Nature, 381:661-666 (1996)).
  • D- chemokines such as RANTES, MIP-ID, MIP-lD, monocyte chemotaclic protein -1 (MCP-I), MCP- 2, MCP-3 and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (
  • the C chemokine lymphotactin shows specificity for lymphocytes (Kelner, et al, Science, 266:1395-1399 (1994)) while the CX 3 C chemokine fractalkine shows specificity for lymphocytes and monocytes (Bazan, et al, Nautre, 385:640-644 (1997)).
  • chemokines bind specific cell-surface receptors belonging to the family of G-protein- coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. ScL, 15,159- 165 (1994)) which are termed "chemokine receptors.” On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration.
  • chemokine receptors There are at least seven human chemokine receptors that demonstrate high affinity for the D -chemokines with the following characteristic pattern: CCRl [MIP-I ⁇ , MIP-I D, MCP-3, RANTES] (Ben-Barruch, et al., J. Biol.
  • the D-chemokines include eotaxin, MIP ("macrophage inflammatory protein"), MCP ("monocyte chemoattractant protein”) and RANTES ("regulation-upon-activation, normal T expressed and secreted").
  • Chemokine receptors such as CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CXCRl, CXCR2, CXCR3, CXCR4, CXCR5, CX 3 CRl, and XCRl have been implicated as being important mediators of inflammatory and immunoregulatory disox-ders and diseases, including asthma, COPD and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
  • MS multiple sclerosis
  • IP-IO, I-TAC and Mig members of the C-X-C chemokine subfamily, were first discovered because they were dramatically uprcgulatcd when monocytic cell lines were stimulated with recombinant interferon ⁇ (IFN ⁇ ) ⁇ Farber 1990 118 /id ⁇ . More recently, it was recognized that these proteins could be produced by a variety of cell types, including neutrophils ⁇ Gasperini, Marchi, et al. 1999 33 /id ⁇ , eosinophils ⁇ Gasperini, Marchi, et al. 1999 33 /id ⁇ , lymphocytes ⁇ Hayglass, Gangur, et al.
  • I-TAC and Mig stand out among all other chemokines in that they are believed to hold a high degree of specificity for activated T- and natural killer (NK) cells. This specificity is achieved through interaction with CXCR3, whose expression among inflammatory cells is limited to activated (but not resting) ThI type T-cells and NK cells. Lower expression has been described on other cell types including dendritic cells, eosiniphilsm neutrophils, epithelial and endothelial cells.
  • CXCR3 This selective expression of CXCR3 stands in striking contrast to the expression patterns reported for the receptors of other chemokines which hold lymphocyte chemotactic ability, such as MCP-I, MCP-2, MIP-I and RANTES; the receptors for these chemokines have been shown to exist on granulocytes and monocytes, as well as on T-lymphocytes.
  • MCP-I lymphocyte chemotactic ability
  • IP-10 is not only important for the selective recruitment of T-cells via interaction with CXCR3, but IP-10 has also been shown to play an important role in leukocyte adhesion and diapedesis by increasing adhesion of T cells to activated vascular endothelium via interaction with CXCR3 ⁇ Piali, Wcbcr, ct al. 199846 /id).
  • the regulatory role of IP-10 in the inflammatory response along with the highly selective expression of CXCR3 on activated T cells makes the chemokine/receptor pair an interesting therapeutic target for treatment of ThI type T-cell mediated diseases.
  • MS multiple sclerosis
  • the compounds of this invention are inhibitors of this chemokine receptor and as such are useful in treating diseases which the CXCR3 chemokine receptor is involved.
  • this invention relates to compounds with a camphor core of formulas IA, IB or IC
  • B is or A and B together form a tri-cyclic ring of formula A/B which is
  • T is O or NH
  • X, Y and Z arc independently C(Ri) or N; m in the [-] of Bl , B5, B6 and B7 is 1 or 2;
  • R 2 and R 3 are independently H 3 -C(O) N(Rs) 2 , halo-substituted d-C 6 a1kyl, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -Ce alkynyl, halo-substituted Ci-C ⁇ alkyl, cycloalkyl, cycloalkenyl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocycloalkyl, group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 8 heterocyclic ring, aryl, heteroaryl, halo, cyano, nitro, -N(Rg) 2 , -OR 8 ' -C(O)
  • R 6 are independently H, OR S , halo, NR 8 R 9 , C r C 6 alkyl; or R 5 and R 6 together form a 3-6 membered heterocyclic ring containing 1 or more hetero atoms which are O or N; R 7 is H, halo, or Cj-C ⁇ alkyl;
  • R 8 is hydrogen, Q.Cealkyl, Ca.C 6 alkenyl s -CO(Ci-C 4 alkyl), , -CO(aryl), -CO(heteroaryl), C 3 -C 8 cycloalkyl, Cs-Cgheterocycloalkyl, C6-Ci 4 aryl, heteroaryl, or aryl-C ⁇ .C 6 aLkyl;
  • R 9 is hydrogen, C 1 .C 6 alkyl, d-C ⁇ alkenyl, -CO(C 1 -C 4 alkyl), -N(R R ) 2 ,
  • Ri 0 is hydrogen, Chalky., C 2 .C 6 alkenyl, C 2 -C 6 alkynyl, -CO(C 1 -C 4 alkyl), -CO(aryl), -CO(hctcroaryl), C 3 -Cg cycloalkyl, C 3 -Cshctcrocycloalkyl, C 6 -Ci 4 aryl, heteroaryl, aryl-Ci.C 6 alkyl; or a pharmaceutically acceptable salt thereof.
  • a pharmaceutically acceptable preparation comprising a compound of formula 1 A, 1 B or 1 C, or a salt thereof, and a pharmaceutically excipient
  • this invention relates to a method for treating a disease in which the inhibition of the enzyme known as CXCR3 results in a beneficial effect, for instance treating asthma.
  • An additional embodiment is the manufacture of a pharmaceutical preparation comprising admixing a compound of formula IA, IB or 1C with a pharmaceutically acceptable excipient.
  • Another useful embodiment is the use of a compound of Formula IA, IB or 1C in the manufacture of a medicament for treating or preventing a condition associated with the inhibition of CXCR3, such as asthma.
  • the present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention.
  • Prodrugs are any covalently bonded compounds that release the active parent drug according to Formula IA, IB or 1C in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including cnantiomcrs and diastcrcomcrs, arc intended to be covered herein.
  • Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques; and an individual enantiomer may be used alone.
  • both the cis (Z) and trans (E) isomers are within the scope of this invention.
  • compounds may exist in tautomeric forms, such as kcto-cnol tautomcrs, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
  • the meaning of any substituent at any one occurrence in formula IA, IB or any sub-formula thereof is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise.
  • substituted means substituted by one or more defined groups.
  • groups may be selected from a number of alternative groups the selected groups may be the same or different.
  • alkyl refers to a straight- or branchcd-chain hydrocarbon radical having the specified number of carbon atoms, so for example, as used herein, the terms “C 1- Ce alkyl” refers to an alkyl group having at least 16 carbon atoms.
  • Examples of such branched or straight-chained alkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, n-pro ⁇ yl, isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and branched analogs of the normal alkancs.
  • Alkylene refers to a straight or branched chain divalent hydrocarbon radical having the specified number of carbon atom. So for example the term “Ci.Cio alkylene” refers to an alkylene group which contains at least 1, and up to 3, or 6, carbon atoms respectively. Examples of “Ci-Ci 0 alkylene” groups include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, n- pentylene, isopentylene, n-hexylene, n-heptylene, n-octylene, n-nonylene, and n-decylene, and the like.
  • alkenyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 5 carbon-carbon double bonds. Examples include ethenyl (or ethenylene) and propenyl (or propcnylcnc).
  • alkynyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 5 carbon-carbon triple bonds. Examples include ethynyl (or ethynylene) and propynyl (or propynylene).
  • cycloalkyl refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing the specified number of carbon atoms. So, for example, the term “C3.Cs cycloalkyl” refers to a non-aromatic cyclic hydrocarbon ring having from five to seven carbon atoms.
  • Exemplary "C 3 -C 8 cycloalkyl” groups useful in the present invention include, but are not limited to, cyuclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Cs-Cscycloalkenyl refers to a non-aromatic monocyclic carboxycyclic ring having the specified number of carbon atoms and up to 3 carbon-carbon double bonds.
  • Cycloalkenyl includes by way of example cyclopentenyl and cyclohexenyl.
  • C 3 -C 8 heterocycloalkyl means a non-aromatic heterocyclic ring containing the specified number ring atoms being saturated or having one or more degrees of unsaturatioii and containing one or more heteroatom substitutions selected from O, S and/or N. Such a ring may be optionally fused to one or more other "heterocyclic" ring(s) or cycloalkyl ring(s).
  • heterocyclic moieties include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, 2,4-piperazinedione, pyrrolidine, imidazolidine, pyrazolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, and the like.
  • Aryl refers to monocyclic and polycarbocyclic unfuscd or fused groups having 6 to 14 carbon atoms and having at least one aromatic ring that complies with H ⁇ ckel's Rule.
  • aryl groups are phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl and the like.
  • Heteroaryl means an aromatic monocyclic ring or polycarbocyclic fused ring system wherein at least one ring complies with H ⁇ ckel's Rule, has the specified number of ring atoms, and that ring contains at least one hctcratom selected from N, O 3 and/or S.
  • heteroaryl groups include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, and indazolyl.
  • C3-C5-cycloalkyl as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane and cyclohexane.
  • Halogen or “halo” means F 3 Cl, Br, and I.
  • solvate refers to a complex of variable stoichiometry formed by a solute and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but arc not limited to, water, methanol, cthanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water.
  • pharmaceutically-acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undcsircd toxicological effects. These pharmaceutically-acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its tree acid or free base form with a suitable base or acid, respectively.
  • A is Al or A2
  • Z is C(Ri) and X and Y are independently C(R 1 ) or N; m in the [-] of Bl, B5 and B6 is 1 or 2;
  • R 2 and R 3 are independently H, -C(O)N(R R ) 2 , halo-substituted Ci-C ⁇ alkyl, or Ci-C 6 alkyl where the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting Of-N(R 9 )(R 8 ) -OR 8 ' -C(O)R 8 , and -C(O)OR 8 ; each R 4 is independently O, NOR 8 , or NNR 8 ;
  • R 5 and R 6 arc independently H, ORg 5 halo, NR 8 R 9 , Ci-C ⁇ alkyl; or R 5 and Rs together form a 3-6 membered heterocyclic ring containing 1 or more hetero atoms which are O or N;
  • R 7 is H, or halo;
  • R 8 is hydrogen, Ci.C ⁇ alkyl;
  • R 9 is hydrogen, -CO(Ci-C 4 alkyl), -CO(NR «Rio), -N(Rs) 2 , or -S(O) 2 Ri 0 ;
  • Rio is hydrogen, Ci.Cealkyl, C 2- C 6 alkenyl, C 2 -C 6 alkynyl, -CO(Ci-C 4 alkyl), -CO(aryl), -CO(heteroaryl), Cs-C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, C 6 -Ci 4 aryl, heteroaryl, aryl-Ci.C ⁇ alkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • A is Al or A2
  • B is or A and B are combined to form a tricyclic ring of formula A/B
  • Z is C(R 1 ) and X and Y are independently C(R 1 ) or N; m in the [-] of Bl, B5 and B6 is 1 or 2;
  • R 2 and R 3 are independently H, -C(O)N(Rg) 2 , halo-substituted Ci-C 6 alkyl, or Ci-C 6 alkyl where the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting Of-N(R 9 )(R 8 ) -OR 8 ' -C(O)R 8 , and -C(O)OR 8 ;
  • R 4 is O, NOR 8 , or NNR 8 ;
  • R 7 is H, or halo
  • Rs is hydrogen, or Ci.C 6 alkyl
  • R 9 is hydrogen, -CO(Ci-C 4 alkyl), -CO(NR 8 RiO), or -N(Rs) 2 .
  • Z is -C(Ri) and X and Y are independently -C(Ri) or N.
  • compounds where X is -C(Ri) and Y is N, and where X is N and Y is -C(Ri) are of interest.
  • compounds where B is independently one of where m in B 1 is 1 or 2, m in B5 is 1 or 2, and m in B6 is 2 are also of interest.
  • a further refinement of compounds of IA within the ambit of this paragraph includes those where A/B is present, that is, those compounds which have the tri-cyclic ring:
  • R 4 is O
  • R 4 is NORg
  • R 4 is NNRs arc of interest.
  • Z is C(Ri) and X and Y are independently C(Ri) or N; m in the [-] of Bl , B5 and B6 is 1 or 2;
  • R 2 and R 3 are independently H, -C(O)N(R 8 ) 2 , halo-substituted Ci-C 6 alkyl, or Ci-Qallcyl where the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting Of-N(R 9 )(R 8 ) -OR 8 ' -C(O)R 8 , and -C(O)OR 8 ;
  • R 5 and R 6 are independently H, OR 8 , halo, NR 8 R 9 , Ci-C 6 allcyl; or R 5 and Re together form a 3-6 membered heterocyclic ring containing 1 or more hetero atoms which are O or N; R7 is H, or halo; Rg is hydrogen, Ci.C ⁇ alkyl, R 9 is hydrogen, -CO(C 1 -C 4 alkyl), -CO(NR 8 R 10 ), -N(Rs) 2 , or -S(O) 2 R 10 ;
  • R 10 is hydrogen, Ci,C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, -CO(C 1 -C 4 alkyl), -CO(aryl), -CO(heteroaryl), C 3 -Cg cycloalkyl, C 3 -C 8 heterocycloalkyl, C ⁇ -Cwaryl, heteroaiyl, aryl-Q.Cealkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • Another useful embodiment is a further refinement of the groups of formula IB described in the foregoing paragraph, namely the compounds of formula IB
  • A is Al
  • Z is C(Ri) and X and Y are independently C(Ri) or N; m in the [-] of Bl is 1; R 1 is bonded to any ring carbon and is H, C 1 -Ce alkyl, difluoromethyl, trifluoromethyl, halo,
  • R 5 and R 6 are independently H, ORg, halo, NR 8 Ry, Ci-C 6 alkyl; or R 5 and Re together form a 3-6 membered heterocyclic ring containing 1 or more hetero atoms which are O or N;
  • R 7 is H, or halo
  • R 8 is hydrogen, Ci.C 6 alkyl
  • R y is hydrogen, -CO(Ci-C 4 alkyl), -CO(NR 8 RiO), -N(Rs) 2 , or -S(O) 2 Ri 0 ; and R 10 is hydrogen, Ci.C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, -CO(Ci-C 4 alkyl), -CO(aryl),
  • A is Al
  • Z is C(R 1 ) and X and Y are independently C(R 1 ) or N; m in the [-] ofBl is 1;
  • R 2 and R 3 are independently H, -C(O)N(Rs) 2 , halo-substituted Ci-C 6 aikyl, or Ci-C 6 alkyl where the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting Of-N(R 9 )(R 8 ) -OR 8 ' -C(O)R 8 , and -C(O)OR 8 ; R 4 Is O;
  • Rg is hydrogen, CiX 6 alkyl,
  • R 9 is hydrogen, -CO(Ci-C 4 alkyl), -CO(NRuR 1 O), -N(Rg) 2 , or -S(O) 2 Ri 0 ; and Rio is hydrogen, Ci.C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, -CO(Ci-C 4 alkyl), -CO(aryl),
  • compounds according to Formula I A, 1 B or 1 C may contain a basic group that is capable of forming pharmaccutically-acccptablc acid addition salts by treatment with a suitable acid.
  • Suitable acids include pharmaceutically-acceptable inorganic acids and pharmaceutically-acceptable organic acids.
  • the compounds of formula IA, IB or 1C may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be solvated, e.g. as the hydrate.
  • This invention includes within its scope stoichiometric solvates (e.g. hydrates) as well as compounds containing variable amounts of solvent (e.g. water).
  • compositions which includes a compound of formula IA, IB or 1C and salts, solvates and the like, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the compounds of formula IA, IB or 1 C and salts, solvates, etc, are as described above.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 1 OO mg of a compound of the formula IA, IB or 1C, depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • Preferred unit dosage compositions are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association a compound of formal IA, IB or 1C with the carricr(s) or cxcipicnt(s).
  • An "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • terapéuticaally effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function. The following abbreviations used herein are defined as follows:
  • 10-camporsulfonyl chloride and a number of ring-substituted analogs of these sulfonyl derivatives as exemplified by formulas IA, IB and IC, are available from commercial sources such as Aldrich Chemical Company, Inc., Milwaukee, WI, USA.
  • Arylchlorides or arylfluorides 1 reacted with unprotected cyclic diamines 2 to give aryldiamines 3, which upon sulfonylation with camphor derived sulfonylchlorides to yield the desired products 4 (Scheme 1 ).
  • the crude sulfonylchloride made above was dissolved in 2ml of DCM and added to a glass reaction vial containing 25mg (0.108mmol) of l-[5-(trifluoromethyl)-2-pyridinyl]piperazine and 120mg (4eq) N,N-(diisopropyl)aminomethyl ⁇ olystyrene (PS-DIEA, Polymer Laboratories, 3.6mmol/g loading).
  • PS-DIEA N,N-(diisopropyl)aminomethyl ⁇ olystyrene
  • Boc-protected diamines 5 can be other types of diamines such as in the following (5a, 5b):
  • n and m are independently O, 1 or 2 with the limitation that the ring must be comprised of 5, 6 or 7 atoms.
  • Camphor-derived sulfonylchlorides 10 reacted with cyclic diamines 9 to form sulfonamides 11, which underwent aromatic nucleophilic substitution or Pd-mediated coupling with arylhalides to produce the desired products 12 (Scheme 4).
  • Ketones 17 underwent reduction to form alcohols 18, which upon fh ⁇ orination to form fluorides 19.
  • Grignard addition to Ketones 17 formed tertiary alcohols 20 and protection of ketones 17 formed cyclic ketyl compounds 21 (Scheme 6).
  • Ketones 17 was reacted with hydroxylamine to form ketone oximes 22, which upon reduction produced primary amines 23.
  • Primary amines 23 underwent amide formation, sulfonylation, urea formation, and reductive alkylation to lead amides 24, sulfonamides 25, ureas 26 and secondary amines 27, respectively (Scheme 8).
  • Fluo 3-loaded CHO-Kl CXCR3 and a microtiter plate-based assay using FLIPR Molecular Devices, Sunnyvale, CA. Briefly, cells (about 80% confluent) were harvested and plated in 96 well black wall/clear bottom plates (Packard view plate) at approximately 40,000 cells/well and grown in the incubator for 18-24 hr. On the day of assay the media was aspirated and replaced with 100 ⁇ l Earls Mimimal Essential Media with Earls salts containing L-glutamine, 0.1% BSA, 4 ⁇ M Fmo-3 acetoxymethyl ester (Fluo-3 AM, Molecular Probes, Eugene, OR, USA) and 1.5 mM sulfinpyrazone.
  • FLIPR Molecular Devices, Sunnyvale, CA.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The instant invention related to camphor derivatives of which are useful in treating diseases wherein inhibition of the exzyme CXCR3 results in beneficial therapy in a mammal.

Description

CAMPHOR-DERIVED CXCR3 ANTAGONISTS
FIELD OF THE INVENTION
This invention relates to certain camphor derivatives and their use as inhibitors of a chemokine receptor knows as CXCR3 and its equivalent chemokine receptors including splice variants.
BACKGROUND OF THE INVENTION
Chemokines are chemolaclic cytokines lhal are released by a variety of cells Lo attract macrophages, T cells, eoxinophils, basophils and neutrophils to sites of inflammation [see Schall, Cytokine, 3:165-183 (1991), Schall, ct al, Curr. Opin. Immunol., 6:865-873 (1994) and Murphy, Rev. Immun., 12:593-663 (1994)1. In addition to stimulating chemotaxis other activities can be selectively induced by chemokines in responsive cells including changes in cell shape, transient rises in the concentration of intracellular free calcium ions, granule exocy losis, inlegrin upregulation, formation of bioactive lipids and respiratory bursts associated with leukocyte activation. Thus, chemokines arc early triggers of the inflammatory response, causing inflammatory mediator release, chemotaxis and estravasation to the sites of infection or inflammation.
There are four classes of chemokines, CXC (D), CC (D), C (D), and CX3C (D), depending on whether the first two cysteines are separated by a single amino acid (C-X-C), are adjacent (C-C), have a missing cysteine pair (C), or are separated by three amino acids (CXC3). The Q-chemoMnes, such as interleuken-8 (IL-8), melanoma growth stimulatory activity protein (MGSA), and stromal cell derived factor 1 (SDF-I) are chemo tactic primarily for neutrophils and lymphocytes, whereas D- chemokines, such as RANTES, MIP-ID, MIP-lD, monocyte chemotaclic protein -1 (MCP-I), MCP- 2, MCP-3 and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, et al. , Nature, 381:661-666 (1996)). The C chemokine lymphotactin shows specificity for lymphocytes (Kelner, et al, Science, 266:1395-1399 (1994)) while the CX3C chemokine fractalkine shows specificity for lymphocytes and monocytes (Bazan, et al, Nautre, 385:640-644 (1997)).
The chemokines bind specific cell-surface receptors belonging to the family of G-protein- coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. ScL, 15,159- 165 (1994)) which are termed "chemokine receptors." On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration. There are at least seven human chemokine receptors that demonstrate high affinity for the D -chemokines with the following characteristic pattern: CCRl [MIP-I α, MIP-I D, MCP-3, RANTES] (Ben-Barruch, et al., J. Biol. Chem., 270, 22123-22128 (1995); Beote, et al, CeE, 72, 415-425 (1993)); CCR-2A and CCR2B [MCP-I, MCP- 3, MCP-4]; CCR3 [eotaxin, RANTES, MCP-3] (Combadiere, et al., J. Biol. Chem., 270, 16491- 16494 (1995); CCR4 [MIP-Ia, RANTES, MCP-I] (Power, et al., J. Biol. Chem., 270, 19495- 19500 (1995)); CCR5 [MIP-Ia, RANTES, MlP-lβ] (Sanson, et al., Biochemistry, 35, 3362-3367 (1996)); and the Duffy blood-group antigen [RANTES, MCP-I] (Chaudhun, et al., J. Biol. Chem., 269, 7835-7838 (1994)). The D-chemokines include eotaxin, MIP ("macrophage inflammatory protein"), MCP ("monocyte chemoattractant protein") and RANTES ("regulation-upon-activation, normal T expressed and secreted").
Chemokine receptors, such as CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CXCRl, CXCR2, CXCR3, CXCR4, CXCR5, CX3CRl, and XCRl have been implicated as being important mediators of inflammatory and immunoregulatory disox-ders and diseases, including asthma, COPD and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. In addition to these diseases, it has been reported that multiple sclerosis (MS) is a T-cell dependent chronic inflammatory disorder of the central nervous system which leads to demyelination of neurons within the white matter of the brain {Martin, McFarland, et al. 1992 128 /id}.
IP-IO, I-TAC and Mig, members of the C-X-C chemokine subfamily, were first discovered because they were dramatically uprcgulatcd when monocytic cell lines were stimulated with recombinant interferon γ (IFNγ) {Farber 1990 118 /id}. More recently, it was recognized that these proteins could be produced by a variety of cell types, including neutrophils {Gasperini, Marchi, et al. 1999 33 /id}, eosinophils {Gasperini, Marchi, et al. 1999 33 /id}, lymphocytes {Hayglass, Gangur, et al. 2000 119 /id}, endothelial cells and fibroblasts {Amichay, Gazzinelli, et al. 1996 120 /id} . IP-10, I-TAC and Mig stand out among all other chemokines in that they are believed to hold a high degree of specificity for activated T- and natural killer (NK) cells. This specificity is achieved through interaction with CXCR3, whose expression among inflammatory cells is limited to activated (but not resting) ThI type T-cells and NK cells. Lower expression has been described on other cell types including dendritic cells, eosiniphilsm neutrophils, epithelial and endothelial cells. This selective expression of CXCR3 stands in striking contrast to the expression patterns reported for the receptors of other chemokines which hold lymphocyte chemotactic ability, such as MCP-I, MCP-2, MIP-I and RANTES; the receptors for these chemokines have been shown to exist on granulocytes and monocytes, as well as on T-lymphocytes. Thus the selective expression of CXCR3 on activated T-cells alone suggests that IP-10, Mig and I-TAC might be involved in the specific recruitment of effector T-cells to sites of inflammation. Recently, it has been shown that IP-10 is not only important for the selective recruitment of T-cells via interaction with CXCR3, but IP-10 has also been shown to play an important role in leukocyte adhesion and diapedesis by increasing adhesion of T cells to activated vascular endothelium via interaction with CXCR3 {Piali, Wcbcr, ct al. 199846 /id). The regulatory role of IP-10 in the inflammatory response along with the highly selective expression of CXCR3 on activated T cells makes the chemokine/receptor pair an interesting therapeutic target for treatment of ThI type T-cell mediated diseases. In addition to the previously mentioned diseases, it is also reported that multiple sclerosis (MS) is a T-cell dependent chronic inflammatory disorder of the central nervous system which leads to demyelination of neurons within the white matter of the brain {Martin, McFarland, et al. 1992 128 /id}.
The compounds of this invention are inhibitors of this chemokine receptor and as such are useful in treating diseases which the CXCR3 chemokine receptor is involved.
SUMMARY OF THE INVENTION
In a first instance, this invention relates to compounds with a camphor core of formulas IA, IB or IC
Figure imgf000004_0001
wherein:
A is
Figure imgf000004_0002
B is
Figure imgf000005_0001
or A and B together form a tri-cyclic ring of formula A/B which is
Figure imgf000005_0002
where T is O or NH;
X, Y and Z arc independently C(Ri) or N; m in the [-] of Bl , B5, B6 and B7 is 1 or 2;
R1 is bonaded to any ring carbon and is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, OCi- C6 alkyl, trifluoromethyl, halo, NO2, cyano, or N(C=O)C1-C6alkyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, or C3-C8 heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocycloalkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Ci .C6 alkyl, C^-Ce cycloalkyl, Gj-Cg heterocyclic ring, aryl, heteroaryl, halo, cyano, nitro, and -OR8;
Figure imgf000005_0003
R2 and R3 are independently H3 -C(O) N(Rs)2, halo-substituted d-C6a1kyl, Ci-C6alkyl, C2-C6 alkenyl, C2-Ce alkynyl, halo-substituted Ci-Cβalkyl, cycloalkyl, cycloalkenyl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocycloalkyl, group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Ci-C6 alkyl, C3-C6 cycloalkyl, C3-C8heterocyclic ring, aryl, heteroaryl, halo, cyano, nitro, -N(Rg)2, -OR8' -C(O)R8, and -C(O)OR8; each R4 is independently O, NORs, or NNR8;
Rs and R6 are independently H, ORS, halo, NR8R9, CrC6alkyl; or R5 and R6 together form a 3-6 membered heterocyclic ring containing 1 or more hetero atoms which are O or N; R7 is H, halo, or Cj-Cβalkyl;
R8 is hydrogen, Q.Cealkyl, Ca.C6alkenyls
Figure imgf000006_0001
-CO(Ci-C4 alkyl), , -CO(aryl), -CO(heteroaryl), C3-C8 cycloalkyl, Cs-Cgheterocycloalkyl, C6-Ci4aryl, heteroaryl, or aryl-Cα.C6aLkyl; R9 is hydrogen, C1.C6alkyl, d-Cβalkenyl,
Figure imgf000006_0002
-CO(C1 -C4 alkyl), -N(RR)2,
-CO(NR8RI0), -CO(aryl), -CO(heteroaryl), C3-C8 cycloalkyl, C3-C3heterocycloalkyl, C6-Ci4aryl, heteroaryl, aryl-Cx.Cβalkyl; -SRi0, -S(O)Ri0, or -S(O)2Ri0;
Ri0 is hydrogen, Chalky., C2.C6alkenyl, C2-C6alkynyl, -CO(C1-C4 alkyl), -CO(aryl), -CO(hctcroaryl), C3-Cg cycloalkyl, C3-Cshctcrocycloalkyl, C6-Ci4aryl, heteroaryl, aryl-Ci.C6alkyl; or a pharmaceutically acceptable salt thereof.
In a second instance, it relates to a pharmaceutically acceptable preparation comprising a compound of formula 1 A, 1 B or 1 C, or a salt thereof, and a pharmaceutically excipient
In a further embodiment, this invention relates to a method for treating a disease in which the inhibition of the enzyme known as CXCR3 results in a beneficial effect, for instance treating asthma.
An additional embodiment is the manufacture of a pharmaceutical preparation comprising admixing a compound of formula IA, IB or 1C with a pharmaceutically acceptable excipient.
Another useful embodiment is the use of a compound of Formula IA, IB or 1C in the manufacture of a medicament for treating or preventing a condition associated with the inhibition of CXCR3, such as asthma.
DETAILED DESCRIPTION OF THE INVENTION Definitions and Specific Embodiments The present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention. Prodrugs are any covalently bonded compounds that release the active parent drug according to Formula IA, IB or 1C in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including cnantiomcrs and diastcrcomcrs, arc intended to be covered herein. Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques; and an individual enantiomer may be used alone. In cases in which compounds have unsaturated carbon- carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as kcto-cnol tautomcrs, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form. The meaning of any substituent at any one occurrence in formula IA, IB or any sub-formula thereof is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise.
Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the present invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984), and which may be found on the Web, for example at http://www.chem.qmul.ac.uk/iupac/.
For the avoidance of doubt, unless otherwise indicated, the term "substituted" means substituted by one or more defined groups. In the case where groups may be selected from a number of alternative groups the selected groups may be the same or different.
The term "independently" means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
As used herein the term "alkyl" refers to a straight- or branchcd-chain hydrocarbon radical having the specified number of carbon atoms, so for example, as used herein, the terms "C1-Ce alkyl" refers to an alkyl group having at least 16 carbon atoms. Examples of such branched or straight-chained alkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, n-proρyl, isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and branched analogs of the normal alkancs. "Alkylene" refers to a straight or branched chain divalent hydrocarbon radical having the specified number of carbon atom. So for example the term "Ci.Cio alkylene" refers to an alkylene group which contains at least 1, and up to 3, or 6, carbon atoms respectively. Examples of "Ci-Ci0 alkylene" groups include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, n- pentylene, isopentylene, n-hexylene, n-heptylene, n-octylene, n-nonylene, and n-decylene, and the like.
When the term "alkenyl" (or "alkenylene") is used it refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 5 carbon-carbon double bonds. Examples include ethenyl (or ethenylene) and propenyl (or propcnylcnc). When the term "alkynyl" (or "alkynylene") is used it refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 5 carbon-carbon triple bonds. Examples include ethynyl (or ethynylene) and propynyl (or propynylene).
When "cycloalkyl" is used it refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing the specified number of carbon atoms. So, for example, the term "C3.Cs cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having from five to seven carbon atoms. Exemplary "C3-C8 cycloalkyl" groups useful in the present invention include, but are not limited to, cyuclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
The term " Cs-Cscycloalkenyl" refers to a non-aromatic monocyclic carboxycyclic ring having the specified number of carbon atoms and up to 3 carbon-carbon double bonds. "Cycloalkenyl" includes by way of example cyclopentenyl and cyclohexenyl.
Where "C3-C8 heterocycloalkyl" is used, it means a non-aromatic heterocyclic ring containing the specified number ring atoms being saturated or having one or more degrees of unsaturatioii and containing one or more heteroatom substitutions selected from O, S and/or N. Such a ring may be optionally fused to one or more other "heterocyclic" ring(s) or cycloalkyl ring(s). Examples of "heterocyclic" moieties include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, 2,4-piperazinedione, pyrrolidine, imidazolidine, pyrazolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, and the like.
"Aryl" refers to monocyclic and polycarbocyclic unfuscd or fused groups having 6 to 14 carbon atoms and having at least one aromatic ring that complies with Hϋckel's Rule. Examples of aryl groups are phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl and the like.
"Heteroaryl" means an aromatic monocyclic ring or polycarbocyclic fused ring system wherein at least one ring complies with Hϋckel's Rule, has the specified number of ring atoms, and that ring contains at least one hctcratom selected from N, O3 and/or S. Examples of "heteroaryl" groups include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, and indazolyl.
"C3-C5-cycloalkyl" as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane and cyclohexane. "Halogen" or "halo" means F3 Cl, Br, and I.
The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but arc not limited to, water, methanol, cthanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water.
Herein, the term "pharmaceutically-acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undcsircd toxicological effects. These pharmaceutically-acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its tree acid or free base form with a suitable base or acid, respectively.
Compounds of particular interest are those of formula IA, IB or 1C:
Figure imgf000009_0001
where
A is Al or A2
B is
Figure imgf000009_0002
or A and B are combined to form a tricyclic ring of formula A/B
Figure imgf000009_0003
Z is C(Ri) and X and Y are independently C(R1) or N; m in the [-] of Bl, B5 and B6 is 1 or 2;
R, is bonded to any ring carbon and is H, C ,-C6 alkyl, difluoromethyl, trifluoromethyl, halo, NO2, or N(C=O)Ci.C6aIkyl; where the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Ci-C6 alkyl, C3-Ce cycloalkyl, C3-C8 heterocyclic ring, aryl, heteroaryl, halo, cyario, nitro, and -OR8; n in the Rib] of Al is 1 - 4, is 0 in A2 and is 1 in ATB;
R2 and R3 are independently H, -C(O)N(RR)2, halo-substituted Ci-Cβalkyl, or Ci-C6alkyl where the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting Of-N(R9)(R8) -OR8' -C(O)R8, and -C(O)OR8; each R4 is independently O, NOR8, or NNR8;
R5 and R6 arc independently H, ORg5 halo, NR8R9, Ci-Cβalkyl; or R5 and Rs together form a 3-6 membered heterocyclic ring containing 1 or more hetero atoms which are O or N;
R7 is H, or halo; R8 is hydrogen, Ci.Cβalkyl;
R9 is hydrogen, -CO(Ci-C4 alkyl), -CO(NR«Rio), -N(Rs)2, or -S(O)2Ri0;
Rio is hydrogen, Ci.Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -CO(Ci-C4 alkyl), -CO(aryl), -CO(heteroaryl), Cs-C8 cycloalkyl, C3-C8heterocycloalkyl, C6-Ci4aryl, heteroaryl, aryl-Ci.Cβalkyl; or a pharmaceutically acceptable salt or solvate thereof.
An further refinement of those compounds of particular interest arc those compounds where, in formula IA
Figure imgf000010_0001
A is Al or A2
Figure imgf000010_0002
B is
Figure imgf000011_0001
or A and B are combined to form a tricyclic ring of formula A/B
Figure imgf000011_0002
Z is C(R1) and X and Y are independently C(R1) or N; m in the [-] of Bl, B5 and B6 is 1 or 2;
Ri is bonded to any ring carbon and is H, Ci-C(J alkyl, difluoromethyl, trifluoromethyl, halo, NO2, or N(C=O)Ci.C6alkyl; n in the RiCn] of Al is 1 - 4, is 1 - 4 in A2 and is 1 - 2 in A/B;
R2 and R3 are independently H, -C(O)N(Rg)2, halo-substituted Ci-C6alkyl, or Ci-C6alkyl where the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting Of-N(R9)(R8) -OR8' -C(O)R8, and -C(O)OR8; R4 is O, NOR8, or NNR8;
R7 is H, or halo;
Rs is hydrogen, or Ci.C6alkyl; and
R9 is hydrogen, -CO(Ci-C4 alkyl), -CO(NR8RiO), or -N(Rs)2.
In the foregoing compounds of formula IA, those compounds wherein Al is
Figure imgf000011_0003
where Z is -C(Ri) and X and Y are independently -C(Ri) or N. In a further refinement, compounds where X is -C(Ri) and Y is N, and where X is N and Y is -C(Ri) are of interest. Additionally, compounds where B is independently one of
Figure imgf000012_0001
where m in B 1 is 1 or 2, m in B5 is 1 or 2, and m in B6 is 2 are also of interest. Also, a further refinement of compounds of IA within the ambit of this paragraph includes those where A/B is present, that is, those compounds which have the tri-cyclic ring:
Figure imgf000012_0002
A/B. Tn addition, compounds where R4 is O are of interest, compounds where R4 is NORg, and compounds where R4 is NNRs arc of interest. Another useful embodiment is one where, in R, [-,], n is 1 - 2 and is Ci -C6 alkyl, difluoromethyl, trifluoromethyl, halo, NO2, or N(C=O)C1.C6alkyl; R5 and R6 are independently H, OR8, halo, NR8R9, CrC6alkyl; R7 is H; R8 is hydrogen, Ci.C6alkyl; R9 is hydrogen, -CO(C1-C4 alkyl), -CO(NR8Ri0), -N(Rs)2, oτ -S(O)2Ri0; and Rio is hydrogen, Ci.Cealkyl, C2_C6alkenyl, C2.C6alkyny1, -CO(Ci-C4 alkyl), -CO(aτyl), -CO(heteroaryl), Cs-C8 cycloalkyl, C3-C8heterocycloalkyl, C6-Ci4aryl, heteroaryl, aryl-Ci.Cβalkyl. A further set of compounds of interest are those of formula IB
Figure imgf000012_0003
where
A is AI ; B is
Figure imgf000013_0001
or A and B are combined to form a tricyclic ring of formula A/B
Figure imgf000013_0002
Z is C(Ri) and X and Y are independently C(Ri) or N; m in the [-] of Bl , B5 and B6 is 1 or 2;
Ri is bonded to any ring carbon and is H, Ci-Ce allcyl, difiuoromethyl, trifluoromethyl, halo, NO2, or N(C=O)Ci_C6alkyl; where the allcyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Ci.Cβ allcyl, C3-C6 cycloalkyl, C3-C8 heterocyclic ring, aryl, heteroaryl, halo, cyano, nitro, and -OR8; n in the RiCn] of Al is 1 - 4, is 0 in A2 and is 1 in A/B;
R2 and R3 are independently H, -C(O)N(R8)2, halo-substituted Ci-C6alkyl, or Ci-Qallcyl where the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting Of-N(R9)(R8) -OR8' -C(O)R8, and -C(O)OR8;
R5 and R6 are independently H, OR8, halo, NR8R9, Ci-C6allcyl; or R5 and Re together form a 3-6 membered heterocyclic ring containing 1 or more hetero atoms which are O or N; R7 is H, or halo; Rg is hydrogen, Ci.Cδalkyl, R9 is hydrogen, -CO(C1-C4 alkyl), -CO(NR8R10), -N(Rs)2, or -S(O)2R10;
R10 is hydrogen, Ci,C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -CO(C1-C4 alkyl), -CO(aryl), -CO(heteroaryl), C3-Cg cycloalkyl, C3-C8heterocycloalkyl, Cβ-Cwaryl, heteroaiyl, aryl-Q.Cealkyl; or a pharmaceutically acceptable salt or solvate thereof.
Another useful embodiment is a further refinement of the groups of formula IB described in the foregoing paragraph, namely the compounds of formula IB
Figure imgf000014_0001
where
A is Al;
B is B1
Figure imgf000014_0002
where
Z is C(Ri) and X and Y are independently C(Ri) or N; m in the [-] of Bl is 1; R1 is bonded to any ring carbon and is H, C1-Ce alkyl, difluoromethyl, trifluoromethyl, halo,
NO2, OrN(C=O)C1-C(SaIlCyI; where the alkyl group is unsubstituted or substituted with one or more substituents independently selected from Hie group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocyclic ring, aryl, heteroaryl, halo, cyano, nitro, and -ORg; n in the R1[^ of Al is 1 - 4; R2 and R3 are independently H, -C(O)N(R8)2, halo-substituted Ci-C6alkyl, or Ci-C6alkyl where the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting Of-N(R9)(R8) -OR8' -C(O)R8, and -C(O)OR8;
R5 and R6 are independently H, ORg, halo, NR8Ry, Ci-C6alkyl; or R5 and Re together form a 3-6 membered heterocyclic ring containing 1 or more hetero atoms which are O or N;
R7 is H, or halo;
R8 is hydrogen, Ci.C6alkyl,
Ry is hydrogen, -CO(Ci-C4 alkyl), -CO(NR8RiO), -N(Rs)2, or -S(O)2Ri0; and R10 is hydrogen, Ci.C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -CO(Ci-C4 alkyl), -CO(aryl),
-CO(heteroaryl), C3-Cs cycloalkyl, C3-C8heterocycloalkyl, C6-Ci4aryl, heteroaryl, aryl-Ci.Cβalkyl.
With regards to formula 1C illustrative useful embodiments are as follows:
Figure imgf000015_0001
where
A is Al
B is
Figure imgf000015_0002
Z is C(R1) and X and Y are independently C(R1) or N; m in the [-] ofBl is 1;
Ri is bonded to any ring carbon and is H, Ci-Ce alkyl, difluoromcthyl, trifluoromcthyl, halo, NO2, or N(C=0)C1-C6alkyl; where the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Ci-C6 alkyl, C3-Ce cycloalkyl, Cs-Cg heterocyclic ring, aryl, heteroaryl, halo, cyano, nitro, and -OR8; n in the RiCn] of Al is 1 - 4;
R2 and R3 are independently H, -C(O)N(Rs)2, halo-substituted Ci-C6aikyl, or Ci-C6alkyl where the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting Of-N(R9)(R8) -OR8' -C(O)R8, and -C(O)OR8; R4 Is O;
Rg is hydrogen, CiX6alkyl,
R9 is hydrogen, -CO(Ci-C4 alkyl), -CO(NRuR1O), -N(Rg)2, or -S(O)2Ri0; and Rio is hydrogen, Ci.C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -CO(Ci-C4 alkyl), -CO(aryl),
-CO(heteroaryl), C3-C8 cycloalkyl, C3-C8heterocycloalkyl, C6-Ci4aryl, heteroaryl, aryl-Ci.Qalkyl. Compounds of specific interest are set out in the Examples.
Tn certain embodiments, compounds according to Formula I A, 1 B or 1 C may contain a basic group that is capable of forming pharmaccutically-acccptablc acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically-acceptable inorganic acids and pharmaceutically-acceptable organic acids.
The compounds of formula IA, IB or 1C may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be solvated, e.g. as the hydrate. This invention includes within its scope stoichiometric solvates (e.g. hydrates) as well as compounds containing variable amounts of solvent (e.g. water).
While it is possible that, for use in therapy, a compound of formula IA, IB or 1C, as well as salts, solvates and the like may be administered as a neat preparation, i.e. no additional carrier, the more usual practice is to present the active ingredient confected with a carrier or diluent. Accordingly, the invention further provides pharmaceutical compositions, which includes a compound of formula IA, IB or 1C and salts, solvates and the like, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of formula IA, IB or 1 C and salts, solvates, etc, are as described above.
Where it is possible for compounds of formula 1 A, 1 B or 1 C to exist in one or more tautomeric forms, all such tautomcrs and mixtures thereof arc included in the scope of the invention.
Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 1 OO mg of a compound of the formula IA, IB or 1C, depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Preferred unit dosage compositions are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.
Pharmaceutical compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association a compound of formal IA, IB or 1C with the carricr(s) or cxcipicnt(s). An "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. The following abbreviations used herein are defined as follows:
OD column - Octyldecal (C- 18) column
AD column - ChiralPak AD column TBAI — tetrabutylammonium iodide
DMSO - Dimethyl sulfoxide,
DIEA - diisopropylethylamine
DCE — dichloroethane,
DCM - dichloromethane, rt/RT- room temperature,
YMC -YMC, Inc.
TFA - trifluoroaeetic acid,
DMF - dimethylformamide,
DAST -Dicthylaminosulfurtrifluoridc THF - tetrahydrofuran,
MP-Borohydride - Macroporous-Borohydride
YMC (C- 18) column - C- 18 column made by YMC, Inc.
PS-DTEA - N,N-(diisopropyl)aminomethylpolystyτene
EDC - l-(3-dimcthylaminopropyl)-3-cthylcarbodiimidc hydrochloride HOAt - l-hydroxy-7-azabenzotriazole EXAMPLES
The following preparations and examples are provided to illustrate how to make compounds of formulas IA, IB, and IC and assays demonstrating testing of the CXCR3 inhibitory properties of these compounds. Sulfonyl-substituted camphor compounds, e.g., (S)-(+)-l O-camphorsulfonic acid and (+)-
10-camporsulfonyl chloride, and a number of ring-substituted analogs of these sulfonyl derivatives as exemplified by formulas IA, IB and IC, are available from commercial sources such as Aldrich Chemical Company, Inc., Milwaukee, WI, USA.
Preparation 1
Arylchlorides or arylfluorides 1 reacted with unprotected cyclic diamines 2 to give aryldiamines 3, which upon sulfonylation with camphor derived sulfonylchlorides to yield the desired products 4 (Scheme 1 ).
Scheme 1
Figure imgf000018_0001
Conditions: a) K2CO3, TBAI, DMSO or DIEA, DMSO, rt or heating; b) Camphor derived sulfonylchlorides, DIEA, DCM, rt. Example 1
Preparation of (15r,4/ϊ)-7,7-dimethyl-l-[({4-[3-nitro-5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl}suIfonyl)methyl]bicycIo[2.2.1]heptan-2-oπe
Figure imgf000019_0001
To a solution of pipcrazinc (447mg, 5.2 mmol) in DMSO (3ml) was added 2-chloro-3- nitro-5-(trifluoromethyl)pyridine (300mg, 1.3 mmol) and DIEA (0.3ml). The mixture was stirred at RT for 2 h. The resulting mixture was partitioned between aqueous HCl (IN, pH=2) and EtOAc. The aqueous layers were separated, then adjusted to pH=12 by adding NaOH (IN) and extracting with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to afford l-[3-fluoro-5-(trifluoromcthyl)-2-pyridinyl]pipcrazinc as a yellow solid (280mg, 78%). MS (ESI): 277 [M+H]+.
To a solution of l-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]piperazine (156mg, O.όmmol) in DCM (4ml) was added DIEA (0.2ml) and [(l£,4i?)-7,7-dimethyl-2-oxobicyclo[2.2. l]hept- 1- yl]methanesu1fonyl chloride (213mg, 0.8mmol). The reaction mixture was stirred at RT for 2h. The solvents were removed in vacuo. The resulting residue was dissolved in DMSO and purified by using a Gilson preparative HPLC system with a Waters Xterra (C- 18) column 100 mm by 50 mm ID, eluting with 20% B to 99% B in 10 min, where A = H2O and B = CH3CN pumped at 150 mL/min to yield the desired product (15',4i?)-7,7-dimethyl-l-[({4-[3-nitro-5-(trifluoromethyl)-2- pyridinyl]-l-piperazinyl}sulfonyl)methyl]bicyclo[2.2.1 ]heptan-2-one as a yellow solid (209mg, 71%). MS (ESI): 491 [M+H]+.
Example 2 Preparation of (lS,4S)-3-bromo-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- pipera/1nyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-one
Figure imgf000020_0001
An aliquot of 40mg (0.13mmol) of (3-bτomo-7 J-dimethyl-2-oxobicyclo[2.2.1]hept-l- yl)metlianesulfonic acid was added to 1 OmI of thionyl chloride in a 25ml round bottom flask. The solution was brought to reflux and stirred at this temperature for 4 hours. The flask was cooled down to room temperature (30 minutes) and the mixture was concentrated in vacuo.
The crude sulfonylchloride made above was dissolved in 2ml of DCM and added to a glass reaction vial containing 25mg (0.108mmol) of l-[5-(trifluoromethyl)-2-pyridinyl]piperazine and 120mg (4eq) N,N-(diisopropyl)aminomethylρolystyrene (PS-DIEA, Polymer Laboratories, 3.6mmol/g loading). The reaction vial was agitated at room temperature for 16 hours. The DCM solution was filtered away from the resin, concentrated to dryness, and purified by using a Gilson preparative HPLC system with a YMC (C- 18) column 50 mm by 20 mm ID, eluting with 10% B to 90% B in 6 min, where A= H2O (0.1% TFA) and B = CH3CN (0.1% TFA) pumped at 25 mL/min to yield (1 S34S)-3-bromo-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- pipcraanyl}sulfonyl)mcthyl]bicyclo[2.2.1]hcptan-2-onc (28.0mg, 49%). MS (ESl): 525 [M+H]+. Proceeding in a similar manner, but replacing 5-(trifluoromethyl)pyridmes in examples 1 and 2 with other pyridines, and/or replacing piperazine with other cyclic diamines, and/or replacing [(ljS',4i?)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-l-yl]methanesulfonyl chloride with other camphor derived sulfonylchlorides (if not commercially available, prepared from the corresponding acids), the compounds listed in Table 1 were prepared.
When {4-[5-(trifluoromethyl)-2-pyridinyl]-2-piperazinyl}methanol (3a) reacted with an excess of [(lS,4i?)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-l-yl]methanesulfonyl chloride in the presence of DIEA yielded the desired product 4a (example 22) and a by-product 4b. Examples 23 and 24 were obtained by heating 4b in the presence of Me2NH-HCl and DIEA (Scheme 2). Scheme 2
Figure imgf000021_0001
Table 1
Figure imgf000021_0002
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000026_0002
Preparation 2
Arylchlorides or arylfluorides (1) reacted with Boc-protected cyclic diamines 5 to give Boc- protected aryldiamines 6. Upon deprotection, the resulting secondary amine 7 underwent sulfonylation with camphor-derived sulfonylchlorides to produce the desired products 8 (Scheme 3).
Scheme 3
Figure imgf000026_0001
Conditions: a) K2CO3, TBAI, DMSO or DIEA, DMSO, heating; b) 50%TFA in DCE, DCM- rt; c) Camphor derived sulfonylchlorides, DIEA, DCM, rt.
Boc-protected diamines 5 can be other types of diamines such as in the following (5a, 5b):
5a
In 5a and 5b, n and m are independently O, 1 or 2 with the limitation that the ring must be comprised of 5, 6 or 7 atoms.
Example 28 Preparation of (15',4Λ)-7,7-dimethyI-l-[({(35r)-3-methyl-4-[5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyllbicyclof2.2.11heptan-2-one
Figure imgf000027_0002
Into a 5-mL-pressure tube (or flask), was added 400mg (2.21mmol) of 2-chloro-5-
(trifluoromethyl)pyridine, 442mg (2.21mmol) of 1,1-dimethylethyl (3S)-3-methyl-l- piperazinecarboxylate, 0.5mL DIEA and 2.5mL DMSO. The mixture was heated at 110° C for two days. The resulting mixture was added to a saturated NaHCOs aqueous solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to yield crude 1,1-dimethylethyl (36)-3-methyl-4-[5-(trifluoromethyl)-2-pyridinyl]-l-piperazinecarboxylate. MS(ESI) 346 [M+H]+.
The above crude product in a 25mL-flask was added 2mL DCM and 2mL 50% TFA in DCE. The mixture was stirred at RT for overnight. The mixture was concentrated in vacuo (extra TFA was removed by adding DCE and re-concentrating) to yield crude TFA salt of (2S)-2-methyl- l-[5-(trifluoromethyl)-2-pyridinyl]piperazine. MS(ESI) 246 [M+H]+. The above crude amine product was added 4.OmL DCM and ImL DIEA. An aliquot of 608mg (2.43mmol) of (S)-(+)-camphor sulfonylchloride in 2.OmL DCM was slowly added at O0C. The mixture was stirred at RT for 2h. The resulting solution was concentrated in vacuo. The residue was purified by using a Gilson preparative HPLC system with a Waters Xterra (C-18) column 100 mm by 50 mm ID, eluting with 20% B to 99% B in 10 min, where A = H2O and B = CH3CN pumped at 150 mL/min to yield (lS,4i$-7,7-dimemyl-l-[({(3S)-3-methyl-4-[5- (trifluoromethyl)-2-pyridinyl]- 1 -piperazinylJsulfonytymethyllbicycloP-^.1 ]heptan-2-one (41 Omg, 40% yield for 3 steps). MS (ESI): 460 [M+H]+.
Proceeding in a similar manner, but replacing 2-chloro-5-(trifluoromcthyl)pyridinc with other arylchlorides or arylfluorides, and/or replacing 1,1-dimethylethyl (35)-3-methyl-l- piperazinecarboxylate with other cyclic diamines, the compounds listed in Table 2 were prepared. For some examples, HPLC purification used acidic eluting solvents (A=H2O plus 1 % TFA; B=CH3CN plus 1 % TFA).
Table 2
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Preparation 3
Camphor-derived sulfonylchlorides 10 reacted with cyclic diamines 9 to form sulfonamides 11, which underwent aromatic nucleophilic substitution or Pd-mediated coupling with arylhalides to produce the desired products 12 (Scheme 4).
Scheme 4
Figure imgf000032_0001
Conditions: a) DTEA. DMF, rt; b) DTEA, DMSO, heating or Pd-cataiysts, THF, heating.
Example 49
Preparation of (l$,4R)-l-({ [4-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl] -3-(hydroxymethyl)-l- piperazinyl]sulfonyl}methyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-one
Figure imgf000032_0002
Into a 25mL flask was added 400mg (3.45mmol) of 2-piperazinylmethanol and ImL DIEA and 4mL DMF. An aliquot of 560mg (2.24mmol) of [(lS,4i?)-7,7-dimethyl-2- oxobicyclo[2.2.1]hept-l-yl]methanesulfonyl chloride in ImL of DMF was added dropwise. The mixture was stirred at rt for 4h. After filtration, the reaction solution was concentrated and the residue was purified by using a Gilson preparative HPLC system with a Waters Xterra (C-18) column 100 mm by 50 mm ID, eluting with 5% B to 99% B in 10 min, where A = H2O and B = CH3CN pumped at 150 mL/min (fraction collection based on UV trace at 214nm with sensitivity set as low as 2) to yield (^^^-^({[S-øiydroxymethy^-l-piperazinyysulfonyllmethyl)-?,?- dimcthylbicyclo[2.2.1]hcptan-2-onc (500mg, 67%). MS (ESI): 331 [M+H]+. To 190mg (0.576mmol) of above (l£,4£)-l-({[3-(hydroxymethyl)-l- piperazinyl]sulfonyl}methyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-one was added 0.2mL of DIEA and ImL DMSO. Then An aliquot of 105mg (0.576mmol) of 2,3-difluoτo~5- trifluoromethylpyridine was added. The mixture was heated at 500C for two days. After filtration, the reaction solution was concentrated (to remove DIEA) and the residue was purified by using a Gilson preparative HPLC system with a Waters Xterra (C- 18) column 100 mm by 50 mm ID, eluting with 20% B to 99% B in 10 min, where A = H2O and B = CH3CN pumped at 150 mL/min to yield ( 1S,4R)- 1 -( { [4- [3-fluoro-5-(trifluoromethyl)-2-pyridiny l]-3 -(hydroxymethyl)- 1 - piperaziiiyllsulfonyllmethyO^J-dimethylbicycloP^.llheptan^-one (125mg, 44%). MS (ESI): 494 [M+H]+.
Examples 50 and 51
Preparation of (lS,4R)-l-({ [(3/?)-4-(5-chloro-4,6-difluoro-2-pyrimidinyl)-3-methyl-l- piperazinyl]sulfonyI}methyl)-7,7-dimethyIbicyclo[2.2.1]heptan-2-one (example 50) and
(l.S',4i?)-l-({[(3/-)-4-(5-chloro-2,6-dmuoro-4-pyrimidinyl)-3-methyl-l- piperazinylJsulfonyl}methyl)-7,7-dimethylbicyclo[2.2.1Jheptan-2-one (example 51)
Figure imgf000033_0001
Into a 250ml flask were added (R)-(-)-2-methylpiperazine (4.Og), diisopropylethylamine (10ml) and dimethylformamide (40ml). (lS)-(+)-10-camphorsulphonyl chloride (6.5g) in dimethylformamide (10ml) was added dropwise. Resultant solution was stirred at room temperature overnight (16h). The mixture was partitioned between saturated sodiumbicarbonate and ethyl acetate. The solid was filtered and the ethyl acetate layer was dried by passing through a hydrophobic frit. It was evaporated in vacuo to give (15',4i?)-7,7-diniethyl-l-({[(3i?)-3-metliyl-l- pipei-azinyl]sulfonyl}methyl)bicyclo[2.2.1]heptan-2-one as a white solid (2.2g). MS (EST): 315 [MH-H]+. In a green house test tube were added (lS,4R)-7,7-dimethyl-l-({[(3i?)-3-methyl-l- piperazinyl]sulfonyl}methyl)bicyclo[2.2. l]heptan-2-one (19ϋmg), 5-chloro-2,4,6 trifluoropyrimidinc (32mg), DMSO (1.0ml) and diisopropylcthylaminc (0.2ml). The resultant mixture was heated to 500C for 16h. The reaction mixture was evaporated to dryness in a vacuum centrifudge and purified on a mass directed auto prep to give the two products as white solids: (1^4i?)-l<{[(3-R)-4-(5-chloro-4,6-difluoro-2-pyrirnidinyl)-3-methyl-l- piperazinyl]sulfonyl}methyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-one (15mg), MS (ESI): 463 [M+H]+; (l,S',4i?)-l-({[(3i?)-4-(5-chloro-2,6-difluoro-4-pyrimidinyl)-3-methyl-l- piperazinyl]sulfonyl}methyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-one (12mg), MS (ESI): 463 [M+H]+.
Example 52
Preparation of (lS,4R)-l-({ [(3S)-4-(4,6-dichloro-2-pyrimidinyl)-3-methyl-l- piperazinyl]sulfonyl}methyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-one
Figure imgf000034_0001
Into a 500ml flask were added (S)-(+)-2-methylpiperazine (5.Og), diisopropylethylamine
(10ml) and dimethylformamide (40ml). (lS)-(+)-10-camphorsulphonyl chloride (8.125g) in dimethylformamide (10ml) was added dropwise. Resultant solution was stirred at room temperature over weekend (6Oh). The mixture was partitioned between saturated sodiumbicarbonate and ethyl acetate. The solid was filtered and the ethyl acetate layer was dried by passing through a hydrophobic frit and evaporated in vacuo to give (15(,4i2)-7,7-dimethyl-l- ({[(3S)-3-methyl-l-piperazinyl]sulfonyl}methyl)bicyclo[2.2.1]heptan-2-one as an off white solid (5.08g). MS (ESI): 315 [M+H]+.
In a green house test tube were added (lS,4i2)-7,7-dimethyl-l-({[(35)-3-methyl-l- piperaτmy1]sulfonyl}methy1)bicyclo[2.2.1 ]heptan-2-one (190mg), DMSO (1.OmI), DTPEA (0.2ml) and 2,4,6-tricliloropyrimidine (34.8mg). The resultant mixture was heated to 500C for 16h. The reaction mixture was evaporated to dryness in a vacuum centrifudge and purified on a mass directed auto prep to give (l)S',4R)-l-({[(3>S)-4-(4,6-dichloro-2-pyrimidinyl)-3-methyl-l- pipcrazinyl]sulfonyl}mcthyl)-7,7-dimcthylbicyclo[2.2.1]hcptan-2-onc as a white solid (8mg). MS (ESl): 462 [M+H]+. Example 53
Preparation of 5-chloro-2-[(25)-4-({[(15,4JR)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-l- yl]methyl}sulfonyl)-2-methyl-l-piperazinyl]-4-pyridinecarbonitrile
Figure imgf000035_0001
In a microwave vial were added *catalyst powder (200mg), 2,5-dichloro-4-pyτidine carbonitrile (34.6mg), (15r,4Λ)-7,7-dimβthyl-l-({[(35)-3-methyl-l piperazinyl]sulfonyl}methyl)bicyclo[2.2.1]heptan-2-one (125mg) and tetrahyrofuran (50μl). The resultant paste was heated in a microwave at 1500C for 30min, after which 50:50 DMSO: methanol was added to the reaction mixture. The solid was filtered and the filterate was purified by MDAP to give 5mg of desired product, 5-chloro-2-[(2S)-4-({[(lS,4R)-7,7-dimetlryl-2- oxobicyclo[2.2.1]heρt-l-yl]methyl}sulfonyl)-2-methyl-l-piperazinyl]-4 pyridinecarbonitrile, as an off white solid. MS (ESI): 451 [M+H]+.
*Catalyst powder composition: Cs2CO3 - Al2O3 (50%), + (l)+(2)+(3) + Pd2dba3 (3g,
25mg, 15mg, 15mg, 20mg); Dry ingredients are stirred vigorously under nitrogen for ~ 1 hour to produce a free-flowing grey/purple powder.
Figure imgf000035_0002
Proceeding in a similar manner, but using different arylhalidcs and/or different cyclic diamines, the compounds listed in Table 3 were prepared. Table 3
Figure imgf000036_0001
Figure imgf000037_0001
Preparation 4
Camphor-derived sulfonylchloridc 10 reacted with Boc-protcctcd cyclic diamines 13 to form sulfonamides 14. Upon deprotection, the resulting secondary amines 15 underwent aromatic nucleophilic substitution with arylfluorides to produce the desired products 16 (Scheme 5). Scheme 5
Figure imgf000038_0001
Figure imgf000038_0003
Figure imgf000038_0002
Conditions: a) DIEA, DCM, rt; b) TFA, DCM, rt; c) DIEA, DMSO, microwave 100° C.
Example 58
Preparation of (l1S',4/ϊ)-l-r({(25)-4-r3-fluoro-5-(trifluororaethyl)-2-pyridinyll-2-methyl-l- piperazinyl}sulfonyl)methyl] -7,7-dimethylbicyclo [2.2.1] heptan-2-one
Figure imgf000038_0004
To a solution of [(l,l-dimethylethyl)oxy][(3iS)-3-methyl-l-piperazinyl]methanol (160mg, 0.8mmol) in DCM (2ml) was added DIEA (0.2ml) and [(15,4i?)-7,7-dimethyl-2- oxobicyclo[2.2.1]hept-l-yl]methanesulfonyl chloride (200mg, 0.8mmol). The mixture was stirred at room temperature for 4h. Solvents were removed and the resulting crude product, 1,1-dimethylethyl (3£)-4-( { [(15,4i?)-7,7-dimethyl-2-oxobicyclo[2.2.1 ]hept- 1 -yljmethyl} sulfonyl)-3 -methyl- 1 - piperazinecarboxylate was used in the next reaction without further purification. To a mixture of the above crude product in MeOH (2ml) was added HCl in dioxane (4M,
0.8ml). The mixture was stirred at room temperature for 18h. Solvents were removed under reduced pressure. The resulting residue was partitioned between DCM and saturated aqueous NaHCCb. The organic layer was washed with water, brine solution and dried over Na2SO4. After solvent was evaporated under reduced pressure, the resulting crude product, (15',4i?)-7,7-dimcthyl- 1 -( {[{2S)-2- methyl-l-piperazinyl]sulfonyl}methyl)bicyclo[2.2.1]heptan-2-one, was used for the next reaction without further purification.
To a mixture of the above crude product in DMSO (1.5ml) in 5mL microwave reactor was added 2,3-difluoro-5-(trifluoromethyl)pyridiτie (150mg, 0.8mτnol) and DTEA (0.15ml). The mixture was heated in Biotagc microwave at 100° C for 5 min. The crude material was purified by using a Gilson preparative HPLC system with a Waters Xterra (C- 18) column 100 mm by 50 mm ID, eluting with 20% B to 99% B in 10 min, where A = H2O and B = CH3CN pumped at 150 mL/min to yield the desired product (l)S',4JR)-l-[({(2iS)-4-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]-2-methyl- l-piperazinyl}sulfonyl)methyl]-7,7-dimethylbicyclo[2.2.1]heptan-2-one as a white solid (249mg, 65% yield over 3 steps). MS (ESl): 478 [M+H]+. Proceeding in a similar manner, but replacing 1,1-dimethylethyl (3S)-3-methyl-l- piperazinecarboxylate with other cyclic diamines, the compounds listed in Table 4 were prepared.
Table 4
Figure imgf000039_0001
( ISAR)- 1 -[({(2i?)-4-[3-fluoro-5-(trifluoromethyl)-
59 2-pyridinyl]-2-methyl-l-piperazinyl}sulfonyl) 478 methyl]-7,7-dimethylbicyclo[2.2.1 ]heptan-2-one
Figure imgf000040_0001
Preparation 5
Ketones 17 underwent reduction to form alcohols 18, which upon fhαorination to form fluorides 19. Grignard addition to Ketones 17 formed tertiary alcohols 20 and protection of ketones 17 formed cyclic ketyl compounds 21 (Scheme 6).
Scheme 6
Figure imgf000040_0002
Conditions: a) NaBH4, EtOH, rt; b) DAST, DCM, rt; c) MeMgBr, THF, rt; d) (CH2)2(OH)2, toluene, reflux. When ketone 17a was treated with LiAlBU in THF at rt, example 63 (18a) was prepared
(Scheme 7). Scheme 7
Figure imgf000041_0001
Example 60
Preparation of (l»S',4Λ)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyrimidinyl]-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-ol
Figure imgf000041_0002
To a slurry of (lJSr,4R)-7,7-dimethyl-l-[({4-[5-(trifluorϋmethyl)-2-pyrimidinyl]-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heρtan-2-one (example 30, 84mg, 0.18τnmol) in EtOH (2ml) was added NaBH4 (excess amount). The mixture was stirred at rt for overnight. The mixture was added to water and extracted with EtOAc. The EtOAc layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by using a Gilson preparative HPLC system with a Waters Xterra (C-18) column 100 mm by 50 mm ID, eluting with 20% B to 99% B in 10 min, where A = H2O and B = CH3CN pumped at 150 mL/min to yield the desired product ( 1 <S',4i?)-7,7-dimethy 1- 1 -[( {4-[5-(trifluoromethyl)-2-pyrimidinyl]- 1 - piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-ol as a white solid (16mg, 19%). MS (ESI): 449 [MH-H]+. Proceeding in a similar manner, but replacing (15',4i?)-7,7-dimethyl-l-[({4-[5- (trifluoromethyl)-2-pyriim'diny I]-I -piperazinyl} sulfonyl)methy l]bicyclo[2.2.1 ]heptan~2-one in example 55 with other ketones, the compounds listed in Table 5 and Table 6 were prepared.
Table 5
Example Structure Name Ms ΓM+HΓ
(lS,4i?)- 1 -[( {(2S)-4-[3-fluoro-5-(trifluoromethyl)-2-
60 pyridinyl]-2-methyl- 1 -piperazinyl} sulfonyl)methyl]- 449 7,7-dimethylbicyclo[2.2.1 ]heptan-2-one
(lS,4i?)-7,7-dimethyl- 1 -[( {(35)-3-methyl-4-
61 [5-(trifluoromemyl)-2-pyrimidiiiyl]- 1 - 463 piperazinyl} sulfonyl)methyl]bicyclo[2.2.1 ]heptan-2-ol
(l£,4i?)-7,7-dimethyl- 1 -[( {4-[6-(trifluoromethyl)-3-
62 pyridazinyl]-l-ρiperazinyl}sulfonyl)methyl]bicycle 449 [2.2.1]heptan-2-ol
(1 S,4Λ)-7,7-dimethyl- 1 -[( {(35)-3-methyl-4-
63 [6-(trifluoromcthyl)-3-pyridazinyl]- 1 - 463 piperazinyl} sulfbnyl)methyl]bicyclo[2.2.1 ]heptan-2-ol
Figure imgf000042_0001
Figure imgf000043_0001
(lS,4i?)-7,7-dimethyl-l-[({(35)-3-methyl-4- [5-(trifluoromethyl)-2-pyridinyl]- 1 - 462 piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-ol
Figure imgf000044_0001
For the example 69, chiral resolution was conducted on Agilent OA LC using Phenomenex Luna with non-polaτ method eluting with 50-90% acetonitrile (0.1% FA) to give two diastereomers in their pure forms (example 70 and 71 in Table 6).
For the example 64, chiral resolution was conducted on 30mm AD column eluting with 20% MeOH at 140 bar, 40° C, with CO2 flow at 75g/min to give two diastereomers in their pure forms (example 72 and 73 in Table 6).
For the example 61, chiral resolution was conducted on OD column eluting with 6.5% McOH at 140 bar, 40° C, with CO2 flow at 50g/min to give two diastereomers in their pure forms (example 74 and 75 in Table 6).
Table 6
Figure imgf000044_0002
Figure imgf000045_0001
Example 76
Preparation of (25)-4-({ [(lS,4i?)-2-fluoro-7,7-dimethylbicyclo [2.2.1] hept-1- yl]methyl}sτιlfonyl)-l-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]-2-methylpiperazine
Figure imgf000046_0001
To a solution of (l^^-l-KKS^^-P-fluoro-S-(trifluoromethy^^-pyridinyy-S-methyl-l- piperazinyl}sulfonyl)methyl]-7,7-dimethylbicyclo[2.2.1]heptan-2-ol (example 59, 131mg, 0.3mmol) in DCM was added DAST (0.4ml, 0.55mmol) by syringe. The reaction mixture was stirred at rt for overnight. Solvent was evaporated and the residue was purified by using a Gilson preparative HPLC system with a Waters Xterra (C- 18) column 100 mm by 50 mm ID, eluting with 20% B to 99% B in 10 min, where A = H2O and B = CH3CN pumped at 150 mL/min to yield the desired product (2S)-4-({[(lS,4R)-2-fluoro-7,7-dimethylbicyclo[2.2.1]hept-l-yl]methyl}sulfonyl)- l-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]-2-methylpiperazine as a solid (20mg, 14%). MS (ESI): 482 [M+H]+.
Example 77
Preparation of (liS',4JR)-2,7,7-trimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-ol
Figure imgf000046_0002
An aliquot of 50 mg (0.1 lmmol) of (lS,4R)-7,7-dimethyl-l-[({4-[5-(trifluoτomethyl)-2- pyridmyl]-l-piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-one was added to a lOπiL round bottom flask and placed under a nitrogen atmosphere. The solid was dissolved in 5mL of anhydrous THF. 70μl (~2eq) of 3M methyl magnesium bromide in diethyl ether was added via syringe. The solution was stirred at room temperature for 16 hours. The contents of the flask were poured into a flask containing diethyl ether/ice/water. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by using a Gilson preparative HPLC system with a YMC (C- 18) column 50 mm by 20 mm ID, eluting with 10% B to 90% B in 6 min, where A = H2O (0.1% TFA) and B = CH3CN (0.1% TFA) pumped at 25 mL/min to yield (lS,4R)-2,7,7-trimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-ol (32.0mg, 62%) MS (ESI): 462 [M+H]+.
Example 78
Preparation of l^l^l^ΛH^-dimethyl-liϊ-spirotbicyclop.Z.llheptane-Z^'-fl^ldioxolan]- l-yl]methyl}sulfonyl)-4-[5-(trifluoromethyl)-2-pyridinyl]piperazine
Figure imgf000047_0001
An aliquot of 50 mg (0.1 lmmol) of (lS,4R)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2- pyridinyl]-l-piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-one was placed in a 1OmL round bottom flask. Then 8ml toluene was added and 5mg (catalytic) para-toluene sulfonic acid. Added to this solution was 20μl ethylene glycol. The flask was attached to a Dean Stark trap and brought to reflux. The solution was stirred at refluxed for 16 hours, cooled to room temperature, concentrated on a rotary evaporator, and purified using a Gilson preparative HPLC system with a YMC (C-18) column 50 mm by 20 mm TD, eluting with 10% B to 90% B in 6 min, where A = H2O (0.1% TFA) and B = CH3CN (0.1% TFA) pumped at 25 mL/min to yield l-({[(lS,4R)-7,7- dimethyl- 1 H-spiro [bicyclo[2.2.1 ]heptane-2,2'-[ 1 ,3] dioxolan]- 1 -yl]methyl) sulfonyl)-4-[5- (trifluoromethyl)-2-pyridinyl]piperazine (9.0mg, 17%) MS (ESI): 490 [M+H]+. 1H NMR (CDCl3,
400MHz) δ: 8.42 (s, IH), 7.68 (d, IH)5 6.70 (d, IH), 3.98 (m, 2H), 3.75 (m, 5H), 3.36 (m, 5H), 3.20 (d, IH), 2.63 (d, IH), 2.32 (m, IH), 2.00 (m, 2H), 1.75 (m, 2H), 1.45 (d, IH), 1.32 (m, IH), 1.02 (s, 3H), 0.92 (s, 3H).
Proceeding in a similar manner, but replacing (15',4i?)-l-[({(3Sr)-4-[3-fluoro-5- (trifluoromethyl)-2-pyridinyl] -3 -methyl- 1 -piperazinyl} sulfonyl)methyl]-7,7- dimethylbicyclo[2.2.1]heptan-2-ol in example 71 with other alcohols, or (lS,4R)-7,7-dimethyl-l- [({4-[5-(trifluoromethyl)-2-pyridinyl]-l-piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-one in examples 72 and 73 with other ketones, the compounds listed in Table 7 were prepared.
MS
Example Structure Name
(2£)-4-( { [( 151,4i?)-2-fluoro-7,7-dimethylbicyclo[2.2.1 ]
76 hept-l-yl]methyl}sulfonyl)-l-[3-fluoro-5- 482
(trifluoromethyl)-2-pyridinyl]-2-methylpiperazine
( 1 £,4i?)-2,7,7-trimethyl- 1 - [( {4- [5-(trifluoromethyl)-2-
77 pyridinyl]- 1 -piperazinyl} sulfonyl)methyl]bicyclo[2.2.1 ] 462 heptan-2-ol
1 -( {[(lS,4i?)-7,7-dimethyl- lH-spiro[bicyclo[2.2.1 ]
78 heptane-2,2'-[l,3]dioxolan]-l-yl]methyl}sulfonyl)-4- 490
[5-(trifluoromethyl)-2-pyridinyl]piperazine
(2S)-4-({[(lS,4i?)-2-fluoro-7,7-dimethylbicyclo[2.2.1]
79 hept- 1 -yl]methyl } sulfonyl)-2-methyl- 1 - 464 [5-(trifluoromethyl)-2-pyridinyl]piperazine
Figure imgf000048_0001
Figure imgf000049_0001
Preparation 6
Ketones 17 was reacted with hydroxylamine to form ketone oximes 22, which upon reduction produced primary amines 23. Primary amines 23 underwent amide formation, sulfonylation, urea formation, and reductive alkylation to lead amides 24, sulfonamides 25, ureas 26 and secondary amines 27, respectively (Scheme 8).
Scheme 8
Figure imgf000050_0001
Conditions: a) Hydroxylamitie HCl, TEA, EtOH, reflux; b) Ammonium acetate, NaCNBH3, TiCl3 (15% in HCl), O0C to rt; c) R3COCl, PS-DIEA, DCM, rt; d) R4SO2CI, DIEA, DCM, rt; e) R5NCO, THF, rt; f) R6CHO, MP-Borohydride, THF, rt. Example 82
Preparation of (15,2JBr,4/f)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-one oxime
Figure imgf000051_0001
An aliquot of 450mg (l.Olmmol) of (lS,4R)-7,7-dimethyl-l-t({4-[5-(trifluoromethyl)-2- pyridinyl]-l-piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-one was placed in a round bottom flask. Then 420mg (6eq) hydroxylamine hydrochloride was added along with 6mL of ethyl alcohol, after which 630μL of triethylamine (4.5eq) was added. The solution was brought to reflux and stirred at this temperature for 16 hours. The solution was cooled to room temperature and the cthanol removed using a rotary evaporator. A 2: 1 mixture of ethyl acctatc/watcr was added to the flask. The organic layer was separated, dried over sodium sulfate, concentrated to dryness, and purified by using a Gilson preparative HPLC system with a YMC (C- 18) column 50 mm by 20 mm ID, eluting with 10% B to 90% B in 6 min, where A = H2O (0.1% TFA) and B = CH3CN (0.1% TFA) pumped at 25 mL/min to yield (1 S,2E,4R)-7,7-dimethyl- 1 ~[({4-[5-(trifluoromethyl)-2- pyridinyl]-l-pipcrazinyl}sulfonyl)mcthyl]bicyclo[2.2.1]hcptan-2-onc oximc. MS (ESI): 461 [M+H]+. 1H NMR (CDCl3, 400MHz) δ: 8.41 (s, IH), 7.65 (d, IH), 6.94 (s, IH), 6.65 (d, IH), 3.73(dd, 4H), 3.41 (m, 5H), 2.89 (d, IH), 2.57 (dt, IH), 2.45 (dd, IH), 2.04 (d, IH), 1.93 (m, 2H), 1.72 (m, IH), 1.31 (m, IH), 1.05 (s, 3H), 0.81 (s, 3H).
Example 83
Preparation of (15r,4i?)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-amine
Figure imgf000052_0001
An aliquot of lOOmg (0.22mmol) of (lS,2E,4R)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)- 2-pyτidinyl]-l-piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-one oxime was placed in a round bottom flask. Then 4mL of methanol was added and the flask was cooled to 0° C in an ice bath. Thereafter 217mg (13eq) of ammonium acetate and 56mg (4eq) sodium cyanoborohydride were added to the stirring solution. Then 600μl of titanium (III) trichloride (15% solution in HCl) was added dropwisc via syringe. The vessel was placed under nitrogen. The contents were left to stir in the ice bath, which slowly warmed to room temperature, for 16 hours. Subsequently 10ml of saturated sodium bicarbonate was added to the flask, followed by the addition of 20ml ethyl acetate. The solution was filtered through celite, and washed through with 30 ml ethyl acetate. The organic layer was separated, dried over sodium sulfate, concentrated to dryness on a rotary evaporator, and purified by using a Gilson preparative HPLC system with a YMC (C- 18) column 50 mm by 20 mm ID, eluting with 10% B to 90% B in 6 min, where A = H2O (0.1% TFA) and B = CH3CN (0.1% TFA) pumped at 25 mL/min to yield (lS,4R)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]- l-piperazinyllsulfony^methyljbicyclop^.ljheptan^-amine. MS (ESI): 447 [M+H]+. 1HNMR (CDCl3, 400MHz) δ: 8.40 (s, IH), 8.07 (bs, 2H), 7.71 (d, IH), 6.72 (d, IH), 3.9-3.7 (m, 4H), 3.66 (d, IH), 3.45 (m, 4H), 2.8 1 (d, IH), 2.10-1.74 (m, 7H), 1.35 (m, IH), 1.05 (s, 3H), 0.91 (s, 3H). Example 84
Preparation of Λ'-{(15',4i?)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyljsulfonyljmethyllbicycloll^.ljhept-l-yljacetamide
Figure imgf000053_0001
An aliquot of (1 S,4R)-7,7-dimethyl- 1 -[( {4-[5 -(trifluoromethyl)-2-pyridinyl]- 1 - piperazinyl}sulfonyl)meihyl]bicyclo[2.2.1]heptan-2-amine (30mg, 0.067mmol)) was placed in a reaction vial and dissolved in 2ml DCM. Added to the vial was 60mg (3eq) of N,N- (diisopropyl)aminomethylpolystyrene (PS-DIEA, Polymer Laboratories, 3.6mmol/g loading) followed by lOμl (2eq) of acetyl chloride. The vial was agitated at room temperature for 2 hours. The DCM solution was filtered away from the resin, concentrated to dryness, and the crude material was purified by using a Gilson preparative HPLC system with a YMC (C- 18) column 50 mm by 20 mm ID, eluting with 10% B to 90% B in 6 min, where A = H2O (0.1% TFA) and B = CH3CN (0.1% TFA) pumped at 25 mL/min to yield N- {(1 S,4R)-7,7-dimethyl-l -[( {4-[5-(trifluoromethyl)-2- pyridinylj-l-piperaκmyljsulfony^methyljbicyclop^.ljhept^-yljacetamide (8.0mg, 25%) MS (ESI): 489 [M+H]+.
Example 85 Preparation of Λ^-{(l1-»,4i?)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- piperazinylJsulfonylJmethyllbicycloIl^.lJhept-Z-ylJmethanesulfonamide
Figure imgf000053_0002
(lS,4R)-7,7-Dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- piρeraziiiyl}sulfonyl)inethyl]bicyclo[2.2.1]heptan-2-amine (20mg, 0.045mmol) was placed in a reaction vial and dissolved in 1ml DCM. Added to the vial was 30μl (3.8 eq) of N,N- diisopropylethylamine and 6μl (1.5eq) methanesulfonyl chloride. The vial was agitated at room temperature for 16 hours. The solution was evaporated to dryness and the crude material was purified by using a Gilson preparative HPLC system with a YMC (C- 18) column 50 mm by 20 mm ID, eluting with 10% B to 90% B in 6 min, where A = H2O (0.1% TFA) and B = CH3CN (0.1% TFA) pumped at 25 mL/min to yield N-{(lS,4R)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2- pyridinylj-l-piperaziny^sulfony^methyljbicyclop^.^hept-l-yljmethanesulfonamide (9.0mg, 38%) MS (EST): 525 [M+H]+.
Example 86
Preparation of iV-{(15',4i?)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]hept-2-yl}-iV-ethylurea
Figure imgf000054_0001
An aliquot of 20mg (0.045mmol) of (lS,4R)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2- pyridinyl]-l-piperazmyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-amine was placed in a reaction vial and dissolved in 2ml THF after which 6μl (1.5eq) of ethyl isocyanate was added. The vial was agitated at room temperature for 4 hours. The solution was evaporated to dryness and the crude material was purified by using a Gilson preparative HPLC system with a YMC (C- 18) column 50 mm by 20 mm ID, eluting with 10% B to 90% B in 6 min, where A = H2O (0.1% TFA) and B = CH3CN (0.1% TFA) pumped at 25 mL/min to yield N-{(lS,4R)-7,7-dimethyl-l-[({4-[5- (trifluoromethy^^-pyridinylj-l-piperazinylJsulfony^methy^bicycloP^. llhept^-ylj-N'-ethylurea (4.5mg, 19%) MS (ESI): 518 [M+H]+. Example 87
Preparation of (l.S,4i-)-iV-ethyl-7,7-dimethyl-l-[({4-[5-(trifliioromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-amine
Figure imgf000055_0001
An aliquot of 20mg (0.045mmol) of (lS,4R)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2- p3Tidinyl]-l-piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-amine was placed in a reaction vial and dissolved in 2ml THF and lOμl (4eq) of acetaldehyde was added. The vial was agitated at room temperature for 4 hours. Then lOOmg (7eq) of macroporous triethylammonium methylpolystyrene borohydride (MP-Borohydride, Polymer Laboratories, 3.2mmol/g loading) was placed in the vial. The vial was agitated at room temperature for 16 hours. The THF was filtered away from the resin, concentrated to dryness, and the crude material was purified by using a Gilson preparative HPLC system with a YMC (C- 18) column 50 mm by 20 mm ID, eluting with 10% B to 90% B in 6 min, where A = H2O (0.1% TFA) and B = CH3CN (0.1% TFA) pumped at 25 mL/min to yield (1 S,4R)-N-ethyl-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- pipcrazinyl}sulfonyl)mcthyl]bicyclo[2.2.1]hcptan-2-aminc (7.5mg, 35%) MS (ESI): 475 [M+H]+. IH NMR (CDCl3) d.
Proceeding in a similar manner as described for examples 77-82, but replacing (l$,4R)-7,7- dimethyl- 1 -[( {4-[5-(trifluoromethyl)-2-pyridinyl]- 1 - ρiperaτήnyl}sulfonyl)methyl]bicyclo[2.2.1 ]heptan-2-one with other ketones, the compounds listed in Table 8 were prepared. Table 8
Figure imgf000056_0001
Figure imgf000057_0001
Preparation 7
Ketone 17a reacted with hydrazine under microwave condition to produce ketone hydrazone 28 and saturated product 29 (Scheme 9).
Scheme 9
Figure imgf000058_0001
Conditions: a) NH2NH2-H2O, bis(ethylene glycol), K2CO3, microwave, 200° C.
Examples 93 and 94
Preparation of (15',2£',4JR)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]bicyclo [2.2.1] heptan-2-one hydrazone and l-({[(lr,4r)-7,7- dimethylbicyclo [2.2.1] hept-1-yl] methyl} sulfonyl)-4-[5-(trifluoromethyl)-2- pyridinyl]piperazine
Figure imgf000058_0002
An aliquot of 200 mg (0.45mmol) of (lS,4R)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2- pyridinyl]-l-ρiperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-one in a microwave tube was added ImL ofbis(ethylene glycol), 1.1 mL (22mmol) of hydrazine hydrate and 250mg (1.8mmol) OfK2COs. The mixture was heated in a Biotage Microwave at 200° C for 30min. The mixture was added EtOAc and saturated NaCl aqueous solution. EtOAc layers were separated, dried over Na2SO4 and concentrated. The residue was purified by using a Gilson preparative HPLC system with a Waters Xterra (C-18) column 100 mm by 50 mm ID, eluting with 20% B to 99% B in 10 min, where A = H2O and B = CH3CN pumped at 150 mL/min to yield the (l(Sr,2.£,4JR)-7,7-dimethyl- 1 -[( {4- [5-(trifluoromethyl)-2-pyridinyl]- 1 -piperazinyl} sulfonyl)methyl]bicyclo[2.2.1 ]heptan-2-one hydrazone (60mg, 29%, MS (ESI): 460 [M+H]+, IHNMR (CDCl3) d ) and l-({[(lr,4r)-7,7- dimethylbicyclo[2.2. ljhept- 1 -yl]methyl}sulfonyl)-4-[5-(trifluoromethyl)-2-pyridmyl]piperazine (15mg, 8%, MS (ESI): 432 [MH-H]+.
Preparation s
Reduction of ketone 17b yielded arylamine 30, which upon acylation produced the amide 31 (Scheme 10).
Scheme 10
Figure imgf000059_0001
Conditions: a) Pd/C, EtOH, H2, rt; b) HOAc, EDC, HOAt, DCM, rt.
Example 95
Preparation of (l-9,4/?)-l-[({4-[3-amino-S-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]-7,7-dimethylbicyclo[2.2.1]heptan-2-one
Figure imgf000060_0001
To a mixture of (l.S',4i?)-7,7-dimethyl-l-[({4-[3-nitro-5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-one (example 1, 50mg, O.lmmol) in EtOH (ImI) was added a catalytic amount of Pd on C. Hydrogen gas was purged through the system by a filled balloon. Reaction was stirred for 2 h. The hydrogen balloon was removed carefully and the reaction mixture was filtered through celite, the filtrate was concentrated and the residue was purified by using a Gilson preparative HPLC system with a Waters Xterra (C- 18) column 100 mm by 50 mm ID, eluting with 20% B to 99% B in 10 min, where A = H2O and B = CH3CN pumped at 150 mL/min to yield the desired compound (lS,4i?)-l-[({4-[3~ammo-5-(trifluoromethyl)-2- pyridinyl]-l-pipcrazinyl}sulfonyl)mcthyl]-7,7-dimcthylbicyclo[2.2.1]hcptan-2-onc as a solid (20mg, 43%). MS (ESI): 461 [M+H]+.
Example 96
Preparation of Λ?-[2-[4-({[(l»S',4Λ)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-l-yl]methyl}sulfonyl)- 1-piperazinylJ -5-(trifluoromethyl)-3-pyridinylJ acetamide
Figure imgf000060_0002
To a mixture of (lJS';!4R)-l-[({4-[3-amino-5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]-7,7-dimetliylbicyclo[2.2.1]heptan-2-one (example 90, 7mg, 15 umol) in DCM (0.5ml) in a 4-ml vial was added acceticacid (15ul), EDC (3mg, 15umol) and HOAc(2mg, 15umol) sequentially. The reaction mixture was capped in the vial and stirred at room temperature for overnight. Solvent was evaporated and the residue was purified by using a Gilson preparative HPLC system with a Waters Xterra (C- 18) column 100 mm by 50 mm ID, eluting with 20% B to 99% B in 10 min, where A = H2O and B = CH3CN pumped at 150 mL/min to yield the desired product N-[2-[4-( {[(l£,4i?)-7,7-dimethyl-2-oxobicyclo[2.2.1 ]hept- 1 -yl]methyl} sulfonyl)- 1 - ρiperazmyl]-5-(trifluoromethyl)-3-ρvridinyl]acetamide as a solid (7mg, 93%). MS (ESI): 503 [M+H]+.
Preparation 9
Di-fluoro compounds 32 reacted with hydroxymethyl-substituted diamines 33 led to arylamines 34. Cyclization of 34 under basic condition gave oxazines 35. Upon deprotection, sulfonylation of amines 36 afforded desired products 37 (Scheme 11).
Scheme 11
Figure imgf000061_0001
Conditions: a) DIEA, DMSO, 80° C; b) tBuOK, DMSO, 100° C; c) TFA, DCM, rt; d) Camphor derived sulfonylchloride, DIEA, DCM, rt. Example 97 Preparation of (l£,4i?)-7,7-dimethyl-l-({ [(6α#)-3-(trifluoromethyl)-6α,7,9,l 0- tetrahydropyrazlno[l,2-flT|pyriclo[3,2-6][l,4]oxazin-8(6fl)- yl] sulfonyl} methyl)bicyclo [2.2.1] heptan-2-one
Figure imgf000062_0001
Into a 5-mL-pressure tube was added 183mg (l.Ommol) of 2,3-difluoro-5- (trifluoromethyl)pyridine, 216mg (l.Ommol) of 1,1-dimethylethyl (3i?)-3-(hydroxymethy I)-I- piperazinecarboxylate, 0.2mL DlEA and 1.OmL DMSO. The mixture was heated at 80° C for overnight. The resulting mixture were filtered and concentrated in vacuo. The residue was purified by using a Gilson preparative HPLC system with a Waters Xterra (C-18) column 100 mm by 50 mm ID, eluting with 20% B to 99% B in 10 min, where A = H2O and B = CH3CN pumped at 150 mL/min to yield 1,1-dimethylethyl (3i?)-4-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]-3- (hydroxymethyl)- 1 -piperazinecarboxylate as a solid. MS(ESI) 380 [M+H] +.
To 20mg (0.053mmol) of 1,1-dimethylethyl (3i?)-4-[3-fluoro-5-(trifluoromethyl)-2- pyridinyl]-3-(hydroxymethyl)-l -piperazinecarboxylate was added 0.5mL DMSO and 20mg of tBuOK in a 5-mL-pressure tube. The mixture was heated at 110° C for overnight. The mixture was filtered and the solution was purified by using a Gilson preparative HPLC system with a Waters Xterra (C- 18) column 100 mm by 50 mm ID, eluting with 20% B to 99% B in 10 min, where A = H2O and B = CH3CN pumped at 150 mL/min to yield 1,1-dimethylethyl (6ai?)-3-(trifluoromethyl)- 6a,7,9,10-tetrahydropyrazino[l,2-rf]pyrido[3,2-ό][l,4]oxazine-8(6H)-carboxylate as a solid. MS(ESI) 360 [M+H]+.
To 40mg of (0.1 lmmol) of 1,1-dimethylethyl (6αi?)-3-(trifluoromethyl)-6α,7,9,10- tetrahydropyrazino[l,2-cr|pyrido[3,2-ύ][l,4]oxazme-8(6H)-carboxylate was added ImL DCM and 0.5mL 50% of TFA in DCE. The mixture was stirred at rt for 6h and concentrated in vacuo (the extra TFA was removed by adding DCE and re-concentrating) to yield crude the TFA salt of (6ocR)- 3-(trifluoromethyl)-6,6α,7,8,9,10-hexahydropyrazino[l,2-rf]pyrido[3,2-A][l,4]oxazine. MS(ESI) 260 [M+H]1. The above TFA salt of (6αi?)-3-(trifluoromethyl)-6,6α,7,8,9,10-hexahydropyrazino[l,2- rf]pyrido[3,2-ib][l,4]oxazine were dissolved in 1.OmL DCM and 0.3mL DIEA. Then lOOmg (mmol) of (S)-(+)-Camphoτ sulfonylchloride in 0.5mL DCM was slowly added at 0° C. The mixture was stirred at rt for 2h. The resulting solution was concentrated in vacuo. The residue was purified by using a Gilson preparative HPLC system with a Waters Xterra (C- 18) column 100 mm by 50 mm ID, eluting with 20% B to 99% B in 10 min, where A = H2O and B = CH3CN pumped at 150 mL/minto yield (l£,4Z?)-7,7-dimethyl-l-({[(6 αi?)-3-(trifluoromethyl)-6 α,7,9,10- tetrahydropyrazino[ 1 ,2-<s?]pyrido[3,2-6] [ J ,4]oxazin-8(6H)-yl]sulfonyl} methyl)bicyclo[2.2.1 ]heptan- 2-one (34mg, 65% yield for 2 steps). MS (ESI): 474 [M+H]+.
Preparation 10
Example 98
Preparation of (15',4JR)-7,7-dimethyl-l-({ [5-(trifluoromethyl)-3%6'-dihydro-2,4'-bipyridin- 1 ' (VH)-yl] sulfonyl} methyl)bicyclo [2.2.1] heptan-2-one
Figure imgf000063_0001
To 2-bromo-5-(trifluoromethyl) pyridine (200mg), were added 1-1- bis(diρhenylpliosphonyl)ferrocenedichloropalladium (TT) chloride 1 :1 complex with dichloromcthanc (lOOmg), Tctrakis-(triphcnylphosphino)-palladium (0) (lOOmg), potassium carbonate (200mg), [N-tert-butoxy carbonyl]-l,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (410mg) and dimethylformamide (3.5ml). Resultant suspension was heated in the microwave at 125°C for 30min. It was then preabsorbed onto silica and purification was done using a 1Og bond elute cartridge eluting with 3:1 cyclohexane: dichloromethane then dichloromethane to give an orange oil. To the orange oil was added trifluroacctic acid : dichloromcthanc (95:5) (1.5ml). The resultant solution was allowed to stand at room temperature for 30min before evaporating in vacuo and purifying on MDAP to give 5-(Mfluoromethyl)-1^2^3^6'-tetrahydro-2,4'-bipyridine as a white solid (70mg). MS(ESI) 229 [M+H]+.
To (l S)-(+) -10- camphorsulphonyl chloride (40mg) were added 5-(trifluoromethyl)- r,2',3',6'-tctrahydro-2,4'-bipyridinc (55mg), diisopropylcthylaminc (10OuI) and Dimethylformamide (ImI). The resultant solution was stirred at room temperature overnight.(l 6hr). The reaction mixture was evaporated in vacuo and purified on Mass Directed Auto prep (MDAP) to give 30mg of (lS,4i?)-7,7-dimethyl-l-({[5-(trifluoromethyl)-31,6'-dihydro-2,41-bipyridm-r(21iϊ)- yl]sulfonyl}methyl)bicyclo[2.2.1]heptan-2-one as a white solid. MS(ESI) 443 [M+H]+.
Preparation 11
Example 99
Preparation of (l»S',4/?)-7,7-diinethyl-l-[({(35)-3-methyl-4-[6-(trifluoromethyl)-3-pyridinyl]-1- piperazinyI}sullOnyl)methyl]bicyclo[2.2.1]heptan-2-one
Figure imgf000064_0001
5-Bromo-2-(trifluoromethyl)pyridine (available from Fluorochem Ltd, 45.2mg) was suspended in dimethylformamide (2mL) and treated with (l£,4i?)-7,7-dirnethyl-l-({[(3£)-3- methyl-l-piperazinyl]sulfonyl}methyl)bicyclo[2.2.1]heptan-2-one (62.8mg) and Caesiimi Carbonate (129.6mg). Nitrogen was bubbled through the suspension for 2mins and the reaction was treated with bis(dibcnzylidcncacctonc)palladiuni (11.5mg, available from acros) and 2- dicyclohexylphosphino-2'-(N,7V-dimethylamino)biphenyl (11.8mg, available from acros) and was then heated at 800C under nitrogen and reflux conditions for 22hrs. The resulting crude was filtered through celite, concentrated, dissolved in 1 : 1 DMSO: Methanol and purified using Mass Directed HPLC. The fractions containing product were evaporated to dryness to give (lS,4i?)-7,7-dimethyl- 1 -[({(3S)-3-methyl-4-[6-(trifluoromethyl)-3-pyridinyl]- 1 - piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-one (0.024g). MS(ESI) 460 [M+H]+.
Biological Assay
Example A Calcium mobilization assay. CXCR3 Ca^+ mobilization studies were carried out using
Fluo 3-loaded CHO-Kl CXCR3 and a microtiter plate-based assay using FLIPR (Molecular Devices, Sunnyvale, CA). Briefly, cells (about 80% confluent) were harvested and plated in 96 well black wall/clear bottom plates (Packard view plate) at approximately 40,000 cells/well and grown in the incubator for 18-24 hr. On the day of assay the media was aspirated and replaced with 100 μl Earls Mimimal Essential Media with Earls salts containing L-glutamine, 0.1% BSA, 4 μM Fmo-3 acetoxymethyl ester (Fluo-3 AM, Molecular Probes, Eugene, OR, USA) and 1.5 mM sulfinpyrazone. Plates were incubated for 60 min at 37° C, media was aspirated and replaced with the same media without Fluo-3 AM, and incubated for 10 min at 37° C. Cells were washed 3 times and incubated at 37° C in 100 μl assay buffer (120 mM NaCl, 4.6 mM KCl, 1.03 niM KH2 PO4, 25 mM NaHCθ3, 1.0 mM CaCl2, 11 mM glucose, 20 mM HEPES (pH 7.4) with 1.5 mM sulfinpyrazone. Plates were placed into FLIPR for analysis as described previously (Sarau et ah, Identification, molecular cloning, expression and characterization of a cysteinyl leukotriene receptor, Molecular Pharm., 56, 657-773,1999). The maximal change in fluorescence after agonist addition was quantitated. The percent of maximal IP-10-induced Ca^+ mobilization was determined for each concentration of antagonist and the IC5Q defined as the concentration of test compound that inhibits 50% of the maximal response induced by 3.3 nM IP-10. For agonist potency the EC50 is defined as the concentration that produces 50% of the maximal IP-10-induced response. For the compounds disclosed herein, the IC50 ^ata fr°m this assay fell into a range between 10 uM and 10 nM and for EC50 in a range of < 10 uM.

Claims

What is claimed is:
1. What is claimed is a compound of formulas IA, IB or IC:
Figure imgf000066_0001
wherein:
A is
Figure imgf000066_0002
B is
Figure imgf000066_0003
or A and B together form a tri-cyclic ring of formula A/B which is
Figure imgf000066_0004
where T is O or NH;
X, Y and Z are independently C(Ri) or N; m in the [-] of B 1 , B5, B6 and B7 is 1 oτ 2;
Ri is bonded to any ring carbon and is H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, OCi-C6 alkyl, trifluoromethyl, halo, NO2, cyano, or
Figure imgf000067_0001
C3-C8 cycloalkyl, C5-C8 cycloalkenyl, or C3-Cs heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocycloalkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting OfCi-C6 alkyl, C3-C6 cycloalkyl, C3-C8 heterocyclic ring, aryl, heteroaryl, halo, cyano, nitro, and -OR8;
Figure imgf000067_0002
R2 and R3 arc independently H, -C(O) N(Rs)2, halo-substituted Ci-C6alkyl, Ci-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-substituted Ci-C6alkyl, cycloalkyl, cycloalkenyl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocycloalkyl, group is unsubstituted or substituted with one or more substituents independently selected from the group consisting Of Ci-C6 alkyl, C3-C6 cycloalkyl, C3-Csheterocyclic ring, aryl, heteroaryl, halo, cyano, nitro, -N(Rs)2, -ORS' -C(O)R8, and -C(O)OR8; each R4 is independently O, NOR8, or NNRg;
R5 and R6 are independently H, OR8, halo, NR8Rg, Ci-C6alkyl; or R5 and R6 together form a 3-6 membered heterocyclic ring containing 1 or more hetero atoms which are O or N;
R7 is H, halo, or Ci-C6alkyl;
R8 is hydrogen, Ci.C6alkyl, C2-C6alkenyl, C^C6alkynyl, -CO(Ci-C4 alkyl), , -CO(aryl), -CO(heteroaryl), C3-C8 cycloalkyl, C3-C8heterocycloalkyl, C6-Ci4aryl, heteroaryl, or aryl-Ci.C6alkyl;
R9 is hydrogen, Q.Qalkyl, C2_C6alkenyl, C^Qalkynyl, -CO(Ci-C4 alkyl), -N(Rs)2, -CO(NRsRio), -CO(aryl), -CO(heteroaryl), C3-Cs cycloalkyl, C3-Csheterocycloalkyl, C6-Ci4aryl, heteroaryl, aryl-Ci-C6alkyl; -SRi0, -S(O)Ri0, or -S(O)2Ri0;
Ri0 is hydrogen, C1-QaIlCyI, C2-C6alkenyl, C2-C6alkynyl, -CO(C1-C4 alkyl), -CO(aryl), -CO(heteroaryl), C3-C8 cycloalkyl, C3-C8heterocycloalkyl, C6-Ci4aryl, heteroaryl, aryl-Ci.C6alkyl; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 comprisint a compound of formula IA, IB or 1C:
Figure imgf000068_0001
where
A is Al or A2
B is
Figure imgf000068_0002
or A and B arc combined to form a tricyclic ring of formula A/B
[Rirts .N
A/B
Z is C(Ri) and X and Y are independently C(Ri) or N; m in the [-] of Bl, B5 and B6 is 1 or 2;
Ri is bonded to any ring carbon and is H, Ci-Cβ alkyl, difluoromethyl, trifluoromethyl, halo, NO2,
Figure imgf000068_0003
where the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Ci-C6 alkyl, C3-C6 cycloalkyl, C3-Cs heterocyclic ring, aryl, heteroaryl, halo, cyano, nitro, and -ORs; n in the Rx[J of Al is 1 - 4, is 0 in A2 and is 1 in A/B;
R2 and R3 are independently H, -C(O)N(Rg)2, halo-substituted Ci-C6alkyl, or Ci-C6alkyl where the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting Of-N(R9)(R8) -OR8' -C(O)R8, and -C(O)OR8; each R4 is independently O, NOR8, or NNR8;
R5 and R5 are independently H, OR8, halo, NR8R9, CrC6alkyl; or R5 and R6 together form a 3-6 mcmbcrcd heterocyclic ring containing 1 or more hctcro atoms which are O or N;
R7 is H, or halo;
R8 is hydrogen, Q.Cealkyl;
R9 is hydrogen, -CO(Ci-C4 alkyl), -CO(NR8Ri0), -N(Rs)2, or -S(O)2Ri0;
Rio is hydrogen, Ci.C6alkyl, C2-C6alkcnyl, C2-C6alkynyl, -CO(C1-C4 alkyl), -CO(aryl), -CO(heteroaryl), C3-C8 cycloalkyl, C3-C8heterocycloalkyl, C6-C^aTyI, heteroaryl, aryl-Ci.C6a]kyl; or a pharmaceutically acceptable salt or solvate thereof.
3. A compound of formula IA according to claim 1
Figure imgf000069_0001
where:
A is Al or A2
Figure imgf000069_0002
B is
Figure imgf000070_0001
or A and B are combined to form a tricyclic ring of formula A/B
Figure imgf000070_0002
Z is C(R1) and X and Y are independently C(Ri) or N; m in the [-] of Bl, B5 and B6 is 1 or 2;
R1 is bonded to any ring carbon and is H, Ci-C6 alkyl, difluoromethyl, trifluoromethyl, halo,
Figure imgf000070_0003
n in the R1[J of Al is 1 - 4, is 1 - 4 in A2 and is 1 - 2 in A/B;
R2 and R3 are independently H, -C(O)N(Rg)2, halo-substituted Ci-C6alkyl, or Ci-C6alkyl where the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting Of-N(R9)(R8) -OR8' -C(O)R8, and -C(O)OR8;
R4 is O, NOR8, or NNR8;
R7 is H, or halo;
R8 is hydrogen, or Ci.Cβalkyl; and
R9 is hydrogen, -CO(Ci-C4 alkyl), -CO(NR8RiO), or -N(Rg)2.
In the foregoing compounds of formula IA, those compounds wherein Al is
Figure imgf000070_0004
where Z is -C(Ri) and X and Y are independently -C(Ri) or N; or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 3 wherein X is -C(Ri); Y is N or -C(Ri); X is N; B is
Figure imgf000071_0001
where m in Bl is 1 or 2, m in B5 is 1 or 2, and m in B6 is 2; or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 1, 2, 3 or 4 which has the ring A/B:
Figure imgf000071_0002
R4 is O; R4 isNORg, or NNR8;
Ri[n], n is 1 - 2 and is Ci-Cβalkyl, difluoromethyl, trifluoromethyl, halo, NO2, or
Figure imgf000071_0003
R5 and Rs are independently H, ORg, halo, NRgRg, Ci-Cβalkyl;
R7 is H; R8 is hydrogen, Ci.C6alkyl; R9 is hydrogen, -CO(Ci-C4 alkyl), -CO(NRgRi0), - N(Rs)2, or -S(O)2Ri0; and
Rio is hydrogen, Ci.C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -CO(Ci-C4 alkyl), -CO(aryl), -CO(heteroaτyl), C3-Cg cycloalkyl, Cs-Cslieterocycloalkyl, Ce-Cuaryl, heteroaryl, aryl-Ci.Cδalkyl; or a pharmaceutically acceptable salt thereof.
6. A compound of formula IB according to claim 1 :
Figure imgf000072_0001
where
A is Al;
B is
Figure imgf000072_0002
or A and B are combined to form a tricyclic ring of formula A/B
Figure imgf000072_0003
Z is C(R1);
X and Y are independently C(R1) or N; m in the [-] of Bl, B5 and B6 is 1 or 2;
Ri is bonded to any ring carbon and is H, C1-C6 alkyl, difluoromethyl, trifluoromethyl, halo, NO2,
Figure imgf000072_0004
where the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Ci-Ce alkyl, C3-Ce cycloalkyl, C3-Cs heterocyclic ring, aryl, heteroaryl, halo, cyano, nitro, and -OR8; n in the RiU of Al is 1 - 4, is 0 in A2 and is 1 in A/B;
R2 and R3 are independently H, -C(O)N(Rs)2, halo-substituted Q-Cealkyl, or d-C6alkyl where the alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting Of-N(R9)(R8) -OR8' -C(O)R8, and -C(O)OR8;
R5 and R6 are independently H, OR8, halo, NR8R9, Ci-C6alkyl; or R5 and Rς together form a 3-6 membered heterocyclic ring containing 1 or more hetero atoms which arc O or N;
R7 is H, or halo;
R8 is hydrogen, Ci.Cβalkyl,
R9 is hydrogen, -CO(Ci-C4 alkyl), -CO(NR8Ri0), -N(Rs)2, or -S(O)2Ri0;
Ri0 is hydrogen, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkyny1, -CO(C1-C4 alkyl), -CO(aryl), -CO(hctcroaryl), C3-CB cycloalkyl, C3-C*shctcrocycloalkyl, Cβ-Cwaryl, heteroaryl, aryl-Ci.Cβalkyl; or a pharmaceutically acceptable salt thereof.
7. A compound of formula 1C according to claim 1:
Figure imgf000073_0001
where
A is Al
B is
Figure imgf000073_0002
Z is C(Ri) and X and Y are independently C(Ri) or N; m in the [-] of Bl is 1; or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 1 which is:
1. (15,4/?)-7,7-dimethyl-l-[({4-[3-nitro-5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-one;
2. (lS,4S)-3-bromo-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heρtan-2-one;
3. (15,4i?)-7,7-dimethyl-l-[({4-[3-nitro-5- (trifluoromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]bicycle[2.2.1]heptan-2-one;
4. (lS,4S)-3-biOmo-7,7-dimethyl-l-[({4-[5-(trifluoiOmethyl)-2-pyridinyl]-l- piperazinyl}sultbnyl)methyl]bicycle[2.2.1]heptan-2-one;
5. (lS,4S)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptane-2,3-dione;
6. (ISAR)-I -[({ 4-[3,6-dichloro-5-(trifluoromethyl)-2-pyridinyl]- 1- piperazinyl}sulfonyl)niethyl]-7,7-dimethylbicyclo[2.2.1]heptan-2-one;
7. (15,4/?)-7,7-dimethyl-l-[({4-[4-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl)sulfonyl)methyl]bicyclo[2.2.1]heptan-2-one;
8. (15,4JR)-l-({[4-(5-bromo-2-pyridinyl)-l-piperazinyl]sulfonyl}methyl)-7,7- dimethylbicyclo[2.2.1]heptan-2-one;
9. (llSr,4i?)-l-({[4-(5-chloro-3-fluoiO-2-pyridinyl)-l-piperazinyl]sulfonyl}methyl)-7,7- dimethylbicyclo[2.2.1]heptan-2-one;
10. (IS^^-l^f ^^S-fluoro^-pyrimidinyD-l-piperazmyllsulfonylJmethyl)-?^- dimethylbicyclo[2.2.1]heptan-2-one;
11. (15,4i?)-l-({[4-(3,5-difluoro-2-pyridinyl)-l-piperazinyl]sulfonyl}methyl)- 7,7- dimethylbicyclo [2.2.1] heptan-2-one ;
12. (li?,4S)-l-[({4-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-l-piperazinyl}sulfonyl)methyl]- 7,7-dimethylbicyclo[2.2.1] heptan-2-one trifluoroacetate;
13. (IRAS)- 1 -[( { 4- [3-chloro-5-(trifluoromethyl)-2-pyridinyl]hexahydro- IH-1 ,4-diazepin-l - yl}sulfonyl)methyl]-7,7-dimethylbicyclo[2.2.1] heptan-2-one trifluoroacetate;
14. (li?,4S)-l-({[4-(5-biOmo-2-pyridinyl)-l-piperazinyl]suLfonyl}methyl)-7,7-dimethylbicyclo [2.2. l]heptan-2-one trifluoroacetate;
15. (l/?,45)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl] bicyclo[2.2. l]heptan-2-one;
16. (15,4i?)-7,7-dimethyl-l-[({2-methyl-4-[5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl} sulfonyl)methyl]bicyclo[2.2.1 ]heptan-2-one;
17. (l^^^J-dimetihiyl-l-KIClS.^-S-tS-(trifluoromethyϋ^-pyridinyll^.S- diazabicyclo[2.2.1]hcpt-2-yl}sulfonyl)mcthyl]bicyclo[2.2.1]hcptan-2-onc;
18. CiSAR)- 1 -({ [4-(5-ethyl-2-pyrimidinyl)- 1 -piperazinyl]sulf onyl }methyl)-7,7- dimethylbicyclo[2.2.1]heptan-2-one;
19. (lS,4i?)-l-({[4-(3-isoquinolinyl)-l-piperazinyl]sulfonyl}melhyl)-7,7- dimethy1bicyclo[2.2.1 ] heptan-2-one;
20. (lR,45)-l-({ [4-(5-bromo-2-pyrimidinyl)-l-pipcrazinyl]su]i'onyl}mcthyl)-7,7-dimcthyl- bicycloF2.2. llheptan-2-one trifluoroacetate;
21. (15,4i?)-l-[({4-[3-chloiO-5-(trifluoromethyl)-2-pyridinyl]-l-piperazinyl}sulfonyl)met±iyl]- 7,7-dimeLhylbicyclo[2.2.1]heptan-2-one;
22. (1 S,4ft)-1 -[({4-[3-chloro-5-(triflTioromethyl)-2-pyridinyl]hexahydro-l HA ,4-diazepin-l - yl } sulf onyl)mcthylj -7 ,7-dimcthylbicy clo L2.2.1 Jhcptan-2-onc ;
23. l-({ F(15',4i?)-7,7-dimethyl-2-oxobicyclor2.2.11hept-l-yllmethyl}sulfonyl)-4-r5- (trifluoromethyl)- 2-pyridinyl] -2-piperazinecarboxamide ;
24. (1 SAR)- 1 - [( { 2-(hydroxymelhyl)-4- [5-(trifluoromelhyl)-2-pyridinyl] - 1 - piperazinyl }sulfonyl)methyl]-7,7-dimethylbicyclo[2.2.1 ]heptan-2-one;
25. (15,4i?)-l-[({2-[(dimethylamino)methyl]-4- [5-(trffluoromethyl)-2-pyridinyl]-l- ρiperazinyl}sulfonyl)methyl]-7,7-dimethylbicyclo[2.2.1] heptan-2-one trifluoroacetate;
26. (15,4i?)-l-[({2-(chloromethyl)-4- [5-(trLfluoromethyl)-2-pyridinyl]-l- piperazinyl}suirυnyl)melhyl]-7,7-dimeLhylbicyclo[2.2.1] heptan-2-one;
27. (15,47?)-l -[({4-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]-l-piperazinyl }sulfonyl)methyl]- 7,7-dimcthylbicyclo[2.2.1]hcptan-2-onc;
28. (1 S,4i?)-7 ,7 -dimethyl- 1 - ["( { 4- r5-(trifluoromethyl)-2-pyridinyl]hexahydro-lH- 1 ,4-diazepin- 1 -yl } sulf onyl)methyl] bicyclo [2.2.1 ]heptan-2-one ;
29. (15,4Λ)-l-[({(2S,5Λ)-2,5-dimethyl-4- [5-(triIluϋromethyl)-2-pyridinyl]-l- piperazinyl }sulfonyl)methyl]-7,7-dimethylbicyclo[2.2.1 ]heptan-2-one;
30. (15,4JR)-7,7-dimethyl-l-[({(35)-3-methyl-4-[5-(trilluoromethyl)-2-pyridmyl]-l- piperazinyl} sulfonyl)methyl]bicyclo[2.2.1]heptan-2-one;
31. (15,4/?)-l-[({4-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]-l-piperazinyl}sulfonyl)methyl]- 7,7-dimethylbicyclo[2.2.1]heptan-2-one;
32. (lS,4i?)-7,7-diniethyl-l-[({4-[5-(tiifluoiOmethyl)-2-pyrimidinyl]-l- piperazinyl}sulfonyl)methyl]bicycle[2.2.1]heptan-2-one;
33. (15,4J?)-7J-dimethyl-l-[({4-[6-(trifluoromethyl)-3-pyridazinyl]-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-one;
34. (^^^-^[({(S^-ΦEό-chloro-S-(trifluoromethy^^-pyridinyll-S-methyl-l- piperazinyllsulfony^methylj-T^-dimeihylbicyclotl.I.llheptan^-one;
35. (15,4/?)-l-[({(3S)-4-[3-chloro-5-(trifluoroniethyl)-2-pyridinyl]-3-methyl-l- pipcrazinyl}sulfbnyl)mcthyl]-7,7-dimcthylbicyclo[2.2.1]hcptan-2-onc;
36. (15,4/?)-! -[({ (3S)-4-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]-3-methyl-l- piperazinyl}sulfonyl)methyl]-7,7-dimethylbicyclot2.2.1]heptan-2-one;
37. (15,4i?)-7,7-dimeUiyl-l-[({(3S)-3-methyl-4-[5-(trinuurumelhyl)-2-pyrimidmyl]-l- pipera/inyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-one;
38. (15,4JR)-7,7-dimcthyl-l-[({(3S)-3-mcthyl-4-[6-(trifluoromcthyl)-3-pyridazinyl]-l- piperazinyl} sulfonyl)methyllbicyclor2.2.1 lheptan-2-one;
39. (lS,4i?)-l-[({(3i?)-4-[3-fluoro-5-(trifluoroinethyl)-2-pyridinyl]-3-methyl-l- piperazinyl}suirϋnyl)melhyl]-7,7-dimelhylbicyclϋ[2.2.1]heplan-2-one;
40. (l1S,4/?)-7,7-dimethyl-l-{[(4-{[5-(trifIuoromethyl)-2-pyridinyl]amino}-l- pipcridinyl)sulfonylJmcthyl}bicyclol2.2.1Jhcptan-2-onc;
41. 1- r(15,4i?)-7,7-dimethyl-2-oxobicyclor2.2.1 Ihept- 1 -yll -N- { 1 - r5-(taifluoromethyl)-2- pyridinyl]-4-piperidinyl}methanesulfonamide;
42. l-KlSΛ^^J-dimeLhyl^-ϋXϋbicycloP^.llhepL-l-yη-N^ l-tS-Clxifluυromethyl)^- pyridinyl]-3-pyiτoHdinyl}methanesulfonamide;
43. (15,4/?)-7,7-dimethyl-l-[({3-methyl-4-[5-(tritluoromethyl)-2-pyridinyl]-l- piperazinyl} sulfonyl)methyl]bicyclo[2.2.1 ]heptan-2-one;
44. (lS,4/?)-7,7-dimethyl-l-{ f(3-{ [5-(trifluoromethyl)-2-pyridinyl] amino }-l- piperidinyl)sulfϋnyl]methyl}bicyclϋ[2.2.1]heptan-2-one Irifluoroacetale;
45. (15,4/?)-7,7-dimethyl-l-[({(3S)-3-methyl-4-[5-(trifluoromethyl)-2-pyridinyl]-l- ρipcrazinylsulfonyl)mcthyl]bicyclo[2.2.1]hcptan-2-on;
46. (lS^^^J-dimethyl-l-rClCS^-S-methyl^-rSKtrifluoromethyD^-pyridinyll-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-one;
47. (lS^^-l-tCfS-eώyl^^S-(trilluorϋmethy^^-pyridinyll-l-piperazmylJsuirϋny^methyl]- 7,7-diτnethylbicyclo[2.2.1 ]heptan-2-one;
48. methyl {4-({[(lS,4i?)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-l-yl]methyl}sulionyl)-l-[5- (trifluoromethyl)-2-pyridinyl]-2-piperazinyl) acetate;
49. (15,4i?)-l-({[(3i?)-4-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]-3-(hydroxymethyl)-l- piperazinyl]suirϋnyl}methyl)-7,7-dimeLhylbicyclϋ[2.2.1]heptan-2-one;
50. (^^^-^({[(S^^-P-fluoro-S-(trifluoiOmethyO^-pyridinyll-S-ChydiOxymethyl)-!- piperazinyl]sulfonyl}methyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-one;
51. (IS^^-l-CI^-P-fluoro-S-(trifluoromethyO^-pyridinyU-S-Chydroxymethyl)-!- piperazinyl]sulfonyl}methyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-one;
52. (l^^-l-CIKS^-ΦCS-chloro-^ό-difluoro^-pyrimidinyO-S-methyl-l- piperazinyysulfonyllmethy^-TJ-dimethylbicyclotl.l.llheptan-l-one;
53. (15,4Λ)-l-({[(3/?)-4-(5-chloro-2,6-difluoro-4-pyrimidinyl)-3-methyl-l- pipcrazinyl]sulfonyl}mcthyl)-7,7-dimcthylbicyclo[2.2.1]hcptan-2-onc;
54. (15,4Λ)-l-({[(3S)-4-(4,6-dichloro-2-pyrimidinyl)-3-methyl-l-piperazinyl]sulfonyl}methyl)- 7,7-dimethylbicyclo[2.2.1]heptan-2-one;
55. 5-chlorυ-2-[(2S)-4-({ [(15,4i?)-7,7-dimethyl-2-ϋXϋbicyclϋ[2.2.1]hept-l-yl]methyl}suironyl)- 2-τnethyl- 1 -piperazinyl]-4 pyridinecarbonitrile
56. (15,4/?)-l-({[(35)-4-(2-chloro-5-tluoro-4-pyrimidinyl)-3-mcthyl-l- piperazinyllsulfonyl}methyl)-7,7-dimethylbicyclor2.2.11heptan-2-one;
57. (15,4JR)-l-[({3-(hydroxymethyl)-4-[5-(trifluoromethyl)-2-ρyridinyl]-l- piperazinyl}sulfonyl)meUiyl]-7,7-dimethylbicyclo[2.2.1]heplan-2-one;
58. 4-({ [(15,4/?)-7,7-dimethyl-2-oxobicyclo[2.2.1 ]hept-1 -yl]methyl }sulfonyl)-l -[5- (trifluoromcthyl)-2-pyridinylJ-2-ρipcrazinccarboxamidc;
59. (1 S, 4R)- 1 - [( { 3-(hydroxymethyl)-4- r5-(trifluoromethyl)-2-pyrimidinyll - 1 - piperazinyl}sulfonyl)methyl]-7,7-dimethylbicyclo[2.2.1]heptan-2-one;
60. (15,4JR)-l-[({(25)-4-[3-riuorϋ-5-(lririuϋromelhyl)-2-pyridinyl]-2-me-hyl-l- piperazinyl }sulfonyl)methyl]-7,7-dimethylbicyclo[2.2.1 ]heptan-2-one
61. (15)4Λ)-l-[({(2/?)-4-[3-tluoro-5-(trifluoromethyl)-2-pyridinyl]-2-methyl-l- piperazinyl}sulfonyl)methyl]-7,7-dimethylbicyclo[2.2.1]heptan-2-one;
62. (15,4i?)-l-[({(2S)-4-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]-2-methyl-l- piperazinyl}suironyl)methyl]-7,7-dimeLhylbicyclo[2.2.1]heplan-2-one;
63. (15,4/?)-7,7-dimethyl-l-[({(3S)-3-τnethyl-4-[5-(trifluoromethyl)-2-pyrimidiτiy1]-1- pipcrazinyl) sulfonyl)mcthyl]bicyclo[2.2.1 ]hcptan-2-ol
64. (15,4/?)-7,7-dimethyl-l-r({4-r6-(trifluoromethyl)-3-pyridazinyll-l- piρerazinyl}sulfonyl)methyl]bicycle[2.2.1]heptan-2-ol;
65. (15,4/?)-7,7-dimethyl-l-[({(35)-3-melhyl-4-[6-(trifluorϋmelhyl)-3-pyridazinyl]-l- piperazinyl }sulfonyl)methyl]bicyclo[2.2.1 ]heptan-2-ol ;
66. (15,4i?)-l-[({(3S)-4-[3-fluoro-5-(tritluoromethyl)-2-pyridinyl]-3-metiiyl-l- piperazinyl}sulfonyl)methyl]-7,7-dimethylbicyclo[2.2.1]heptan-2-ol;
67. (15,4i?)-7,7-dimethyl-l-[({3-methyl-4-[5-(ttifluoroniethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]bicycle[2.2.1]heplan-2-ol;
68. (l.S,4/-)-7,7-dimelliyl-l-[({4-[5-(tiifluoiOmethyl)-2-pyiidmyl]-l- piperazinyl}sullbnyl)methyl]bicycle[2.2.1]heptan-2-ol;
69. (lR,4S)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]bicycle[2.2.1]heptan-2-ol;
70. (15,4i?)-l-[({4-[5-(difluoromethyl)-2-pyridinyl]-l-piperazinyl}sulfonyl)methyl]-7,7- dimethylbicyclo[2.2.1]heptan-2-ol;
71. (l1S,4i?)-7,7-dimethyl-l-[({(35)-3-methyl-4-[5-(trifluoromethyl)-2-pyridinyl]-l- pipcrazinyl}sulfonyl)mcthyl]bicyclo[2.2.1]hcptan-2-ol;
72. (lS^Λ^^^J-dimethyl-l-KICS^-S-methyl^ES-ζtrifluoromethy^^-pyridinyll-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-ol;
73. (lS,25,4i?)-7,7-dimelhyl-l-[({(35)-3-melhyl-4-[5-(lrilluϋromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-ol;
74. (lS,2i?,4Λ)-l-[({(35)-4-[3-tluoro-5-(tritluoromcthyl)-2-pyridinyl]-3-mcthyl-l- piperazinyl}sulfonyl)methyll-7,7-dimethylbicyclor2.2.11heptan-2-ol;
75. (IS, 2SAR)- 1- [( { (35)-4-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]-3-met±iyl- 1 - piperazinyl}sulfonyl)melhyl]-7,7-diinelliylbicyclϋ[2.2.1]heptan-2-ϋl;
76. (1 S,2ft,4/?)-7,7-dimethyl-1 -[({ (3S)-3-methyl-4-[5-(trifluoromethyl)-2-pyrimidiτiyl]-1 - pipcrazinyl} sulfonyl)mcthyljbicyclol2.2.1 Jhcptan-2-ol ;
77. (15,25,4i?)-7,7-dimetiiyl-l-[({(35)-3-methyl-4-[5-(trifluoromethyl)-2-pyriinidinyll-l- piperazinyl} sulfonyl)methyl]bicyclo[2.2.1 ]heptan-2-ol ;
78. (25)-4-({[(15,4i?)-2-nuoro-7,7-dimelhylbicyclo[2.2.1]hepL-l-yl]meLhyl}suironyl)-l-[3- fluoro-5-(trifluoromethyl)-2-pyridinyl]-2-methylpipera7.ine;
79. (lS,4i?)-2,7,7-trimethyl-l-[({4-[5-(tritluoromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-ol;
80. l-Ci tClS^^^J-dimethyl-l/Z-spirotbicycloP^.llheptane^^'-El^ldioxolan]-!- yl]melhyl}sulfonyl)-4-[5-(lrifluorυmelhyl)-2-pyridinyl]piperazine;
81. (2S)-4-({[(lS,4/?)-2-fluoro-7,7-dimethylbicyclo[2.2.1]hept-l -yl]methyl}sulfonyl)-2-methyl- l-[5-(tritluoromcthyl)-2-pyridinyl]pipcrazinc;
82. (lS^^-l-rClCSSl^-rS-fluoro-S-(txifluoromethy^^-pyridinyll-S-methyl-l- piperazinyl}sulfonyl)methyl]-2,7,7-trimethylbicyclo[2.2.1]heptan-2-ol;
83. (2S)-4-({[(lS,4R)-7,7-dimethyl-lH-spirϋ[bicyclϋ[2.2.1]heptane-2,2'-[l,3]dioxolan]-l- yl]τnethyl}sulfonyl)-l-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]-2-methylpiperaziτie;
84. (16\2£',4JK)-7>7-dimcthyl-l-L({4-L5-(trifluoromcthyl)-2-pyridinylJ-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]heptan-2-one oxime;
85. (lS,4R)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl}suirϋnyl)melhyl]bicyclϋ[2.2.1]hepLan-2-amme;
86. N-{(lS,4R)-7,7-dimethyl-l-[({4-t5-(tiifluoiOmethyl)-2-pyiidinyl]-l- piperazinyl } sulfonyl)methyl]bicyclo[2.2.1 ]hept-2-yl } acetamide;
87. N-{(lS,4R)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]hept-2-yl} methanesulfonamide;
88. N-{(lS,4R)-7J-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- piperazinyl}sulfonyl)methyl]bicyclo[2.2.1]hept-2-yl}-N'-et±iylurea;
89. (lS,4R)-N-ethyl-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyl]-l- pipcrazinyl}sulfonyl)mcthyl]bicyclo[2.2.1]hcptan-2-aininc;
90. (lS^E^^-l-tCiCS^^^S-fluoro-S-(trifluoromethyO^-pyridinyll-S-inethyl-l- piperazinyl}sulfonyl)methyl]-7,7-dimethylbicyclo[2.2.1]heptan-2-one oxime;
91. (15,4i?)-l-[({(35)-4-[3-fluυrϋ-5-(trinuorϋmelhyl)-2-pyridinyl]-3-meLhyl-l- pipera7.inyl }sulfonyl)methyl]-7,7-dimethylbicyclo[2.2.1]heptan-2-amine;
92. N-cthyl-Λπ-{(lS,4i?)-14({(3S)-4-[3-fluoro-5-(trmuoromcthyl)-2-pyridinyl]-3-mct±iyl-l- piperazinyl}sulfonyl)methyll-7,7-dimethylbicyclor2.2.11hept-2-yl}urea;
93. N- { (1S,4R> 1 -[( { (3S)-4- [3-fluoro-5-(trifluoromethyl)-2-ρyridinyl]-3-methyl-l - piperazinyl}suironyl)melhyl]-7,7-dimeLhylbicyclo[2.2.1]hepl-2-yl}acetamide;
94. ^-{(IS^^-i-KiCS^^-ES-fluoro-S-(trifluoromethyO^-pyridinyU-S-Tnethyl-l- pipcrazinyl } sulfonyl)mcthylj -7 ,7-dimcthylbicyclo 12.2.1 Jhcpt-2-yl } mcthancsulf onamidc;
95. (15,2E,4i?)-7,7-dimethyl-l-[({4-[5-(trifluoromethyl)-2-pyridinyll-l- piperazinyl} sulfonyl)methyl]bicyclo[2.2.1 ]heptan-2-one hydrazone;
96. l-({[(lr,4r)-7,7-dimethylbicyclo[2.2.1]hept-l-yl]met±iyl}sulfonyl)-4-t5-(tiifluoromethyl)- 2-pyridinyl]piperazine;
97. (l,S,4/?)-l-[({4-[3-amino-5-(tritluoiOmethyl)-2-pyridinyl]-l-piperazinyl}sulfonyl)inethyl]- 7,7-dimethylbicyclo[2.2.1]heptan-2-one;
98. N-P-μ^ltClS^^^J-dimethyl^-oxobicycloP^.ljhept-l-yllmethylJsulfonyl)-!- piperazinyl]-5-(lrifluϋromelhyl)-3-pyridinyl]acetamide;
99. (lS,4JR)-7,7-dimelhyl-l-({[(6cxΛ)-3-(lriJluoromelhyl)-6α,7,9,10-tetrahydrϋpyraziiiϋ[l,2- d]pyήdo[3,2-b] [1 ^loxazin-SCό/^-yllsulfonylJmethyObicycloP^. l]heptan~2-one;
100. (15,4i?)-7,7-dimethyl-l-({[5-(trifluorometihyl)-3\6'-dihydro-2,4'-bipyridin-r(21H)- yl]sulfonyl}methyl)bicyclo[2.2.1]heptan-2-one; or
101. (15,4i?)-7,7-dimethyl-l-[({(3S)-3-methyl-4-[6-(trifluoromethyl)-3-pyridinyl]-l- piperazinyl} sulfonyl)methyl]bicyclo[2.2.1 ]heptan-2-one; or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a compound of formula 1 according to claim 1 alone or in admixture with a pharmaceutically acceptable excipient.
10. A method for treating asthma, COPD and allergic diseases in a mammal which method comprises administering an effect amount of a compound of formula 1 according to claim 1 alone or admixed with a pharmaceutically acceptable carrier to a mammal suffering from one of said diseases.
PCT/US2006/062222 2005-12-21 2006-12-18 Camphor-derived cxcr3 antagonists Ceased WO2007076318A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US75273205P 2005-12-21 2005-12-21
US60/752,732 2005-12-21

Publications (2)

Publication Number Publication Date
WO2007076318A2 true WO2007076318A2 (en) 2007-07-05
WO2007076318A3 WO2007076318A3 (en) 2007-12-27

Family

ID=38218786

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/062222 Ceased WO2007076318A2 (en) 2005-12-21 2006-12-18 Camphor-derived cxcr3 antagonists

Country Status (1)

Country Link
WO (1) WO2007076318A2 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9266876B2 (en) 2012-02-02 2016-02-23 Actelion Pharmaceuticals Ltd. 4-(benzoimidazol-2-yl)-thiazole compounds and related aza derivatives
US9572833B2 (en) 2011-11-07 2017-02-21 The General Hospital Corporation Treatment of red blood cells
US9951063B2 (en) 2014-03-24 2018-04-24 Idorsia Pharmaceuticals Ltd 8-(piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinoline derivatives
US10047080B2 (en) 2015-01-15 2018-08-14 Idorsia Pharmaceuticals Ltd. (R)-2-methyl-piperazine derivatives as CXCR3 receptor modulators
US10053457B2 (en) 2015-01-15 2018-08-21 Idorsia Pharmaceuticals Ltd. Hydroxyalkyl-piperazine derivatives as CXCR3 receptor modulators
US10259807B2 (en) 2013-07-22 2019-04-16 Idorsia Pharmaceuticals Ltd. 1-(piperazin-1-yl)-2-([1,2,4]triazol-1-yl)-ethanone derivatives

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR033517A1 (en) * 2000-04-08 2003-12-26 Astrazeneca Ab PIPERIDINE DERIVATIVES, PROCESS FOR THE PREPARATION AND USE OF THESE DERIVATIVES IN THE MANUFACTURE OF MEDICINES
US20050107420A1 (en) * 2002-05-23 2005-05-19 Boehringe Ingelheim Pharma Gmbh & Co. Kg Combination of a PDE4 inhibitor and tiotropium or derivative thereof for treating obstructive airways and other inflammatory diseases

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9572833B2 (en) 2011-11-07 2017-02-21 The General Hospital Corporation Treatment of red blood cells
US9266876B2 (en) 2012-02-02 2016-02-23 Actelion Pharmaceuticals Ltd. 4-(benzoimidazol-2-yl)-thiazole compounds and related aza derivatives
US10259807B2 (en) 2013-07-22 2019-04-16 Idorsia Pharmaceuticals Ltd. 1-(piperazin-1-yl)-2-([1,2,4]triazol-1-yl)-ethanone derivatives
US9951063B2 (en) 2014-03-24 2018-04-24 Idorsia Pharmaceuticals Ltd 8-(piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinoline derivatives
US10047080B2 (en) 2015-01-15 2018-08-14 Idorsia Pharmaceuticals Ltd. (R)-2-methyl-piperazine derivatives as CXCR3 receptor modulators
US10053457B2 (en) 2015-01-15 2018-08-21 Idorsia Pharmaceuticals Ltd. Hydroxyalkyl-piperazine derivatives as CXCR3 receptor modulators

Also Published As

Publication number Publication date
WO2007076318A3 (en) 2007-12-27

Similar Documents

Publication Publication Date Title
JP5797792B2 (en) Polycyclic heteroaryl substituted triazoles useful as Axl inhibitors
JP6253631B2 (en) Substituted triazoles useful as Axl inhibitors
EP2802577B1 (en) Triazolyl-substituted pyridyl compounds useful as kinase inhibitors
AU2002334205B2 (en) Dihydroxypyrimidine carboxamide inhibitors of HIV integrase
JP6495918B2 (en) Imidazo pyrimidine derivatives as modulators of TNF activity
JP6522602B2 (en) Tricyclic pyrido-carboxamide derivatives as ROCK inhibitors
US8541576B2 (en) Substituted pyrazolo-quinazoline derivatives as kinase inhibitors
CN105814060B (en) Imidazo-triazine derivative as TNF active regulators
US20040106574A1 (en) 2-Arylamino-pyrimidines for the treatment of gsk3-related disorders
JP2008502628A (en) Pyridazin-3 (2H) -one derivatives and their use as inhibitors of PDE4
JP2003517479A (en) Substituted imidazole neuropeptide YY5 receptor antagonist
TW200400167A (en) Benzamide derivatives
JP2019530699A (en) Imidazopyridazine compounds useful as modulators of IL-12, IL-23 and / or IFN alpha responses
JP2017505288A (en) Fused bicyclic heteroaromatic derivatives as modulators of TNF activity
JP2008546843A (en) Anti-inflammatory aryl nitrile compounds
CZ20011760A3 (en) Pyrrolidine derivatives functioning as CCR-3 receptor antagonists
JP2008504301A (en) Condensed pyrimidine derivatives as CXCR3 receptor modulators and compositions thereof useful for the prevention and treatment of inflammatory and immunoregulatory disorders and diseases
JP2008504304A (en) Tetrahydroquinazolin-4 (3H) -one related and tetrahydropyrido [2,3-D] pyrimidin-4 (3H) -one related compounds, compositions and methods of their use
TW201038554A (en) Nicotinamide derivatives, their preparation and their therapeutic application
CA3147422A1 (en) Inhibitors of cyclin-dependent kinases
JP5487100B2 (en) Triazolo [1,5-A] quinoline as adenosine A3 receptor ligand
US12187723B2 (en) Substituted benzimidazolone compounds
JP5205276B2 (en) Enzyme inhibitor
JP2007507466A (en) Imidazopyridine derivatives as inducible NO synthase inhibitors
EP3870589B1 (en) Substituted indole dimer compounds

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06848449

Country of ref document: EP

Kind code of ref document: A2