(19)
(11)EP 3 066 082 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
20.12.2017 Bulletin 2017/51

(21)Application number: 14802329.4

(22)Date of filing:  04.11.2014
(51)Int. Cl.: 
C07D 237/28  (2006.01)
A61P 37/00  (2006.01)
A61P 17/06  (2006.01)
A61K 31/502  (2006.01)
A61P 19/02  (2006.01)
(86)International application number:
PCT/EP2014/073621
(87)International publication number:
WO 2015/067575 (14.05.2015 Gazette  2015/19)

(54)

5,6,7,8-TETRAHYDRO-5,8-METHANOCINNOLINE DERIVATIVES AS RORC MODULATORS FOR THE TREATMENT OF AUTOIMMUNE DISEASES

5,6,7,8-TETRAHYDRO-5,8-METHANOCINNOLINE DERIVATE ALS RORC MODULATOREN FÜR DIE BEHANDLUNG VON AUTOIMMUN-ERKRANKUNGEN

DÉRIVÉS DE 5,6,7,8-TETRAHYDRO-5,8-MÉTHANOCINNOLINE EN TANT QUE MODULATEURS DU RÉCEPTEUR RORC POUR LE TRAITEMENT DE MALADIES AUTOIMMUNES


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 05.11.2013 US 201361900000 P
09.10.2014 US 201462062033 P

(43)Date of publication of application:
14.09.2016 Bulletin 2016/37

(73)Proprietor: F. Hoffmann-La Roche AG
4070 Basel (CH)

(72)Inventors:
  • BODIL VAN NIEL, Monique
    Harlow Essex CM19 5TR (GB)
  • CRIDLAND, Andrew
    Harlow Essex CM19 5TR (GB)
  • FAUBER, Benjamin
    South San Francisco, California 94080 (US)
  • GOBBI, Alberto
    South San Francisco, California 94080 (US)
  • HURLEY, Christopher
    Harlow Essex CM19 5TR (GB)
  • HURST, David
    Harlow Essex CM19 5TR (GB)
  • MAXEY, Robert
    Flex Meadow Harlow Essex CM19 5TR (GB)
  • KILLEN, Jonathan
    Harlow Essex CM19 5TR (GB)
  • WARD, Stuart
    Harlow Essex CM19 5TR (GB)

(74)Representative: Bernard, Guillaume 
F. Hoffmann-La Roche AG Patent Department Grenzacherstrasse 124
4070 Basel
4070 Basel (CH)


(56)References cited: : 
WO-A1-2010/006940
WO-A2-2007/003521
WO-A1-2013/092941
  
      
    Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


    Description

    FIELD OF THE INVENTION



    [0001] The invention pertains to compounds that modulate the function of retinoid-receptor related orphan receptor RORc (RORγ) and discloses the use of such compounds for treatment of autoimmune diseases

    BACKGROUND OF THE INVENTION



    [0002] T helper 17 cells (Th17) are interleukin (IL)-17 secreting CD4+ T cells involved in pathogenesis of autoimmune diseases such as rheumatoid arthritis, irritable bowel disease, psoriasis, psoriatic arthritis and spondyloarthridities. The retinoic acid-related orphan receptor γ (RORγ or RORc) is recognized as a transcription factor necessary for Th17 cell differentiation. RORc is an orphan member of the nuclear hormone receptor subfamily that includes RORα (RORa) and RORβ (RORb). RORc controls gene transcription by binding to DNA as a monomer. Selective modulation of RORc has been proposed as a route to discovery and development of Th17 cell-associated autoimmune diseases.

    [0003] WO 2013/092941 A1 ((HOFFMANN LA ROCHE [CH]) 27 June 2013 (2013-06-27)) discloses benzyl sulfonamide derivatives, which are retinoid-receptor related orphan receptor (ROR)-gamma inhibitors for treating e.g. arthritis, osteoarthritis, chronic obstructive pulmonary disease, asthma, bronchospasm, gastrointestinal disease, pain and migraine. There is accordingly a need for compounds that inhibit RORc for use in treatment of autoimmune diseases such as rheumatoid arthritis, irritable bowel disease, psoriasis, psoriatic arthritis and spondyloarthridities.

    SUMMARY OF THE INVENTION



    [0004] The invention provides compounds of formula I:

    or pharmaceutical salts thereof, wherein:

    X is:

    a bond;

    -C1-6alkylene-;

    -NRa-;

    -NRa-C1-6alkylene;

    -C1-6alkylene-NRa-;

    -O-; -O-C1-6alkylene-;

    -C1-6alkylene-O-; or

    -C1-6alkylene-O-C1-6alkylene-;

    R1 is:

    hydrogen;

    C1-6alkyl; or

    halo-C1-6alkyl;

    R2 is:

    hydrogen;

    C1-6alkyl;

    oxo; or

    halo-C1-6alkyl;

    R3 is:

    hydrogen;

    C1-6alkyl;

    halo;

    hydroxy;

    C1-6alkoxy; -

    -O-C(O)-Re;

    -CN;

    carboxy;

    oxo; or

    =CH2;

    wherein the C1-6alkyl moieties each may be unsubstituted or substituted one or more times with halo;
    or R2 and R3 together with the atoms to which they are attached may form a double bond;

    R4 is:

    C1-6alkyl;

    halo-C1-6alkyl;

    halo;

    hydroxy;

    hydroxy-C1-6alkyl;

    C1-6alkoxy-C1-6alkyl;

    C1-6alkoxy-C1-6alkoxy-C1-6alkyl;

    cyano;

    cyano- C1-6alkyl;

    aminosulfonylC1-6alkyl;

    -(CRfRg)m-NRhRi;

    -(CRfR8)m-C(O)-NRjRk;

    -(CRfRg)m-C(O)-Rm;

    -(CRfR8)m-NRp-C(O)-Rn;

    -(CRfRg)m-O-C(O)-Rn;

    a six membered heteroaryl selected from pyridazin-2-yl, 1-methylpyridin-2-one-6-yl, pyridin-2-yl, and pyridin-3-yl,

    a five membered heteroaryl selected from oxazolyl, isoxazolyl, oxadiazolyl,thiadiazolyl imidazolyl, triazolyl and pyrazolyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, C1-6alkoxy, hydroxy-C1-6alkyl, C1-6alkoxy-C1-6alkyl, oxo, C3-6cycloalky, halo-C1-6alkyl, amino, N-C1-6alkyl-amino, N,N-di-C1-6alkyl-amino amino-C1-6alkyl, cyano-C1-6alkyl, or C1-6alkoxycarbonyl;

    heteroaryl- CH2-, wherein the heteroaryl moiety is selected from pyrazolyl and oxadiazolyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, hydroxy-C1-6alkyl, halo-C1-6alkyl, hydroxy, C1-6alkoxy, C1-6alkoxy-C1-6alkyl, amino-C1-6alkyl, or oxo;

    heteroaryloxy-CH2-, wherein the heteroaryl moiety is selected from oxadiazolyl, pyridinyl, and pyrazinyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, hydroxy-C1-6alkyl, halo-C1-6alkyl, hydroxy, C1-6alkoxy, C1-6alkoxy-C1-6alkyl, amino-C1-6alkyl, or oxo;

    phenyl-C1-6alkoxy- CH2-, wherein the phenyl moiety may be unsubstituted or substituted one or more times with C1-6alkoxy-carbonyl, carboxy, or aminocarbonyl;

    heterocyclyl selected from pyrrolidinyl, imidazolidinyl, oxazolidinyl, and 1,1-dioxoisothiazolidinyl, each of which may be unsubstituted or substituted one or more times with with C1-6alkyl, or oxo; or

    heterocyclyl- CH2-, wherein the heterocyclyl moiety is selected from imidazolidinyl, morpholin-4-yl, and azetidinyl each of which may be unsubstituted or substituted one or more times with C1-6alkyl, oxo, morpholinylethyl, or cyano;
    m is from 0 to 2;

    R5 is C1-6alkyl which may be unsubstituted or substituted one or more times with halo;

    R6 is C1-6alkyl which may be unsubstituted or substituted one or more times with halo or C1-6alkylcarbonyloxy;
    or R5 and R6 together with the atoms to which they are attached may form a three to seven membered carbocyclic ring which may be unsubstituted or substituted one or more times with Rx, and wherein a ring atom may be substituted with a heteroatom selected from O, N and S;

    R7 is:

    hydrogen;

    C1-6alkyl;

    halo; or

    halo-C1-6alkyl;

    Ar1 is:

    aryl; or

    heteroaryl selected from pyridinyl, pyrimidinyl, pyridazinyl and thienyl;

    wherein the aryl and heteroaryl each may be unsubstituted or substituted one or more times with C1-6alkyl or halo;

    Re is:

    C1-6alkyl; or

    C1-6alkoxy;

    each of which may be unsubstituted or substituted one or more times with halo;

    Rf and Rg each independently is:

    hydrogen; or

    C1-6alkyl;

    Rh is:

    hydrogen;

    C1-6alkyl;

    C1-6alkoxy-C1-6alkyl;

    hydroxy-C1-6alkyl;

    amino-C1-6alkyl;

    N-C1-6alkyl-amino-C1-6alkyl;

    N,N-di-C1-6alkyl-amino-C1-6alkyl; or

    halo-C1-6alkyl;

    Ri is:

    C1-6alkyl;

    C1-6alkoxy-C1-6alkyl;

    halo-C1-6alkyl;

    hydroxy-C1-6alkyl;

    C1-6alkylsulfonyl;

    C1-6alkylcarbonyl;

    hydroxy-C1-6alkoxy;

    aminocarbonyl-C1-6alkyl,

    hydroxy-C1-6alkyl-carbonyl;

    cyano-C1-6alkyl;

    oxetanyl;

    C1-6alkylsulfonyl;

    halo-C1-6alkylsulfonyl; or

    heteroaryl selected from oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, each of which which may be unsubstituted or substituted one or more times with C1-6alkyl, hydroxy-C1-6alkyl, oxo, or halo-C1-6alkyl;

    Rj is:

    hydrogen;

    C1-6alkyl; or

    benzyl

    Rk is:

    hydrogen;

    C1-6alkyl;

    halo-C1-6alkyl;

    cyano-C1-6alkyl;

    hydroxy-C1-6alkoxy;

    C1-6alkoxy;

    C3-6cycloalkyl;

    C3-6Cycloalkyl-C1-6alkyl;

    heteroaryl selected from oxadiazolyl, or pyridinyl, each of which which may be unsubstituted or substituted one or more times with C1-6alkyl, cyano, C1-6alkylsulfonyl, or halo;

    phenyl which which may be unsubstituted or substituted one or more times with C1-6alkylsulfonyl; or

    benzyl, the phenyl portion of which which may be unsubstituted or substituted one or more times with C1-6alkyl, halo,
    or Rj and Rk together with the atoms to which they are attached may form a four to seven membered heterocyclyl selected from:

    azetidinyl,

    morpholinyl,

    pyrolidinyl,

    azabicyclo [3.1.0]hexanyl,

    piperidinyl,

    piperazinyl,

    2-oxa-5-azabicyclo[2.2.1]heptan-5-yl,

    3-azabicyclo[3.1.0]hexanyl,

    2-azabicyclo[2.1.1]hexanyl,

    tetrahydro- 1H-furo [3,4-c]pyrrolyl,

    2-oxa-6-azaspiro[3.4]octanyl,

    5-oxa-2-azaspiro[3.4]octanyl,

    2-azabicyclo[3.1.0]hexanyl,

    2,5-diazabicyclo[2.2.1]heptanyl,

    2-azaspiro[3.3]heptanyl,

    7-azabicyclo[2.2.1]heptanyl, or

    8-azabicyclo[3.2.1]octanyl,

    each of which may be unsubstituted or substituted one or more times with C1-6alkyl,

    halo,

    amino,

    N-C1-6alkyl-amino,

    N,N-di-C1-6alkyl-amino,

    hydroxy,

    C1-6alkoxy-carbonyl,

    C1-6alkoxy,

    C1-6alkylsulfonyl,

    hydroxy-C1-6alkyl,

    C1-6alkoxy-C1-6alkyl,

    halo-C1-6alkyl,

    cyano,

    cyano-C1-6alkyl,

    amino-carbonyl,

    N-C1-6alkyl-amino-carbonyl,

    N,N-di-C1-6alkyl-amino-carbonyl,

    C1-6alkyl-carbonyl-amino,

    C1-6alkoxy-carbonyl-amino,

    C1-6alkoxy-carbonyl-amino-C1-6alkyl,

    benzyloxy,

    pyrrolidinyl which may be unsubstituted or substituted one or more times with C1-6alkyl or halo; or

    heteroaryl selected from pyrazolyl, pyrimidinyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, oxo or halo;

    Rm is:

    hydrogen;

    C1-6alkyl;

    cyano-C1-6alkyl;

    halo-C1-6alkyl;

    hydroxy-C1-6alkyl;

    C1-6alkoxy;

    C3-6cycloalkyl;

    C3-6cycloalkyl-C1-6alkyl;

    C1-6alkoxy-C1-6alkyl;

    hydroxy-C1-6alkyl

    amino-C1-6alkyl;

    heteroaryl selected from pyridinyl, indolyl, and indolinyl; each of which which may be unsubstituted or substituted one or more times with C1-6alkyl, halo, cyano, halo-C1-6alkyl, or C1-6alkyl-sulfonyl

    phenyl which which may be unsubstituted or substituted one or more times with C1-6alkyl,

    phenyl-C1-6alkyl wherein the phenyl portion thereof may be unsubstituted or substituted one or more times with C1-6alkyl, or

    heterocyclyl selected from azetidinyl, or oxetanyl, each of which which may be unsubstituted or substituted one or more times with C1-6alkyl, halo, cyano, or halo-C1-6alkyl, Rn is:

    hydrogen;

    C1-6alkyl;

    halo-C1-6alkyl;

    hydroxy-C1-6alkyl;

    hydroxy-C1-6alkoxy;

    C3-6cycloalkyl;

    C3-6Cycloalkyl-C1-6alkyl;

    C1-6alkoxy,

    C1-6alkoxy-C1-6alkyl;

    hydroxy-C1-6alkyl,

    amino,

    N-C1-6alkyl-amino,

    N,N-di-C1-6alkyl-amino,

    amino-C1-6alkyl,

    N-C1-6alkyl-amino-C1-6alkyl,

    N,N-di-C1-6alkyl-amino-C1-6alkyl,

    amino-carbonyl-C1-6alkyl,

    N-C1-6alkyl-amino-carbonyl-C1-6alkyl,

    N,N-di -C1-6alkyl-amino-carbonyl-C1-6alkyl,

    amino-carbonyl-amino-C1-6alkyl,

    5 -methylisoxazole-3 -yl;

    cyano-C1-6alkyl;

    C1-6alkylsulfonyl;

    C1-6alkylcarbonyl-amino-C1-6alkyl, or

    C1-6alkylsulfonyl-C1-6alkyl; and

    Rp is:

    hydrogen;

    C1-6alkyl;

    halo-C1-6alkyl;

    hydroxy-C1-6alkyl;

    C1-6alkoxycarbonyl-C1-6alkyl; or

    cyano-C1-6alkyl;
    provided that when X is a bond, R1, R2 and R3 are hydrogen and R4 is C1-6alkyl, then Ar1 is 2,6-dihalophenyl.



    [0005] The invention also provides pharmaceutical compositions comprising the compounds and discloses methods of using the compounds, and methods of preparing the compounds.

    DETAILED DESCRIPTION OF THE INVENTION


    Definitions



    [0006] Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an," and "the" include plural referents unless the context clearly dictates otherwise. In some instances dashes ("-") may be used interchangeably within definitions (for example, "alkoxyalkyl" omits the dash found in the equivalent term "alkoxyalkyl").

    [0007] "Alkyl" means the monovalent linear or branched saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms. "Lower alkyl" refers to an alkyl group of one to six carbon atoms, i.e. C1-C6alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

    [0008] "Alkenyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.

    [0009] "Alkynyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynyl, propynyl, and the like.

    [0010] "Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.

    [0011] "Alkoxy" and "alkyloxy", which may be used interchangeably, mean a moiety of the formula -OR, wherein R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

    [0012] "Alkoxyalkyl" means a moiety of the formula Ra-O-Rb-, where Ra is alkyl and Rb is alkylene as defined herein. Exemplary alkoxyalkyl groups include, by way of example, 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and 1-(2-methoxyethyl)-3 -methoxypropyl.

    [0013] "Alkoxyalkoxy' means a group of the formula -O-R-R' wherein R is alkylene and R' is alkoxy as defined herein.

    [0014] "Alkylcarbonyl" means a moiety of the formula -C(O)-R, wherein R is alkyl as defined herein.

    [0015] "Alkoxycarbonyl" means a group of the formula -C(O)-R wherein R is alkoxy as defined herein.

    [0016] "Alkylcarbonylamino" means a group of the formula -R-C(O)-NR'- wherein R is alkyl and R' is hydrogen or alkyl.

    [0017] "Alkylcarbonylalkyl" means a group of the formula -R-C(O)-R' wherein R is alkylene and R' is alkyl as defined herein.

    [0018] "Alkoxyalkylcarbonyl" means a moiety of the formula -C(O)-R-R', wherein R is alkylene and R' is alkoxy as defined herein.

    [0019] "Alkoxycarbonylalkyl" means a group of the formula -R-C(O)-R wherein R is alkylene and R' is alkoxy as defined herein.

    [0020] "Alkoxycarbonylamino" means a moiety of the formula R-C(O)-NR'-, wherein R is alkoxy and R' is hydrogen or alkyl as defined herein.

    [0021] "Alkoxycarbonylaminoalkyl" means a moiety of the formula R-C(O)-NR'-R"-, wherein R is alkoxy, R' is hydrogen or alkyl, and R" is alkylene as defined herein.

    [0022] "Alkoxycarbonylalkoxy"means a group of the formula -O-R-C(O)-R' wherein R is alkylene and R' is alkoxy as defined herein.

    [0023] "Hydroxycarbonylalkoxy" means a group of the formula -O-R-C(O)-OH wherein R is alkylene as defined herein.

    [0024] "Alkylaminocarbonylalkoxy" means a group of the formula -O-R-C(O)-NHR' wherein R is alkylene and R' is alkyl as defined herein.

    [0025] "Dialkylaminocarbonylalkoxy" means a group of the formula -O-R-C(O)-NR'R" wherein R is alkylene and R' and R" are alkyl as defined herein.

    [0026] "Alkylaminoalkoxy" means a group of the formula -O-R-NHR' wherein R is alkylene and R' is alkyl as defined herein.

    [0027] "Dialkylaminoalkoxy" means a group of the formula -O-R-NR'R' wherein R is alkylene and R' and R" are alkyl as defined herein.

    [0028] "Alkylsulfonyl" means a moiety of the formula - SO2-R, wherein R is alkyl as defined herein.

    [0029] "Alkylsulfonylalkyl means a moiety of the formula -R'-SO2-R" where where R' is alkylene and R" is alkyl as defined herein.

    [0030] "Alkylsulfonylalkoxy" means a group of the formula -O-R-SO2-R' wherein R is alkylene and R' is alkyl as defined herein.

    [0031] "Amino means a moiety of the formula -NRR' wherein R and R' each independently is hyrdogen or alkyl as defined herein. "Amino thus includes "alkylamino (where one of R and R' is alkyl and the other is hydrogen) and "dialkylamino (where R and R' are both alkyl.

    [0032] "Aminocarbonyl" means a group of the formula -C(O)-R wherein R is amino as defined herein.

    [0033] "N-hydroxy-aminocarbonyl" means a group of the formula -C(O)-NR-OH wherein R is hydrogen or alkyl as defined herein.

    [0034] "N-alkoxy-aminocarbonyl" means a group of the formula -C(O)-NR-R' wherein R is hydrogen or alkyl and R' is alkoxy as defined herein.

    [0035] "Aminocarbonylaminoalkyl" means a group of the formula R2N-C(O)-NR'-R"- wherein each R is independently hydrogen or alkyl, R' is hydrogen or alkyl, and R" is alkylene as defined herein.

    [0036] "N-alkyl-aminocarbonyl means a group of the formula -C(O)-NH-R wherein R is alkyl as defined herein.

    [0037] "N-hydroxy-N-alkylaminocarbonyl means a group of the formula -C(O)-NRR' wherein R is alkyl as defined herein and R' is hydroxy.

    [0038] "N-alkoxy-N-alkylaminocarbonyl" means a group of the formula -C(O)-NRR' wherein R is alkyl and R' is alkoxy as defined herein.

    [0039] "N,N-di-C1-6alkyl-aminocarbonyl" means a group of the formula -C(O)-NRR' wherein R and R' are alkyl as defined herein.

    [0040] "Aminosulfonyl" means a group of the formula -SO2-NH2.

    [0041] "N-alkylaminosulfonyl" means a group of the formula -SO2-NHR wherein R is alkyl as defined herein.

    [0042] "N,N-dialkylaminosulfonyl" means a group of the formula -SO2-NRR' wherein R and R' are alkyl as defined herein.

    [0043] "Alkylsulfonylamino" means a group of the formula -NR'-SO2-R wherein R id alkyl and R' is hydrogen or alkyl as defined herein.

    [0044] "N-(alkylsulfonyl)-aminoalkyl" means a group of the formula -R-NH-SO2-R' wherein R is alkylene and R' is alkyl as defined herein.

    [0045] "N-(Alkylsulfonyl)aminocarbonyl" means a group of the formula -C(O)-NH-SO2-R wherein wherein R is alkyl as defined herein.

    [0046] "N-(Alkylsulfonyl)-N-alkylaminocarbonyl" means a group of the formula -C(O)-NR-SO2-R' wherein wherein R and R' are alkyl as defined herein.

    [0047] "N-Alkoxyalkyl-aminocarbonyl" means a group of the formula -C(O)-NR-R'-OR" wherein R is hydrogen or alkyl, R' is alkylene, and R" is alkyl as defined herein.

    [0048] "N-Hydroxyalkyl-aminocarbonyl" means a group of the formula -C(O)-NR-R'-OH" wherein R is hydrogen or alkyl and R' is alkylene as defined herein.

    [0049] "Alkoxyamino" means a moiety of the formula -NR-OR' wherein R is hydrogen or alkyl and R' is alkyl as defined herein.

    [0050] "Alkylsulfanyl" means a moiety of the formula -SR wherein R is alkyl as defined herein.

    [0051] "Aminoalkyl" means a group -R-R' wherein R' is amino and R is alkylene as defined herein.

    [0052] "Aminoalkyl" includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like. The amino moiety of "aminoalkyl" may be substituted once or twice with alkyl to provide "alkylaminoalkyl" and "dialkylaminoalkyl" respectively. "Alkylaminoalkyl" includes methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyl and the like. "Dialkylaminoalkyl" includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminoethyl, and the like.

    [0053] "Aminoalkoxy" means a group -OR-R' wherein R' is amino and R is alkylene as defined herein.

    [0054] "Alkylsulfonylamido" means a moiety of the formula -NR'SO2-R wherein R is alkyl and R' is hydrogen or alkyl.

    [0055] "Aminocarbonyloxyalkyl" or "carbamylalkyl" means a group of the formula -R-O-C(O)-NR'R" wherein R is alkylene and R', R" each independently is hydrogen or alkyl as defined herein.

    [0056] "Alkynylalkoxy" means a group of the formula -O-R-R' wherein R is alkylene and R' is alkynyl as defined herein.

    [0057] "Aryl" means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi- or tricyclic aromatic ring. The aryl group can be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, of which may be optionally substituted as defined herein.

    [0058] "Arylalkyl" and "Aralkyl", which may be used interchangeably, mean a radical-RaRb where Ra is an alkylene group and Rb is an aryl group as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like are examples of arylalkyl.

    [0059] "Arylsulfonyl means a group of the formula -SO2-R wherein R is aryl as defined herein. "Aryloxy" means a group of the formula -O-R wherein R is aryl as defined herein.

    [0060] "Aralkyloxy" means a group of the formula -O-R-R" wherein R is alkylene and R' is aryl as defined herein.

    [0061] "Carboxy" or "hydroxycarbonyl", which may be used interchangeably, means a group of the formula -C(O)-OH.

    [0062] "Cyanoalkyl" " means a moiety of the formula -R'-R", where R' is alkylene as defined herein and R" is cyano or nitrile.

    [0063] "Cycloalkyl" means a monovalent saturated carbocyclic moiety consisting of mono- or bicyclic rings. Particular cycloalkyl are unsubstituted or substituted with alkyl. Cycloalkyl can optionally be substituted as defined herein. Unless defined otherwise, cycloalkyl may be optionally substitued with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated (cycloalkenyl) derivatives thereof.

    [0064] "Cycloalkenyl" means a cycloalkyl as defined herein that includes at least one double bond or unsaturation. Exemplary cycloalkenyl include cyclohexenyl, cyclopentenyl, cyclobutenyl and the like.

    [0065] "Cycloalkylalkyl" means a moiety of the formula -R'-R", where R' is alkylene and R" is cycloalkyl as defined herein.

    [0066] "Cycloalkylalkoxy" means a group of the formula -O-R-R' wherein R is alkylene and R' is cycloalkyl as defined herein.

    [0067] "Cycloalkylcarbonyl" means a moiety of the formula -C(O)-R, wherein R is cycloalkyl as defined herein.

    [0068] "C3-6cycloalkyl-C1-6alkyl-carbonyl" means a moiety of the formula -C(O)-R, wherein R is cycloalkylalkyl as defined herein.

    [0069] "Cyanoalkylcarbonyl" means a moiety of the formula -C(O)-R-R', wherein R is alkylene as defined herein and R' is cyano or nitrile.

    [0070] "N-Cyano-aminocarbonyl" means a moiety of the formula -C(O)-NHR, wherein R is cyano or nitrile.

    [0071] "N-Cyano-N-alkyl-aminocarbonyl" means a moiety of the formula -C(O)-NRR'-R, wherein R' is alkyl as defined herein and R is cyano or nitrile.

    [0072] "Cycloalkylsulfonyl" means a group of the formula -SO2-R wherein R is cycloalkyl as defined herein.

    [0073] "Cycloalkylalkylsulfonyl" means a group of the formula -SO2-R wherein R is cycloalkylalkyl as defined herein.

    [0074] "Formyl" means a moiety of the formula -C(O)-H.

    [0075] "Heteroaryl" means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like, each of which may be optionally substituted as defined herein.

    [0076] Heteroarylalkyl" or "heteroaralkyl" means a group of the formula -R-R' wherein R is alkylene and R' is heteroaryl as defined herein.

    [0077] "Heteroarylsulfonyl means a group of the formula -SO2-R wherein R is heteroaryl as defined herein.

    [0078] "Heteroaryloxy" means a group of the formula -O-R wherein R is heteroaryl as defined herein.

    [0079] "Heteroaralkyloxy" means a group of the formula -O-R-R" wherein R is alkylene and R' is heteroaryl as defined herein.

    [0080] The terms "halo", "halogen" and "halide", which may be used interchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.

    [0081] "Haloalkyl" means alkyl as defined herein in which one or more hydrogen has been replaced with same or different halogen. Exemplary haloalkyls include -CH2Cl,
    -CH2CF3, -CH2CCl3, perfluoroalkyl (e.g., -CF3), and the like.

    [0082] "Haloalkoxy" means a moiety of the formula -OR, wherein R is a haloalkyl moiety as defined herein. An exemplary haloalkoxy is difluoromethoxy.

    [0083] "Heterocycloamino" means a saturated ring wherein at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

    [0084] "Heterocyclyl" means a monovalent saturated moiety, consisting of one to three rings, incorporating one, two, or three or four heteroatoms (chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may be optionally substituted as defined herein. Examples of heterocyclyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepinyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl and the like. Such heterocyclyl may be optionally substituted as defined herein.

    [0085] "Heterocyclylalkyl" means a moiety of the formula -R-R' wherein R is alkylene and R' is heterocyclyl as defined herein.

    [0086] "Heterocyclyloxy" means a moiety of the formula -OR wherein R is heterocyclyl as defined herein.

    [0087] "Heterocyclylalkoxy" means a moiety of the formula -OR-R' wherein R is alkylene and R' is heterocyclyl as defined herein.

    [0088] "Hydroxyalkoxy" means a moiety of the formula -OR wherein R is hydroxyalkyl as defined herein.

    [0089] "Hydroxyalkylamino" means a moiety of the formula -NR-R' wherein R is hydrogen or alkyl and R' is hydroxyalkyl as defined herein.

    [0090] "Hydroxyalkylaminoalkyl" means a moiety of the formula -R-NR'-R" wherein R is alkylene, R' is hydrogen or alkyl, and R" is hydroxyalkyl as defined herein.

    [0091] "Hydroxycarbonylalkyl" or "carboxyalkyl" means a group of the formula -R-(CO)-OH where R is alkylene as defined herein.

    [0092] "Hydroxycarbonylalkoxy" means a group of the formula -O-R-C(O)-OH wherein R is alkylene as defined herein.

    [0093] "Hydroxyalkylcarbonyl" means a moiety of the formula -C(O)-R-R', wherein R is alkylene as defined herein and R' is hydroxy.

    [0094] "Hydroxyalkyloxycarbonylalkyl" or "hydroxyalkoxycarbonylalkyl" means a group of the formula -R-C(O)-O-R-OH wherein each R is alkylene and may be the same or different.

    [0095] "Hydroxyalkyl" means an alkyl moiety as defined herein, substituted with one or more, for example, one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl

    [0096] "Hydroxycycloalkyl" means a cycloalkyl moiety as defined herein wherein one, two or three hydrogen atoms in the cycloalkyl radical have been replaced with a hydroxy substituent. Representative examples include, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.

    [0097] "Oxo" means a group of the formula =O (i.e., an oxygen with a double bond). Thus, for example, a 1-oxo-ethyl group is an acetyl group.

    [0098] "Alkoxy hydroxyalkyl" and "hydroxy alkoxyalkyl", which may be used interchangeably, means an alkyl as defined herein that is substituted at least once with hydroxy and at least once with alkoxy.

    [0099] "Alkoxy hydroxyalkyl" and "hydroxy alkoxyalkyl" thus encompass, for example, 2-hydroxy-3-methoxy-propan-1-yl and the like.

    [0100] "Urea"or "ureido" means a group of the formula -NR'-C(O)-NR"R'" wherein R', R" and R'" each independently is hydrogen or alkyl.

    [0101] "Carbamate" means a group of the formula -O-C(O)-NR'R" wherein R' and R" each independently is hydrogen or alkyl.

    [0102] "Carboxy" means a group of the formula -O-C(O)-OH.

    [0103] "Sulfonamido" means a group of the formula -SO2-NR'R" wherein R', R" and R'" each independently is hydrogen or alkyl.

    [0104] "Optionally substituted" when used in association with an "aryl", phenyl", "heteroaryl" "cycloalkyl" or "heterocyclyl" moiety means that such moiety may be unsubstituted (i.e., all open valencies are occupied by a hydrogen atom) or substituted with specific groups as related herein.

    [0105] "Leaving group" means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions. Examples of leaving groups include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.

    [0106] "Modulator" means a molecule that interacts with a target. The interactions include, but are not limited to, agonist, antagonist, and the like, as defined herein.

    [0107] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.

    [0108] "Disease" and "Disease state" means any disease, condition, symptom, disorder or indication.

    [0109] "Inert organic solvent" or "inert solvent" means the solvent is inert under the conditions of the reaction being described in conjunction therewith, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert solvents.

    [0110] "Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.

    [0111] "Pharmaceutically acceptable salts" of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound.

    [0112] It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.

    [0113] "Protective group" or "protecting group" means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this invention rely upon the protective groups to block reactive nitrogen and/or oxygen atoms present in the reactants. For example, the terms "amino-protecting group" and "nitrogen protecting group" are used interchangeably herein and refer to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures. Exemplary nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. The artisan in the art will know how to chose a group for the ease of removal and for the ability to withstand the following reactions.

    [0114] "Solvates" means solvent additions forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, such combination being able to form one or more hydrate.

    [0115] "Arthritis" means a disease or condition that causes damage to joints of the body and pain associated with such joint damage. Arthritis includes rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, and other arthritic conditions.

    [0116] "Respiratory disorder" refers to, without limitation, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and the like.

    [0117] "Subject" means mammals and non-mammals. Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term "subject" does not denote a particular age or sex.

    [0118] "Therapeutically effective amount" means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The "therapeutically effective amount" will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.

    [0119] The terms "those defined above" and "those defined herein" when referring to a variable incorporates by reference the broad definition of the variable as well as particular definitions, if any.

    [0120] "Treating" or "treatment" of a disease state includes, inter alia, inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, and/or relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.

    [0121] The terms "treating", "contacting" and "reacting" when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.

    Nomenclature and Structures



    [0122] In general, the nomenclature and chemical names used in this Application are based on ChembioOffice™ by CambridgeSoft™. Any open valency appearing on a carbon, oxygen sulfur or nitrogen atom in the structures herein indicates the presence of a hydrogen atom unless indicated otherwise. Where a nitrogen-containing heteroaryl ring is shown with an open valency on a nitrogen atom, and variables such as Ra, Rb or Rc are shown on the heteroaryl ring, such variables may be bound or joined to the open valency nitrogen. Where a chiral center exists in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral center are encompassed by the structure. Where a structure shown herein may exist in multiple tautomeric forms, all such tautomers are encompassed by the structure. The atoms represented in the structures herein are intended to encompass all naturally occurring isotopes of such atoms. Thus, for example, the hydrogen atoms represented herein are meant to include deuterium and tritium, and the carbon atoms are meant to include C13 and C14 isotopes. One or more carbon atom(s) of a compound of the invention may be replaced by a silicon atom(s), and it is contemplated that one or more oxygen atom(s) of a compound of the invention may be replaced by a sulfur or selenium atom(s).

    Compounds of the Invention



    [0123] The invention provides compounds of formula I:

    or pharmaceutical salts thereof,
    wherein:

    X is: a bond; -C1-6alkylene-; -NRa-; -NRa-C1-6alkylene; -C1-6alkylene-NRa-; -O-; -O-C1-6alkylene-; -C1-6alkylene-O-; or -C1-6alkylene-O-C1-6alkylene-;

    R1 is: hydrogen; C1-6alkyl; or halo-C1-6alkyl;

    R2 is: hydrogen; C1-6alkyl; oxo; or halo-C1-6alkyl;

    R3 is: hydrogen; C1-6alkyl; halo; hydroxy; C1-6alkoxy; -D-C(O)-Rc; CN; carboxy; oxo; or =CH2; wherein the C1-6alkyl moieties each may be unsubstituted or substituted one or more times with Rv;

    R4 is: C1-6alkyl; halo; hydroxy; C1-6alkoxy; -A-CN; -A-SO2-NRaRb; -A-NRaRb; -A-C(O)-NRaRb; -A-NRa-C(O)-NRaRb; -A-C(O)-O-Rc; -B-SO2-Rd; -D-C(O)-Rc; -D-Ar2; or -D-heterocyclyl; wherein the C1-6alkyl moieties each may be unsubstituted or substituted one or more times with Rw; and wherein the heterocyclyl may be unsubstituted or substituted one or more times with Rx;

    R5 is C1-6alkyl which may be unsubstituted or substituted one or more times with halo;

    R6 is C1-6alkyl which may be unsubstituted or substituted one or more times with halo or C1-6alkylcarbonyloxy;

    or R5 and R6 together with the atoms to which they are attached may form a three to seven membered carbocyclic ring which may be unsubstituted or substituted one or more times with Rx, and wherein a ring atom may be substituted with a heteroatom selected from O, N and S;

    R7 is: hydrogen; C1-6alkyl; halo; or halo-C1-6alkyl;

    Ar1 is: aryl; or heteroaryl; wherein the aryl and heteroaryl each may be unsubstituted or substituted one or more times with Ry;

    Ar2 is: aryl; or heteroaryl; wherein the aryl and heteroaryl each may be unsubstituted or substituted one or more times with Rz;
    -A- is: a bond; or -C1-6alkylene-
    -B- is: a bond; -C1-6alkylene-; -O-; or -NRd-;
    -D- is: a bond; -C1-6alkylene-; -NRd-; -NRd-C1-6alkylene; -C1-6alkylene-NRd-; -O-; -O-C1-6alkylene-; -C1-6alkylene-O-; or -C1-6alkylene-O-C1-6alkylene-;

    Ra is: hydrogen; or C1-6alkyl which may be unsubstituted or substituted one or more times with Rw;

    Rb is: hydrogen; C1-6alkyl; C1-6alkoxy; C3-6cycloalkyl; C3-6cycloalkyl-C1-6alkyl; -A-CN; -A-SO2-Rd; -A-C(O)-Rc; -A-C(O)-NRaRb;-A-heterocyclyl; or -A-Ar2; wherein the C1-6alkyl and C3-6cycloalkyl moieties each may be unsubstituted or substituted one or more times with Rw; and wherein the heterocyclyl may be unsubstituted or substituted one or more times with Rx;
    or Ra and Rb together with the atoms to which they are attached may form a three- to six-membered heterocyclyl that is be unsubstituted or substituted one or more times with Rx;

    Rc is hydrogen; C1-6alkyl; C3-6cycloalkyl; C3-6cycloalkyl-C1-6alkyl; or -A-Ar2; wherein the C1-6alkyl and C3-6cycloalkyl moieties each may be unsubstituted or substituted one or more times with Rw;

    Rd is hydrogen; C1-6alkyl; C3-6cycloalkyl; C3-6cycloalkyl-C1-6alkyl; or -NRaRb; wherein the C1-6alkyl and C3-6cycloalkyl moieties each may be unsubstituted or substituted one or more times with Rw;

    Rv is: halo; hydroxy; or C1-6alkoxy;

    Rw is: halo; hydroxy; C1-6alkoxy; cyano; or amino;

    Rx is: C1-6alkyl; halo-C1-6alkyl; halo; hydroxy; hydroxy-C1-6alkyl; C1-6alkoxy; C1-6alkoxy-C1-6alkyl; oxo; amino; C1-6alkylcarbonyl; C1-6alkoxy; -A- C(O)-NRaRb; -A-C(O)-O-Rc; -D-heterocyclyl; -D-Ar2; or D-C(O)-Rc; or two vicinal or geminal Rx may form an alkylene;

    Ry is: C1-6alkyl; halo-C1-6alkyl; halo; hydroxy; C1-6alkoxy;cyano; phenyloxy; or heterocyclyl which may be unsubstituted or substituted one or more times with Rx; and

    Rz is: C1-6alkyl; halo-C1-6alkyl; halo; hydroxy; oxo; hydroxy-C1-6alkyl; C1-6alkoxy; C1-6alkoxy-C1-6alkyl; cyano; phenyloxy; C3-6cycloalkyl; C3-6cycloalkyl-C1-6alkyl; -A-heterocyclyl; -A-NRaRb; -A-C(O)-NRaRb; -A-C(O)-O-Rc; -A-C(O)-Rc; or -B-SO2-Rd; wherein the heterocyclyl may be unsubstituted or substituted one or more times with Rx;

    provided that when X is a bond, R1, R2 and R3 are hydrogen and R4 is C1-6alkyl, then Ar1 is 2,6-dihalophenyl.



    [0124] In another aspect the invention provides compounds of formula I:

    or pharmaceutical salts thereof,
    wherein:

    X is:

    a bond;

    -C1-6alkylene-;

    -NRa-;

    -NRa-C1-6alkylene;

    -C1-6alkylene-NRa-;

    -O-; -O-C1-6alkylene-;

    -C1-6alkylene-O-; or

    -C1-6alkylene-O-C1-6alkylene-;

    R1 is:

    hydrogen;

    C1-6alkyl; or

    halo-C1-6alkyl;

    R2 is:

    hydrogen;

    C1-6alkyl;

    oxo; or

    halo-C1-6alkyl;

    R3 is:

    hydrogen;

    C1-6alkyl;

    halo;

    hydroxy;

    C1-6alkoxy; -

    -O-C(O)-Re;

    -CN;

    carboxy;

    oxo; or

    =CH2;

    wherein the C1-6alkyl moieties each may be unsubstituted or substituted one or more times with halo;

    or R2 and R3 together with the atoms to which they are attached may form a double bond;

    R4 is:

    C1-6alkyl;

    halo-C1-6alkyl;

    halo;

    hydroxy;

    hydroxy-C1-6alkyl;

    C1-6alkoxy-C1-6alkyl;

    C1-6alkoxy-C1-6alkoxy-C1-6alkyl;

    cyano;

    cyano- C1-6alkyl;

    aminosulfonylC1-6alkyl;

    -(CRfRg)m-NRhRi;

    -(CRfR8)m-C(O)-NRjRk;

    -(CRfRg)m-C(O)-Rm;

    -(CRfRg)m-NRp-C(O)-Rn;

    -(CRfRg)m-O-C(O)-Rn;

    a six membered heteroaryl selected from pyridazin-2-yl, 1-methylpyridin-2-one-6-yl, pyridin-2-yl, and pyridin-3-yl,

    a five membered heteroaryl selected from oxazolyl, isoxazolyl, oxadiazolyl,thiadiazolyl imidazolyl, triazolyl and pyrazolyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, C1-6alkoxy, hydroxy-C1-6alkyl, C1-6alkoxy-C1-6alkyl, oxo, C3-6cycloalky, halo-C1-6alkyl, amino, N-C1-6alkyl-amino, N,N-di-C1-6alkyl-amino amino-C1-6alkyl, cyano-C1-6alkyl, or C1-6alkoxycarbonyl;

    heteroaryl- CH2-, wherein the heteroaryl moiety is selected from pyrazolyl and oxadiazolyl each of which may be unsubstituted or substituted one or more times with C1-6alkyl, hydroxy-C1-6alkyl, halo-C1-6alkyl, hydroxy, C1-6alkoxy, C1-6alkoxy-C1-6alkyl, amino-C1-6alkyl, or oxo;

    heteroaryloxy-CH2-, wherein the heteroaryl moiety is selected from oxadiazolyl, pyridinyl, and pyrazinyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, hydroxy-C1-6alkyl, halo-C1-6alkyl, hydroxy, C1-6alkoxy, C1-6alkoxy-C1-6alkyl, amino-C1-6alkyl, or oxo;

    phenyl-C1-6alkoxy- CH2-, wherein the phenyl moiety may be unsubstituted or substituted one or more times with C1-6alkoxy-carbonyl, carboxy, or aminocarbonyl;

    heterocyclyl selected from pyrrolidinyl, imidazolidinyl, oxazolidinyl, and 1,1-dioxoisothiazolidinyl, each of which may be unsubstituted or substituted one or more times with with C1-6alkyl, or oxo; or

    heterocyclyl- CH2-, wherein the heterocyclyl moiety is selected from imidazolidinyl, morpholin-4-yl, and azetidinyl each of which may be unsubstituted or substituted one or more times with C1-6alkyl, oxo, morpholinylethyl, or cyano;

    m is from 0 to 2.

    R5 is

    C1-6alkyl which may be unsubstituted or substituted one or more times with halo;

    R6 is

    C1-6alkyl which may be unsubstituted or substituted one or more times with halo or C1-6alkylcarbonyloxy;

    or R5 and R6 together with the atoms to which they are attached may form a three to seven membered carbocyclic ring which may be unsubstituted or substituted one or more times with Rx, and wherein a ring atom may be substituted with a heteroatom selected from O, N and S;

    R7 is:

    hydrogen;

    C1-6alkyl;

    halo; or

    halo-C1-6alkyl;

    Ar1 is:

    aryl; or

    heteroaryl selected from pyridinyl, pyrimidinyl, pyridazinyl and thienyl;

    wherein the aryl and heteroaryl each may be unsubstituted or substituted one or more times with C1-6alkyl or halo;

    Re is:

    C1-6alkyl; or

    C1-6alkoxy;

    each of which may be unsubstituted or substituted one or more times with halo;

    Rf and Rg each independently is:

    hydrogen; or

    C1-6alkyl;

    Rh is:

    hydrogen;

    C1-6alkyl;

    C1-6alkoxy-C1-6alkyl;

    hydroxy-C1-6alkyl;

    amino-C1-6alkyl;

    N-C1-6alkyl-amino-C1-6alky;

    N,N-di-C1-6alkyl-amino-C1-6alkyl; or

    halo-C1-6alkyl;

    Ri is:

    C1-6alkyl;

    C1-6alkoxy-C1-6alkyl;

    halo-C1-6alkyl;

    hydroxy-C1-6alkyl;

    C1-6alkylsulfonyl;

    C1-6alkylcarbonyl;

    hydroxy-C1-6alkoxy;

    aminocarbonyl-C1-6alkyl,

    hydroxy-C1-6alkyl-carbonyl,

    cyano-C1-6alkyl;

    oxetanyl;

    C1-6alkylsulfonyl;

    halo-C1-6alkylsulfonyl; or

    heteroaryl selected from oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, each of which which may be unsubstituted or substituted one or more times with C1-6alkyl, hydroxy-C1-6alkyl, oxo, or halo-C1-6alkyl;

    Rj is:

    hydrogen;

    C1-6alkyl; or

    benzyl

    Rk is:

    hydrogen;

    C1-6alkyl;

    halo-C1-6alkyl;

    cyano-C1-6alkyl;

    hydroxy-C1-6alkoxy;

    C1-6alkoxy;

    C3-6cycloalkyl;

    C3-6cycloalkyl-C1-6alkyl;

    heteroaryl selected from oxadiazolyl, or pyridinyl, each of which which may be unsubstituted or substituted one or more times with C1-6alkyl, cyano, C1-6alkylsulfonyl, or halo;

    phenyl which which may be unsubstituted or substituted one or more times with C1-6alkylsulfonyl; or

    benzyl, the phenyl portion of which which may be unsubstituted or substituted one or more times with C1-6alkyl, halo,

    or Rj and Rk together with the atoms to which they are attached may form a four to seven membered heterocyclyl selected from:

    azetidinyl,

    morpholinyl,

    pyrolidinyl,

    azabicyclo[3.1.0]hexanyl,

    piperidinyl,

    piperazinyl,

    2-oxa-5-azabicyclo[2.2.1]heptan-5-yl,

    3-azabicyclo[3.1.0]hexanyl,

    2-azabicyclo[2.1.1]hexanyl,

    tetrahydro-1H-furo[3,4-c]pyrrolyl,

    2-oxa-6-azaspiro[3.4]octanyl,

    5-oxa-2-azaspiro[3.4]octanyl,

    2-azabicyclo[3.1.0]hexanyl,

    2,5-diazabicyclo[2.2.1]heptanyl,

    2-azaspiro[3.3]heptanyl,

    7-azabicyclo[2.2.1]heptanyl, or

    8-azabicyclo[3.2.1]octanyl,

    each of which may be unsubstituted or substituted one or more times with

    C1-6alkyl,

    halo,

    amino,

    N-C1-6alkyl-amino,

    N,N-di-C1-6alkyl-amino,

    hydroxy,

    C1-6alkoxy-carbonyl,

    C1-6alkoxy,

    C1-6alkylsulfonyl,

    hydroxy-C1-6alkyl,

    C1-6alkoxy-C1-6alkyl,

    halo-C1-6alkyl,

    cyano,

    cyano-C1-6alkyl,

    amino-carbonyl,

    N-C1-6alkyl-amino-carbonyl,

    N,N-di-C1-6alkyl-amino-carbonyl,

    C1-6alkyl-carbonyl-amino,

    C1-6alkoxy-carbonyl-amino,

    C1-6alkoxy-carbonyl-amino-C1-6alkyl,

    benzyloxy,

    pyrrolidinyl which may be unsubstituted or substituted one or more times with C1-6alkyl or halo; or

    heteroaryl selected from pyrazolyl, pyrimidinyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, oxo or halo;

    Rm is:

    hydrogen;

    C1-6alkyl;

    cyano-C1-6alkyl;

    halo-C1-6alkyl;

    hydroxy-C1-6alkyl;

    C1-6alkoxy;

    C3-6cycloalkyl;

    C3-6cycloalkyl-C1-6alkyl;

    C1-6alkoxy-C1-6alkyl;

    hydroxy-C1-6alkyl

    amino-C1-6alkyl;

    heteroaryl selected from pyridinyl, indolyl, and indolinyl; each of which which may be unsubstituted or substituted one or more times with C1-6alkyl, halo, cyano, halo-C1-6alkyl, or C1-6alkyl-sulfonyl

    phenyl which which may be unsubstituted or substituted one or more times with C1-6alkyl,

    phenyl-C1-6alkyl wherein the phenyl portion thereof may be unsubstituted or substituted one or more times with C1-6alkyl, or

    heterocyclyl selected from azetidinyl, or oxetanyl, each of which which may be unsubstituted or substituted one or more times with C1-6alkyl, halo, cyano, or halo-C1-6alkyl,

    Rn is:

    hydrogen;

    C1-6alkyl;

    halo-C1-6alkyl;

    hydroxy-C1-6alkyl;

    hydroxy-C1-6alkoxy;

    C3-6cycloalkyl;

    C3-6cycloalkyl-C1-6alkyl;

    C1-6alkoxy,

    C1-6alkoxy-C1-6alkyl;

    hydroxy-C1-6alkyl,

    amino,

    N-C1-6alkyl-amino,

    N,N-di-C1-6alkyl-amino,

    amino-C1-6alkyl,

    N-C1-6alkyl-amino-C1-6alkyl,

    N,N-di-C1-6alkyl-amino-C1-6alkyl,

    amino-carbonyl-C1-6alkyl,

    N-C1-6alkyl-amino-carbonyl-C1-6alkyl,

    N,N-di-C1-6alkyl-amino-carbonyl-C1-6alkyl,

    amino-carbonyl-amino-C1-6alkyl,

    5-methylisoxazole-3 -yl;

    cyano-C1-6alkyl;

    C1-6alkylsulfonyl;

    C1-6alkylcarbonyl-amino-C1-6alkyl, or

    C1-6alkylsulfonyl-C1-6alkyl; and

    Rp is:

    hydrogen;

    C1-6alkyl;

    halo-C1-6alkyl;

    hydroxy-C1-6alkyl;

    C1-6alkoxycarbonyl-C1-6alkyl; or

    cyano-C1-6alkyl;
    provided that when X is a bond, R1, R2 and R3 are hydrogen and R4 is C1-6alkyl, then Ar1 is 2,6-dihalophenyl.



    [0125] In certain embodiments, when Ar1 is 2-halophenyl, then R4 is not C1-6alkyl.

    [0126] In certain embodiments, X is a bond.

    [0127] In certain embodiments, X is -C1-6alkylene-.

    [0128] In certain embodiments, X is -NRa-.

    [0129] In certain embodiments, X is -NRa-C1-6alkylene.

    [0130] In certain embodiments, X is -C1-6alkylene-NRa-.

    [0131] In certain embodiments, X is -O-.

    [0132] In certain embodiments, X is -O-C1-6alkylene-.

    [0133] In certain embodiments, X is -C1-6alkylene-O-.

    [0134] In certain embodiments, X is -C1-6alkylene-O-C1-6alkylene-.

    [0135] In certain embodiments, R1 is hydrogen.

    [0136] In certain embodiments, R1 is C1-6alkyl.

    [0137] In certain embodiments, R1 is halo-C1-6alkyl.

    [0138] In certain embodiments, R2 is hydrogen.

    [0139] In certain embodiments, R2 is C1-6alkyl.

    [0140] In certain embodiments, R2 is oxo.

    [0141] In certain embodiments, R2 is halo-C1-6alkyl.

    [0142] In certain embodiments, R3 is hydrogen.

    [0143] In certain embodiments, R3 is C1-6alkyl which may be unsubstituted or substituted one or more times with Rv.

    [0144] In certain embodiments, R3 is halo.

    [0145] In certain embodiments, R3 is hydroxy.

    [0146] In certain embodiments, R3 is C1-6alkoxy wherein the C1-6alkyl moiety may be unsubstituted or substituted one or more times with Rv.

    [0147] In certain embodiments, R3 is C1-6alkylcarbonyloxy wherein the C1-6alkyl moiety may be unsubstituted or substituted one or more times with Rv.

    [0148] In certain embodiments, R3 is carboxy.

    [0149] In certain embodiments, R3 is oxo.

    [0150] In certain embodiments, R3 is =CH2.

    [0151] In certain embodiments, R3 is -C(O)-Re.

    [0152] In certain embodiments, R4 is: C3-6alkyl; halo; hydroxy;C1-6alkylcarbonyloxy; C1-6alkylcarbonyloxy-C1-6alkyl;C1-6alkoxy; -A-CN;-A-NRaRb; -A-C(O)-NRaRb; -A-C(O)-O-Rc; -D-C(O)-Rc; -D-phenyl;-D-heteroaryl; or -D-heterocyclyl; wherein the C1-6alkyl moieties each may be unsubstituted or substituted one or more times with Rw; and wherein the phenyl, heteroaryl and heterocyclyl may be unsubstituted or substituted one or more times with Rx.

    [0153] In certain embodiments, R4 is: C3-6alkyl; halo; hydroxy; C1-6alkylcarbonyloxy; C1-6alkylcarbonyloxy-C1-6alkyl; C1-6alkoxy; -A-CN; -A-SO2-NRaRb; -A-NRaRb; -A-C(O)-NRaRb; -A-NRa-C(O)-NRaRb; -A-C(O)-O-Rc; -B-SO2-Rd; -D-C(O)-Rc; -D-Ar2; or -D-heterocyclyl; wherein the C1-6alkyl moieties each may be unsubstituted or substituted one or more times with Rw; and wherein the heterocyclyl may be unsubstituted or substituted one or more times with Rx.

    [0154] In certain embodiments, R4 is: halo; hydroxy; C1-6alkylcarbonyloxy; C1-6alkylcarbonyloxy-C1-6alkyl; C1-6alkoxy; -A-CN; -A-SO2-NRaRb; -A-NRaRb; -A-C(O)-NRaRb; -A-NRa-C(O)-NRaRb; -A-C(O)-O-Rc; -B-SO2-Rd; -D-C(O)-Rc; -D-Ar2; or -D-heterocyclyl; wherein the C1-6alkyl moieties each may be unsubstituted or substituted one or more times with Rw; and wherein the heterocyclyl may be unsubstituted or substituted one or more times with Rx.

    [0155] In certain embodiments, R4 is: C1-6alkylcarbonyloxy; C1-6alkylcarbonyloxy-C1-6alkyl; -A-CN; -A-SO2-NRaRb; -A-NRaRb; -A-C(O)-NRaRb; -A-NRa-C(O)-NRaRb; -A-C(O)-O-Rc; -B-SO2-Rd; -D-C(O)-Rc; -D-Ar2; or -D-heterocyclyl; wherein the C1-6alkyl moieties each may be unsubstituted or substituted one or more times with Rw; and wherein the heterocyclyl may be unsubstituted or substituted one or more times with Rx.

    [0156] In certain embodiments, R4 is: -A-SO2-NRaRb; -A-NRaRb; -A-C(O)-NRaRb; -A-NRa-C(O)-NRaRb; -A-C(O)-O-Rc; -B-SO2-Rd; -D-C(O)-Rc; -D-Ar2; or -D-heterocyclyl; wherein the C1-6alkyl moieties each may be unsubstituted or substituted one or more times with Rw; and wherein the heterocyclyl may be unsubstituted or substituted one or more times with Rx.

    [0157] In certain embodiments, R4 is: -A-SO2-NRaRb; -A-NRaRb; -A-C(O)-NRaRb; -D-Ar2; or -D-heterocyclyl; wherein the C1-6alkyl moieties each may be unsubstituted or substituted one or more times with Rw; and wherein the heterocyclyl may be unsubstituted or substituted one or more times with Rx.

    [0158] In certain embodiments, R4 is: halo; hydroxy; C1-6alkoxy; -A-CN; -A-SO2-NRaRb; -A-NRaRb; -A-C(O)-NRaRb; -A-NRa-C(O)-NRaRb; -A-C(O)-O-Rc; -B-SO2-Rd; -D-C(O)-Rc; -D-Ar2; or -D-heterocyclyl; wherein the C1-6alkyl moieties each may be unsubstituted or substituted one or more times with Rw; and wherein the heterocyclyl may be unsubstituted or substituted one or more times with Rx.

    [0159] In certain embodiments, R4 is: -A-CN; -A-SO2-NRaRb; -A-NRaRb; -A-C(O)-NRaRb; -A-NRa-C(O)-NRaRb; -A-C(O)-O-Rc; -B-SO2-Rd; -D-C(O)-Rc; -D-Ar2; or -D-heterocyclyl; wherein the C1-6alkyl moieties each may be unsubstituted or substituted one or more times with Rw; and wherein the heterocyclyl may be unsubstituted or substituted one or more times with Rx.

    [0160] In certain embodiments, R4 is:-A-SO2-NRaRb; -A-NRaRb; -A-C(O)-NRaRb; -B-SO2-Rd; -D-C(O)-Rc; -D-Ar2; or -D-heterocyclyl; wherein the C1-6alkyl moieties each may be unsubstituted or substituted one or more times with Rw; and wherein the heterocyclyl may be unsubstituted or substituted one or more times with Rx.

    [0161] In certain embodiments, R4 is: -A-SO2-NRaRb; -A-NRaRb; -A-C(O)-NRaRb; -D-Ar2; or -D-heterocyclyl; wherein the C1-6alkyl moieties each may be unsubstituted or substituted one or more times with Rw; and wherein the heterocyclyl may be unsubstituted or substituted one or more times with Rx.

    [0162] In certain embodiments, R4 is: -A-NRaRb; -A-C(O)-NRaRb; -D-Ar2; or -D-heterocyclyl; wherein the C1-6alkyl moieties each may be unsubstituted or substituted one or more times with Rw; and wherein the heterocyclyl may be unsubstituted or substituted one or more times with Rx.

    [0163] In certain embodiments, R4 is C1-6alkyl which may be unsubstituted or substituted one or more times with Rw.

    [0164] In certain embodiments, R4 is C3-6alkyl which may be unsubstituted or substituted one or more times with Rw.

    [0165] In certain embodiments, R4 is halo.

    [0166] In certain embodiments, R4 is hydroxy.

    [0167] In certain embodiments, R4 is C1-6alkylcarbonyloxy wherein the C1-6alkyl moiety may be unsubstituted or substituted one or more times with Rv.

    [0168] In certain embodiments, R4 is C1-6alkylcarbonyloxy-C1-6alkyl wherein the C1-6alkyl moieties may be unsubstituted or substituted one or more times with Rv.

    [0169] In certain embodiments, R4 is C1-6alkoxy wherein the C1-6alkyl moiety may be unsubstituted or substituted one or more times with Rv.

    [0170] In certain embodiments, R4 is -A-CN.

    [0171] In certain embodiments, R4 is -A-SO2-NRaRb.

    [0172] In certain embodiments, R4 is -A-NRaRb.

    [0173] In certain embodiments, R4 is -A-C(O)-NRaRb.

    [0174] In certain embodiments, R4 is -A-NRa-C(O)-NRaRb.

    [0175] In certain embodiments, R4 is -A-C(O)-O-Rc.

    [0176] In certain embodiments, R4 is -B-SO2-Rd.

    [0177] In certain embodiments, R4 is -D-C(O)-Rc.

    [0178] In certain embodiments, R4 is -D-Ar2.

    [0179] In certain embodiments, R4 is -D-heterocyclyl.

    [0180] In certain embodiments, R4 is -D-phenyl.

    [0181] In certain embodiments, R4 is -D-heteroaryl.

    [0182] In certain embodiments, R4 is:

    halo-C1-6alkyl;

    halo;

    hydroxy;

    hydroxy-C1-6alkyl;

    C1-6alkoxy-C1-6alkyl;

    C1-6alkoxy-C1-6alkoxy-C1-6alkyl;

    cyano;

    cyano- C1-6alkyl;

    -(CRfRg)m-NRhRi;

    -(CRfRg)m-C(O)-NRjRk;

    -(CRfRg)m-C(O)-Rm;

    -(CRfRg)m-NRp-C(O)-Rn;

    -(CRfRg)m-O-C(O)-Rn;

    a six membered heteroaryl selected from pyridazin-2-yl, 1-methylpyridin-2-one-6-yl, pyridin-2-yl, and pyridin-3-yl,

    a five membered heteroaryl selected from oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and pyrazolyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, C1-6alkoxy, hydroxy-C1-6alkyl, C1-6alkoxy-C1-6alkyl, oxo, C3-6cycloalky, halo-C1-6alkyl, amino, N-C1-6alkyl-amino, N,N-di-C1-6alkyl-amino amino-C1-6alkyl, cyano-C1-6alkyl, or C1-6alkoxycarbonyl;

    heteroaryl- CH2-, wherein the C1-6alkyl moity may be unsubstituted or substituted one or more times with hydroxy or C1-6alkoxy, and wherein the heteroaryl moiety is selected from pyrazolyl, oxadiazolyl and pyridinyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, hydroxy-C1-6alkyl, halo-C1-6alkyl, hydroxy, C1-6alkoxy, C1-6alkoxy-C1-6alkyl, amino-C1-6alkyl, or oxo;

    heteroaryloxy- CH2-, wherein the heteroaryl moiety is selected from oxadiazolyl, pyridinyl, and pyrazinyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, hydroxy-C1-6alkyl, halo-C1-6alkyl, hydroxy, C1-6alkoxy, C1-6alkoxy-C1-6alkyl, amino-C1-6alkyl, or oxo;

    phenyl-C1-6alkoxy- CH2-, wherein the phenyl moiety may be unsubstituted or substituted one or more times with C1-6alkoxy-carbonyl, carboxy, or aminocarbonyl;

    heterocyclyl selected from pyrrolidinyl, imidazolidinyl, oxazolidinyl, and 1,1-dioxoisothiazolidinyl, each of which may be unsubstituted or substituted one or more times with with C1-6alkyl, or oxo;

    heterocyclyl- CH2-, wherein the heterocyclyl moiety is selected from imidazolidinyl, morpholinyl, and azetidinyl each of which may be unsubstituted or substituted one or more times with C1-6alkyl, oxo, morpholinylethyl, or cyano;



    [0183] In certain embodiments, R4 is C1-6alkyl.

    [0184] In certain embodiments, R4 is halo-C1-6alkyl.

    [0185] In certain embodiments, R4 is halo.

    [0186] In certain embodiments, R4 is hydroxy.

    [0187] In certain embodiments, R4 is C1-6alkoxy.

    [0188] In certain embodiments, R4 is hydroxy-C1-6alkyl.

    [0189] In certain embodiments, R4 is C1-6alkoxy-C1-6alkyl.

    [0190] In certain embodiments, R4 is C1-6alkoxy-C1-6alkoxy-C1-6alkyl.

    [0191] In certain embodiments, R4 is cyano;

    [0192] In certain embodiments, R4 is cyano- C1-6alkyl.

    [0193] In certain embodiments, R4 is -(CRfRg)m-NRhRi.

    [0194] In certain embodiments, R4 is -(CRfRg)m-C(O)-NRjRk.

    [0195] In certain embodiments, R4 is -(CRfRg)m-C(O)-Rm.

    [0196] In certain embodiments, R4 is -(CRfRg)m-NRp-C(O)-Rn.

    [0197] In certain embodiments, R4 is -(CRfRg)m-O-C(O)-Rn.

    [0198] In certain embodiments, R4 is -NRhRi.

    [0199] In certain embodiments, R4 is -CH2-NRhRi.

    [0200] In certain embodiments, R4 is -C(O)-NRjRk.

    [0201] In certain embodiments, R4 is -CH2-C(O)-NRjRk.

    [0202] In certain embodiments, R4 is -C(O)-Rm.

    [0203] In certain embodiments, R4 is -CH2-C(O)-Rm.

    [0204] In certain embodiments, R4 is -NRp-C(O)-Rn.

    [0205] In certain embodiments, R4 is -CH2-NRp-C(O)-Rn.

    [0206] In certain embodiments, R4 is -O-C(O)-Rn.

    [0207] In certain embodiments, R4 is -CH2-O-C(O)-Rn.

    [0208] In certain embodiments, R4 is:-NRhRi; -CH2-NRhRi; -C(O)-NRjRk; -CH2-C(O)-NRjRk; -C(O)-Rm; -CH2-C(O)-Rm; -NRp-C(O)-Rn; -CH2-NRp-C(O)-Rn; -O-C(O)-Rn; or -CH2-O-C(O)-Rn.

    [0209] In certain embodiments, R4 is: -CH2-NRhRi; -C(O)-NRjRk; or -CH2-NRp-C(O)-Rn.

    [0210] In certain embodiments, R4 is a six membered heteroaryl selected from pyridazin-2-yl, 1-methylpyridin-2-one-6-yl, pyridin-2-yl, and pyridin-3-yl.

    [0211] In certain embodiments, R4 is a five membered heteroaryl selected from oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and pyrazolyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, C1-6alkoxy, hydroxy-C1-6alkyl, C1-6alkoxy-C1-6alkyl, oxo, C3-6cycloalky, halo-C1-6alkyl, amino, N-C1-6alkyl-amino, N,N-di-C1-6alkyl-amino amino-C1-6alkyl, cyano-C1-6alkyl, or C1-6alkoxycarbonyl.

    [0212] In certain embodiments, R4 is heteroaryl- CH2-,, wherein the C1-6alkyl moity may be unsubstituted or substituted one or more times with hydroxy or C1-6alkoxy, and wherein the heteroaryl moiety is selected from pyrazolyl, oxadiazolyl and pyridinyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, hydroxy-C1-6alkyl, halo-C1-6alkyl, hydroxy, C1-6alkoxy, C1-6alkoxy-C1-6alkyl, amino-C1-6alkyl, or oxo.

    [0213] In certain embodiments, R4 is heteroaryloxy- CH2-, wherein the heteroaryl moiety is selected from oxadiazolyl, pyridinyl, and pyrazinyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, hydroxy-C1-6alkyl, halo-C1-6alkyl, hydroxy, C1-6alkoxy, C1-6alkoxy-C1-6alkyl, amino-C1-6alkyl, or oxo.

    [0214] In certain embodiments, R4 is phenyl-C1-6alkoxy- CH2-, wherein the phenyl moiety may be unsubstituted or substituted one or more times with C1-6alkoxy-carbonyl, carboxy, or aminocarbonyl.

    [0215] In certain embodiments, R4 is heterocyclyl selected from pyrrolidinyl, imidazolidinyl, oxazolidinyl, and 1,1-dioxoisothiazolidinyl, each of which may be unsubstituted or substituted one or more times with with C1-6alkyl, or oxo.

    [0216] In certain embodiments, R4 is heterocyclyl- CH2-, wherein the heterocyclyl moiety is selected from imidazolidinyl, morpholinyl, and azetidinyl each of which may be unsubstituted or substituted one or more times with C1-6alkyl, oxo, morpholinylethyl, or cyano.

    [0217] In certain embodiments, m is 0 or 1.

    [0218] In certain embodiments, m is 0.

    [0219] In certain embodiments, m is 1.

    [0220] In certain embodiments, R5 is C1-6alkyl which may be unsubstituted or substituted one or more times with halo.

    [0221] In certain embodiments, R6 is C1-6alkyl which may be unsubstituted or substituted one or more times with halo or C1-6alkylcarbonyloxy.

    [0222] In certain embodiments, R5 and R6 together with the atoms to which they are attached form a three to seven membered carbocyclic ring which may be unsubstituted or substituted one or more times with Rx, and wherein a ring atom may be substituted with a heteroatom selected from O, N and S.

    [0223] In certain embodiments, R7 is: hydrogen; or C1-6alkyl.

    [0224] In certain embodiments, R7 is hydrogen.

    [0225] In certain embodiments, Ar1 is aryl which may be unsubstituted or substituted one or more times with Ry.

    [0226] In certain embodiments, Ar1 is phenyl which may be unsubstituted or substituted one or more times with Ry.

    [0227] In certain embodiments, Ar1 is 2,6-dihalo-phenyl.

    [0228] In certain embodiments, Ar1 is 2-halo-phenyl.

    [0229] In certain embodiments, Ar1 is 2,6-difluoro-phenyl.

    [0230] In certain embodiments, Ar1 is 2-fluoro-phenyl.

    [0231] In certain embodiments, Ar1 is heteroaryl which may be unsubstituted or substituted one or more times with Ry.

    [0232] In certain embodiments wherein Ar1 is heteroaryl, such heteroaryl may be pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, ir thiadiazolyl, each of which may be unsubstituted or substituted one or more times with Ry.

    [0233] In certain embodiments, Ar1 is pyridinyl which may be unsubstituted or substituted one or more times with Ry.

    [0234] In certain embodiments, Ar2 is aryl which may be unsubstituted or substituted one or more times with Rz.

    [0235] In certain embodiments, Ar2 is phenyl which may be unsubstituted or substituted one or more times with Rz.

    [0236] In certain embodiments, Ar2 is heteroaryl which may be unsubstituted or substituted one or more times with Rz.

    [0237] In certain embodiments wherein Ar2 is heteroaryl, such heteroaryl may be pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl, each of which may be unsubstituted or substituted one or more times with Rz.

    [0238] In certain embodiments, -A- is a bond.

    [0239] In certain embodiments, -A- is -C1-6alkylene-.

    [0240] In certain embodiments, -B- is: a bond; or -C1-6alkylene-.

    [0241] In certain embodiments, -B- is a bond.

    [0242] In certain embodiments, -B- is -C1-6alkylene-.

    [0243] In certain embodiments, -B- is -O-.

    [0244] In certain embodiments, -B- is -NRd-.

    [0245] In certain embodiments, -D- is: a bond; -C1-6alkylene-; -NRd-; or -O-.

    [0246] In certain embodiments, -D- is: a bond; or -C1-6alkylene-.

    [0247] In certain embodiments, -D- is a bond.

    [0248] In certain embodiments, -D- is -C1-6alkylene-.

    [0249] In certain embodiments, -D- is -NRd-.

    [0250] In certain embodiments, -D- is -NRd-C1-6alkylene.

    [0251] In certain embodiments, -D- is -C1-6alkylene-NRd-.

    [0252] In certain embodiments, -D- is -O-.

    [0253] In certain embodiments, -D- is O-C1-6alkylene-.

    [0254] In certain embodiments, -D- is -C1-6alkylene-O-.

    [0255] In certain embodiments, -D- is -C1-6alkylene-O-C1-6alkylene-;

    [0256] In certain embodiments, Ra is hydrogen.

    [0257] In certain embodiments, Ra is C1-6alkyl.

    [0258] In certain embodiments, Rb is hydrogen.

    [0259] In certain embodiments, Rb is C1-6alkyl which may be unsubstituted or substituted one or more times with Rw.

    [0260] In certain embodiments, Rb is C1-6alkoxy wherein the C1-6alkyl moiety may be unsubstituted or substituted one or more times with Rw.

    [0261] In certain embodiments, Rb is C3-6cycloalkyl which may be unsubstituted or substituted one or more times with Rw.

    [0262] In certain embodiments, Rb is C3-6cycloalkyl-C1-6alkyl wherein the heterocyclyl may be unsubstituted or substituted one or more times with Rx.

    [0263] In certain embodiments, Rb is -A-heterocyclyl wherein the heterocyclyl may be unsubstituted or substituted one or more times with Rx.

    [0264] In certain embodiments, Rb is -A-Ar2.

    [0265] In certain embodiments, Rb is -A-CN.

    [0266] In certain embodiments, Rb is -A-SO2-Rd.

    [0267] In certain embodiments, Rb is -A-C(O)-Rc.

    [0268] In certain embodiments, Rb is -A-C(O)-NRaRb.

    [0269] In certain embodiments, Ra and Rb together with the atoms to which they are attached form a three- to six- membered heterocyclyl that is be unsubstituted or substituted one or more times with Rx.

    [0270] In embodiments wherein Ra and Rb together with the atoms to which they are attached form a three- to six- membered heterocyclyl, such heterocyclyl may be: imidazolinyl; azetidinyl; pyrrolidinyl; piperidinyl; piperazinyl; morpholinyl; thiomorpholinyl; 1,1-dioxythiomorpholinyl; tetrahydrofuranyl; tetrahydropyranyl;tetrahydrothiofuranyl; tetrahydrothiopyranyl; 1,1-dioxytetrahydrothiofuranyl; 1,1-dioxytetrahydrothiopyranyl; or 2,3-dihydroindolyl; each of which may be unsubstituted or substituted one or more times with Rx.

    [0271] In embodiments wherein Ra and Rb together with the atoms to which they are attached form a heterocyclyl, such heterocyclyl may be imidazolinyl, which may be unsubstituted or substituted one or more times with Rx.

    [0272] In embodiments wherein Ra and Rb together with the atoms to which they are attached form a heterocyclyl, such heterocyclyl may be azetidinyl, which may be unsubstituted or substituted one or more times with Rx.

    [0273] In embodiments wherein Ra and Rb together with the atoms to which they are attached form a heterocyclyl, such heterocyclyl may be pyrrolidinyl, which may be unsubstituted or substituted one or more times with Rx.

    [0274] In embodiments wherein Ra and Rb together with the atoms to which they are attached form a heterocyclyl, such heterocyclyl may be piperidinyl, which may be unsubstituted or substituted one or more times with Rx.

    [0275] In embodiments wherein Ra and Rb together with the atoms to which they are attached form a heterocyclyl, such heterocyclyl may be piperaziny, which may be unsubstituted or substituted one or more times with Rx.

    [0276] In embodiments wherein Ra and Rb together with the atoms to which they are attached form a heterocyclyl, such heterocyclyl may be morpholinyl.

    [0277] In embodiments wherein Ra and Rb together with the atoms to which they are attached form a heterocyclyl, such heterocyclyl may be thiomorpholinyl, which may be unsubstituted or substituted one or more times with Rx.

    [0278] In embodiments wherein Ra and Rb together with the atoms to which they are attached form a heterocyclyl, such heterocyclyl may be 1,1-dioxythiomorpholinyl, which may be unsubstituted or substituted one or more times with Rx.

    [0279] In embodiments wherein Ra and Rb together with the atoms to which they are attached form a heterocyclyl, such heterocyclyl may be tetrahydrofuranyl, which may be unsubstituted or substituted one or more times with Rx.

    [0280] In embodiments wherein Ra and Rb together with the atoms to which they are attached form a heterocyclyl, such heterocyclyl may be tetrahydropyranyl, which may be unsubstituted or substituted one or more times with Rx.

    [0281] In embodiments wherein Ra and Rb together with the atoms to which they are attached form a heterocyclyl, such heterocyclyl may be tetrahydrothiofuranyl, which may be unsubstituted or substituted one or more times with Rx.

    [0282] In embodiments wherein Ra and Rb together with the atoms to which they are attached form a heterocyclyl, such heterocyclyl may be tetrahydrothiopyrany, which may be unsubstituted or substituted one or more times with Rx.

    [0283] In embodiments wherein Ra and Rb together with the atoms to which they are attached form a heterocyclyl, such heterocyclyl may be 1,1-dioxytetrahydrothiofuranyl, which may be unsubstituted or substituted one or more times with Rx.

    [0284] In embodiments wherein Ra and Rb together with the atoms to which they are attached form a heterocyclyl, such heterocyclyl may be 1,1-dioxytetrahydrothiopyranyl, which may be unsubstituted or substituted one or more times with Rx.

    [0285] In embodiments wherein Ra and Rb together with the atoms to which they are attached form a heterocyclyl, such heterocyclyl may be 2,3-dihydroindolyl, which may be unsubstituted or substituted one or more times with Rx.

    [0286] In embodiments wherein R4 is -D-heterocyclyl, such heterocyclyl may be: imidazolinyl; azetidinyl; pyrrolidinyl; piperidinyl; piperazinyl; morpholinyl; thiomorpholinyl; 1,1-dioxythiomorpholinyl; tetrahydrofuranyl; tetrahydropyranyl ;tetrahydrothiofuranyl; tetrahydrothiopyranyl; 1,1-dioxytetrahydrothiofuranyl; 1,1-dioxytetrahydrothiopyranyl; or 2,3-dihydroindolyl; each of which may be unsubstituted or substituted one or more times with Rx.

    [0287] In embodiments wherein R4 is -D-heterocyclyl, such heterocyclyl may be imidazolinyl, which may be unsubstituted or substituted one or more times with Rx.

    [0288] In embodiments wherein R4 is -D-heterocyclyl, such heterocyclyl may be azetidinyl, which may be unsubstituted or substituted one or more times with Rx.

    [0289] In embodiments wherein R4 is -D-heterocyclyl, such heterocyclyl may be pyrrolidinyl, which may be unsubstituted or substituted one or more times with Rx.

    [0290] In embodiments wherein R4 is -D-heterocyclyl, such heterocyclyl may be piperidinyl, which may be unsubstituted or substituted one or more times with Rx.

    [0291] In embodiments wherein R4 is -D-heterocyclyl, such heterocyclyl may be piperaziny, which may be unsubstituted or substituted one or more times with Rx.

    [0292] In embodiments wherein R4 is -D-heterocyclyl, such heterocyclyl may be morpholinyl.

    [0293] In embodiments wherein R4 is -D-heterocyclyl, such heterocyclyl may be thiomorpholinyl, which may be unsubstituted or substituted one or more times with Rx.

    [0294] In embodiments wherein R4 is -D-heterocyclyl, such heterocyclyl may be 1,1-dioxythiomorpholinyl, which may be unsubstituted or substituted one or more times with Rx.

    [0295] In embodiments wherein R4 is -D-heterocyclyl, such heterocyclyl may be tetrahydrofuranyl, which may be unsubstituted or substituted one or more times with Rx.

    [0296] In embodiments wherein R4 is -D-heterocyclyl, such heterocyclyl may be tetrahydropyranyl, which may be unsubstituted or substituted one or more times with Rx.

    [0297] In embodiments wherein R4 is -D-heterocyclyl, such heterocyclyl may be tetrahydrothiofuranyl, which may be unsubstituted or substituted one or more times with Rx.

    [0298] In embodiments wherein R4 is -D-heterocyclyl, such heterocyclyl may be tetrahydrothiopyrany, which may be unsubstituted or substituted one or more times with Rx.

    [0299] In embodiments wherein R4 is -D-heterocyclyl, such heterocyclyl may be 1,1-dioxytetrahydrothiofuranyl, which may be unsubstituted or substituted one or more times with Rx.

    [0300] In embodiments wherein R4 is -D-heterocyclyl, such heterocyclyl may be 1,1-dioxytetrahydrothiopyranyl, which may be unsubstituted or substituted one or more times with Rx.

    [0301] In embodiments wherein R4 is -D-heterocyclyl, such heterocyclyl may be 2,3-dihydroindolyl, which may be unsubstituted or substituted one or more times with Rx.

    [0302] In certain embodiments, Rc is hydrogen.

    [0303] In certain embodiments, Rc is C1-6alkyl which may be unsubstituted or substituted one or more times with Rw.

    [0304] In certain embodiments, Rc is C3-6cycloalkyl may be unsubstituted or substituted one or more times with Rw.

    [0305] In certain embodiments, Rc is C3-6cycloalkyl-C1-6alkyl wherein the C1-6alkyl and C3-6cycloalkyl moieties each may be unsubstituted or substituted one or more times with Rw.

    [0306] In certain embodiments, Rc is -A-Ar2.

    [0307] In certain embodiments, Rd is hydrogen.

    [0308] In certain embodiments, Rd is C1-6alkyl which may be unsubstituted or substituted one or more times with Rw.

    [0309] In certain embodiments, Rd is C3-6cycloalkyl which may be unsubstituted or substituted one or more times with Rw.

    [0310] In certain embodiments, Rd is C3-6cycloalkyl-C1-6alkyl wherein the C1-6alkyl and C3-6cycloalkyl moieties each may be unsubstituted or substituted one or more times with Rw.

    [0311] In certain embodiments, Rd is -NRaRb.

    [0312] In certain embodiments, Rd is halo.

    [0313] In certain embodiments, Re is C1-6alkyl which may be unsubstituted or substituted one or more times with halo.

    [0314] In certain embodiments, Re is C1-6alkoxy which may be unsubstituted or substituted one or more times with halo.

    [0315] In certain embodiments, Rf is hydrogen.

    [0316] In certain embodiments, Rf is C1-6alkyl.

    [0317] In certain embodiments, Rg is hydrogen.

    [0318] In certain embodiments, Rg is C1-6alkyl.

    [0319] In certain embodiments, Rh is hydrogen.

    [0320] In certain embodiments, Rh is C1-6alkyl.

    [0321] In certain embodiments, Rh is C1-6alkoxy-C1-6alkyl.

    [0322] In certain embodiments, Rh is hydroxy-C1-6alkyl.

    [0323] In certain embodiments, Rh is amino-C1-6alkyl.

    [0324] In certain embodiments, Rh is N-C1-6alkyl-amino-C1-6alkyl.

    [0325] In certain embodiments, Rh is N,N-di-C1-6alkyl-amino-C1-6alkyl.

    [0326] In certain embodiments, Rh is halo-C1-6alkyl.

    [0327] In certain embodiments, Ri is C1-6alkyl.

    [0328] In certain embodiments, Ri is C1-6alkoxy-C1-6alkyl.

    [0329] In certain embodiments, Ri is halo-C1-6alkyl.

    [0330] In certain embodiments, Ri is hydroxy-C1-6alkyl.

    [0331] In certain embodiments, Ri is C1-6alkylsulfonyl.

    [0332] In certain embodiments, Ri is C1-6alkylcarbonyl.

    [0333] In certain embodiments, Ri is hydroxy-C1-6alkoxy.

    [0334] In certain embodiments, Ri is aminocarbonyl-C1-6alkyl.

    [0335] In certain embodiments, Ri is hydroxy-C1-6alkyl-carbonyl.

    [0336] In certain embodiments, Ri is cyano-C1-6alkyl.

    [0337] In certain embodiments, Ri is oxetanyl.

    [0338] In certain embodiments, Ri is C1-6alkylsulfonyl.

    [0339] In certain embodiments, Ri is halo-C1-6alkylsulfonyl.

    [0340] In certain embodiments, Ri is heteroaryl selected from oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, each of which which may be unsubstituted or substituted one or more times with C1-6alkyl, hydroxy-C1-6alkyl, oxo, or halo-C1-6alkyl.

    [0341] In certain embodiments, Rj is hydrogen.

    [0342] In certain embodiments, Rj is C1-6alkyl.

    [0343] In certain embodiments, Rj is benzyl.

    [0344] In certain embodiments, Rk is hydrogen.

    [0345] In certain embodiments, Rk is C1-6alkyl.

    [0346] In certain embodiments, Rk is halo-C1-6alkyl.

    [0347] In certain embodiments, Rk is cyano-C1-6alkyl.

    [0348] In certain embodiments, Rk is hydroxy-C1-6alkoxy.

    [0349] In certain embodiments, Rk is C1-6alkoxy.

    [0350] In certain embodiments, Rk is C3-6cycloalkyl.

    [0351] In certain embodiments, Rk is C3-6cycloalkyl-C1-6alkyl.

    [0352] In certain embodiments, Rk is heteroaryl selected from oxadiazolyl or pyridinyl, each of which which may be unsubstituted or substituted one or more times with C1-6alkyl, cyano, C1-6alkylsulfonyl, or halo.

    [0353] In certain embodiments, Rk is phenyl which which may be unsubstituted or substituted one or more times with C1-6alkylsulfonyl.

    [0354] In certain embodiments, Rk is benzyl, the phenyl portion of which which may be unsubstituted or substituted one or more times with C1-6alkyl, halo.

    [0355] In certain embodiments, Rj and Rk together with the atoms to which they are attached form a four to seven membered heterocyclyl selected from: azetidinyl, morpholinyl, pyrrolidinyl, azabicyclo[3.1.0]hexanyl, piperidinyl, piperazinyl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, tetrahydro-1H-furo[3,4-c]pyrrolyl, 2-oxa-6-azaspiro[3.4]octanyl, 5-oxa-2-azaspiro[3.4]octanyl, 2-azabicyclo[3.1.0]hexanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-azaspiro[3.3]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 8-azabicyclo[3.2.1]octanyl; each of which may be unsubstituted or substituted one or more times with C1-6alkyl, halo, amino, N-C1-6alkyl-amino,N,N-di-C1-6alkyl-amino,hydroxy, C1-6alkoxy-carbonyl, C1-6alkoxy, C1-6alkylsulfonyl, hydroxy-C1-6alkyl, C1-6alkoxy-C1-6alkyl, halo-C1-6alkyl, cyano, cyano-C1-6alkyl, aminocarbonyl, N-C1-6alkyl-amino-carbonyl, N,N-di-C1-6alkyl-amino-carbonyl, C1-6alkyl-carbonyl-amino, C1-6alkoxy-carbonyl-amino, C1-6alkoxy-carbonyl-amino-C1-6alkyl, benzyloxy, pyrrolidinyl which may be unsubstituted or substituted one or more times with C1-6alkyl or halo; or heteroaryl selected from pyrazolyl, pyrimidinyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, oxo or halo.

    [0356] In certain embodiments, Rj and Rk together with the atoms to which they are attached form azetidinyl, which may be unsubstituted or substituted one or more times as described herein.

    [0357] In certain embodiments, Rj and Rk together with the atoms to which they are attached form morpholinyl, which may be unsubstituted or substituted one or more times as described herein.

    [0358] In certain embodiments, Rj and Rk together with the atoms to which they are attached form pyrrolidinyl, which may be unsubstituted or substituted one or more times as described herein.

    [0359] In certain embodiments, Rm is hydrogen.

    [0360] In certain embodiments, Rm is C1-6alkyl.

    [0361] In certain embodiments, Rm is cyano-C1-6alkyl.

    [0362] In certain embodiments, Rm is halo-C1-6alkyl.

    [0363] In certain embodiments, Rm is hydroxy-C1-6alkyl.

    [0364] In certain embodiments, Rm is C1-6alkoxy.

    [0365] In certain embodiments, Rm is C3-6cycloalkyl.

    [0366] In certain embodiments, Rm is C3-6cycloalkyl-C1-6alkyl.

    [0367] In certain embodiments, Rm is C1-6alkoxy-C1-6alkyl; hydroxy-C1-6alkyl.

    [0368] In certain embodiments, Rm is amino-C1-6alkyl.

    [0369] In certain embodiments, Rm is heteroaryl selected from pyridinyl, indolyl, and indolinyl; each of which which may be unsubstituted or substituted one or more times with C1-6alkyl, halo, cyano, halo-C1-6alkyl, or C1-6alkyl-sulfonyl.

    [0370] In certain embodiments, Rm is phenyl which which may be unsubstituted or substituted one or more times with C1-6alkyl.

    [0371] In certain embodiments, Rm is phenyl-C1-6alkyl wherein the phenyl portion thereof may be unsubstituted or substituted one or more times with C1-6alkyl.

    [0372] In certain embodiments, Rm is heterocyclyl selected from azetidinyl, or oxetanyl, each of which which may be unsubstituted or substituted one or more times with C1-6alkyl, halo, cyano, or halo-C1-6alkyl.

    [0373] In certain embodiments, Rn is hydrogen.

    [0374] In certain embodiments, Rn is C1-6alkyl.

    [0375] In certain embodiments, Rn is halo-C1-6alkyl.

    [0376] In certain embodiments, Rn is hydroxy-C1-6alkyl.

    [0377] In certain embodiments, Rn is hydroxy-C1-6alkoxy.

    [0378] In certain embodiments, Rn is C3-6cycloalkyl.

    [0379] In certain embodiments, Rn is C3-6cycloalkyl-C1-6alkyl.

    [0380] In certain embodiments, Rn is C1-6alkoxy.

    [0381] In certain embodiments, Rn is C1-6alkoxy-C1-6alkyl.

    [0382] In certain embodiments, Rn is hydroxy-C1-6alkyl.

    [0383] In certain embodiments, Rn is amino.

    [0384] In certain embodiments, Rn is N-C1-6alkyl-amino.

    [0385] In certain embodiments, Rn is N,N-di-C1-6alkyl-amino.

    [0386] In certain embodiments, Rn is amino-C1-6alkyl.

    [0387] In certain embodiments, Rn is N-C1-6alkyl-amino-C1-6alkyl.

    [0388] In certain embodiments, Rn is N,N-di-C1-6alkyl-amino-C1-6alkyl.

    [0389] In certain embodiments, Rn is amino-carbonyl-C1-6alkyl.

    [0390] In certain embodiments, Rn is N-C1-6alkyl-amino-carbonyl-C1-6alkyl. In certain embodiments, Rn is N,N-di-C1-6alkyl-amino-carbonyl-C1-6alkyl. In certain embodiments, Rn is amino-carbonyl-amino-C1-6alkyl. In certain embodiments, Rn is 5-methylisoxazole-3-yl. In certain embodiments, Rn is cyano-C1-6alkyl. In certain embodiments, Rn is C1-6alkylsulfonyl. In certain embodiments, Rn is C1-6alkylcarbonyl-amino-C1-6alkyl. In certain embodiments, Rn is C1-6alkylsulfonyl-C1-6alkyl. In certain embodiments, Rp is hydrogen.

    [0391] In certain embodiments, Rp is C1-6alkyl.

    [0392] In certain embodiments, Rp is halo-C1-6alkyl.

    [0393] In certain embodiments, Rp is hydroxy-C1-6alkyl. In certain embodiments, Rp is C1-6alkoxycarbonyl-C1-6alkyl. In certain embodiments, Rp is cyano-C1-6alkyl. In certain embodiments, Rv is hydroxy.

    [0394] In certain embodiments, Rv is C1-6alkoxy.

    [0395] In certain embodiments, Rw is halo.

    [0396] In certain embodiments, Rw is hydroxy.

    [0397] In certain embodiments, Rw is C1-6alkoxy.

    [0398] In certain embodiments, Rw is cyano.

    [0399] In certain embodiments, Rw is amino.

    [0400] In certain embodiments, Rx is C1-6alkyl.

    [0401] In certain embodiments, Rx is halo-C1-6alkyl.

    [0402] In certain embodiments, Rx is halo.

    [0403] In certain embodiments, Rx is hydroxy.

    [0404] In certain embodiments, Rx is hydroxy-C1-6alkyl. In certain embodiments, Rx is C1-6alkoxy.

    [0405] In certain embodiments, Rx is C1-6alkoxy-C1-6alkyl. In certain embodiments, Rx is oxo.

    [0406] In certain embodiments, Rx is amino.

    [0407] In certain embodiments, Rx is C1-6alkylcarbonyl. In certain embodiments, Rx is C1-6alkoxy.

    [0408] In certain embodiments, Rx is -A- C(O)-NRaRb. In certain embodiments, Rx is -A-C(O)-O-Rc.

    [0409] In certain embodiments, Rx is -D-heterocyclyl.

    [0410] In certain embodiments, Rx is -D-Ar2.

    [0411] In certain embodiments, Rx is -D-C(O)-Rc;

    [0412] In certain embodiments, Ry is C1-6alkyl.

    [0413] In certain embodiments, Ry is halo-C1-6alkyl.

    [0414] In certain embodiments, Ry is halo.

    [0415] In certain embodiments, Ry is hydroxy.

    [0416] In certain embodiments, Ry is C1-6alkoxy.

    [0417] In certain embodiments, Ry is cyano.

    [0418] In certain embodiments, Ry is phenyloxy.

    [0419] In certain embodiments, Ry is heterocyclyl which may be unsubstituted or substituted one or more times with Rx.

    [0420] In certain embodiments, Rz is C1-6alkyl.

    [0421] In certain embodiments, Rz is halo-C1-6alkyl.

    [0422] In certain embodiments, Rz is halo.

    [0423] In certain embodiments, Rz is hydroxy.

    [0424] In certain embodiments, Rz is oxo; hydroxy-C1-6alkyl.

    [0425] In certain embodiments, Rz is C1-6alkoxy.

    [0426] In certain embodiments, Rz is C1-6alkoxy-C1-6alkyl.

    [0427] In certain embodiments, Rz is cyano.

    [0428] In certain embodiments, Rz is phenyloxy.

    [0429] In certain embodiments, Rz is C3-6cycloalkyl.

    [0430] In certain embodiments, Rz is C3-6cycloalkyl-C1-6alkyl.

    [0431] In certain embodiments, Rz is -A-heterocyclyl wherein the heterocyclyl may be unsubstituted or substituted one or more times with Rx.

    [0432] In certain embodiments, Rz is -A-NRaRb.

    [0433] In certain embodiments, Rz is -A-C(O)-NRaRb.

    [0434] In certain embodiments, Rz is -A-C(O)-O-Rc.

    [0435] In certain embodiments, Rz is -A-C(O)-Rc.

    [0436] In certain embodiments, Rz is -B-SO2-Rd.

    [0437] In embodiments wherein Rz is -A-heterocyclyl, such heterocyclyl may be: imidazolinyl; azetidinyl; pyrrolidinyl; piperidinyl; piperazinyl; morpholinyl; thiomorpholinyl; 1,1-dioxythiomorpholinyl; tetrahydrofuranyl; tetrahydropyranyl;tetrahydrothiofuranyl; tetrahydrothiopyranyl; 1,1-dioxytetrahydrothiofuranyl; 1,1-dioxytetrahydrothiopyranyl; or 2,3-dihydroindolyl; each of which may be unsubstituted or substituted one or more times with Rx.

    [0438] In certain embodiments the subject compounds may be of formula II:

    or a pharmaceutical salt thereof,
    wherein

    R8 is halo;

    R9 is: hydrogen; or halo; and

    R4 is as defined herein.
    In certain embodiments, R8 is fluoro and R9 is hydrogen or fluoro.
    In certain embodiments, R8 and R9 are halo.
    In certain embodiments, R8 and R9 are fluoro.


    Methods



    [0439] The invention also discloses a method for treating a disease or condition mediated by or otherwise associated with the RORc receptor, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention.

    [0440] The disease may be arthritis such as rheumatoid arthritis or osteoarthritis.

    [0441] The disease may be asthma or COPD.

    [0442] Representative compounds in accordance with the methods of the invention are shown in the experimental examples below.

    Synthesis



    [0443] Compounds of the present invention can be made by a variety of methods depicted in the illustrative synthetic reaction schemes shown and described below.

    [0444] The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application.

    [0445] The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

    [0446] Unless specified to the contrary, the reactions described herein may be conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about -78 °C to about 150 °C, for example, from about 0 °C to about 125 °C, or conveniently at about room (or ambient) temperature, e.g., about 20 °C.

    [0447] Scheme A below illustrates one synthetic procedure usable to prepare specific compounds of formula I, wherein R is lower alkyl, X is a leaving group, and R1, R2, R3, R4, R5, R6 and R7 are as defined herein.



    [0448] In step 1 of Scheme A, camphor compound a is reacted with an alpha halo ester reagent b in the presence of strong base to afford ester compound c. In step 2, ester compound undergoes a cyclization by reaction with hydrazine, followed by heating, to give diaza compound d. Compound d is then reduced in step 3 to provide cinnolinone compound e. Cinnolinone compound e is then treated with POCl3 or like chlorinating agent in step 4 to give chlorocinnoline compond f. In step 5, chlorocinnoline is reated with aryl boronic acid compound g to affoed aryl cinnoline h, which is a compound of formula I in accordance with the invention.

    [0449] Many variations on the procedures of Scheme A are possible and will suggest themselves to those skilled in the art. Specific details for producing compounds of the invention are described in the Examples below.

    Administration and Pharmaceutical Composition



    [0450] The invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.

    [0451] In general, the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, for example 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease.

    [0452] Compounds of the invention may be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. A particular manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.

    [0453] A compound or compounds of the invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.

    [0454] The compounds of the invention may be formulated in a wide variety of oral administration dosage forms. The pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active component. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets may contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration.

    [0455] Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

    [0456] The compounds of the invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.

    [0457] The compounds of the invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatine and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

    [0458] The compounds of the invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.

    [0459] The compounds of the invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

    [0460] The subject compounds may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.

    [0461] The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatine or blister packs from which the powder may be administered by means of an inhaler.

    [0462] When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial. Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support. The compound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecylazacycloheptan-2-one). Sustained release delivery systems are inserted subcutaneously into the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polylactic acid.

    [0463] The pharmaceutical preparations may be in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

    [0464] Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Representative pharmaceutical formulations containing a compound of the present invention are described below.

    Utility



    [0465] The compounds of the invention are useful for treatment of immune disorders generally. The compounds may be used for treatment of arthritis, including rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, and other arthritic conditions.

    [0466] The compounds may be used for treatment of respiratory disorders such as chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and the like.

    [0467] The compounds may be used for treatment of gastrointestinal disorder ("GI disorder") such as Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, pain associated with GI distension, and the like.

    [0468] The compounds may be used for treatment of pain conditions such as inflammatory pain; arthritic pain, surgical pain; visceral pain; dental pain; premenstrual pain; central pain; pain due to burns; migraine or cluster headaches; nerve injury; neuritis; neuralgias; poisoning; ischemic injury; interstitial cystitis; cancer pain; viral, parasitic or bacterial infection; post-traumatic injury; or pain associated with irritable bowel syndrome.

    [0469] The compounds may be used for treatment of muscular sclerosis, Sjogren's disease, lupus, and pulmonary fibrosis.

    GENERAL EXPERIMENTAL


    LCMS methods:



    [0470] High Pressure Liquid Chromatography - Mass Spectrometry (LCMS) experiments to determine retention times (RT) and associated mass ions were performed using one of the following methods:

    Method A: Compounds were analysed using the following conditions: Experiments were performed on a Waters ZMD single quadrupole mass spectrometer linked to a Hewlett Packard HP1100 LC system with UV diode array detector and 100 position autosampler. The spectrometer has an electrospray source operating in positive and negative ion mode. This system uses a Phenomenex Luna 3 µm C18(2) 30 x 4.6 mm column at ambient temperature and a 2.0 mL / minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. This was maintained for 1 minute before returning to 95% solvent A and 5% solvent B over the next 0.5 minute. Total run time was 6 minutes.

    Method B: Compounds were analysed using the following conditions: Experiments were performed on a Waters Micromass ZQ2000 quadrupole mass spectrometer linked to a Waters Acquity UPLC system with a PDA UV detector. The spectrometer has an electrospray source operating in positive and negative ion mode. This system uses an Acquity BEH C18 1.7 µm 100 x 2.1 mm column, maintained at 40 °C or an Acquity BEH Shield RP18 1.7 µm 100 x 2.1 mm column, maintained at 40 °C and a 0.4 mL / minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.4 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 5.6 minutes. This was maintained for 0.8 minute before returning to 95% solvent A and 5% solvent B over the next 1.2 minutes. Total run time was 8 minutes.


    NMR methods:



    [0471] 1H NMR spectra were recorded at ambient temperature or at 80 °C where indicated using one of the following machines: Varian Unity Inova (400 MHz) spectrometer with a triple resonance 5mm probe, Bruker Avance DRX 400 (400 MHz) spectrometer with a triple resonance 5mm probe, a Bruker Avance DPX 300 (300 MHz) equipped with a standard 5mm dual frequency probe for detection of 1H and 13C, Bruker Fourier 300MHz system equipped with a standard 5mm 1H / 13C probe, a Bruker AVIII (400 MHz) using a BBI Broad Band Inverse 5mm probe, or a Bruker AVIII (500 MHz) using a QNP (Quad Nucleus detect) 5mm probe. Chemical shifts are expressed in ppm relative to an internal standard, tetramethylsilane (ppm = 0.00). The following abbreviations have been used: br = broad signal, s = singlet, d = doublet, dd = double doublet, t = triplet, td = triplet doublet, dddd = doublet doublet doublet doublet, q = quartet, m = multiplet, or any combination thereof.

    Microwave reactor:



    [0472] Microwave reactions were carried out using a Biotage® Initiator® in vials appropriate to the scale of the reaction and at the temperature and time described in the experimental details.

    Purification Equipment:



    [0473] Purifications were carried out using pre-packed silica gel cartridges either on a Teledyne ISCO CombiFlash® or Biotage® Isolera Four® or using compressed air to apply external pressure. Solvents and gradients shown in the experimental details were used.

    [0474] Reverse Phase High Pressure Liquid Chromatography (HPLC) was used to purify compounds where indicated. Separation using gradient elution on a Phenomenex Gemini C18 column (250 x 21.2 mm, 5 micron) as stationary phase and using mobile phase indicated, operating at a 18 mL/min flow rate using a Gilson UV/Vis -155 dual channel detector and Gilson GX-271 automated liquid handler.

    [0475] Phase separator cartridges are supplied by Biotage® as Isolute® phase separator cartridges.

    LIST OF ABBREVIATIONS



    [0476] 
    AcOH
    Acetic acid
    AIBN
    2,2'-Azobis(2-methylpropionitrile)
    Atm.
    Atmosphere
    BOC
    tert-Butyloxycarbonyl group
    (BOC)2O
    Di-tert-butyl dicarbonate
    CrO3
    Chromium (VI) oxide
    CDCl3
    Deuterated chloroform
    DavePhos
    2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl
    DCM
    Dichloromethane / methylene chloride
    DMA
    N,N-Dimethylacetamide
    DIAD
    Diisopropyl azodicarboxylate
    DIPEA
    DIPEA
    DMAP
    4-Dimethylaminopyridine
    DME
    1,2-Dimethoxyethane
    DMF
    N,N-Dimethylformamide
    DMSO
    Dimethyl sulfoxide
    DPPF
    1,1'-Bis(diphenylphosphino)ferrocene
    ES
    Electrospray
    Et2O
    Diethyl ether
    Et3N
    Triethylamine
    EtOH
    Ethanol/Ethyl alcohol
    EtOAc
    Ethyl acetate
    H2O
    Water
    H2SO4
    Sulfuric acid
    HATU
    2-(1H-7-Azabenzotriazol-1-yl)--1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium
    HBTU
    O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate
    HCO2H
    Formic acid
    HCl
    Hydrochloric acid
    HOBT
    1-Hydroxybenzotriazole
    HPLC
    High pressure liquid chromatography
    RP HPLC
    Reverse phase high pressure liquid chromatography
    IBX
    2-Iodoxybenzoic acid
    IMS
    Industrial methylated spirit
    KOH
    Potassium hydroxide
    K2CO3
    Potassium carbonate
    LDA
    Lithium diisopropylamide
    i-PrOH
    Isopropanol / isopropyl alcohol / propan-2-ol
    LCMS
    Liquid Chromatograph / Mass Spectroscopy
    LiOH
    Lithium hydroxide
    MgSO4
    Magnesium sulphate
    MeOH
    Methanol / Methyl alcohol
    MW
    Microwaves
    NaH
    Sodium hydride
    NaCl
    Sodium chloride
    NaOH
    Sodium hydroxide
    Na2SO4
    Sodium sulfate
    Na2CO3
    Sodium carbonate
    NaHCO3
    Sodium bicarbonate / Sodium hydrogen carbonate
    NBS
    N-Bromosuccinimide
    NH4Cl
    Ammonium chloride
    NMP
    1-Methyl-2-pyrrolidinone
    POCl3
    Phosphorus oxychloride
    PhCH3
    Toluene
    Pd2(dba)3
    Tris(dibenzylideneacetone)dipalladium (0)
    PSI
    Pound per square inch
    RT
    Room temperature
    sat.
    Saturated
    SCX-2
    Pre-packed Isolute® silica-based sorbent with a chemically bonded propylsulfonic acid functional group
    TBDMS
    tert-Butyldimethylsilyl
    TFA
    Trifluoroacetic acid
    THF
    Tetrahydrofuran
    TIPS
    Triisopropylsilyl
    TLC
    Thin layer chromatography
    XantPhos
    4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

    Example 1: (5R,8S)-3-(2,6-Difluorophenyl)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0477] 


    Step 1: ((1S,4S)-4,7,7-Trimethyl-3-oxo-bicyclor[2.2.1]hept-2-yl)-acetic acid methyl ester



    [0478] A solution of LDA at -78 °C was prepared by standard procedure [diisopropylamine (20 mL, 150 mmol), hexamethylphosphoramide (26 mL, 15 mmol), n-BuLi (150 mmol, 2.5 M solution in hexane)] and was added at 5 °C under N2 atmosphere within 15 min to a solution of (-)-camphor (15.2 g, 100 mmol) in anhydrous THF (50 mL). The mixture was stirred for 20 min, then BrCH2COOMe (16.7 mL, 150 mmol) was added. The reaction was stirred for 0.5 h and then quenched with 2 N aqueous HCl (100 ml). The organic layer was separated, extracted with Et2O and the combined organic solutions were dried with Na2SO4 and concentrated in vacuo. The crude product was used in the next step.

    Step 2: (5S,8S)-8,9,9-trimethyl-4,4a,5,6,7,8-hexahydro-5,8-methanocinnolin-3(2H)-one



    [0479] To a solution of the product from Step 1 in EtOH (200 mL) was added hydrazine hydrate (30 mL). The reaction was refluxed for 12 hours, cooled to ambient temperature, evaporated under reduced pressure, and the residue was extracted into DCM. The organic layers were washed with H2O and brine, dried over MgSO4, filtered, and evaporated under reduced pressure to give an oil. Purification by chromatography on silica (EtOAc) gave ((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]hept-2-yl)-acetic acid hydrazide (not shown) as a white solid (10.7 g). LCMS (m/z) 225 [M+1]+. A solution of the hydrazide (10.7 g, 47.8 mmol) in NMP (500 mL) was then heated to 230 °C for 3 h, cooled to RT and poured into H2O. The aqueous layer was extracted with EtOAc and the organic layers were combined, washed with brine and H2O, dried over MgSO4, filtered, and concentration in vacuo. Purification by chromatography on silica (1:1 EtOAc in hexanes) gave the title compound as a white solid (7.0 g, 71.1%). LCMS (m/z) 207 [M+1]+

    Step 3: (5R,8S)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-3(2H)-one



    [0480] A solution of the product from Step 2 (7.0 g, 34 mmol) and Pd/C (2 g, 10% wet) in diphenyl ether (50 mL) was heated at 250 °C for 2 h. Pd/C (1 g) was added every half hour until TLC indicated completion of the reaction. The reaction was cooled to RT and purified by chromatography on silica (EtOAc) to give the title compound as a white solid (4.2 g, 60%). 1H NMR (400 MHz, DMSO-d6) δ 12.32 - 12.07 (m, 1H), 6.53 (s, 1H), 2.77 (s, 1H), 2.16 - 2.03 (m, 1H), 1.92 - 1.81 (m, 1H), 1.25 (ddd, J = 26.4, 15.5, 7.6 Hz, 2H), 1.10 (s, 3H), 0.95 (s, 3H), 0.61 (s, 3H). LCMS (m/z) 205 [M+1]+.

    Step 4: (5R,8S)-3-chloro-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0481] The product from Step 3 (6.36 g) and POCl3 (15 mL) were heated at 70 °C for 4 h. The reaction was cooled to ambient temperature and poured into saturated aqueous NaHCO3 and extracted into EtOAc. The combined organic extracts were washed with saturated aqueous NaHCO3, water, brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by chromatography on silica (0 to 40 % EtOAc-cyclohexane) gave the title compound as a white solid (4.2 g, 60%). 1H NMR (300 MHz, CDCl3): δ 7.17 (s, 1 H); 2.91 (d, J = 4.3 Hz, 1 H); 2.21 (ddt, J = 12.5, 10.5, 4.2 Hz, 1 H); 1.98 (ddd, J = 12.6, 10.5, 3.9 Hz, 1 H); 1.43 (s, 3 H); 1.33-1.35 (m, 1 H); 1.18 (ddd, J = 12.6, 9.2, 3.9 Hz, 1 H); 1.04 (s, 3 H); 0.58 (s, 3 H).

    Step 5: (5R,8S)-3-(2,6-difluorophenyl)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0482] A flask containing THF (16 mL) and 0.5 M K3PO4 (32 mL) was sealed with a septum and de-gassed by passing argon gas through the solution. A sonication bath was used in pulses for 3 minutes to help with the de-gassing of the solution. The de-gassed solution was transferred via syringe into a flask containing the product from Step 5 (1.84 g, 8.28 mmol), 2,6-difluorophenylboronic acid (4.26 g, 27 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1 ' -biphenyl)palladium (II) (210 mg, 3 mol%) under an argon atmosphere. The reaction flask was immediately placed in a pre-heated bath at 50 °C for 1 h. The reaction was cooled to ambient temperature and partitioned between H2O-EtOAc, and the organic extract was dried over Na2SO4, filtered, and concentrated. Purification by chromatography on silica (0 to 20% EtOAc-cyclohexanes) gave the title compound as a colourless solid (1.24 g, 50%). 1H NMR (300 MHz, CDCl3): δ 7.38 (tt, J = 8.4, 6.2 Hz, 1 H); 7.30 (s, 1 H); 7.02 (t, J = 7.9 Hz, 2 H); 2.96 (d, J = 4.3 Hz, 1 H); 2.21-2.23 (m, 1 H); 2.00-2.01 (m, 1 H); 1.50 (s, 3 H); 1.23-1.25 (m, 2 H); 1.07 (s, 3 H); 0.62 (s, 3 H). LCMS (m/z, Method B) ES+ 301 [M+1]+.

    Example 2: (5R,8S)-3-(2-Chloro-6-fluorophenoxy)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0483] 



    [0484] A solution of (1S,8R)-5-chloro-1,11,11-trimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2,4,6-triene (49 mg, 0.22 mmol), 2-chloro-6-fluorophenol (65 mg), K2CO3 (152 mg) in DMSO was heated at 150 °C for 24 h. Additional 2-chloro-6-fluorophenol (65 mg) was added and heating continued for 5 h. The cooled reaction was partitioned between H2O-EtOAc, extracted, the combined organic phases washed with H2O, dried over MgSO4, filtered, concentrated, and purified by RP HPLC using a gradient of MeCN-H2O/0.1% HCO2H (50-98%) over 0.5 h. 1H NMR (400 MHz, CDCl3): δ 7.23 (dt, J = 8.0, 1.6 Hz, 1 H); 7.10-7.11 (m, 2 H); 7.01 (s, 1 H); 2.94 (d, J = 4.3 Hz, 1 H); 2.20 (ddt, J = 12.5, 10.6, 4.2 Hz, 1 H); 1.95-1.96 (m, 1 H); 1.36 (s, 3 H); 1.24-1.25 (m, 1 H); 1.04 (s, 4 H); 0.60 (s, 3 H). LCMS (m/z, Method B) ES+ 333 [M+1]+.

    Example 3: (5R,8R)-3-(2,6-Difluorophenyl)-8-(methoxymethyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0485] 


    Step 1: (1R.4S)-7,7-Dimethyl-2-oxo-bicyclo[2.2.1]heptane-1-carboxylic acid methyl ester



    [0486] Thionyl chloride (45 mL) was added dropwise to MeOH (700 mL) at 0 °C. (-)-ketopinic acid (24.38g) was added and the cooling bath removed after addition was completed. After stirring for 17 h, the reaction was concentrated in vacuo and purified by chromatography on silica (0 to 25% EtOAc in cyclohexane) to give the title compound as a light brown oil (27.27 g). 1H NMR (300 MHz, CDCl3): δ 3.76 (s, 3 H); 2.54 (dt, J = 18.4, 3.9 Hz, 1 H); 2.36-2.38 (m, 1 H); 2.06-2.08 (m, 3 H); 1.80 (ddd, J = 14.1, 9.3, 4.7 Hz, 1 H); 1.41-1.43 (m, 1 H); 1.16 (s, 3 H); 1.09 (s, 3 H).

    Step 2: (1S,4S)-1-Hydroxymethyl-7,7-dimethyl-bicyclo[2.2.1]heptan-2-one



    [0487] A solution of LDA was prepared by standard procedure at -78 °C [diisopropylamine (505 mg, 5 mmol), n-BuLi (2 mL, 5 mmol, 2.5M solution in hexane)] and was allowed to warm to 0 °C over 0.5 h and then re-cooled to -78 °C. The solution of LDA was added over 1 minute to a solution of the product from Step 1 (980 mg, 5 mmol) in anhydrous THF (10 mL) under a nitrogen atmosphere at -78 °C, and stirred for 40 minutes. LiAlH4 (2.5 mL, 5 mmol, 2 M solution in THF) was added and the reaction allowed to warm to -40 °C over 1h. The reaction was carefully poured into 1 N aqueous HCl with vigorous stirring, extracted into Et2O, dried over MgSO4, filtered, and concentrated in vacuo. Purification by chromatography on silica (0 to 23% EtOAc in cyclohexane) gave the title compound as a white solid (492 mg). 1H NMR (300 MHz, CDCl3): δ 3.89 (d, J = 11.9 Hz, 1 H); 3.65 (d, J = 11.9 Hz, 1 H); 2.40-2.43 (m, 1 H); 2.02-2.04 (m, 2 H); 1.86-1.88 (m, 2 H); 1.61 (ddd, J = 13.7, 9.2, 4.5 Hz, 1 H); 1.39-1.40 (m, 1 H); 1.00 (d, J = 6.9 Hz, 6 H).

    Step 3: (1S,4S)-1,7,7-Trimethyl-bicyclo[2.2.1]heptan-2-one



    [0488] To a solution of the product from Step 2 (168 mg) in anhydrous THF (3 mL) was added NaH (48 mg, 60 % dispersion in oil) followed after 10 min. by MeI (170 mg). After 18 hours of stirring, the reaction was partitioned between H2O-EtOAc, the organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by chromatography on silica (0 to 15% EtOAc in cyclohexanes) gave the the title compound as a colourless oil that crystallised on standing (151 mg). 1H NMR (300 MHz, CDCl3): δ 3.51-3.52 (m, 2 H); 3.35 (s, 3 H); 2.38-2.40 (m, 1 H); 1.99-2.02 (m, 3 H); 1.84 (d, J = 18.3 Hz, 1 H); 1.36 (d, J = 8.2 Hz, 2 H); 1.05 (s, 3 H); 0.95 (s, 3 H).

    Steps 4: (5R,8R)-3-(2,6-Difluorophenyl)-8-(methoxymethyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0489] The product from Step 3 was reacted in a similar manner to that described in steps 1-5 of Example 1 to give the title compound. 1H NMR (400 MHz, CDCl3): δ 7.38 (tt, J = 8.4, 6.3 Hz, 1 H); 7.32 (t, J = 1.4 Hz, 1 H); 7.02 (t, J = 7.9 Hz, 2 H); 4.25 (d, J = 10.6 Hz, 1 H); 4.02 (d, J = 10.6 Hz, 1 H); 3.49 (s, 3 H); 2.91 (d, J = 4.2 Hz, 1 H); 2.42 (ddd, J = 12.4, 10.6, 3.8 Hz, 1 H); 2.27 (ddt, J = 12.3, 10.6, 4.1 Hz, 1 H); 1.35-1.36 (m, 1 H); 1.24 (ddd, J = 12.3, 9.2, 3.8 Hz, 1 H); 1.19 (s, 3 H); 0.72 (s, 3 H). LCMS (m/z, Method B) ES+ 331 [M+1]+.

    Example 4: (5S,8R)-3-(2-Fluorophenyl)-9,9-dimethyl-8-(1H-pyrazol-1-ylmethyl)-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0490] 


    Step 1: (1R,4R)-1-Benzyloxymethyl-7,7-dimethyl-bicyclo[2.2.1]heptan-2-one



    [0491] Sodium hydride (1 g, 25 mmol, 60% dispersion in oil) was added to a solution of (1R,4R)-1-hydroxymethyl-7,7-dimethyl-bicyclo[2.2.1]heptan-2-one (3.74 g, 22.26 mmol) in anhydrous THF (50 mL) and stirred at room temperature for 15 min when benzyl bromide (4.28 g, 25 mmol) was added. After stirring overnight, the solution was diluted with H2O and Et2O and the organic phase was dried with MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica (0 to 5% EtOAc in cyclohexane) gave the title compound as almost colourless oil (4.95 g). 1H NMR (300 MHz, CDCl3): δ 7.28-7.29 (m, 5 H); 4.53 (s, 2 H); 3.62 (d, J = 4.7 Hz, 2 H); 2.39-2.41 (m, 1 H); 2.04-2.06 (m, 3 H); 1.85 (d, J = 18.3 Hz, 1 H); 1.37-1.38 (m, 2 H); 1.07 (s, 3 H); 0.95 (s, 3 H).

    Step 2: (1S,8S)-1-Benzyloxymethyl-5-(2-fluoro-phenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-triene



    [0492] The product from Step 1 was reacted in a similar manner to that described in Steps 1-5 of Example 1 to give the title compound. 1H NMR (400 MHz, CDCl3): δ 8.11 (td, J = 7.9, 1.9 Hz, 1 H); 7.65 (d, J = 2.6 Hz, 1 H); 7.34-7.36 (m, 7 H); 7.17 (ddd, J = 11.5, 8.2, 1.2 Hz, 1 H); 4.70 (s, 2 H); 4.23 (dd, J = 84.5, 10.5 Hz, 2 H); 2.91 (d, J = 4.2 Hz, 1 H); 2.48-2.49 (m, 1 H); 2.27 (tt, J = 11.4, 4.0 Hz, 1 H); 1.29-1.31 (m, 2 H); 1.21 (s, 3 H); 0.70 (s, 3 H). LCMS (m/z, Method A) ES+ 389.3 [M+1]+.

    Step 3: Acetic acid (1S,8S)-5-(2-fluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-trien-1-ylmethyl ester



    [0493] The product from Step 2 (1.24g, 3.19 mmol) was dissolved in AcOH (3 mL) and 33% hydrogen bromide in AcOH (10 mL) was added. The resulting solution was stirred at room temperature for 1h, and then poured into H2O and Et2O and carefully basified with NaHCO3. The organic phase was dried (MgSO4), filtered, and evaporated in vacuo. Purification by chromatography on silica (0-60% EtOAc in cyclohexane) gave the title compound as a white solid (1.07 g). 1H NMR (400 MHz, CDCl3): δ 8.14 (td, J = 7.9, 1.9 Hz, 1 H); 7.68 (d, J = 2.6 Hz, 1 H); 7.42-7.43 (m, 1 H); 7.29 (td, J = 7.6, 1.2 Hz, 1 H); 7.18 (ddd, J = 11.5, 8.2, 1.2 Hz, 1 H); 4.80-4.81 (m, 2 H); 2.96 (d, J = 3.6 Hz, 1 H); 2.26-2.28 (m, 2 H); 2.11 (s, 3 H); 1.43-1.44 (m, 1 H); 1.27-1.29 (m, 1 H); 1.17 (s, 3 H); 0.74 (s, 3 H). LCMS (m/z, Method A) ES+ 341.3 [M+1]+.

    Step 4: [(1S,8S)-5-(2-Fluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-trien-1-yl]-methanol



    [0494] The product from Step 3 (1.02 g, 3 mmol) was dissolved in MeOH (30 mL) and 1 M aqueous NaOH and stirred at room temperature for 1.5 h. The reaction was then evaporated in vacuo and the residue was partitioned between EtOAc and H2O, the organic phase dried with Na2SO4, filtered, and evaporated. Purification of the crude residue by chromatography on silica (0-70% EtOAc in cyclohexane) gave a white solid which was triturated with pentane to give the title compound (858 mg). 1H NMR (400 MHz, CDCl3): δ 8.06 (td, J = 7.8, 1.8 Hz, 1 H); 7.69 (d, J = 2.6 Hz, 1 H); 7.45 (dddd, J = 8.3, 7.4, 5.1, 1.9 Hz, 1 H); 7.30 (td, J = 7.6, 1.2 Hz, 1 H); 7.19 (ddd, J = 11.4, 8.3, 1.2 Hz, 1 H); 4.37 (dd, J = 11.9, 4.7 Hz, 1 H); 4.04 (dd, J = 11.9, 8.9 Hz, 1 H); 3.62 (dd, J = 8.9, 4.8 Hz, 1 H); 2.97 (d, J = 4.2 Hz, 1 H); 2.29 (ddt, J = 12.6, 10.5, 4.2 Hz, 1 H); 2.15 (ddd, J = 12.8, 10.5, 3.9 Hz, 1 H); 1.65 (ddd, J = 12.8, 9.3, 4.1 Hz, 1 H); 1.30 (ddd, J = 12.6, 9.3, 4.0 Hz, 1 H); 1.12 (s, 3 H); 0.74 (s, 3 H). LCMS (m/z, Method A) ES+ 299.3 [M+1]+.

    Step 5: Trifluoro-methanesulfonic acid (1S,8S)-5-(2-fluoro-phenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-trien-1-ylmethyl ester



    [0495] Trifluoromethanesulphonic anhydride (282 mg, 1 mmol) was added to stirred solution of the product from Step 4 in pyridine (0.2 mL) and DCM (3 mL) at 0 °C for 30 minutes. The resulting solution was diluted with H2O and DCM and filtered through a phase separator. The filtrate was evaporated in vacuo and the residue purified by chromatography on silica (0-25% EtOAc in 40-60 petrol) to give the title compound as a colourless gum (124 mg). 1H NMR (300 MHz, CDCl3): δ 8.10 (td, J = 7.8, 1.9 Hz, 1 H); 7.72 (d, J = 2.5 Hz, 1 H); 7.44-7.46 (m, 1 H); 7.31 (td, J = 7.6, 1.2 Hz, 1 H); 7.19 (ddd, J = 11.5, 8.2, 1.2 Hz, 1 H); 5.30 (dd, J = 79.5, 11.0 Hz, 2 H); 3.02 (d, J = 4.1 Hz, 1 H); 2.39-2.41 (m, 2 H); 1.49-1.51 (m, 1 H); 1.32-1.35 (m, 1 H); 1.24-1.25 (m, 3 H); 0.78 (s, 3 H). LCMS (m/z, Method A) ES+ 431.1 [M+1]+.

    Step 6: (5S,8R)-3-(2-Fluorophenyl)-9,9-dimethyl-8-(1H-pyrazol-1-ylmethyl)-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0496] Sodium hydride (23 mg, 0.58 mmol, 60% dispersion in oil) was added to a stirred solution of imidazole (39 mg, 0.58 mmol) in anhydrous THF (3 mL) and stirred for 10 minutes. The resulting suspension was added to a solution of the product from Step 5 (124 mg, 0.29 mmol) in anhydrous THF (2 mL) and heated at 60 °C for 1.5 h. The mixture was cooled, diluted with EtOAc and H2O, the organic phase dried with Na2SO4, filtered, and evaporated in vacuo. The residue was purified by chromatography on silica (0-10% MeOH in DCM) and triturated with 1:1 diethyl ether/40-60 petrol to give the title compound as a white solid (54 mg). 1H NMR (400 MHz, CDCl3): δ 8.12 (td, J = 7.8, 1.8 Hz, 1 H); 7.77 (s, 1 H); 7.69 (d, J = 2.5 Hz, 1 H); 7.43-7.46 (m, 2 H); 7.32 (td, J = 7.6, 1.2 Hz, 1 H); 7.18-7.19 (m, 1 H); 7.03 (s, 1 H); 4.64-4.65 (m, 2 H); 2.97 (d, J = 4.2 Hz, 1 H); 2.24-2.26 (m, 1 H); 2.09-2.10 (m, 1 H); 1.27-1.29 (m, 2 H); 1.13 (s, 3 H); 0.53 (s, 3 H). LCMS (m/z, Method B) ES+ 349.2 [M+1]+.

    Example 5: (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(5-methyl-1,3,4-oxadiazol-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0497] 


    Step 1: 2-(2,6-Difluorophenyl)-2-oxoacetaldehyde



    [0498] A mixture of selenium dioxide (111 g, 1000 mmol) in dioxane/H2O (500 mL/20 mL) at 55 °C was stirred for 30 min and then added 1-(2,6-difluorophenyl)ethanone (156 g, 1000 mmol). The mixture was refluxed for 20 h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by fractional distillation collecting the fractions between 90 - 94 °C, under roughly 1 mm mercury, to afford the title compound as yellow oil (98.5 g, 58%). 1H NMR (500 MHz, DMSO-d6): δ 9.48 (t, J = 2.0 Hz, 1H), 7.79-7.76 (m, 1H), 7.33-7.29 (m, 2H); MS (ESI): [M+H]+ 171.

    Step 2: Methyl (1R)-3-[2-(2,6-difluorophenyl)-2-oxoethylidene]-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylate and (1R)-methyl 3-(2-(2,6-difluorophenyl)-1-hydroxy-2-oxoethyl)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylate



    [0499] A solution of (1R)-methyl 7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylate (19.6 g, 100 mmol) in anhydrous THF (100 mL) at -78 °C under nitrogen was added LDA (75 mL, 2 M in THF) dropwise. The mixture was stirred at -78 °C for 1 hour, and then 2-(2,6-difluorophenyl)-2-oxoacetaldehyde (20.4 g, 120 mmol) in THF (50 mL) was added. The mixture was stirred at -78 °C for 1 hour and allowed to warm to room temperature. The reaction mixture was quenched with 1 N aqueous HCl (100 mL) and concentrated under reduced pressure. The residue was extracted with EtOAc (100 mL × 3). The combined organic layers were concentrated under reduced pressure and the residue was purified by chromatography on silica (1: 30 EtOAc in petroleum ether) to afford the title compounds as yellow solids: methyl (1R)-3-[2-(2,6-difluorophenyl)-2-oxoethylidene]-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylate, (2.12 g, 6%), 1H NMR (500 MHz, DMSO-d6): δ 7.72-7.66 (m, 1H), 7.29-7.26 (m, 2H), 6.99 (s, 1H), 3.72 (s, 3H), 3.30-3.29 (m, 1H), 2.45-2.39 (m, 1H), 2.24-2.17 (m, 1H), 1.79-1.74 (m, 1H), 1.43-1.38 (m, 1H), 1.07 (s, 3 H), 1.03 (s, 3H); MS (ESI): [M+H]+ 349.1; (1R)-methyl 3-(2-(2,6-difluorophenyl)-1-hydroxy-2-oxoethyl)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylate, (5.51 g, 15%), 1H NMR (500 MHz, DMSO-d6): δ 7.65-7.58 (m, 1H), 7.24-7.20 (m, 2H), 6.27 (d, J=7.5 Hz, 1H), 4.63-4.60 (m, 1H), 3.66 (s, 3H), 2.28-2.23 (m, 1H), 2.04-1.97 (m, 2H), 1.87-1.81 (m, 1H), 1.51-1.46 (m, 1H), 1.89 (s, 3 H), 0.99 (s, 3H); MS (ESI): [M+H]+ 367.1.

    Step 3: Methyl (1R)-5-(2,6-fluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene-1-carboxylate



    [0500] A mixture of methyl (1R)-3-[2-(2,6-difluorophenyl)-2-oxoethylidene]-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylate (2.09 g, 6.0 mmol) and hydrazine hydrochloride (4.08 g, 60 mmol) in butan-1-ol (100 mL) was heated at 135 °C for 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in H2O (100 mL) and extracted with EtOAc (20 mL × 3). The combined organic fractions were concentrated under reduced pressure and the residue was purified by chromatography on silica (3:1 petroleum ether/EtOAc) to afford the title compound as yellow solid (1.78 g, 84%). MS (ESI): [M+H]+ 345.1.

    [0501] Following the procedure as described above and starting with (1R)-methyl 3-(2-(2,6-difluorophenyl)-1-hydroxy-2-oxoethyl)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylate (5.49 g, 15 mmol), the title compound was obtained as a yellow solid (4.39 g, 84%). MS (ESI): [M+H]+ 345.1.

    Step 4: (1R)-5-(2,6-Fluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene-1-carboxylic acid



    [0502] A mixture of the product from Step 3 (5.16 g, 15 mmol) and LiOH monohydrate (0.84 g, 63.5 mmol) in THF/H2O (50 mL/5 mL) was heated at 30 °C for 20 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in H2O (100 mL) and IN aqueous HCl added slowly until pH 3 was achieved. The mixture was extracted with EtOAc (20 mL × 3) and the combined organic fractions were concentrated under reduced pressure to afford the title compound as yellow solid (4.21 g, 85%). 1H NMR (500 MHz, DMSO-d6): δ 12.88 (s, 1H), 7.75 (s, 1H), 7.65-7.59 (m, 1H), 7.32-7.29 (m, 1H), 3.16-3.15 (m, 1H), 2.61-2.54 (m, 1H), 2.32-2.27 (m, 1H), 1.52-1.47 (m, 1H), 1.18-1.13 (m, overlap, 4H), 0.79 (s, 3H); MS (ESI): [M+H]+ 331.1.

    Step 5: (1R,8R)-5-(2,6-Difluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-triene-1-carboxylic acid N'-acetyl-hydrazide



    [0503] Oxalyl chloride (85 mg, 0.67 mmol) was added to a solution of the product from Step 4 and DMF (1 drop) in DCM (5 mL) and stirred for 30 minutes before being evaporated in vacuo and azeotroped with PhCH3. The residue was dissolved in DCM (5 mL) and acethydrazide (37 mg, 0.5 mmol) and Et3N (101 mg, 1 mmol) were added and the mixture stirred for 1 h. DCM and H2O were added and the mixture filtered through a phase separator and the filtrate evaporated in vacuo to give the title compound as a yellow oil (133 mg). LCMS (m/z, Method A) ES+ 387.2 [M+1]+.

    Step 6: (5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-8-(5-methyl-1,3,4-oxadiazol-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0504] A solution of the product from Step 5 (130 mg, 0.33 mmol) and POCl3 (178 mg, 1.33 mmol) in PhCH3 (4 mL) was stirred and heated at 85 °C for 18 h then cooled and evaporated in vacuo. The residue was dissolved in EtOAc and H2O and the organic phase dried over Na2SO4, filtered, and evaporated. Purification of the residue by chromatography on silica (20-100% EtOAc in cyclohexane) and trituration with 1:1 Et2O/cyclohexane gave the title compound as a white solid (43 mg). 1H NMR (400 MHz, CDCl3): δ 7.40-7.43 (m, 2 H); 7.05 (t, J = 7.9 Hz, 2 H); 3.17 (d, J = 4.2 Hz, 1 H); 2.94-2.99 (m, 1 H); 2.61 (s, 3 H); 2.46 (t, J = 11.4 Hz, 1 H); 1.96 (ddd, J = 13.2, 9.2, 4.2 Hz, 1 H); 1.37-1.43 (m, 1 H); 1.19 (s, 3 H); 0.93 (s, 3 H). LCMS (m/z, Method B) 369.2 [M+1]+.

    Example 6: Azetidin-1-yl[(5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methanone



    [0505] 


    Step 1: (1S,8S)-5-(2,6-Difluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-triene-1-carboxylic acid



    [0506] A solution of Jones reagent was prepared using CrO3 (2.67 g) in conc. H2SO4 (2.3 mL) and H2O (10 mL). Jones reagent (1.8 mL) was added to an ice-cold solution of [(5S,8S)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methanol (525 mg) in acetone (30 mL) and the reaction stirred for 1 h. MeOH (2 mL) was added and the reaction evaporated, the residue dissolved in H2O-EtOAc and made alkaline with 2 M aqueous KOH. The alkaline phase was separated and acidified with AcOH, extracted into EtOAc and filtered. The organic fitrate was dried over Na2SO4, filtered, evaporated and then azeotroped with PhCH3 to give the title compound as a pink solid (424 mg). 1H NMR (300 MHz, CDCl3): δ 7.47-7.50 (m, 2 H); 7.08 (t, J = 8.1 Hz, 2 H); 3.10 (d, J = 4.1 Hz, 1 H); 2.71-2.78 (m, 1 H); 2.50 (t, J = 11.3 Hz, 1 H); 1.76-1.83 (m, 1 H); 1.44 (s, 4 H); 0.80 (s, 3 H). LCMS (m/z, Method A) ES+ 331 [M+1]+.

    Step 2: Azetidin-1-yl[(5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methanone



    [0507] The product from Step 1 (36 mg) was combined with oxalyl chloride (1 mL) and DMF (1 drop) in DCM (5 ml) and stirred for 30 minutes at 23 °C before being evaporated in vacuo and azeotroped with PhCH3 to give (1S,8S)-5-(2,6-Difluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-triene-1-carbonyl chloride (not shown), which was dissolved in DCM (1 mL) and azetidine (30 µL) was added. After 18 h, the reaction was partitioned between H2O-EtOAc, the organic phase was dried over Na2SO4, and concentrated in vacuo. Purification by chromatography on silica (0 to 60% EtOAc in cyclohexane) and trituation with Et2O gave the title compound as a colourless solid (16 mg). 1H NMR (400 MHz, CDCl3): δ 7.40-7.41 (m, 2 H); 7.04 (t, J = 8.0 Hz, 2 H); 4.78-4.81 (m, 1 H); 4.38 (q, J = 7.9 Hz, 1 H); 4.23-4.27 (m, 1 H); 4.12-4.16 (m, 1 H); 2.93 (d, J = 4.2 Hz, 1 H); 2.58 (ddd, J = 12.6, 10.5, 4.0 Hz, 1 H); 2.28-2.34 (m, 3 H); 1.73-1.74 (m, 1 H); 1.27 (s, 4 H); 0.98 (s, 3 H). LCMS (m/z, Method B) ES+ 370 [M+1]+.

    Example 7: (5S,8S)-3-(2-Fluorophenyl)-8-(2-methoxyethyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0508] 


    Step 1: [(1S,8S)-5-(2-Fluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-trien-1-yl]-acetonitrile



    [0509] A mixture of trifluoro-methanesulfonic acid (1S,8S)-5-(2-fluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-trien-1-ylmethyl ester (717 mg, 1.66 mmol) and sodium cyanide (123 mg, 2.5 mmol) in CH3CN (10 mL) was stirred and heated at 80 °C for 20 h then cooled, diluted with EtOAc and H2O, the organic phase was dried with Na2SO4, filtered, and evaporated in vacuo. Purification by chromatography on silica (0-40% EtOAc in cyclohexane) gave the title compound as a yellow solid (448 mg). 1H NMR (400 MHz, CDCl3): δ 8.11 (td, J = 7.9, 1.8 Hz, 1 H); 7.70 (d, J = 2.5 Hz, 1 H); 7.45 (dddd, J = 8.3, 7.4, 5.1, 1.9 Hz, 1 H); 7.30 (td, J = 7.6, 1.2 Hz, 1 H); 7.19 (ddd, J = 11.5, 8.3, 1.2 Hz, 1 H); 3.42 (d, J = 17.7 Hz, 1 H); 3.03 (d, J = 4.2 Hz, 1 H); 2.87 (d, J = 17.7 Hz, 1 H); 2.46 (ddd, J = 12.4, 10.5, 3.7 Hz, 1 H); 2.35-2.36 (m, 1 H); 1.51-1.52 (m, 1 H); 1.34 (ddd, J = 12.5, 9.3, 3.7 Hz, 1 H); 1.28 (s, 3 H); 0.72 (s, 3 H). LCMS (m/z, Method A) ES+ 308.3 [M+1]+.

    Step 2: [(1S,8S)-5-(2-Fluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-trien-1-yl]-acetic acid



    [0510] The product from Step 1 (177 mg, 0.58 mmol) was dissolved in EtOH (8 mL) and 4 M aqueous KOH (8 mL) and heated at 90 °C for 26 h, and then left to stand at room temperature for 4 days, followed by evaporation in vacuo. The residue was dissolved in Et2O and H2O and the aqueous phase separated, acidified with AcOH and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered, evaporated in vacuo, and azeotroped with PhCH3 to give the title compound as a colourless gum (181 mg). 1H NMR (300 MHz, CDCl3: δ 8.05 (t, J = 7.7 Hz, 1 H); 7.84 (s, 1 H); 7.49-7.53 (m, 1 H); 7.34 (t, J = 7.4 Hz, 1 H); 7.18-7.21 (m, 1 H); 3.15 (d, J = 13.9 Hz, 1 H); 2.70 (d, J = 14.1 Hz, 1 H); 2.32-2.35 (m, 1 H); 2.10 (s, 2 H); 1.58 (t, J = 10.0 Hz, 1 H); 1.33-1.39 (m, 1 H); 1.14 (s, 3 H); 0.69 (s, 3 H). LCMS (m/z, Method A) ES+ 327.2 [M+1]+.

    Step 3: 2-[(1S,8S)-5-(2-Fluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-trien-1-yl]-ethanol



    [0511] 1 M THF:Borane complex solution (0.76 mL) was added to the product from Step 2 (124 mg, 0.38 mmol) in anhydrous THF at 0 °C and stirred for 2 h. The reaction was quenched by addition of H2O and EtOAc. The organic phase was dried over Na2SO4, filtered, evaporated in vacuo, and the residue dissolved in MeOH and stirred for 1 h before being evaporated in vacuo. The residue was purified by chromatography on silica (10-60% EtOAc in cyclohexane) to give the title compound as a colourless oil (51 mg). 1H NMR (300 MHz, CDCl3) δ 8.05 (t, J = 7.8 Hz, 1 H); 7.70 (s, 1 H); 7.42-7.47 (m, 1 H); 7.22-7.24 (m, 2 H); 4.02-4.15 (m, 2 H); 3.03 (d, J = 4.2 Hz, 1 H); 2.22-2.33 (m, 2 H); 1.95-2.04 (m, 1 H); 1.84 (d, J = 14.8 Hz, 1 H); 1.62 (t, J = 10.8 Hz, 1 H); 1.26-1.46 (m 1 H); 1.06 (s, 3 H); 0.67 (s, 3 H). LCMS (m/z, Method A) ES+ 313.2 [M+1]+.

    Step 4: (5S,8S)-3-(2-Fluorophenyl)-8-(2-methoxyethyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0512] Sodium hydride (10 mg, 0.25 mmol, 60% dispersion in oil) was added to a solution of the product from Step 3 (51 mg, 0.16 mmol) in anhydrous THF (3 mL) and stirred at room temperature for 10 minutes when iodomethane (48 mg, 0.33 mmol) was added. The mixture was stirred for an additional 2 h, heated at 55°C for 5 h, and then cooled to room temperature and diluted with EtOAc and H2O. The organic phase was dried over Na2SO4, filtered, evaporated in vacuo, and the residue purified by chromatography on silica (0-30% EtOAc in cyclohexane) and then (0-40% methyl tert-butyl ether in cyclohexane) to give the title compound as a white solid (33 mg). 1H NMR (400 MHz, CDCl3): δ 8.14 (td, J = 7.9, 1.9 Hz, 1 H); 7.64 (d, J = 2.6 Hz, 1 H); 7.42 (dddd, J = 8.2, 7.4, 5.1, 1.9 Hz, 1 H); 7.28-7.29 (m, 1 H); 7.17 (ddd, J = 11.5, 8.2, 1.2 Hz, 1 H); 4.28 (td, J = 9.2, 5.4 Hz, 1 H); 3.85 (td, J = 9.1, 6.1 Hz, 1 H); 3.43 (s, 3 H); 2.92 (d, J = 4.2 Hz, 1 H); 2.37-2.38 (m, 1 H); 2.23-2.24 (m, 1 H); 2.12 (ddd, J = 12.6, 10.5, 3.8 Hz, 1 H); 1.91 (ddd, J = 13.5, 9.3, 6.1 Hz, 1 H); 1.44 (ddd, J = 12.7, 9.2, 3.9 Hz, 1 H); 1.24-1.26 (m, 1 H); 1.08 (s, 3 H); 0.65 (s, 3 H). LCMS (m/z, Method B) ES+ 327.2 [M+1]+.

    Example 8: (5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-8-(1,2,4-oxadiazol-3-ylmethyl)-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0513] 


    Step 1: 2-[(1R,8R)-5-(2,6-Difluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-trien-1-yl]-1-methyl-ethylideneamine



    [0514] A solution of [(1R,8R)-5-(2,6-difluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2,4,6-trien-1-yl]-acetonitrile (625 mg, 1.92 mmol) and 50% aqueous hydroxylamine (0.4 mL, 6 mmol) in EtOH (15 mL) was stirred at 80 °C for 7 h, left to cool overnight, and then evaporated in vacuo. The residue was dissolved in EtOAc and H2O, the organic phase was dried with Na2SO4, filtered, and evaporated to give the title compound as yellow foam (681 mg). 1H NMR (300 MHz, CDCl3): δ 7.24-7.25 (m, 2 H); 6.89 (t, J = 8.0 Hz, 2 H); 2.85 (d, J = 3.9 Hz, 1 H); 2.76 (d, J = 14.3 Hz, 1 H); 2.24 (d, J = 14.3 Hz, 1 H); 2.06-2.09 (m, 2 H); 1.29-1.31 (m, 1 H); 1.09 (t, J = 7.1 Hz, 1 H); 0.96 (s, 3 H); 0.49 (s, 3 H). LCMS (m/z, Method A) ES+ 359.2 [M+1]+.

    Step 2: (5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-8-(1,2,4-oxadiazol-3-ylmethyl)-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0515] The product from Step 1 (179mg, 0.5 mmol) and pyridinium p-toluenesulphonate (10 mg, 0.04 mmol) was dissolved in triethyl orthoformate (3 mL) and heated at 110 °C for 2 h, and then cooled and evaporated in vacuo. The residue was purified by chromatography on silica (0-40% EtOAc in DCM) followed by trituration with 1:1 Et2O/cyclohexane to give the title compound as a white solid (79 mg). 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1 H); 7.39 (tt, J = 8.4, 6.3 Hz, 1 H); 7.34 (t, J = 1.4 Hz, 1 H); 7.03 (t, J = 8.0 Hz, 2 H); 3.61 (dd, J = 182.4, 15.3 Hz, 2 H); 2.94 (d, J = 4. 3 Hz, 1 H); 2.48 (ddd, J = 13.0, 10.5, 4.0 Hz, 1 H); 2.24 (ddt, J = 12.7, 10.5, 4.3 Hz, 1 H); 1.66 (ddd, J = 13.0, 9.3, 4.2 Hz, 1 H); 1.28-1.29 (m, 1 H); 0.93 (s, 3 H); 0.76 (s, 3 H). LCMS (m/z, Method B) ES+ 369.3 [M+1]+.

    Example 9: 3'-(2-Fluorophenyl)-8'-(methoxymethyl)-5',6',7',8'-tetrahydrospiro[cyclopropane-1,9'-[1,2]diaza[5,8]methanocinnoline]



    [0516] 


    Step 1: 1-(Methoxymethyl)spiro[bicyclo[2.2.1]heptane-7,1'-cyclopropan]-2-one



    [0517] A solution of 1-(hydroxymethyl)spiro[bicyclo[2.2.1]heptane-7,1'-cyclopropan]-2-one (1.0 g, 6.02 mmol; J. Org. Chem. 2002, 67, 3682) in dry THF (10 mL) at 0 °C was treated with NaH (301 mg, 7.53 mmol, 60% dispersion in oil) and stirred for 20 minutes at 0 °C. Iodomethane (562 µL, 9.03 mmol) was added and after 1 hour the reaction was quenched with a sat. aqueous NH4Cl solution and extracted with EtOAc. The combined organic extracts were washed with H2O, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica (0-20% EtOAc in cyclohexane) to afford the title compound as a colourless oil (794 mg). 1H NMR (300 MHz, CDCl3) δ 3.38 (s, 2H), 3.27 (s, 3H), 2.44-2.34 (m, 1H), 2.10-2.02 (m, 1H), 2.01-1.95 (m, 1H), 1.88-1.83 (m, 1H), 1.56-1.44 (m, 3H), 0.77-0.72 (m, 2H), 0.56-0.40 (m, 2H). LCMS (m/z, Method A) ES+ 181.2 [M+1]+.

    Step 2: Diethyl [4-(methoxymethyl)-3-oxospiro[bicyclo[2.2.1]heptane-7,1'-cyclopropan]-2-yl]phosphonate



    [0518] The product from Step 1 (220 mg, 1.22 mmol) was dissolved in dry THF (2.5 mL) at -78 °C under a nitrogen atmosphere and was treated with LDA (671 µL, 1.34 mmol, 2 M solution in THF/ heptane/ ethyl benzene) and stirred for 45 minutes. Diethyl chlorophosphate (194 µL, 1.34 mmol) was added and the mixture stirred at 0 °C for 1 hour, and then re-cooled to -78 °C and treated with a further portion of LDA (1.34 mL, 2.68 mmol, 2 M solution in THF/ heptane/ ethyl benzene). The reaction was stirred at ambient temperature for 1 hour, and then quenched with a sat. aqueous NH4Cl solution and extracted with EtOAc (2x). The combined organic extracts were washed with H2O, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica (0-100% EtOAc in cyclohexane) to yield the title compound as a pale yellow oil (271 mg). 1H NMR (300 MHz, CDCl3) δ 4.33-4.07 (m, 4H), 3.47-3.32 (m, 2H), 3.28-3.25 (m, 3H), 3.02 (dd, J = 24.4, 4.3 Hz, 0.75H), 2.70 (d, J = 26.1 Hz, 0.25H), 2.39-1.83 (m, 3H), 1.65-1.47 (m, 2H), 1.38-1.30 (m, 6H), 0.84-0.76 (m, 2H), 0.55-0.50 (m, 2H). LCMS (m/z, Method A) ES+ 317.2 [M+1]+.

    Step 3: Ethyl-2-[4-(methoxymethyl)-3-oxospiro[bicyclo[2.2.1]heptane-7,1'-cyclopropan]-2-ylidene]acetate



    [0519] A solution of the product from Step 2 (100 mg, 316 µmol) in dry THF (2.5 mL) at -78 °C under a nitrogen atmosphere was treated with n-butyllithium (2.5 M solution in hexanes, 140 µL, 348 µmol) and stirred cold for 1 hour. Ethyl glyoxalate (69 µL, 0.348 µmol, -50% solution in toluene) was added and after 15 minutes the mixture was allowed to warm to ambient temperature, stirred for 2 hours, and then quenched with a sat. aqueous NH4Cl solution and extracted with EtOAc. The combined organic extracts were washed with H2O, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica (0-20% EtOAc in cyclohexane) to yield the title compound as a pale yellow oil (66 mg). 1H NMR (300 MHz, CDCl3) δ 6.37 (d, J = 1.0 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.44 (dd, J = 18.0, 10.5 Hz, 2H), 3.22-3.28 (m, 4H), 2.23-2.01 (m, 2H), 1.69-1.48 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H), 0.86-0.78 (m, 1H), 0.74-0.66 (m, 1H), 0.58-0.44 (m, 2H). LCMS (m/z, Method A) ES+265.2 [M+1]+.

    Step 4: 8'-(Methoxymethyl)-5',6',7',8'-tetrahydrospiro[cyclopropane-1,9'-[1,2]diaza[5,8]methanocinnolin]-3'-ol



    [0520] A mixture of the product from Step 3 (105 mg, 397 µmol) and hydrazine hydrate (228 µL, 3.97 mmol) in AcOH (250 µL) and EtOH (IMS grade, 2.5 mL) was heated at reflux in a sealed tube for 18 hours. The cooled mixture was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the product as colourless residue which was used without purification in the next step (87 mg). LCMS (m/z, Method A) ES+233.2 [M+1]+.

    Step 5: 3'-Chloro-8'-(methoxymethyl)-5',6',7',8'-tetrahydrospiro[cyclopropane-1,9'-[1,2]diaza[5,8]methanocinnoline]



    [0521] A mixture of crude product from Step 4 (85 mg, 366 µmol) and POCl3 (341 µL, 3.66 mmol) in PhCH3 (3 mL) was heated at 80 °C for 2 hours. The cooled mixture was diluted with EtOAc, washed with a sat. aqueous NaHCO3, H2O, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica (0-50% EtOAc in cyclohexane) to yield the title compound as a pale yellow residue (34 mg). 1H NMR (300 MHz, CDCl3) δ 7.20 (s, 1H), 3.92 (dd, J = 59.8, 10.6 Hz, 2H), 3.39 (s, 3H), 2.71 (d, J = 3.8 Hz, 1H), 2.37-2.22 (m, 2H), 1.44-1.33 (m, 2H), 0.95-0.87 (m, 1H), 0.75-0.66 (m, 1H), 0.52-0.39 (m, 2H). LCMS (m/z, Method A) ES+251.2 [M+1]+.

    Step 6: 3'-(2-Fluorophenyl)-8'-(methoxymethyl)-5',6',7',8'-tetrahydrospiro[cyclopropane-1,9'-[1,2]diaza[5,8]methanocinnoline]



    [0522] A mixture of the product from Step 5 (50 mg, 200 µmol), 2-fluorophenyl boronic acid (84 mg, 600 µmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 20.0 µmol) and K2CO3 (300 µL, 600 µmol, 2 M aqueous solution) in PhCH3 (2 mL) and EtOH (IMS grade, 2 mL) was degassed, purged with nitrogen and heated at 80 °C for 1 hour. The cooled mixture was partitioned between 1 M aqeous NaOH and EtOAc. The organic phase was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (0-40% EtOAc in cyclohexane) followed by trituration with pentane afforded the title compound as an off-white solid (34 mg). 1H NMR (400 MHz, CDCl3) δ 8.11 (td, J = 7.9, 1.9 Hz, 1H), 7.65 (d, J = 2.6 Hz, 1H), 7.45-7.39 (m, 1H), 7.30-7.26 (m, 1H), 7.20-7.13 (m, 1H), 4.00 (dd, J = 72.6, 10.5 Hz, 2H), 3.43 (s, 3H), 2.77 (d, J = 3.8 Hz, 1H), 2.37-2.24 (m, 2H), 1.49-1.38 (m, 2H), 0.94-0.88 (m, 1H), 0.77-0.71 (m, 1H), 0.53-0.44 (m, 2H). LCMS (m/z, Method B) ES+ 311.1 [M+1]+

    Example 10: (5S,7S,8R)-3-(2-Fluorophenyl)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-7-yl acetate



    [0523] 


    Step 1: Acetic acid (1S,2S,4S)-1,7,7-trimethyl-5,6-dioxo-bicyclo[2.2.1]hept-2-yl ester



    [0524] A mixture of (1S,2S,4S)-1,7,7-trimethyl-5-oxo-bicyclo[2.2.1]hept-2-yl ester (12.04 g, 57.33 mmol; Can. J. Chem. 1979, 733) was dissolved in 1,4-dioxane (90 mL) and H2O (9 mL) and selenium dioxide (19.09 g, 172 mmol) was added. The resulting mixture was stirred and heated at 105 °C for 48 h then cooled to ambient temperature and evaporated in vacuo. The residue was dissolved in EtOAc/H2O and the organic fraction was dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by chromatography on silica (0-100% DCM in cyclohexane) then rechromatographed (0-25% EtOAc in cyclohexane) to give the title compound as an orange solid (3.31 g). 1H NMR (300 MHz, CDCl3): δ 4.86 (dd, J = 7.3, 4.7 Hz, 1 H); 2.85 (dd, J = 4.6, 1.4 Hz, 1 H); 2.30-2.31 (m, 2 H); 2.10 (s, 3 H); 1.26 (s, 3 H); 1.10 (s, 3 H); 0.94 (s, 3 H).

    Step 2: Acetic acid (1S,2S,4S)-5-[2-(2-Fluoro-phenyl)-2-oxo-ethylidene]-1,7,7-trimethyl-6-oxo-bicyclo[2.2.1]hept-2-yl ester



    [0525] Potassium tert-butoxide (2.93 g, 26.16 mmol) was added to a solution of [2-(2-fluoro-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester (6.43 g, 26.16 mmol) in tert-butanol (120 mL) and stirred at room temperature for 30 minutes. The product from Step 1 was added and the mixture heated at 90 °C for 2 h, and then cooled to ambient temperature and evaporated in vacuo. The residue was dissolved in EtOAc/H2O and the organic layers was dried over Na2SO4, filtered, and evaporated in vacuo. Purification by chromatography on silica (0-20% EtOAc in 40-60 petrol) gave the title compound as yellow oil (4.19 g). LCMS (m/z, Method A) ES+ 345.3 [M+1]+.

    Step 3: (5S,7S,8R)-3-(2-Fluorophenyl)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-7-yl acetate



    [0526] A mixture of the product from Step 2 (4.18 g, 12.15 mmol), hydrazine hydrate (10 mL), AcOH (20 mL), EtOH (90 mL) and H2O (15 mL) was stirred and heated at 90°C for 41 h, and then cooled to ambient temperature and evaporated in vacuo. The residue was dissolved in EtOAc/H2O and the organic layer was dried over Na2SO4, filtered, and evaporated in vacuo. Purification by chromatography on silica (firstly 0-20% EtOAc in DCM and then 0-40% EtOAc in 40-60 petrol) gave title compound as a colourless gum which crystallised on standing (1.17 g). 1H NMR (400 MHz, CDCl3) δ 8.11 (td, J = 7.9, 1.9 Hz, 1 H); 7.62 (d, J = 2.5 Hz, 1 H); 7.43 (dddd, J = 8.3, 7.4, 5.1, 1.9 Hz, 1 H); 7.29 (td, J = 7.6, 1.2 Hz, 1 H); 7.17 (ddd, J = 11.5, 8.2, 1.2 Hz, 1 H); 4.76 (dd, J = 7.7, 3.6 Hz, 1 H); 3.06 (d, J = 4.1 Hz, 1 H); 2.19 (dt, J = 13.8, 3.9 Hz, 1 H); 2.12 (s, 3 H); 2.05-2.06 (m, 1 H); 1.49 (s, 3 H); 1.29 (s, 3 H); 0.68 (s, 3 H). LCMS (m/z, Method B) ES+ 341.3 [M+1]+

    Example 11: (5R,8R)-9-(Bromomethyl)-3-(2-fluorophenyl)-8,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0527] 



    [0528] (1R,4R)-7-Bromomethyl-1,7-dimethyl-bicyclo[2.2.1]heptan-2-one (T. Money, Natural Product Reports 1985, 253) was reacted in a similar manner to that described in Example 1 to give the title compound. 1H NMR (400 MHz, CDCl3): δ 8.12 (td, J = 7.9, 1.9 Hz, 1 H); 7.68 (d, J = 2.5 Hz, 1 H); 7.42-7.43 (m, 1 H); 7.29 (td, J = 7.6, 1.2 Hz, 1 H); 7.18 (ddd, J = 11.5, 8.2, 1.2 Hz, 1 H); 3.67-3.69 (m, 1 H); 3.35 (t, J = 2.1 Hz, 2 H); 2.21-2.22 (m, 1 H); 2.05-2.06 (m, 1 H); 1.54 (d, J = 3.1 Hz, 3 H); 1.47-1.48 (m, 1 H); 1.33 (ddd, J = 12.9, 9.4, 3.7 Hz, 1 H); 0.81 (s, 3 H). LCMS (m/z, Method B) ES+362 [M+1]+.

    Example 12: [(5R,8R)-3-(2-Fluorophenyl)-8,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-9-yl]methyl acetate



    [0529] 



    [0530] A solution of (5R,8R)-9-(bromomethyl)-3-(2-fluorophenyl)-8,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline (200 mg) in anhydrous DMF (0.75 mL) was added to a mixture of cesium acetate (0.12 g) in anhydrous DMF (0.75 mL) and the reaction heated at 110 °C for 20h. The reaction was cooled to ambient temperature and partitioned between H2O-EtOAc, the organic fraction was washed with H2O, brine, dried over MgSO4, filtered, and evaporated. Purification by chromatography on silica (0 to 40% EtOAc in cyclohexanes) gave the title compound as a gum (50 mg). 1H NMR (400 MHz, CDCl3): δ 8.13 (td, J = 7.9, 1.9 Hz, 1 H); 7.66 (d, J = 2.6 Hz, 1 H); 7.42-7.43 (m, 1 H); 7.29 (td, J = 7.6, 1.2 Hz, 1 H); 7.18 (ddd, J = 11.5, 8.2, 1.2 Hz, 1 H); 4.26 (d, J = 11.3 Hz, 1 H); 4.07 (d, J = 11.3 Hz, 1 H); 3.23 (d, J = 4.2 Hz, 1 H); 2.24-2.25 (m, 1 H); 2.13 (s, 3 H); 2.06-2.07 (m, 1 H); 1.55 (s, 3 H); 1.47-1.48 (m, 1 H); 1.29-1.30 (m, 1 H); 0.72 (s, 3 H). LCMS (m/z, Method B) ES+341 [M+1]+.

    Example 13: (1R,8S,10R)-5-(2-Fluoro-phenyl)-1,11,11-trimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2,4,6-triene-10-carboxylic acid amide



    [0531] 


    Steps 1 and 2: (1R,2R,4S)-1,7,7-Trimethyl-bicyclo[2.2.1]heptane-2-carboxylic acid



    [0532] α-Pinene was converted to (1R,2R,4S)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2-carboxylic acid following a similar protocol to the two step synthesis outlined in Synlett 1992, 12, 992.

    Step 3: (1R,2R,4S)-1,7,7-Trimethyl-bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester



    [0533] A mixture of the product from Step 1 (16.4 g, 90.0 mmol) and concentrated H2SO4 (12 mL) in MeOH (120 mL) was heated at reflux for 24 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was taken up in EtOAc, washed with a sat. aqueous NaHCO3, H2O, brine, dried over Na2SO4, and concentrated in vacuo to give the title compound as a pale yellow oil (14.4 g). 1H NMR (300 MHz, CDCl3) δ 3.68 (s, 3H), 2.66 (dd, J = 11.2, 4.9 Hz, 1H), 1.95-1.84 (m, 1H), 1.76-1.64 (m, 3H), 1.40-1.26 (m, 3H), 0.98 (s, 3H), 0.88 (s, 3H), 0.88 (s, 3H).

    Step 4: (1R,2R,4S)-1,7,7-Trimethyl-5-oxo-bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester



    [0534] The product from Step 3 (4.75 g, 24.2 mmol) was dissolved in AcOH (50 mL) and treated protion-wise with CrO3 (7.26 g, 72.6 mmol), and then heated at 75 °C for 18 hours. A further portion of CrO3 (2.42 g, 24.2 mmol) was added and heating continued for 24 hours. The cooled mixture was left to stand at ambient temperature for 3 days, poured onto H2O, and extracted with EtOAc. The combined organic extracts were washed with H2O (2x), sat. aqueous NaHCO3, brine, dried over Na2SO4, and concentrated in vacuo. Purification by chromatography on silica (0-35% EtOAc in cyclohexane) gave the title compound as a colourless oil (1.51 g). 1H NMR (300 MHz, CDCl3) δ 3.71 (s, 3H), 2.94-2.86 (m, 1H), 2.25-1.90 (m, 5H), 1.15 (s, 3H), 1.01 (s, 3H), 0.96 (s, 3H). LCMS (m/z, Method A) ES+211.2 [M+1]+.

    Step 5: (1R,2R,4S)-1,7,7-Trimethyl-5,6-dioxo-bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester



    [0535] A mixture of the product from Step 4 and selenium dioxide (1.57 g, 14.27 mmol) in bromobenzene (10 mL) was heated at reflux for 18 hours. The mixture was cooled to ambient temperature, filtered through Celite® washing with EtOAc, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica (0-40% EtOAc in cyclohexane) to give the title compound as a bright yellow solid (1.30 g). 1H NMR (300 MHz, CDCl3) δ 3.65 (s, 3H), 3.02 (dd, J = 11.3, 4.8 Hz, 1H), 2.69 (d, J = 5.3 Hz, 1H), 2.47 (m, 1H), 2.08 (dd, J = 14.2, 4.8 Hz, 1H), 1.17 (s, 3H), 1.11 (s, 3H), 0.93 (s, 3H). LCMS (m/z, Method A) ES+247.2 [M+Na]+.

    Step 6: (1R,2R,4S)-5-[2-(2-Fluoro-phenyl)-2-oxo-eth-(Z)-ylidene]-1,7,7-trimethyl-6-oxo-bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester



    [0536] A solution of [2-(2-fluoro-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester (252 mg, 1.03 mmol) in tert-butanol (2 mL) was treated with potassium tert-butoxide (1.03 mL, 1.03 mmol, 1 M solution in tert-butanol) and stirred at ambient temperature for 20 minutes. The product from Step 5 (115 mg, 513 µmol) was added in one portion and the mixture heated at reflux for 3 hours. The mixture was cooled to ambient temperature and diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica (0-35% EtOAc in cyclohexane) to give the title compound as a yellow solid (141 mg). 1H NMR (300 MHz, CDCl3) δ 7.82 (td, J = 7.6, 1.9 Hz, 1H), 7.58-7.49 (m, 1H), 7.37 (d, J = 3.8 Hz, 1H), 7.28-7.22 (m, 1H), 7.15 (dd, J = 10.9, 8.3 Hz, 1H), 3.63 (m, 4H), 2.92 (dd, J = 11.1, 4.6 Hz, 1H), 2.54-2.43 (m, 1H), 1.97 (dd, J = 13.3, 4.6 Hz, 1H), 1.12 (m, 3H), 1.06 (s, 3H), 0.83 (s, 3H). LCMS (m/z, Method A) ES+ 345.2 [M+1]+.

    Step 7: (1R,2R,4S)-5-[2-(2-Fluoro-phenyl)-2-hydrazono-eth-(Z)-ylidene]-1,7,7-trimethyl-6-oxo-bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester



    [0537] A solution of the product from Step 6 (1.02 g, 2.96 mmol), AcOH (420 µL, 7.40 mmol) and hydrazine hydrate (424 µL, 7.40 mmol) in MeOH (25 mL) was stirred at ambient temperature for 18 hours. The mixture was concentrated to low volume in vacuo and partitioned between EtOAc and H2O. The organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica (0-60% EtOAc in cyclohexane) to give the title compound as a yellow residue (835 mg). 1H NMR (300 MHz, CDCl3) δ 7.50-7.43 (m, 1H), 7.37-7.01 (m, 4H), 5.90 (br s, 2H), 3.68-3.60 (m, 3H), 2.85-2.71 (m, 1H), 2.27-1.74 (m, 3H), 1.09-1.02 (m, 3H), 0.91-0.70 (m, 6H). LCMS (m/z, Method A) ES+ 359.3 [M+1]+.

    Step 8: (1R,8S,10R)-5-(2-Fluoro-phenyl)-1,11,11-trimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2,4,6-triene-10-carboxylic acid methyl ester



    [0538] A solution of the product from Step 7 (900 mg, 2.51 mmol) in xylene (10 mL) was heated at reflux using a Dean-Stark apparatus for 4 days. The cooled mixture was concentrated in vacuo and purified by chromatography on silica (0-75% EtOAc in cyclohexane) to afford the title compound as a pale orange foam (496 mg). 1H NMR (300 MHz, CDCl3) δ 8.17 (td, J = 7.9, 1.9 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.46-7.37 (m, 1H), 7.30-7.24 (m, 1H), 7.21-7.12 (m, 1H), 3.52 (s, 3H), 3.15 (dd, J = 9.9, 4.3 Hz, 1H), 3.03 (d, J = 4.3 Hz, 1H), 2.50-2.39 (m, 1H), 1.78 (dd, J = 13.0, 4.3 Hz, 1H), 1.60 (s, 3H), 1.12 (s, 3H), 0.63 (s, 3H). LCMS (m/z, Method A) ES+ 341.2 [M+1]+.

    Step 9: (1R,8S,10R)-5-(2-Fluoro-phenyl)-1,11,11-trimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2,4,6-triene-10-carboxylic acid



    [0539] A solution of the product from Step 8 (50 mg, 147µmmol) in MeOH (5 mL) was treated with 1 M aqueous NaOH (441 µL, 441 µmol) and heated at 50 °C for 5 hours. The mixture was cooled to ambient temperature and concentrated to low volume in vacuo, followed by dilution with H2O. The solution was washed with EtOAc, acidified to pH 1-2 using 1 M aqueous HCl, and extracted into EtOAc (2x). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica (0-10% MeOH in DCM) followed by trituration with Et2O/ pentane to afford the title compound as a pale yellow solid (32 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 8.08 (td, J = 7.9, 1.8 Hz, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.36 (m, 1H), 7.20 (td, J = 7.6, 1.2 Hz, 1H), 7.11 (m, 1H), 3.24 (dd, J = 9.8, 4.4 Hz, 1H), 3.03 (d, J = 4.3 Hz, 1H), 2.49-2.40 (m, 1H), 1.81 (dd, J = 13.0, 4.4 Hz, 1H), 1.73 (s, 3H), 1.15 (s, 3H), 0.64 (s, 3H). LCMS (m/z, Method A) ES+ 327.2 [M+1]+.

    Step 10 (1R,8S,10R)-5-(2-Fluoro-phenyl)-1,11,11-trimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2,4,6-triene-10-carbonyl chloride



    [0540] A solution of the product from Step 9 (340 mg, 1.04 mmol) in DCM (5 mL) was treated with oxalyl chloride (661 mg, 5.21 mmol), followed by DMF (1 drop), and stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo to give the title compound which was used immediately.

    Step 11 (1R,8S,10R)-5-(2-Fluoro-phenyl)-1,11,11-trimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2,4,6-triene-10-carboxylic acid amide



    [0541] A solution of the product from Step 10 (240 mg, 696 µmol) in CH3CN (5 mL) was treated dropwise with ammonium hydroxide (1 mL) and stirred at ambient temperature for 30 minutes. The mixture was concentrated in vacuo, dissolved in DCM, washed with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica (0-10% MeOH in DCM) followed by trituration with Et2O to afford the title compound as a pale yellow solid (218 mg). 1H NMR (400 MHz, CDCl3) δ 8.16 (td, J = 7.9, 1.8 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.46-7.39 (m, 1H), 7.31-7.25 (m, 1H), 7.20-7.13 (m,1H), 5.63 (br s, 1H), 5.26 (br s, 1H), 3.10-3.02 (m, 2H), 2.62-2.53 (m, 1H) 1.70 (dd, J = 13.1, 4.7 Hz, 1H), 1.62 (s, 3H), 1.14 (s, 3H), 0.64 (s, 3H). LCMS (m/z, Method A) ES+ 326.1 [M+1]+.

    Example 14: (5S,8R)-3-(2-Fluorophenyl)-9,9-dimethyl-8-(1H-pyrazol-1-ylmethyl)-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0542] 


    Step 1: [(1R,8S)-5-(2-Fluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-trien-1-yl]-carbamic acid tert-butyl ester



    [0543] A mixture of (1R,8R)-5-(2-fluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2,4,6-triene-1-carboxylic acid (1.94 g, 5.88 mmol), diphenylphosphoryl azide (1.89 g, 6.85 mmol) and Et3N (773 mg, 7.65 mmol) in tert-butanol (30 mL) was stirred and heated at 85 °C for 18 h then cooled to ambient temperature and evaporated in vacuo. The residue was purified by chromatography on silica (0-100% EtOAc in cyclohexane) to give the title compound as a light coloured foam (950 mg). 1H NMR (300 MHz, CDCl3): δ 8.09 (td, J = 7.8, 1.9 Hz, 1 H); 7.67 (d, J = 2.6 Hz, 1 H); 7.42-7.46 (m, 1 H); 7.31 (td, J = 7.6, 1.2 Hz, 1 H); 7.19 (dd, J = 11.5, 8.2 Hz, 1 H); 5.88 (s, 1 H); 2.92 (d, J = 4.4 Hz, 1 H); 2.33-2.40 (m, 1 H); 2.05 (s, 1 H); 1.50 (s, 9 H); 1.43 (s, 1 H); 1.27-1.30 (m, 4 H); 0.63 (s, 3 H). LCMS (m/z, Method A) ES+ 384.3 [M+1]+.

    Step 2: (1R,8S)-5-(2-Fluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-trien-1-ylamine



    [0544] The product from Step 1 was dissolved 4 M HCl in dioxane (10 mL) and stirred at room temperature for 30 minutes, and then evaporated in vacuo. The residue was partitioned between EtOAc and aqueous K2CO3 solution. The organic fraction was dried over Na2SO4, filtered, and evaporated in vacuo to give the title compound as a pale yellow solid (671 mg). 1H NMR (400 MHz, CDCl3): δ 8.10 (td, J = 7.8, 1.9 Hz, 1 H); 7.63 (d, J = 2.6 Hz, 1 H); 7.43 (dddd, J = 8.2, 7.4, 5.1, 1.9 Hz, 1 H); 7.29 (td, J = 7.6, 1.2 Hz, 1 H); 7.18 (ddd, J = 11.4, 8.2, 1.2 Hz, 1 H); 2.97 (d, J = 4.4 Hz, 1 H); 2.29 (ddt, J = 12.7, 10.7, 4.2 Hz, 1 H); 2.11 (ddd, J = 12.3, 10.6, 4.1 Hz, 1H); 1.87 (s, 2 H); 1.55 (ddd, J = 12.7, 9.3, 4.1 Hz, 1 H); 1.29 (ddd, J = 12.7, 9.3, 4.1 Hz, 1 H); 1.14 (s, 3 H); 0.61 (s, 3 H). LCMS (m/z, Method A) ES+ 284.2 [M+1]+.

    Step 3: (5S,8R)-3-(2-fluorophenyl)-9,9-dimethyl-8-(1H-pyrazol-1-ylmethyl)-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0545] A 40% aqueous glyoxal solution (0.142 mL, 1.24 mmol) was added to a solution of the product from Step 2 (142 mg, 0.5 mmol) in MeOH (2.5 mL), followed by a 37% aqueous formaldehyde solution (0.082 mL, 1.1 mmol) and ammonium acetate (77 mg, 1 mmol). The mixture was stirred at reflux for 19 h. The resulting solution was cooled to ambient temperature, diluted with EtOAc and H2O, and the organic phase was dried over Na2SO4, filtered, and evaporated in vacuo. Purification of the residue by chromatography on silica (0-8% MeOH in DCM) and trituration with Et2O gave the title compound as a white solid (129 mg). 1H NMR (400 MHz, CDCl3): δ 8.17 (td, J = 7.9, 1.8 Hz, 1 H); 8.00 (t, J = 1.1 Hz, 1 H); 7.81 (d, J = 2.4 Hz, 1 H); 7.47 (dddd, J = 8.3, 7.4, 5.1, 1.9 Hz, 1 H); 7.32-7.33 (m, 2 H); 7.20-7.21 (m, 2 H); 3.17 (d, J = 4.3 Hz, 1 H); 2.92 (ddd, J = 12.5, 10.7, 4.1 Hz, 1 H); 2.50 (ddt, J = 12.9, 10.7, 4.3 Hz, 1 H); 1.96 (ddd, J = 12.5, 9.3, 4.1 Hz, 1 H); 1.45 (ddd, J = 12.9, 9.3, 4.1 Hz, 1 H); 1.14 (s, 3 H); 0.75 (s, 3 H). LCMS (m/z, Method B) ES+ 335.2 [M+1]+.

    Example 15: (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(1,3-oxazol-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0546] 


    Step 1: (1R,8R)-5-(2,6-Difluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-triene-1-carboxylic acid (2,2-dimethoxy-ethyl)-amide



    [0547] Oxalyl chloride (189 mg, 1.5 mmol) was added to a solution of (1R,8R)-5-(2-fluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2,4,6-triene-1-carboxylic acid (220 mg, 0.67 mmol) and DMF (1 drop) in DCM (5 mL) and stirred at room temperature for 30 minutes. The reaction was evaporated in vacuo and azeotroped with toluene. The residue was dissolved in DCM (5 mL) and aminoacetaldehyde dimethyl acetal (84 mg, 0.8 mmol) and Et3N (202 mg, 2 mmol) were added and stirred for 1 h. The resulting solution was diluted with DCM and H2O, filtered through a phase separator, and the filtrate evaporated in vacuo. Purification by chromatography on silica (0-50% EtOAc in cyclohexane) gave the title compound as a gum which crystallised on standing (256 mg). 1H NMR (300 MHz, CDCl3): δ 9.25 (s, 1 H); 7.42-7.46 (m, 2 H); 7.06 (t, J = 8.0 Hz, 2 H); 4.56 (t, J = 5.6 Hz, 1 H); 3.59-3.62 (m, 1 H); 3.41 (d, J = 6.8 Hz, 6 H); 2.99 (d, J = 4.1 Hz, 1 H); 2.83 (ddd, J = 12.7, 10.6, 4.1 Hz, 1 H); 2.41-2.47 (m, 1 H); 1.57-1.61 (m, 2 H); 1.41 (s, 3 H); 1.26-1.28 (m, 1 H); 0.75 (s, 3 H). LCMS (m/z, Method A) ES+ 418.2 [M+1]+.

    Step 2: (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(1,3-oxazol-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0548] Phosphorus pentoxide (341 mg, 2.4 mmol) was added to a mixture of the product from Step 1 and methanesulphonic acid (3.4 ml) and stirred at 130 °C under nitrogen atmosphere. The resulting mixture was cooled to ambient temperature, diluted with EtOAc and H2O, and made alkaline with an aqueous KOH solution. The organic fraction was dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by chromatography on silica (0-80% EtOAc in cyclohexane). The product was dissolved in 1:1 Et2O/cyclohexane and left to crystallise then filtered off, dissolved in DCM, evaporated in vacuo and the residue dissolved in Et2O and left to crystallise. The solid was filtered off to give the title compound as an off-white solid (46 mg). 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 0.8 Hz, 1 H); 7.39-7.40 (m, 2 H); 7.22 (d, J = 0.8 Hz, 1 H); 7.03 (t, J = 7.9 Hz, 2 H); 3.13 (d, J = 4.2 Hz, 1 H); 2.98 (ddd, J = 13.1, 10.6, 4.2 Hz, 1 H); 2.43 (ddt, J = 12.7, 10.6, 4.3 Hz, 1 H); 1.93 (ddd, J = 13.1, 9.3, 4.2 Hz, 1 H); 1.38 (ddd, J = 12.7, 9.3, 4.2 Hz, 1 H); 1.14 (s, 3 H); 0.93 (s, 3 H). LCMS (m/z, Method B) ES+ 354.3 [M+1]+.

    Example 16: (5S,8R)-3-(2-fluorophenyl)-4,8,9,9-tetramethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0549] 


    Step 1: 2-Hydroxy-2-((1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]hept-2-yl)-propionic acid ethyl ester



    [0550] To a solution of LDA at -78 °C, prepared by standard procedure under N2 atmosphere [diisopropylamine (2.65 mL, 18.9 mmol), n-BuLi (7.56 mL, 2.5M solution in hexanes), anhydrous THF (40 mL)] and DMPU (8.23 mL, 68.04 mmol) was added a solution of (+)-camphor (1.6 g, 10.8 mmol) in anhydrous THF (20 mL). After 0.5h, a solution of ethyl pyruvate (2.1 mL, 18.9 mmol) in THF (10 mL) was added, followed after 2h by H2O (3 mL) and the reaction allowed to warm to room temperature. The reaction was partitioned between EtOAc and saturated aqueous NH4Cl. The organic fraction was dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica (2-30% EtOAc in cyclohexane) to give the title compound as a colourless oil (2.52g). 1H NMR (300 MHz, CDCl3): δ 4.28 (q, J = 7.1 Hz, 2 H); 2.70 (d, J = 4.5 Hz, 1 H); 2.04-2.05 (m, 1 H); 1.85 (t, J = 8.8 Hz, 1 H); 1.72 (s, 3 H); 1.60-1.63 (m, 3 H); 1.33 (t, J = 7.1 Hz, 3 H); 0.91 (t, J = 13.1 Hz, 8 H).

    Step 2: (1R,8S)-1,6,11,11-Tetramethyl-3,4-diaza-tricyclor6.2.1.0*2,7*]undeca-2(7),3,5-trien-5-ol



    [0551] The product from Step 1 (2.32 g) was reacted in a similar manner to Example 1, Step 2 to give the product as white flakes (0.79 g).

    Steps 3: (5S,8R)-3-(2-Fluorophenyl)-4,8,9,9-tetramethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline



    [0552] The product from Step 2 (0.79 g) was reacted in a similar manner to Example 1, Steps 4 and 5 to give the title compound as pale yellow oil (119 mg). 1H NMR (400 MHz, CDCl3): δ 7.51 (td, J = 7.5, 1.9 Hz, 1 H); 7.42-7.43 (m, 1 H); 7.25-7.29 (m, 1 H); 7.15 (ddd, J = 10.1, 8.3, 1.1 Hz, 1 H); 3.03 (d, J = 4.2 Hz, 1 H); 2.20 (ddt, J = 12.5, 10.3, 4.2 Hz, 1 H); 2.15 (d, J = 2.1 Hz, 3 H); 1.99-2.00 (m, 1 H); 1.48 (s, 3 H); 1.38-1.39 (m, 1 H); 1.17 (ddd, J = 12.5, 9.2, 4.0 Hz, 1 H); 1.06 (s, 3 H); 0.62 (s, 3 H). LCMS (m/z, Method B) ES+ 297.2 [M+1]+.

    [0553] The above compounds, together with additional compounds made using the above procedure, are shown in Table 1 below, together with RORc IC50 (micromolar) data for selected compounds determined from the assay described below.
    Table 1
    #Structure1H NMRIUPAC nameIC50 (µM)
    1

    (CDCl3): δ 7.38 (tt, J = 8.4, 6.2 Hz, 1H), 7.30 (s, 1H), 7.02 (t, J = 7.9 Hz, 2H), 2.96 (d, J = 4.3 Hz, 1H), 2.23-2.21 (m, 1H), 2.01-2.00 (m, 1H), 1.50 (s, 3H), 1.25-1.23 (m, 2H), 1.07 (s, 3H), 0.62 (s, 3H). (5R,8S)-3-(2,6-difluorophenyl)- 8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.114
    2

    (CDCl3): δ 7.32-7.33 (m, 2 H); 7.23 (d, J = 0.8 Hz, 1H); 7.12-7.12 (m, 1 H); 2.96 (d, J = 4.3 Hz, 1 H); 2.23 (ddt, J = 12.6, 10.5, 4.2 Hz, 1 H); 2.02 (ddd, J = 12.7, 10.4, 4.1 Hz, 1 H); 1.50 (s, 3 H); 1.43-1.44 (m, 1 H); 1.24 (ddd, J = 12.6, 9.1, 4.1 Hz, 1 H); 1.07 (s, 3 H); 0.62 (s, 3 H). (5R,8S)-3-(2-chloro-6-fluorophenyl)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.059
    3

    (CDCl3): δ 7.38 (tt, J = 8.4, 6.2 Hz, 1 H); 7.30 (s, 1 H); 7.02 (t, J = 7.9 Hz, 2 H); 2.96 (d, J = 4.3 Hz, 1 H); 2.21-2.23 (m, 1 H); 2.00-2.01 (m, 1 H); 1.50 (s, 3 H); 1.23-1.25 (m, 2 H); 1.07 (s, 3 H); 0.62 (s, 3 H). (5S,8R)-3-(2,6-difluorophenyl)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.080
    4

      (1S,8R)-5-(2-Fluoro-benzyloxy) -1,11,11-trimethyl-3,4-diaza-tricyclo[6.2.1.0%2,7 &]unde ca-2(7),3,5-triene 2.27
    5

    (CDCl3): δ 8.12 (td, J = 7.9, 1.9 Hz, 1H), 7.68 (d, J = 2.5 Hz, 1H), 7.43-7.42 (m, 1H), 7.29 (td, J = 7.6, 1.2 Hz, 1H), 7.18 (ddd, J = 11.5, 8.2, 1.2 Hz, 1H), 3.69-3.67 (m, 1H), 3.35 (t, J = 2.1 Hz, 2H), 2.22-2.21 (m, 1H), 2.06-2.05 (m, 1H), 1.54 (d, J = 3.1 Hz, 3H), 1.48-1.47 (m, 1H), 1.33 (ddd, J = 12.9, 9.4, 3.7 Hz, 1H), 0.81 (s, 3H). (5R,8R)-9-(bromomethyl)-3-(2-fluorophenyl)-8,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.778
    6

    (CDC13): δ 8.13 (td, J = 7.9, 1.9 Hz, 1H), 7.66 (d, J = 2.6 Hz, 1H), 7.43-7.42 (m, 1H), 7.29 (td, J = 7.6, 1.2 Hz, 1H), 7.18 (ddd, J = 11.5, 8.2, 1.2 Hz, 1H), 4.26 (d, J = 11.3 Hz, 1H), 4.07 (d, J = 11.3 Hz, 1H), 3.23 (d, J = 4.2 Hz, 1H), 2.25-2.24 (m, 1H), 2.13 (s, 3H), 2.07-2.06 (m, 1H), 1.55 (s, 3H), 1.48-1.47 (m, 1H), 1.30-1.29 (m, 1H), 0.72 (s, 3H). [(5R,8R)-3-(2-fluorophenyl)-8,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-9-yl]methyl acetate 2.46
    7

    (CDCl3): δ 8.15 (td, J = 7.9, 1.8 Hz, 1 H); 7.73 (d, J = 2.6 Hz, 1 H); 7.41-7.44 (m, 1 H); 7.30 (td, J = 7.6, 1.2 Hz, 1H); 7.17-7.18 (m, 1 H); 3.32 (s, 3 H); 3.11 (s, 3 H); 2.88 (d, J = 4.3 Hz, 1 H); 2.56-2.57 (m, 1 H); 2.34-2.35 (m, 1 H); 1.98 (ddd, J = 12.7, 9.4, 4.2 Hz, 1 H); 1.37-1.38 (m, 1 H); 1.34 (s, 3 H); 0.93 (s, 3 H). (5S,8S)-3-(2-fluorophenyl)-N,N,9,9-tetramethyl-6,7-dihydro-5,8-methanocinnoline-8(5H)-carboxamide 0.186
    8

      (5S,8S)-8-(chloromethyl)-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.391
    9

      1-[(5R,8R)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]-N,N-dimethylmethanesulfonami de 2.3
    10

      (5S,8R)-3-(2-chloro-6-fluorophenyl)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.045
    11

    (CDCl3): δ 8.11 (td, J = 7.9, 1.9 Hz, 1 H); 7.65 (d, J = 2.6 Hz, 1 H); 7.34-7.36 (m, 7 H); 7.17 (ddd, J = 11.5, 8.2, 1.2 Hz, 1 H); 4.70 (s, 2H); 4.23 (dd, J = 84.5, 10.5 Hz, 2 H); 2.91 (d, J = 4.2 Hz, 1 H); 2.48-2.49 (m, 1 H); 2.27 (tt, J = 11.4, 4.0 Hz, 1 H); 1.29-1.31 (m, 2 H); 1.21 (s, 3 H); 0.70 (s, 3 H). (5S,8S)-8-[(benzyloxy)methyl]-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.084
    12

    (CDCl3): δ 8.14 (td, J = 7.9, 1.9 Hz, 1 H); 7.68 (d, J = 2.6 Hz, 1 H); 7.42-7.43 (m, 1 H); 7.29 (td, J = 7.6, 1.2 Hz, 1 H); 7.18 (ddd, J = 11.5, 8.2, 1.2 Hz, 1 H); 4.80-4.81 (m, 2 H); 2.96 (d, J = 3.6 Hz, 1 H); 2.26-2.28 (m, 2 H); 2.11 (s, 3 H); 1.43-1.44 (m, 1 H); 1.27-1.29 (m, 1 H); 1.17 (s, 3 H); 0.74 (s, 3 H). [(5S,8S)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methyl acetate 0.045
    13

    (CDCl3): δ 8.06 (td, J = 7.8, 1.8 Hz, 1 H); 7.69 (d, J = 2.6 Hz, 1 H); 7.45 (dddd, J = 8.3, 7.4, 5.1, 1.9 Hz, 1 H); 7.30 (td, J = 7.6, 1.2 Hz, 1 H); 7.19 (ddd, J = 11.4, 8.3, 1.2 Hz, 1 H); 4.37 (dd, J = 11.9, 4.7 Hz, 1H); 4.04 (dd, J = 11.9, 8.9 Hz, 1 H); 3.62 (dd, J = 8.9, 4.8 Hz, 1 H); 2.97 (d, J = 4.2 Hz, 1 H); 2.29 (ddt, J = 12.6, 10.5, 4.2 Hz, 1 H); 2.15 (ddd, J = 12.8, 10.5, 3.9 Hz, 1 H); 1.65 (ddd, J = 12.8, 9.3, 4.1 Hz, 1 H); 1.30 (ddd, J = 12.6, 9.3, 4.0 Hz, 1 H); 1.12 (s, 3 H); 0.74 (s, 3 H). [(5S,8S)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methanol 0.80
    14

    (DMSO): δ 7.88 (dd, J = 8.7, 7.1 Hz, 1 H); 7.75 (d, J = 2.5 Hz, 1 H); 7.53-7.56 (m, 1 H); 7.37-7.39 (m, 2 H); 3.99 (dd, J = 61.6, 10.4 Hz, 2 H); 3.40 (s, 3 H); 3.03 (d, J = 3.9 Hz, 1 H); 2.23-2.28 (m, 2 H); 1.12 (m, 5 H); 0.62 (s, 3 H). (5S,8S)-3-(2-fluorophenyl)-8-(methoxymethyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.033
    15

    (CDCl3): δ 8.17 (td, J = 7.9, 1.9 Hz, 1 H); 7.72 (d, J = 2.5 Hz, 1 H); 7.42-7.43 (m, 1 H); 7.29 (td, J = 7.6, 1.2 Hz, 1 H); 7.17 (ddd, J = 11.6, 8.2, 1.2 Hz, 1H); 3.91 (s, 3 H); 3.03 (d, J = 4.2 Hz, 1 H); 2.70 (ddd, J = 13.2, 10.6, 4.1 Hz, 1 H); 2.33 (ddt, J = 12.7, 10.6, 4.3 Hz, 1 H); 1.71 (ddd, J = 13.2, 9.3, 4.3 Hz, 1 H); 1.27 (ddd, J = 12.8, 9.2, 4.0 Hz, 1 H); 1.21 (s, 3 H); 0.90 (s, 3 H). methyl (5S,8S)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnoline-8(5H)-carboxylate 0.219
    16

      [(5S,8S)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]acetonitrile 1.55
    17

    (CDCl3): δ 8.12 (td, J = 7.8, 1.8 Hz, 1 H); 7.77 (s, 1 H); 7.69 (d, J = 2.5 Hz, 1 H); 7.43-7.46 (m, 2 H); 7.32 (td, J = 7.6, 1.2 Hz, 1 H); 7.18-7.19 (m, 1 H); 7.03 (s, 1 H); 4.64-4.65 (m, 2 H); 2.97 (d, J = 4.2 Hz, 1 H); 2.24-2.26 (m, 1 H); 2.09-2.10 (m, 1 H); 1.27-1.29 (m, 2 H); 1.13 (s, 3 H); 0.53 (s, 3 H). (5S,8R)-3-(2-fluorophenyl)-8-(1H-imidazol-1-ylmethyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 3.17
    18

      1-{[(5S,8R)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methyl}pyrrolidin-2-one 4.81
    19

    (CDCl3): δ 8.11 (td, J = 7.9, 1.9 Hz, 1 H); 7.62 (d, J = 2.5 Hz, 1 H); 7.43 (dddd, J = 8.3, 7.4, 5.1, 1.9 Hz, 1 H); 7.29 (td, J = 7.6, 1.2 Hz, 1 H); 7.17 (ddd, J = 11.5, 8.2, 1.2 Hz, 1 H); 4.76 (dd, J = 7.7, 3.6 Hz, 1 H); 3.06 (d, J = 4.1 Hz, 1 H); 2.19 (dt, J = 13.8, 3.9 Hz, 1 H); 2.12 (s, 3 H); 2.05-2.06 (m, 1 H); 1.49 (s, 3 H); 1.29 (s, 3 H); 0.68 (s, 3 H). (5S,7S,8R)-3-(2-fluorophenyl)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-7-yl acetate 0.683
    20

      (5R,7R,8S)-3-(2-fluorophenyl)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-7-yl acetate 1.2
    21

    (CDCl3): δ 7.34-7.35 (m, 7 H); 7.25 (d, J = 0.8 Hz, 1 H); 7.12 (ddd, J = 8.9, 7.8, 1.6 Hz, 1 H); 4.70 (d, J = 2.5 Hz, 2 H); 4.25 (dd, J = 96.0, 10.6 Hz, 2 H); 2.92 (d, J = 4.2 Hz, 1 H); 2.52 (ddd, J = 12.6, 10.6, 3.9 Hz, 1 H); 2.27-2.28 (m, 1 H); 1.43 (s, 1 H); 1.26-1.27 (m, 1 H); 1.22 (s, 3 H); 0.70 (s, 3 H). (5S,8S)-8-[(benzyloxy)methyl]-3-(2-chloro-6-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.022
    22

      [(5S,8S)-3-(2-chloro-6-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methyl acetate 0.015
    23

      [(5S,8S)-3-(2-chloro-6-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methanol 0.381
    24

    (CDCl3): δ 7.31-7.32 (m, 2 H); 7.25 (d, J = 0.8 Hz, 1 H); 7.12 (ddd, J = 8.9, 7.8, 1.6 Hz, 1 H); 4.14 (dd, J = 97.5, 10.6 Hz, 2 H); 3.50 (s, 3 H); 2.91 (d, J = 4.2 Hz, 1 H); 2.43 (ddd, J = 12.5, 10.6, 3.8 Hz, 1 H); 2.28 (ddt, J = 12.3, 10.6, 4.1 Hz, 1 H); 1.37-1.38 (m, 1 H); 1.26 (ddd, J = 12.4, 9.3, 3.8 Hz, 1 H); 1.19 (s, 3 H); 0.72 (s, 3 H). (5S,8S)-3-(2-chloro-6-fluorophenyl)-8-(methoxymethyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.045
    25

      (5S,8S)-8-(ethoxymethyl)-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.139
    26

      (5S,8S)-3-(2-fluorophenyl)-8-[(2-methoxyethoxy)methyl]-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.789
    27

      (5S,8R)-3-(2-fluorophenyl)-9,9-dimethyl-8-(1H-pyrazol-1-ylmethyl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.366
    28

      (5R,8R)-3-(2-fluorophenyl)-8-(methoxymethyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.21
    29

      (5R,8R)-3-(2-chloro-6-fluorophenyl)-8-(methoxymethyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.041
    30

    (CDCl3): δ 7.38 (tt, J = 8.4, 6.3 Hz, 1 H); 7.32 (t, J = 1.4 Hz, 1 H); 7.02 (t, J = 7.9 Hz, 2 H); 4.25 (d, J = 10.6 Hz, 1 H); 4.02 (d, J = 10.6 Hz, 1 H); 3.49 (s, 3 H); 2.91 (d, J = 4.2 Hz, 1 H); 2.42 (ddd, J = 12.4, 10.6, 3.8 Hz, 1 H); 2.27 (ddt, J = 12.3, 10.6, 4.1 Hz, 1 H); 1.35-1.36 (m, 1 H); 1.24 (ddd, J = 12.3, 9.2, 3.8 Hz, 1 H); 1.19 (s, 3 H); 0.72 (s, 3 H). (5R,8R)-3-(2,6-difluorophenyl)-8-(methoxymethyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.045
    31

      (5R,7R,8S)-7-fluoro-3-(2-fluorophenyl)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 2.13
    32

    (CDCl3): δ 8.11 (td, J = 7.9, 1.9 Hz, 1 H); 7.61 (d, J = 2.5 Hz, 1 H); 7.44 (dddd, J = 8.3, 7.4, 5.1, 1.9 Hz, 1 H); 7.29 (td, J = 7.6, 1.2 Hz, 1 H); 7.17 (ddd, J = 11.5, 8.3, 1.2 Hz, 1 H); 4.69 (dd, J = 7.3, 2.5 Hz, 0.5 H); 4.55 (dd, J = 7.3, 2.5 Hz, 0.5 H); 3.09 (d, J = 4.2 Hz, 1 H); 2.45 (dddd, J = 29.6, 14.1, 4.3, 2.5 Hz, 1 H); 1.99 (td, J = 13.5, 7.3 Hz, 1 H); 1.59 (d, J = 1.1 Hz, 3 H); 1.30 (d, J = 1.7 Hz, 3 H); 0.69 (s, 3 H). (5S,7S,8R)-7-fluoro-3-(2-fluorophenyl)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.969
    33

    (CDCl3): δ 7.51 (td, J = 7.5, 1.9 Hz, 1 H); 7.42-7.43 (m, 1 H); 7.25-7.29 (m, 1 H); 7.15 (ddd, J = 10.1, 8.3, 1.1 Hz, 1 H); 3.03 (d, J = 4.2 Hz, 1 H); 2.20 (ddt, J = 12.5, 10.3, 4.2 Hz, 1 H); 2.15 (d, J = 2.1 Hz, 3 H); 1.99-2.00 (m, 1 H); 1.48 (s, 3 H); 1.38-1.39 (m, 1 H); 1.17 (ddd, J = 12.5, 9.2, 4.0 Hz, 1 H); 1.06 (s, 3 H); 0.62 (s, 3 H). (5S,8R)-3-(2-fluorophenyl)-4, 8,9,9-tetramethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 1.22
    34

      1-{[(5S,8R)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methyl}imidazolidin-2-one 0.245
    35

      (5S,8R)-8-ethyl-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.037
    36

      2-[(5S,8S)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]-N,N-dimethylacetamide 5.17
    37

      2-[(5S,8S)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]-N-methyl acetamide 0.88
    38

      (5S,8S)-3-(2-fluorophenyl)-9,9-dimethyl-8-[(propan-2-yloxy)methyl]-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.281
    39

    (CDCl3): δ 8.14 (td, J = 7.9, 1.9 Hz, 1 H); 7.66 (d, J = 2.6 Hz, 1 H); 7.41-7.42 (m, 1 H); 7.28-7.29 (m, 1 H); 7.17 (ddd, J = 11.5, 8.2, 1.2 Hz, 1 H); 3.49 (dd, J = 178.7, 15.3 Hz, 2 H); 2.92 (d, J = 4.3 Hz, 1 H); 2.60 (s, 3 H); 2.48 (ddd, J = 13.0, 10.5, 4.0 Hz, 1 H); 2.22-2.23 (m, 1 H); 1.61-1.62 (m, 1 H); 1.43 (s, 2 H); 1.28 (ddd, J = 12.7, 9.2, 3.9 Hz, 1 H); 0.95 (s, 3 H); 0.74 (s, 3 H). (5S,8S)-3-(2-fluorophenyl)-9,9-dimethyl-8-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-5,6,7,8-tetrahydro-5,8-methanocinnoline 1.73
    40

    (CDCl3) δ 8.11 (td, J = 7.9, 1.9 Hz, 1H), 7.65 (d, J = 2.6 Hz, 1H), 7.45-7.39 (m, 1H), 7.30-7.26 (m, 1H), 7.20-7.13 (m, 1H), 4.00 (dd, J = 72.6, 10.5 Hz, 2H), 3.43 (s, 3H), 2.77 (d, J = 3.8 Hz, 1H), 2.37-2.24 (m, 2H), 1.49-1.38 (m, 2H), 0.94-0.88 (m, 1H), 0.77-0.71 (m, 1H), 0.53-0.44 (m, 2H). 3'-(2-fluorophenyl)-8'-(methoxymethyl)-5',6',7',8'-tetrahydrospiro[cyclopropa ne-1,9'-[1,2]diaza[5,8]methanocinn oline] 0.35
    41

      (5S,8S)-3-(2-fluorophenyl)-8-(2-methoxyethyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.054
    42

      (5S,8S)-3-(2-fluorophenyl)-9,9-dimethyl-8-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.238
    43

      1-{[(5S,8R)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methyl}-1,3-dimethylurea 0.624
    44

      (5S,8R)-3-(2-fluorophenyl)-9,9-dimethyl-8-[(3-methyl-1H-pyrazol-1-yl)methyl]-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.607
    45

      (3-{[(5S,8S)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methyl}-1,2,4-oxadiazol-5-yl)methanol 0.756
    46

      1-{[(5S,8R)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methyl}-3-methylimidazolidin-2-one 1.45
    47

      (5S,8R)-3-(2-fluorophenyl)-9,9-dimethyl-8-[(4-methyl-1H-pyrazol-1-yl)methyl]-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.267
    48

      1-{[(5S,8R)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methyl}-3-[2-(morpholin-4-yl)ethyl]imidazolidin-2-one 0.643
    49

    (CDCl3) δ 7.40-7.41 (m, 2 H); 7.04 (t, J = 8.0 Hz, 2 H); 4.78-4.81 (m, 1 H); 4.38 (q, J = 7.9 Hz, 1 H); 4.23-4.27 (m, 1 H); 4.12-4.16 (m, 1 H); 2.93 (d, J = 4.2 Hz, 1 H); 2.58 (ddd, J = 12.6, 10.5,4.0 Hz, 1 H); 2.28-2.34 (m, 3 H); 1.73-1.74 (m, 1 H); 1.27 (s, 4 H); 0.98 (s, 3 H) azetidin-1-yl[(5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methanone 0.044
    50

      (5S,8R)-3-(2-fluorophenyl)-8,9,9-trimethyl-5,8-dihydro-5,8-methanocinnolin-7(6H)-one 2.42
    51

      (5S,8R)-3-(2-fluorophenyl)-8,9,9-trimethyl-7-methylidene-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.657
    52

      (5S,8S)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnoline-8(5H)-carbonitrile 1.53
    53

      (5S,8S)-3-(2,6-difluorophenyl)-N,9,9-trimethyl-6,7-dihydro-5,8-methanocinnoline-8(5H)-carboxamide 0.139
    54

      [(5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl](morpholin-4-yl)methanone 0.042
    55

      (5S,8S)-3-(2,6-difluorophenyl)- N-methoxy-N,9,9-trimethyl-6,7-dihydro-5,8-methanocinnoline-8(5H)-carboxamide 0.124
    56

      (5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(morpholin-4-ylmethyl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.252
    57

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(1,2,4-oxadiazol-3-ylmethyl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.085
    58

      3-{[(5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methyl}-1,2,4-oxadiazol-5-ol 1.05
    59

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.106
    60

      (5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(3-methyl-1,2,4-oxadiazol-5-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.415
    61

      (3-{[(5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methyl}-1,2,4-oxadiazol-5-yl)methanol 0.323
    62

      (5R,8R)-3-(2,6-difluorophenyl)-8-{[5-(methoxymethyl)-1,2,4-oxadiazol-3-yl]methyl}-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.129
    63

      methyl 4-({[(5S,8S)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methoxy }methyl)benzoa te 0.136
    64

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(3-methyl-1,2,4-oxadiazol-5-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.067
    65

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.131
    66

      1-(3-{[(5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methyl}-1,2,4-oxadiazol-5-yl)-N,N-dimethylmethanamine 0.298
    67

    (CDCl3): δ 7.40-7.43 (m, 2 H); 7.05 (t, J = 7.9 Hz, 2 H); 3.17 (d, J = 4.2 Hz, 1 H); 2.94-2.99 (m, 1 H); 2.61 (s, 3 H); 2.46 (t, J = 11.4 Hz, 1 H); 1.96 (ddd, J = 13.2, 9.2, 4.2 Hz, 1 H); 1.37-1.43 (m, 1 H); 1.19 (s, 3 H); 0.93 (s, 3 H). (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(5-methyl-1,3,4-oxadiazol-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.031
    68

      {5-[(5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]-1,3,4-oxadiazol-2-yl}methanol 0.116
    69

      [(5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl](pyrrolidin-1-yl)methanone 0.023
    70

      (5S,8S)-N-cyclobutyl-3 - (2,6-difluorophenyl)-N,9,9-trimethyl-6,7-dihydro-5,8-methanocinnoline-8(5H)-carboxamide 0.215
    71

      4-({[(5S,8S)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methoxy }methyl)benzoi c acid 0.284
    72

      4-({[(5S,8S)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methoxy }methyl)benza mide 0.158
    73

      (5S,8S)-3-(2,6-difluorophenyl)-N,N,9,9-tetramethyl-6,7-dihydro-5,8-methanocinnoline-8(5H)-carboxamide 0.029
    74

      [(5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl](3,3-dimethylazetidin-1-yl)methanone 0.693
    75

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.089
    76

      (5-{[(5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methyl}-1,3,4-oxadiazol-2-yl)methanol 0.388
    77

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnoline-8(5H)-carboxamide 1.46
    78

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnoline-8(5H)-carbonitrile 0.925
    79

      [(5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl][3-(dimethylamino)azetidin-1-yl]methanone 1.12
    80

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(5-methyl-1,2,4-oxadiazol-3-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.136
    81

      N-[(5R,8R)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]acetamide 2.07
    82

      (5R,8R)-3-(2,6-difluorophenyl)-N,N,9,9-tetramethyl-6,7-dihydro-5,8-methanocinnoline-8(5H)-carboxamide 0.856
    83

      N-[(5R,8R)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]-2-methoxyacetamide 1.17
    84

      (5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-N -(5-methyl-1,3,4-oxadiazol-2-yl)-6,7-dihydro-5,8-methanocinnoline-8(5H)-carboxamide 1.01
    85

      (5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-N -(3-methyl-1,2,4-oxadiazol-5-yl)-6,7-dihydro-5,8-methanocinnoline-8(5H)-carboxamide 5.65
    86

      [(5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl](3-hydroxyazetidin-1-yl)methanone 0.097
    87

      N-[(5R,8R)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]-2-methylpropanamide 5.19
    88

      N-[(5R,8R)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]-2-hydroxyacetamide 1.44
    89

      N-[(5R,8R)-3-(2-fluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]-N∼2∼,N∼2∼-dimethylglycinamide 5.19
    90

      (5R,8R)-3-(2-fluorophenyl)-N,N,9,9-tetramethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-amine 0.192
    91

      (5S,8S)-3-(2,6-difluorophenyl)- N-methoxy-9,9-dimethyl-6,7-dihydro-5,8-methanocinnoline-8(5H)-carboxamide 0.384
    92

      [(5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl](3-hydroxy-3-methylazetidin-1-yl)methanone 2.99
    93

      [(5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl](3-fluoroazetidin-1-yl)methanone 0.127
    94

      [3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl](3-fluoropyrrolidin-1-yl)methanone 0.047 6
    95

      N-{ 5-[(5R,8S)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-3-yl]pyridin-2-yl }acetamide 3.32
    96

      (5R,8S)-8,9,9-trimethyl-3-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 5.48
    97

    (CDCl3): δ 7.23 (dt, J = 8.0, 1.6 Hz, 1 H); 7.10-7.11 (m, 2 H); 7.01 (s, 1 H); 2.94 (d, J = 4.3 Hz, 1 H); 2.20 (ddt, J = 12.5, 10.6, 4.2 Hz, 1 H); 1.95-1.96 (m, 1 H); 1.36 (s, 3 H); 1.24-1.25 (m, 1 H); 1.04 (m, 4 H); 0.60 (s, 3 H) (5R,8S)-3-(2-chloro-6-fluorophenoxy)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.087
    98

    (CDCl3): δ 7.26 (s, 1 H); 7.13-7.14 (m, 1 H); 6.97-6.98 (m, 3 H); 2.94 (d, J = 4.3 Hz, 1 H); 2.18-2.22 (m, 1 H); 1.94-1.95 (m, 1 H); 1.36 (m, 4 H); 1.24 (ddd, J = 12.5, 9.1, 4.0 Hz, 1 H); 1.04 (s, 3 H); 0.60 (s, 3 H). (5R,8S)-3-(2-fluorophenoxy)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.6
    99

    (CDCl3): δ 7.13-7.14 (m, 1 H); 6.97-6.98 (m, 3 H); 2.94 (d, J = 4.3 Hz, 1 H); 2.18-2.22 (m, 1 H); 1.94-1.95 (m, 1 H); 1.36 (m, 4 H); 1.24 (ddd, J = 12.5, 9.1, 4.0 Hz, 1 H); 1.04 (s, 3 H); 0.60 (s, 3 H). (5R,8S)-3-(2,6-difluorophenoxy)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.28
    100

    (DMSO): δ 7.73 (s, 1 H); 7.60-7.61 (m, 1 H); 7.29 (t, J = 8.1 Hz, 2 H); 4.52 (dt, J = 101.7, 8.3 Hz, 1 H); 4.10-4.13 (m, 2 H); 3.56 (ddd, J = 23.0, 9.8, 5.5 Hz, 1 H); 3.03 (d, J = 4.1 Hz, 1 H); 2.64-2.77 (m, 1 H); 2.46 (s, 1 H); 2.22-2.27 (m, 1 H); 1.63-1.68 (m, 1 H); 1.24 (s, 4 H); 1.14 (s, 3 H); 0.82 (s, 3 H). [(5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl](3-methylazetidin-1-yl)methanone 0.070
    101

    (CDCl3): δ 8.56 (s, 1 H); 7.43-7.44 (m, 2 H); 7.05 (t, J = 8.0 Hz, 2 H); 3.19 (d, J = 4.2 Hz, 1 H); 3.01 (ddd, J = 13.1, 10.6, 4.1 Hz, 1 H); 2.49 (ddt, J = 12.8, 10.6, 4.3 Hz, 1 H); 2.01 (ddd, J = 13.1, 9.3, 4.3 Hz, 1 H); 1.44 (ddd, J = 12.8, 9.2, 4.2 Hz, 1 H); 1.20 (s, 3 H); 0.95 (s, 3 H). (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(1,3,4-oxadiazol-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.192
    102

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(1,3-oxazol-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.017
    103

    (CDCl3):) δ 7.42-7.43 (m, 2 H); 7.05 (t, J = 8.0 Hz, 2 H); 3.17 (d, J = 4.2 Hz, 1 H); 2.97 (ddd, J = 13.1, 10.6, 4.1 Hz, 1 H); 2.61 (s, 3 H); 2.46 (ddt, J = 12.8, 10.6, 4.3 Hz, 1 H); 1.96 (ddd, J = 13.1, 9.3, 4.3 Hz, 1 H); 1.40-1.41 (m, 1 H); 1.19 (s, 3 H); 0.93 (s, 3 H). (5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(5-methyl-1,3,4-oxadiazol-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.205
    104

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(1,3-oxazol-5-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.222
    105

    (CDCl3): δ 7.41-7.42 (m, 2 H); 7.04 (t, J = 8.0 Hz, 2 H); 4.21 (s, 3 H); 3.14 (d, J = 4.2 Hz, 1 H); 2.92 (ddd, J = 13.2, 10.6, 4.1 Hz, 1 H); 2.43 (ddt, J = 12.8, 10.6, 4.3 Hz, 1 H); 1.91 (ddd, J = 13.2, 9.3, 4.3 Hz, 1 H); 1.39 (ddd, J = 12.8, 9.3, 4.1 Hz, 1 H); 1.19 (s, 3 H); 0.94 (s, 3 H). (5R,8R)-3-(2,6-difluorophenyl)-8-(5-methoxy-1,3,4-oxadiazol-2-yl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.261
    106

      (5R,8R)-3-(2-fluorophenyl)-8-(1H-imidazol-1-yl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 1.8
    107

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(4H-1,2,4-triazol-4-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 1.5
    108

    (CDCl3): δ 7.46-7.46 (m, 1 H); 7.36-7.37 (m, 2 H); 7.23 (s, 2 H); 7.00 (t, J = 7.9 Hz, 2 H); 3.08 (d, J = 4.2 Hz, 1 H); 2.95 (ddd, J = 13.1, 10.6, 4.2 Hz, 1 H); 2.38 (ddt, J = 12.7, 10.6, 4.3 Hz, 1 H); 2.22 (d, J = 1.3 Hz, 3 H); 1.86 (ddd, J = 13.1, 9.3, 4.2 Hz, 1 H); 1.33 (ddd, J = 12.7, 9.3, 4.2 Hz, 1 H); 1.10 (s, 3 H); 0.89 (s, 3 H). (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(4-methyl-1,3-oxazol-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.096
    109

      1-[(5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]pyrrolidin-2-one 0.201
    110

      (5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(1,3,4-oxadiazol-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.186
    111

      {5-[(5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]-1,3,4-oxadiazol-2-yl}methanol 0.195
    112

    (400 MHz, CDCl3) d 7.39 - 7.34 (m, 2H), 7.00 (dd, J=8.0, 8.0 Hz, 2H), 6.77 (d, J=1.2 Hz, 1H), 3.08 (d, J=4.2 Hz, 1H), 2.91 (ddd, J=4.1, 10.6, 13.2 Hz, 1H), 2.34 - 2.33 (m, 4H), 1.89 - 1.82 (m, 1H), 1.36 - 1.28 (m, 1H), 1.10 (s, 3H), 0.90 (s, 3H). (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(5-methyl-1,3-oxazol-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.027
    113

      (5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.043
    114

      (5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(1,3-oxazol-4-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.039
    115

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(5-propyl-1,3,4-oxadiazol-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.025
    116

      (5R,8R)-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 7
    117

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(2-methyl-1,3-oxazol-5-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.019
    118

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(4-methyl-1,3-oxazol-5-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.134
    119

      (5R,8R)-3-(2,6-difluorophenyl)-8-(1H-imidazol-2-yl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.843
    120

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-[(pyridin-2-yloxy)methyl]-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.126
    121

      1-{[(5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl]methyl}pyridin-2(1H)-one 0.199
    122

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(5-ethyl-1,3,4-oxadiazol-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.017
    123

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.109
    124

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(5-ethyl-1,3,4-thiadiazol-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.117
    125

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(5-isopropyl-1,3,4-oxadiazol-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.811
    126

      (5R,8S)-3-(2,6-difluorophenyl)-8,9,9-trimethyl-5,8-dihydro-5,8-methanocinnoline 0.34
    127

      (5R,8S)-3-(2-fluorophenyl)-8,9,9-trimethyl-7,8-dihydro-5,8-methanocinnolin-6(5H)-one 1.7
    128

      (5S,8S)-N-(5-cyanopyridin-2-yl)-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 0.848
    129

      (5S,8S)-3-(2-fluorophenyl)-9,9-dimethyl-N-(2-(methylsulfonyl)phenyl)-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 1.79
    130

      (5S,8S)-N-(2,2-difluoroethyl)- 3 -(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 1.12
    131

      (5S,8S)-3-(2-fluorophenyl)-N-isobutyl-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 1.33
    132

      (5S,8S)-N-(cyclopropylmethyl)- 3 -(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 0.707
    133

      (5S,8S)-N-(4-fluorobenzyl)-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 0.876
    134

      (5S,8S)-N-ethyl-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 0.211
    135

      (3,3-difluoroazetidin-1-yl)((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methanone 0.643
    136

      methyl 1-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carbonyl)azetidine-3-carboxylate 0.524
    137

      ((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(3-(methoxymethyl)azetidin-1-yl)methanone 0.182
    138

      2-(difluoromethyl)-5-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-1,3,4-oxadiazole 0.170
    139

      (3,3-difluoroazetidin-1-yl)((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methanone 0.030
    140

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(3-(methoxymethyl)azetidin-1-yl)methanone 0.019
    141

      azetidin-1-yl((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methanone 0.608
    142

      ((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(3,3-dimethylazetidin-1-yl)methanone 1.42
    143

      2-(((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methoxy)-5-methyl-1,3,4-oxadiazole 0.286
    144

      N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-5-methyl-1,3,4-oxadiazol-2-amine 1.37
    145

      ((5R,8R)-3-(2,6-difluorophenoxy)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methanol 2.0
    146

      N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N,5-dimethyl-1,3,4-oxadiazol-2-amine 0.011
    147

      3-azabicyclo[3.1.0]hexan-3-yl((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methanone 0.008
    148

      N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N-ethyl-5-methyl-1,3,4-oxadiazol-2-amine 0.019
    149

      N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N-(2-methoxyethyl)-5-methyl-1,3,4-oxadiazol-2-amine 0.054
    150

      ((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)((3S)-3-fluorocyclopentyl)methano ne 0.023
    151

      ((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)((3S)-3-methoxycyclopentyl)metha none 0.034
    152

      N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N-isopropyl-5-methyl-1,3,4-oxadiazol-2-amine 0.019
    153

      (5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(pyridin-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.024
    154

      (5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(pyridin-3-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.023
    155

      2-((((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)(5-methyl-1,3,4-oxadiazol-2-yl)amino)ethanol 0.067
    156

      N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N-ethylmethanesulfonamide 0.046
    157

      N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N-ethylacetamide 0.019
    158

      N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N-ethyl-5-methylisoxazole-3-carboxamide 0.006
    159

      1-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-1-ethylurea 0.026
    160

      2-cyano-N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N-ethylacetamide 0.027
    161

      (5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(pyrazin-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.09
    162

      N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N-ethyl-2-hydroxyacetamide 0.008
    163

      N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N-ethylpyridin-2-amine 0.006
    164

      N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N-ethylpyrimidin-2-amine 0.004
    165

      6-((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-1-methylpyridin-2(1H)-one 0.008
    166

      N-(2,2-difluoroethyl)-N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-5-methyl-1,3,4-oxadiazol-2-amine 0.009
    167

      (5S,8S)-8-(chloromethyl)-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.391
    168

      tert-butyl (2-(1-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carbonyl)azetidin-3-yl)ethyl)carbamate 2.97
    169

      (5R,8R)-N-(6-cyanopyridin-3-yl)-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 3.27
    170

      ((5R,8R)-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(5-(methylsulfonyl)indolin-1-yl)methanone 3.89
    171

      (5R,8R)-N-(2-cyanophenyl)-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 3.38
    172

      (3,3-difluoroazetidin-1-yl)((5R,8R)-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methanone 1.41
    173

      ((5R,8R)-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(4-methoxypiperidin-1-yl)methanone 2.47
    174

      (5R,8R)-N-(2-cyanopropan-2-yl)-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 3.08
    175

      (5R,8R)-N-cyclopentyl-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 1.16
    176

      (5R,8R)-3-(2-fluorophenyl)-N-(2-hydroxyethyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 2.67
    177

      (5R,8R)-N-cyclobutyl-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 1.5
    178

      (5R,8R)-3-(2-fluorophenyl)-N,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 2.05
    179

      ((5R,8R)-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(3-(4-methyl-1 H-pyrazol-3-yl)azetidin-1-yl)methanone 2.81
    180

      4-((5R,8R)-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carbonyl)-N-methylmorpholine-2-carboxamide 3.81
    181

      ((5R,8R)-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(3-(4-methylpyrimidin-2-yl)azetidin-1-yl)methanone 2.75
    182

      (3-(1H-pyrazol-3-yl)azetidin-1-yl)((5R,8R)-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methanone 3.0
    183

      (5R,8R)-3-(2-fluorophenyl)-9,9-dimethyl-N-(1-phenylethyl)-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 1.0
    184

    (400 MHz, CDC13) d 7.40 - 7.34 (m, 2H), 7.01 (dd, J=8.0, 8.0 Hz, 2H), 4.53 - 4.46 (m, 1H), 4.27 (s, 1H), 3.75 - 3.37 (m, 4H), 2.85 (d, J=4.4 Hz, 1H), 2.35 - 2.25 (m, 1H), 1.80 - 1.72 (m, 1H), 1.26 (s, 3H), 1.24 - 1.16 (m, 1H), 0.86 (s, 3H). 1-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)imidazolidin-2-one 0.171
    185

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(1H-1,2,4-triazol-5-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 2.2
    186

      (5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(1-methyl-1H-pyrazol-3-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.152
    187

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-N-(oxetan-3-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 2.4
    188

      ((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(3-methoxyazetidin-1-yl)methanone 2.46
    189

      2-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-5-isopropyl-1,3,4-oxadiazole 0.811
    190

      ((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(3-isopropoxyazetidin-1-yl)methanone 1.84
    191

      (5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(3-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.123
    192

      4-((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-2-methyloxazole 0.202
    193

      4-((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-5-methyloxazole 0.068
    194

      5-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)isoxazole 0.050
    195

      2-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-5-methoxyoxazole 0.040
    196

      1-(5-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-1,3,4-oxadiazol-2-yl)-N,N-dimethylmethanamine 1.89
    197

      3-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)isoxazole 0.044
    198

      (3-(benzyloxy)azetidin-1-yl)((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methanone 3.25
    199

      ((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(3-hydroxyazetidin-1-yl)methanone 0.461
    200

      (5R,8S)-3-(2-fluorophenyl)-8-iodo-9 ,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.338
    201

      (5S,8S)-N-cyclobutyl-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 0.759
    202

      (5S,8S)-N-(cyclopropylmethyl)-3 - (2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 0.193
    203

      N-(1-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carbonyl)pyrrolidin-3-yl)-N-methylacetamide 1.22
    204

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone 0.60
    205

      (5S,8S)-N-(5-cyanopyridin-2-yl)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 2.82
    206

      (5S,8S)-N-cyclopentyl-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 1.23
    207

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(3,3-difluoropyrrolidin-1-yl)methanone 0.191
    208

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(3-(trifluoromethyl)pyrrolidin-1-yl)methanone 0.142
    209

      (5S,8S)-3-(2,6-difluorophenyl)-N-isobutyl-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 1.55
    210

      (5S,8S)-N-(2,2-difluoroethyl)-3 -(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 0.528
    211

      1-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carbonyl)-N,N-dimethylpyrrolidine-3-carboxamide 0.726
    212

      (1,5S,6R)-3-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carbonyl)-N-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide 2.14
    213

      methyl 1-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carbonyl)pyrrolidine-3-carboxylate 0.032
    214

      2-azabicyclo[2.1.1]hexan-2-yl((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methanone 0.22
    215

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone 1.13
    216

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methanone 0.83
    217

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(tetrahydro-1H-furo [3,4-c]pyrrol-5(3H)-yl)methanone 0.144
    218

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(2-oxa-6-azaspiro[3.4]octan-6-yl)methanone 2.44
    219

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(3-hydroxy-3-methylpyrrolidin-1-yl)methanone 1.1
    220

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)((3R,4S)-3-hydroxy-4-methylpyrrolidin-1-yl)methanone 2.94
    221

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(5-oxa-2-azaspiro[3.4]octan-2-yl)methanone 0.612
    222

      (1R,5S,6S)-3-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carbonyl)-N-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide 1.43
    223

      2-azabicyclo[3.1.0]hexan-2-yl((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methanone 0.196
    224

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(2-(trifluoromethyl)pyrrolidin-1-yl)methanone 0.327
    225

      N-((S)-1-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carbonyl)pyrrolidin-3-yl)acetamide 2.72
    226

      5-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one 0.124
    227

      5-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-4-methyloxazole 0.139
    228

      4-((5S,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-5-methyloxazole 0.137
    229

      (5R,8R,E)-N-(3,5-dimethyl-1,3,4-oxadiazol-2(3H)-ylidene)-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-amine 1.53
    230

      N-((5R,8R)-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-N,5-dimethyl-1,3,4-oxadiazol-2-amine 1.82
    231

      (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methanone 0.241
    232

      (3-(1H-pyrazol-1-yl)azetidin-1-yl)((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methanone 0.232
    233

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(3-(hydroxymethyl)azetidin-1-yl)methanone 0.819
    234

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)((S)-2-methylpyrrolidin-1-yl)methanone 0.238
    235

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(3-isopropoxyazetidin-1-yl)methanone 0.844
    236

      (R)-1-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carbonyl)pyrrolidine-3-carbonitrile 0.405
    237

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(3,3-dimethylpyrrolidin-1-yl)methanone 0.498
    238

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)((R)-3-hydroxypyrrolidin-1-yl)methanone 0.236
    239

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)((1 S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)methanone 0.892
    240

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(2-azaspiro[3.3]heptan-2-yl)methanone 0.217
    241

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methanone 0.327
    242

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)((R)-3-(dimethylamino)pyrrolidin-1-yl)methanone 0.707
    243

      1-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carbonyl)-N-methylpyrrolidine-2-carboxamide 2.95
    244

      1-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carbonyl)-N-methylpyrrolidine-3-carboxamide 0.904
    245

      1-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carbonyl)pyrrolidine-3-carbonitrile 0.126
    246

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)((S)-2-(methoxymethyl)pyrrolidin-1-yl)methanone 2.84
    247

      7-azabicyclo[2.2.1]heptan-7-yl((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methanone 1.11
    248

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(3-((S)-3-fluoropyrrolidin-1-yl)azetidin-1-yl)methanone 0.387
    249

      1-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carbonyl)pyrrolidine-3-carboxamide 3.12
    250

      (S)-1-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carbonyl)pyrrolidine-2-carboxamide 3.09
    251

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(1-methyl-1H-1,2,4-triazol-5-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.61
    252

      1-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)imidazolidin-2-one 1.58
    253

      1-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)pyrrolidin-2-one 0.961
    254

      3-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)oxazolidin-2-one 0.866
    255

      5-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-1,3,4-oxadiazol-2-amine 0.822
    256

      tert-butyl ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)carbamate 2.33
    257

    (400 MHz, CDCl3) d 7.41 - 7.36 (m, 2H), 7.02 (dd, J=8.1, 8.1 Hz, 2H), 4.73 - 4.66 (m, 1H), 4.47 - 4.31 (m, 2H), 3.75 - 3.65 (m, 2H), 2.90 (d, J=4.4 Hz, 1H), 2.38 - 2.29 (m, 1H), 1.77 - 1.69 (m, 1H), 1.28 (s, 3H), 1.27 -1.19 (m, 1H), 0.86 (s, 3H). 3-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)oxazolidin-2-one 0.438
    258

      (5S,8S)-N-(2-cyanoethyl)-3-(2,6-difluorophenyl)-N,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 1.13
    259

      1-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carbonyl)azetidine-3-carbonitrile 0.345
    260

      N1-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N2,N2-dimethyl-N1-(5-methyl-1,3,4-oxadiazol- 2-yl)ethane-1,2-diamine 3.41
    261

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)methanone 1.14
    262

      ((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(3-(2-hydroxyethyl)pyrrolidin-1-yl)methanone 0.314
    263

      5-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one 0.471
    264

      2-(1-((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carbonyl)azetidin-3-yl)acetonitrile 0.307
    265

      (5S,8S)-3-(2,6-difluorophenyl)-N,9,9-trimethyl-N-(pyridin-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 1.04
    266

      N-benzyl-N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-5-methyl-1,3,4-oxadiazol-2-amine 0.214
    267

      (5R,8S)-3-(2,6-difluorophenyl)-8-(1-(2-methoxyethyl)-1H-pyrazol-5-yl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.339
    268

      1-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)imidazolidin-2-one 0.321
    269

      2-(5-((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-1H-pyrazol-1-yl)ethanol 0.423
    270

      (5S,8S)-5-methyl-1,3,4-oxadiazol-2-yl 3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxylate 1.38
    271

      N-(2-((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)propan-2-yl)-N-ethyl-2-hydroxyacetamide 0.189
    272

      2-((((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)(pyrimidin-2-yl)amino)ethanol 0.124
    273

      1-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)pyrrolidin-2-one 0.453
    274

      methyl ((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(methyl)carbamate 0.301
    275

      (5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-(1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.146
    276

      3-(5-((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-1H-pyrazol-1-yl)propanenitrile 0.466
    277

    (400 MHz, CDCl3) d 7.43 - 7.34 (m, 1H), 7.33 (s, 1H), 7.02 (dd, J=8.0, 8.0 Hz, 2H), 4.23 - 4.06 (m, 3H), 3.96 (s, 1H), 3.85 - 3.68 (m, 3H), 2.93 (d, J=3.8 Hz, 1H), 2.34 - 2.20 (m, 2H), 1.34 - 1.15 (m, 10H), 0.66 (s, 3H). ethyl (((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)(ethyl)carbamate 0.005
    278

    (400 MHz, CDCl3) d 7.40 - 7.30 (m, 2H), 7.02 (dd, J=8.0, 8.0 Hz, 2H), 4.16 - 4.11 (m, 1H), 3.76 - 3.60 (m, 3H), 2.89 (d, J=4.0 Hz, 1H), 2.83 (s, 6H), 2.28 - 2.20 (m, 2H), 1.33 - 1.21 (m, 2H), 1.20 - 1.13 (m, 6H), 0.65 (s, 3H). 1-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-1-ethyl-3,3-dimethylurea 0.036
    279

      3-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)oxazolidin-2-one 0.222
    280

      tert-butyl((5S,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(methyl)carbamate 2.24
    281

      tert-butyl ((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(methyl)carbamate 0.218
    282

      N-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methanesulfonamide 0.984
    283

      1-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-1-(2-hydroxyethyl)urea 0.226
    284

      2-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)isothiazolidine 1,1-dioxide 0.856
    285

      1-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-3-ethyl-1-methylurea 2.07
    286

      N-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-N-methylmethanesulfonamide 0.219
    287

      3-(3-((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-1H-pyrazol-1-yl)propanenitrile 0.623
    288

      1-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-1,3-diethylurea 0.021
    289

      N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N-(2-hydroxyethyl)acetamide 0.258
    290

      2-(N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)acetamido)ethyl acetate 0.121
    291

      N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-2,2-difluoroethanamine 0.149
    292

      ethyl (2,2-difluoroethyl)(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)carbamate 0.007
    293

      1-(2,2-difluoroethyl)-1-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-3-ethylurea 0.042
    294

      (R)-3-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-4-methyloxazolidin- 2-one 0.103
    295

      (S)-3-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-4-methyloxazolidin- 2-one 1.11
    296

      (5-((((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)(ethyl)amino)-1,3,4-oxadiazol-2-yl)methanol 0.022
    297

      2-((((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)amino)ethanol 2.42
    298

      2-acetamido-N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N-(2-hydroxyethyl)acetamide 0.705
    299

      2-hydroxyethyl ((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(methyl)carbamate 1.48
    300

      2-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)propan-2-ol 0.028
    301

      6-((((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)(ethyl)amino)pyr idin-2(1H)-one 0.012
    302

      2-((((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)(ethyl)amino)pyr imidin-4(3H)-one 0.108
    303

      N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N-ethyl-5-(trifluoromethyl)-1,3,4-oxadiazol-2-amine 0.010
    304

      2-((((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)(ethyl)amino)ace tamide 0.056
    305

      2-((2,2-difluoroethyl)(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)amino)acetamide 0.437
    306

      2-(((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(methyl)amino)acetamid e 0.92
    307

      (5R,8R)-N-(2,2-difluoroethyl)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-amine 0.071
    308

      N-(2,2-difluoroethyl)-N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-2-hydroxyacetamide 0.022
    309

      3-((((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)amino)propaneni trile 0.59
    310

      1-(2-cyanoethyl)-1-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)urea 0.363
    311

      N-(2-cyanoethyl)-N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-2-methoxyacetamide 0.176
    312

      ethyl (2-cyanoethyl)(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)carbamate 0.045
    313

      N-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-2-hydroxy-N-methylacetamide 0.393
    314

      (R)-3-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-5-methyloxazolidin- 2-one 0.454
    315

      (S)-3-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-5-methyloxazolidin- 2-one 0.35
    316

      N-(2-cyanoethyl)-N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-2-hydroxyacetamide 0.233
    317

      N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)oxetan-3-amine 1.92
    318

      N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N-ethyl-2-(methylsulfonyl)acetamide 0.033
    319

      N-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-1,1,1-trifluoro-N-methylmethanesulfonamide 0.052
    320

      3-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-1,1-dimethylurea 1.5
    321

      N-(2-((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)propan-2-yl)acetamide 0.079
    322

      N-(2,2-difluoroethyl)- N-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-2-hydroxyacetamide 1.46
    323

      6-((((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)(ethyl)amino)pyr azin-2(1H)-one 0.012
    324

      (S)-N-(2-cyanoethyl)-N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-2-hydroxypropanamide 0.732
    325

      1-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-1,3,3-trimethylurea 0.944
    326

      1-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)azetidine-3-carbonitrile 1.92
    327

      ethyl 5-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-1,3,4-oxadiazole-2-carboxylate 1.39
    328

      N-(((5S,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-2,2-difluoroethanamine 0.074
    329

      (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-8-((pyrazin-2-yloxy)methyl)-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.271
    330

      6-(((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methoxy)pyrazin-2(1H)-one 1.98
    331

      N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)ethanamine 0.877
    332

      (3,3-difluoroazetidin-1-yl)((5S,8S)-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methanone 1.4
    333

      (5S,8S)-N-cyclobutyl-3 -(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 1.5
    334

      (5S,8S)-3-(2-fluorophenyl)-N,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide 2.1
    335

      ((5S,8S)-3-(2-fluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(3-(4-methyl-1 H-pyrazol-3-yl)azetidin-1-yl)methanone 2.8
    336

    (400 MHz, CDCl3) d 7.11 (s, 2H), 6.95 (dd, J=8.0, 8.0 Hz, 2H), 3.11 (d, J=4.3 Hz, 1H), 2.85 (ddd, J=4.2, 10.8, 13.1 Hz, 1H), 2.51 (s, 3H), 2.50 - 2.35 (m, 1H), 1.92 - 1.84 (m, 1H), 1.44 - 1.36 (m, 1H), 1.14 (s, 3H), 0.90 (s, 3H). 2-((5R,8R)-3-(2,6-difluorophenoxy)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)-5-methyl-1,3,4-oxadiazole 0.049
    337

    (400 MHz, CDCl3) d 7.18 -7.08 (m, 1H), 7.04 (s, 1H), 6.96 (dd, J=7.9, 7.9 Hz, 2H), 4.66 - 4.57 (m, 1H), 4.27 - 3.98 (m, 3H), 2.86 (d, J=4.3 Hz, 1H), 2.45 (ddd, J=3.9, 10.7,12.4 Hz, 1H), 2.31 - 2.15 (m, 3H), 1.72 - 1.63 (m, 1H), 1.30 - 1.21 (m, 1H), 1.20 (s, 3H), 0.95 (s, 3H). azetidin-1-yl((5R,8R)-3-(2,6-difluorophenoxy)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methanone 0.54
    338

      (5R,8R)-8-((benzyloxy)methyl)-3-(2,6-difluorophenoxy)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline 0.066
    339

      ((5R,8R)-3-(2,6-difluorophenoxy)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl acetate 0.10
    340

      ((5R,8R)-3-(2,6-difluorophenoxy)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)(pyrrolidin-1-yl)methanone  
    341

      (5R,8R)-3-(2,6-difluorophenoxy)-N,N,9,9-tetramethyl-5,6,7,8-tetrahydro-5,8-methanocinnoline-8-carboxamide  
    342

      N1-(((5S,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N1-ethylsuccinamide 0.028
    343

      N-(((5S,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N-ethyl-3-ureidopropanamide 0.032
    344

      N1-(((5S,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N1-ethyl-N4,N4-dimethylsuccinamide 0.031
    345

      N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N-ethyl-3,3,3-trifluoropropane-1-sulfonamide 0.011
    Table 1

    Example 17 In vitro RORc Ligand Binding Assay



    [0554] This assay was used to determine a compound's potency in inhibiting activity of RORc by determining, Kiapp, IC50, or percent inhibition values. Consumables used in this Example are shown in Table 2 below.
    Table2
    ConsumableSupplier and product code
    GFB Unifilter plates Perkin Elmer 6005177
    3-[(3-Cholamidopropyl)dimethylammoni o]-1-propanesulfonate (CHAPS) Sigma C5070
    96-well polypropylene U-bottom assay plate Nunc 267245
    HEPES buffer, 1 M Sigma H3375
    Magnesium chloride (MgCl2) Sigma M8266
    D,L-Dithiothreitol (DTT) Sigma D0632
    Sodium chloride (NaCl) Sigma 71382
    Bovine serum albumin (BSA) Sigma A7030 [lyophilized powder, >98% (agarose gel electrophoresis), Essentially fatty acid free, essentially globulin free]
    25 -hydroxycholesterol Sigma H1015
    25-[26,27-3H]hydroxycholesterol Perkin Elmer NET674250UC American Radiolabeled Chemicals ART0766
    RORc ligand binding domain Genentech (e.g., PUR 28048), expressed in E. coli
    Plate seals Perkin Elmer 6005185
    Microscint 0 Perkin Elmer 6013611
    Table 2

    Filter Plate Preparation



    [0555] On day of the assay, 100 uL of 0.05% CHAPS (in deionized H2O) was added to all wells of the GFB Unifilter plate and allowed soak for 1 h. A wash buffer of 50 mM HEPES (pH 7.4), 150 mM NaCl, and 5 mM MgCl2 was prepared to wash the filter plate. To prepare an assay buffer, BSA was added to the wash buffer to reach 0.01% and DTT was added to reach 1 mM

    Compounds



    [0556] For IC50 mode, 10 mM compound stocks were serially diluted in DMSO with DMSO to give 20x required final concentration in DMSO (15 uL compound + 30 uL DMSO). The 20x compound stocks were diluted in DMSO with Assay Buffer 4-fold to reach 5x the final test concentration in 25% DMSO (10 uL compound + 30 uL Assay Buffer). Solutions were mixed by aspiration several times with a pipette set on 50 uL volume. For the assay, 10 uL of 5x compound stock solutions in 25% DMSO were added to the assay plate in duplicate.

    [0557] For two point screening, 10 mM stock compound solutions were diluted in DMSO to obtain 200 uM (20x the high test concentration) and then diluted 10-fold further to reach 20 uM (20x the low test concentration). The 20x stocks were diluted 4-fold with Assay Buffer (10 uL compound + 30 uL Assay Buffer) to reach 5x the test concentrations (50 uM and 5 uM) and 10 uL were added to two assay plates for the duplicate wells. With each concentration tested on 2 plates, each set of 80 compounds used 4 assay plates (1 uM and 10 uM, with n=2).

    Nonspecific binding (NSB) samples, Total Binding (TB) samples and No Receptor (No R) samples



    [0558] 25-hydroxycholesterol (1 uM) was used to determine the level of NSB signal is prepared in DMSO as for compounds above, then diluted in Assay Buffer to give a final concentration of 5 uM. For 25-hydroxycholesterol in 25% DMSO/75% Assay Buffer; 10 uL per well was used for NSB samples. Wells for Total Binding and No Receptor sample determination contained 10 uL of 25% DMSO/75% Assay Buffer per well.

    Radioligand (25-[3H]hydroxycholesterol) Preparation



    [0559] 25-[3H]hydroxycholesterol was diluted in Assay Buffer to obtain 15 nM and vortex to mix. Add 20 uL to all wells to reach 6 nM final concentration in the assay.

    Receptor Preparation



    [0560] The optimal concentration for RORc receptor was found to be 0.6 ug/mL. Stock receptor solution was diluted in assay buffer to obtain 1.5 ug/mL in Assay Buffer. 20 uL was added to all wells. For No Receptor samples, 20 uL Assay Buffer was substituted for receptor solution.

    Sample addition to Plates and Incubation



    [0561] Assay plates were 96-well polypropylene V-bottom plates. 10 uL of 5x compound in 25% DMSO/75% Assay Buffer was added to Test wells. 10 uL of 25% DMSO/75% Assay Buffer was added to Total Binding or No Receptor wells. 10 uL of 5 uM 25-hydroxycholesterol in 25% DMSO/75% Assay Buffer was added to NSB wells. 20 uL of 15 nM 25-[3H]hydroxycholesterol prepared in Assay Buffer was added to all wells. 20 uL of 1.5 ug/mL RORc receptor was added to wells (or 40 uL Assay Buffer to No R wells). Following addition to the wells, the plates were incubated 3 h at 25°C.

    Filtration



    [0562] Using a Packard Filtermate Harvester, the filter plate were washed 4 times following transfer of the incubated samples. Plates were dry-filtered completely (2 h at 50 °C or overnight at room temperature). 50 uL Microscint 0 was added to all wells and read on Topcount protocol Inverted.

    Final concentrations



    [0563] Final concentrations were as follows: 50 mM HEPES buffer (pH 7.4); 150 mM NaCl; 1 mM DTT; 5 mM MgCl2; 0.01% BSA; 5% DMSO; 0.6 ug/mL RORc receptor; 6 nM 25-[3H]hydroxycholesterol. For NSB wells, 1 uM 25-hydroxycholesterol was also present.

    Example 18: RORc Coactivator Peptide Binding Assay



    [0564] Assays were carried out in 16-microL reaction volumes in black 384 Plus F Proxiplates (PerkinElmer 6008269). All assay components except test ligand were mixed in coregulator buffer D (Invitrogen

    [0565] PV4420) containing 5 mM DTT and added to the plate at twice their final concentrations in a volume of 8 microL. Test ligands at 2x the final concentration were then added to the wells in 8 L of coregulator buffer D containing 5 mM DTT and 4% DMSO. Final incubations contained 1x coregulator buffer D, 5 mM DTT, test ligand, 2% DMSO, 50 nM biotinyl-CPSSHSSLTERKHKILHRLLQEGSPS (American Peptide Company; Vista, CA), 2 nM Europium anti-GST (Cisbio 61GSTKLB), 12.5 nM streptavidin-D2 (Cisbio 610SADAB), 50 mM KF, and 10 nM of bacterially-expressed human RORc ligand binding domain protein containing an N-terminal 6xHis-GST-tag and residues 262-507 of Accession NP_005051. Ten test ligand concentrations were tested in duplicate. After the reaction plates were incubated for 3 h in the dark at room temperature (22-23 °C), the plate was read on an EnVision plate reader (PerkinElmer) following the Europium/D2 HTRF protocol (ex 320, em 615 and 665, 100 s lag time, 100 flashes, 500 µs window). The time-resolved FRET signal at 665 nm was divided by that at 615 nm to generate the signal ratio of each well. The signal ratio of wells containing RORc and peptide but no test ligand were averaged and set to 0% Effect while the signal ratios of the blank wells containing coactivator peptide but no RORc were averaged and set to -100% Effect. RORc exhibits a basal (constitutive) signal in this assay and test ligands can increase or decrease the signal ratio relative to this basal signal level. RORc agonists increase the signal ratio in this assay and result in a positive % Effect value. Inverse agonists decrease the signal ratio, and result in a negative % Effect value. The EC50 value is the concentration of test compound that provides half-maximal effect (increased or decreased assay signal) and is calculated by Genedata Screener® software (Genedata; Basel, Switzerland) using the following equation:

    where S0 equals the activity level at zero concentration of test compound, Sinf is the activity level at infinite concentration of test compound, EC50 is the concentration at which the activity reaches 50% of the maximal effect, c is the concentration in logarithmic units corresponding to the values on the x-axis of the dose-response curve plot, and n is the Hill coefficient (the slope of the curve at the EC50).

    Example 19: Arthritis Mouse Model



    [0566] 8 to 10-week old male DBA/1 (DBA/1OlaHsd, Harlan Laboratories) mice are housed in a specific pathogen free (SPF) animal facility. Arthritis is induced by two injections of collagen subcutaneously in the base of the tail. The initial injection (on day 0) uses bovine type II collagen (2 mg/ml from Chondrex, Redmond, Wash.) emulsified in equal volume of CFA containing 4 mg/ml of M. tuberculosis (Chondrex). The CII booster injection on Day 29 is emulsified in incomplete Freund's adjuvant (IFA). Each animal receives 0.1 ml of emulsion by subcutaneous/intradermal injection in the tail 2 to 3 cm from the body of the mouse. The booster injection site is in the vicinity of but different from the initial injection site and closer to the body of the animal. OR-1050 was formulated in HRC-6 as above. On weekdays, the animals receive two doses (a.m. and p.m.) of HRC-6 or 50 mg/kg OR-1050 p.o. (2.5 mls/kg). On weekends, a single dose of 100 mg/kg is administered (5 mls/kg).

    [0567] The mice are observed daily for clinical symptoms of CIA based on the following qualitative scale. Each paw was examined individually and scored. Grade 0, normal; grade 1, mild but definite redness and swelling of the ankle or wrist, or apparent redness and swelling limited to individual digits, regardless of the number of affected digits; grade 2, moderate redness and swelling of ankle or wrist; grade 3, severe redness and swelling of the entire paw including digits; grade 4, maximally inflamed limb with involvement of multiple joints. To estimate cumulative disease severity for each animal, an area under the curve score is calculated for each animal by totaling the sum of the daily hind paw measurements betweens days 24 and 48.

    Example 20: Muscular Sclerosis Mouse Model I



    [0568] Experiments are conducted on female mice aged 4-6 weeks belong to the C57BL/6 strain weighing 17-20 g. Experimental autoimmune encephalomyelitis (EAE) is actively induced using 95% pure synthetic myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) (Invitrogen). Each mouse is anesthetized and receives 200 ug of MOG35-55 peptide and 15 ug of Saponin extract from Quilija bark emulsified in 100 uL of phosphate-buffered saline. A 25 uL volume is injected subcutaneously over four flank areas. Mice are also intraperitoneally injected with 200 ng of pertussis toxin in 200 uL of PBS. A second, identical injection of pertussis toxin is given after 48 h.

    [0569] A compound of the invention is administered at selected doses. Control animals receive 25 uL of DMSO. Daily treatment extends from day 26 to day 36 post-immunization. Clinical scores are obtained daily from day 0 post-immunization until day 60. Clinical signs are scored using the following protocol: 0, no detectable signs; 0.5, distal tail limpness, hunched appearance and quiet demeanor; 1, completely limp tail; 1.5, limp tail and hindlimb weakness (unsteady gait and poor grip with hind limbs); 2, unilateral partial hind limb paralysis; 2.5, bilateral hind limb paralysis; 3, complete bilateral hindlimb paralysis; 3.5, complete hindlimb paralysis and unilateral forelimb paralysis; 4, total paralysis of hind limbs and forelimbs (Eugster et al., Eur J Immunol 2001, 31, 2302-2312).

    [0570] Inflammation and demyelination may be assessed by histology on sections from the CNS of EAE mice. Mice are sacrificed after 30 or 60 days and whole spinal cords are removed and placed in 0.32 M sucrose solution at 4° C. overnight. Tissues are prepared and sectioned. Luxol fast blue stain is used to observe areas of demyelination. Haematoxylin and eosin staining is used to highlight areas of inflammation by darkly staining the nuclei of mononuclear cells. Immune cells stained with H&E are counted in a blinded manner under a light microscope. Sections are separated into gray and white matter and each sector is counted manually before being combined to give a total for the section. T cells are immunolabeled with anti-CD3+ monoclonal antibody. After washing, sections are incubated with goat anti-rat HRP secondary antibody. Sections are then washed and counterstained with methyl green. Splenocytes isolated from mice at 30 and 60 days post-immunization are treated with lysis buffer to remove red blood cells. Cells are then re-suspended in PBS and counted. Cells at a density of about 3x106 cells/mL are incubated overnight with 20 ug/mL of MOG peptide. Supernatants from stimulated cells are assayed for IFNgamma protein levels using an appropriate mouse IFN-gamma immunoassay system.

    Example 21: Muscular Sclerosis Mouse Model II



    [0571] In this model, female rodents are anesthetized with isoflurane and injected with Freund's Incomplete Adjuvant containing 1 mg/mL neuronal antigen (e.g. myelin basic protein, myelin oligodendrocyte glycoprotein, proteolipid protein) and 4 mg/mL mycobacterium tuberculosis at two sites on the back on day 0 of this study. A compound of interest is then dosed daily in a sub-cutaneous, intraperitoneally, or oral manner from day 0 until the end of study at an efficacious dose. Daily observations of degree of paralysis are taken as measures of efficacy.

    Example 22: Psoriasis Mouse Model I



    [0572] The severe, combined immunodeficient (SCID) mouse model can be used to evaluate the efficacy of compounds for treating psoriasis in humans (Boehncke, Ernst Schering Res Found Workshop 2005, 50, 213-34; and Bhagavathula et al., J Pharmacol Expt'l Therapeutics 2008, 324(3), 938-947). Briefly, SCID mice are used as tissue recipients. One biopsy for each normal or psoriatic volunteer (human) is transplanted onto the dorsal surface of a recipient mouse. Treatment is initiated 1 to 2 weeks after transplantation. Animals with the human skin transplants are divided into treatment groups. Animals are treated twice daily for 14 days. At the end of treatment, animals are photographed and then euthanized. The transplanted human tissue along with the surrounding mouse skin is surgically removed and fixed in 10% formalin and samples obtained for microscopy. Epidermal thickness is measured. Tissue sections are stained with an antibody to the proliferation-associated antigen Ki-67 and with an anti-human CD3.sup.+ monoclonal antibody to detect human T lymphocytes in the transplanted tissue. Sections are also probed with antibodies to c-myc and beta-catenin. A positive response to treatment is reflected by a reduction in the average epiderma thickness of the psoriatic skin transplants. A positive response is also associated with reduced expression of Ki-67 in keratinocytes.

    Example 23: Psoriasis Mouse Model II



    [0573] Using the Imidquimod model of skin inflammation (Fits et al, Journal of Immunology, 2009, 182: 5836-5845), 10-12 week old BALB/c, Il17c+/+ or Il17c-/-, or Il17re+/+ or Il17re-/- mice were administered 50 mg Aldara cream (5% Imidquimod in Graceway, 3M) in the shaved back and right ear daily for 5 days. Clinical scoring and ear thickness measurements were performed daily. Scoring was based upon the manifestation of psoriatic symptoms, such as erythema, scaling and thickness: 0, No disease. 1, Very mild erythema with very mild thickening and scaling involving a small area. 2, Mild erythema with mild thickening and scaling involving a small area. 3, Moderate erythema with moderate thickening and scaling (irregular and patchy) involving a small area (<25%). 4, Severe erythema with marked thickening and scaling (irregular and patchy) involving a moderate area (25-50%). 5, Severe erythema with marked thickening and scaling (irregular and patchy) involving a large area (>50%). Ear and back tissue were harvested on day 5 for histological evaluation. Efficacy of compounds is compared in the imiquimod (IMQ) mouse model of psoriasis. Balb/c mice (10 males/group) received daily topical IMQ (5% cream) on shaved back and right ear for 5 days as described above. Animals received oral dose of a representative compound or DMF (45 or 90 mg-eq MMF/kg twice daily) or vehicle from Day -5 to Day +5. Erythema score is the primary outcome measure. The Erythema score values of the compounds tested at an oral dose of 90 mg-eq MMF/kg BID for 10 days in male Balb/C mice are set forth in Table 3, below. The data shows that the compounds of the disclosure are equipotent to DMF.

    Example 24: Irritable Bowel Disease Mouse Model I



    [0574] Effectiveness in treatment of inflammatory bowel disease may be evaluated as described by Jurjus et al., J Pharmaocol Toxicol Methods 2004, 50, 81-92; Villegas et al., Int'l Immunopharmacol 2003, 3, 1731-1741; and Murakami et al., Biochemical Pharmacol 2003, 66, 1253-1261. Briefly, female ICR mice are divided into treatment groups which are given either water (control), 5% DSS in tap water is given at the beginning of the experiment to induce colitis, or various concentrations of test compound. After administering test compound for 1 week, 5% DSS in tap water is also administered to the groups receiving test compound for 1 week. At the end of the experiment, all mice are sacrificed and the large intestine is removed. Colonic mucosa samples are obtained and homogenized. Proinflammatory mediators (e.g., IL-lalpha, IL-1beta, TNFalpha, PGE2, and PGF2alpha.) and protein concentrations are quantified. Each excised large intestine is histologically examined and the damage to the colon scored.

    Example 25: Chronic Obstructive Pulmonary Disease Mouse Model



    [0575] The cigarette smoke model of Martorana et al., Am J Respir Crit Care Med 2005, 172, 848-835; and Cavarra et al., Am J Respir Crit Care Med 2001, 164, 886-890 can be used for assessing efficacy in treating emphysema. Briefly, six-week old C57B1/6J male mice are exposed either to room air or to the smoke of five cigarettes for 20 minutes. For the acute study, mice are divided into three groups of 40 animals each. These groups are then divided into four subgroups of 10 mice each as follows: (1) no treatment/air-exposed; (2) no treatment/smoke-exposed; (3) a first dose of test compound plus smoke-exposed; and (4) a second dose of test compound. In the first group, trolox equivalent antioxidant capacity is assessed at the end of the exposure in bronchoalveolar lavage fluid. In the second group, cytokines and chemokines are determined in bronchoalveolar lavage fluid using a commercial cytokine panel at 4 hours; and in the third group bronchoalveolar lavage fluid cell count is assessed at 24 hours.

    [0576] In a chronic study, the mice are exposed to either room air or to the smoke of three cigarettes/day, for 5 days/week, for 7 months. Five groups of animals are used: (1) no treatment/air-exposed; (2) a first dose of a test compound plus air-exposed; (3) no treatment/smoke-exposed; (4) a second dose of the test compound plus smoke-exposed; and (5) the first dose of the test compound plus smoke exposed. Seven months after chronic exposure to room air or cigarette smoke, 5 to 12 animals from each group are sacrificed and the lungs fixed intratracheally with formalin. Lung volume is measured by water displacement. Lungs are stained. Assessment of emphysema includes mean linear intercept and internal surface area. The volume density of macrophages, marked immunohistochemically with anti-mouse Mac-3 monoclonal antibodies is determined by point counting. A mouse is considered to have goblet cell metaplasia when at least one or more midsize bronchi/lung showed a positive periodic acid-Schiff staining for the determination of desmosine, fresh lungs are homogenized, processed, and analyzed by high-pressure liquid chromatography.

    Example 26: Asthma Mouse Model



    [0577] A single inhaled allergen challenge can induce an acute increase in airway responsiveness in some individuals and animal models. However, repeated allergen inhalations have demonstrated more pronounced, consistent, and prolonged increases in airway responsiveness. This mouse model of long-term repeated inhalations of allergen has been used to study the long term effect of allergic diseases in the lung, and to delineate the cells, mechanisms, molecules, and mediators involved in the induction of airway hyperresponsiveness of lung in humans.

    [0578] Crystalline OVA is obtained from Pierce Chem. Co. (Rockford, Ill.) aluminum potassium sulfate (alum) from Sigma Chem. Co. (St. Louis, Mo.), pyrogen-free distilled water from Baxter, Healthcare Corporation (Deerfield, 111.), 0.9% sodium chloride (normal saline) from Lymphomed (Deerfield, Ill.) and Trappsol.TM. HPB-L100 (aqueous hydroxypropylbeta cyclodextrin; 45 wt/vol % aqueous solution) from Cyclodextrin Technologies Development, Inc. (Gainesville, Fla.). The OVA (500 ug/ml in normal saline) is mixed with equal volumes of 10% (wt/vol) alum in distilled water. The mixture (pH 6.5 using 10 N NaOH) after incubation for 60 minutes at room temperature is centrifuged at 750 g for 5 minutes; the pellet resuspended to the original volume in distilled water and used within one hour. The selective 5-lipoxtgenase inhibitor, Zileuton (N-[1-benzo[b]thien-2-ylethyl]-N-hydroxyurea; J. Pharmacol Exp Ther. 1991; 256: 929-937) is dissolved in Trappsol.TM. Histatek, Inc. (Seattle, Wash.) to provide the mast cell degranulation inhibitor, f-Met-Leu-Phe-Phe ("HK-X").

    [0579] Female BALB/c Once (6-8 wk of age) receive an i.p. injection of 0.2 ml (100 ug) of OVA with alum on the different protocols of Standard (FIG. 5A) and Resolution (FIG. 5B) (J. Exp Med. 1996; 184: 1483-1494). Mice are anesthetized with 0.2 ml i.p. of ketamine (0.44 mg/ml)/xylazine (6.3 mg/ml) in normal saline before receiving an intranasal (i.n.) dose of 100 ug OVA in 0.05 ml normal saline and an i.n. dose of 50 ug OVA in 0.05 ml normal saline separately on different days. Two control groups are used: the first group receives normal saline with alum i.p. and normal saline without alum i.n.; and the second group receives OVA with alum i.p., OVA without alum i.n., and normal saline, alone.

    [0580] The trachea and left lung (the right lung may be used for bronchoalveolar lavage ("BAL") as described below) are obtained and fixed in 10% neutral formaldehyde solution at room temperature for about 15 h. After being embedded in paraffin, the tissues are cut into 5-um sections and processed with the different staining or immunolabling further. Discombe's eosinophil staining is used for counting the cell numbers with the counterstain of methylene blue. The eosinophil number per unit airway area (2,200 um2) is determined by morphometry (J. Pathol. 1992; 166: 395-404; Am Rev Respir Dis. 1993; 147:448-456). Fibrosis is identified with the Masson's trichrome staining. Airway mucus iss identified by the following staining method: methylene blue, hematoxylin and eosin, mucicarmine, alcian blue, and alcian blue/periodic acid-Schiff (PAS) reaction (Troyer, H., "Carbohydrates" in Principles and Techniques of Histochemistry, Little, Brown and Company, Boston, Mass., 1980: 89-121; Sheehan, D. C., et al., "Carbohydrates" in Theory and Practice of Histotechnology, Battle Press, Columbus, Ohio, 1980: 159-179) Mucin is stained with mucicarmine solution; metanil yellow counterstain is employed. Acidic mucin and sulfated mucosubstances are stained with alcian blue, pH 2.5; nuclear fast red counterstain is used. Neutral and acidic mucosubstances are identified by alcian blue, pH 2.5, and PAS reaction. The degree of mucus plugging of the airways (0.5-0.8 mm in diameter) is also assessed by morphometry. The percent occlusion of airway diameter by mucus iss classified on a semiquantitative scale from 0 to 4+. The histologic and morphometric analyses may be performed by individuals blinded to the protocol design.

    [0581] On day 28, 24 hours after the last i.n. administration of either normal saline or OVA, pulmonary mechanics to intravenous infusion of methacholine may be determined in mice in vivo by a plethysmographic method as previously described (10, 1958; 192: 364-368; J. Appl. Physiol. 1988; 64: 2318-2323; J. Exp. Med. 1996; 184: 1483-1494).

    [0582] After tying off the left lung at the mainstem bronchus, the right lung may be lavaged three times with 0.4 ml of normal saline. Bronchoalveolar lavage (BAL) fluid cells from a 0.05-ml aliquot of the pooled sample are counted using a hemocytometer and the remaining fluid centrifuged at 4°C. for 10 minutes at 200 g. The supernatant may be stored at 70.degree. C. until eicosanoid analysis is performed. After resuspension of the cell pellet in normal saline containing 10% bovine serum albumin ("BSA"), BAL cell smears are made on glass slides. To stain eosinophils, dried slides are stained with Discombe's diluting fluid (0.05% aqueous eosin and 5% acetone (vol/vol) in distilled water; J. Exp. Med. 1970; 131: 1271-1287) for 5-8 minutes, rinsed with water for 0.5 minutes, and counterstained with 0.07% methylene blue for 2 minutes.


    Claims

    1. A compound of formula I

    or a pharmaceutical salt thereof,
    wherein:

    X is:

    a bond;

    -C1-6alkylene-;

    -NRa-;

    -NRa-C1-6alkylene;

    -C1-6alkylene-NRa-;

    -O-; -O-C1-6alkylene-;

    -C1-6alkylene-O-; or

    -C1-6alkylene-O-C1-6alkylene-;

    R1 is:

    hydrogen;

    C1-6alkyl; or

    halo-C1-6alkyl;

    R2 is:

    hydrogen;

    C1-6alkyl;

    oxo; or

    halo-C1-6alkyl;

    R3 is:

    hydrogen;

    C1-6alkyl;

    halo;

    hydroxy;

    C1-6alkoxy; -

    -O-C(O)-Re;

    -CN;

    carboxy;

    oxo; or

    =CH2;

    wherein the C1-6alkyl moieties each may be unsubstituted or substituted one or more times with halo;
    or R2 and R3 together with the atoms to which they are attached may form a double bond;

    R4 is:

    C1-6alkyl;

    halo-C1-6alkyl;

    halo;

    hydroxy;

    hydroxy-C1-6alkyl;

    C1-6alkoxy-C1-6alkyl;

    C1-6alkoxy-C1-6alkoxy-C1-6alkyl;

    cyano;

    cyano- C1-6alkyl;

    aminosulfonylC1-6alkyl

    -(CRfRg)m-NRhRi;

    -(CRfRg)m-C(O)-NRjRk;

    -(CRfRg)m-C(O)-Rm;

    -(CRfRg)m-NRp-C(O)-Rn;

    -(CRfRg)m-O-C(O)-Rn;

    a six membered heteroaryl selected from pyridazin-2-yl, 1-methylpyridin-2-one-6-yl, pyridin-2-yl, and pyridin-3-yl,

    a five membered heteroaryl selected from oxazolyl, isoxazolyl, oxadiazolyl,thiadiazolyl imidazolyl, triazolyl and pyrazolyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, C1-6alkoxy, hydroxy-C1-6alkyl, C1-6alkoxy-C1-6alkyl, oxo, C3-6cycloalky, halo-C1-6alkyl, amino, N-C1-6alkyl-amino, N,N-di-C1-6alkyl-amino amino-C1-6alkyl, cyano-C1-6alkyl, or C1-6alkoxycarbonyl;

    heteroaryl-CH2-, wherein the heteroaryl moiety is selected from pyrazolyl and oxadiazolyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, hydroxy-C1-6alkyl, halo-C1-6alkyl, hydroxy, C1-6alkoxy, C1-6alkoxy-C1-6alkyl, amino-C1-6alkyl, or oxo;

    heteroaryloxy-CH2-, wherein the heteroaryl moiety is selected from oxadiazolyl, pyridinyl, and pyrazinyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, hydroxy-C1-6alkyl, halo-C1-6alkyl, hydroxy, C1-6alkoxy, C1-6alkoxy-C1-6alkyl, amino-C1-6alkyl, or oxo;

    phenyl-C1-6alkoxy- CH2-, wherein the phenyl moiety may be unsubstituted or substituted one or more times with C1-6alkoxy-carbonyl, carboxy, or aminocarbonyl;

    heterocyclyl selected from pyrrolidinyl, imidazolidinyl, oxazolidinyl, and 1,1-dioxoisothiazolidinyl, each of which may be unsubstituted or substituted one or more times with with C1-6alkyl, or oxo; or

    heterocyclyl- CH2-, wherein the heterocyclyl moiety is selected from imidazolidinyl, morpholin-4-yl, and azetidinyl each of which may be unsubstituted or substituted one or more times with C1-6alkyl, oxo, morpholinylethyl, or cyano;
    m is from 0 to 2;

    R5 is

    C1-6alkyl which may be unsubstituted or substituted one or more times with halo;

    R6 is

    C1-6alkyl which may be unsubstituted or substituted one or more times with halo or C1-6alkylcarbonyloxy;
    or R5 and R6 together with the atoms to which they are attached may form a three to seven membered carbocyclic ring which may be unsubstituted or substituted one or more times with Rx, and wherein a ring atom may be substituted with a heteroatom selected from O, N and S;

    R7 is:

    hydrogen;

    C1-6alkyl;

    halo; or

    halo-C1-6alkyl;

    Ar1 is:

    aryl; or

    heteroaryl selected from pyridinyl, pyrimidinyl, pyridazinyl and thienyl;

    wherein the aryl and heteroaryl each may be unsubstituted or substituted one or more times with C1-6alkyl or halo;

    Re is:

    C1-6alkyl; or

    C1-6alkoxy;

    each of which may be unsubstituted or substituted one or more times with halo;

    Rf and Rg each independently is:

    hydrogen; or

    C1-6alkyl;

    Rh is:

    hydrogen;

    C1-6alkyl;

    C1-6alkoxy-C1-6alkyl;

    hydroxy-C1-6alkyl;

    amino-C1-6alkyl;

    N-C1-6alkyl-amino-C1-6alky;

    N,N-di-C1-6alkyl-amino-C1-6alkyl; or

    halo-C1-6alkyl;

    Ri is:

    C1-6alkyl;

    C1-6alkoxy-C1-6alkyl;

    halo-C1-6alkyl;

    hydroxy-C1-6alkyl;

    C1-6alkylsulfonyl;

    C1-6alkylcarbonyl;

    hydroxy-C1-6alkoxy;

    aminocarbonyl-C1-6alkyl,

    hydroxy-C1-6alkyl-carbonyl,

    cyano-C1-6alkyl;

    oxetanyl;

    C1-6alkylsulfonyl;

    halo-C1-6alkylsulfonyl; or

    heteroaryl selected from oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, each of which which may be unsubstituted or substituted one or more times with C1-6alkyl, hydroxy-C1-6alkyl, oxo, or halo-C1-6alkyl;

    Rj is:

    hydrogen;

    C1-6alkyl; or

    benzyl

    Rk is:

    hydrogen;

    C1-6alkyl;

    halo-C1-6alkyl;

    cyano-C1-6alkyl;

    hydroxy-C1-6alkoxy;

    C1-6alkoxy;

    C3-6cycloalkyl;

    C3-6cycloalkyl-C1-6 alkyl;

    heteroaryl selected from oxadiazolyl, or pyridinyl, each of which which may be unsubstituted or substituted one or more times with C1-6alkyl, cyano, C1-6alkylsulfonyl, or halo;

    phenyl which which may be unsubstituted or substituted one or more times with C1-6alkylsulfonyl; or

    benzyl, the phenyl portion of which which may be unsubstituted or substituted one or more times with C1-6alkyl, halo,
    or Rj and Rk together with the atoms to which they are attached may form a four to seven membered heterocyclyl selected from:

    azetidinyl,

    morpholinyl,

    pyrolidinyl,

    azabicyclo[3.1.0]hexanyl,

    piperidinyl,

    piperazinyl,

    2-oxa-5-azabicyclo[2.2.1]heptan-5-yl,

    3-azabicyclo[3.1.0]hexanyl,

    2-azabicyclo[2.1.1]hexanyl,

    tetrahydro-1H-furo[3,4-c]pyrrolyl,

    2-oxa-6-azaspiro[3.4]octanyl,

    5-oxa-2-azaspiro[3.4]octanyl,

    2-azabicyclo[3.1.0]hexanyl,

    2,5-diazabicyclo[2.2.1]heptanyl,

    2-azaspiro [3.3]heptanyl,

    7-azabicyclo[2.2.1]heptanyl, or

    8-azabicyclo[3.2.1]octanyl,

    each of which may be unsubstituted or substituted one or more times with

    C1-6alkyl,

    halo,

    amino,

    N-C1-6alkyl-amino,

    N,N-di-C1-6alkyl-amino,

    hydroxy,

    C1-6alkoxy-carbonyl,

    C1-6alkoxy,

    C1-6alkylsulfonyl,

    hydroxy-C1-6alkyl,

    C1-6alkoxy-C1-6alkyl,

    halo-C1-6alkyl,

    cyano,

    cyano-C1-6alkyl,

    amino-carbonyl,

    N-C1-6alkyl-amino-carbonyl,

    N,N-di-C1-6alkyl-amino-carbonyl,

    C1-6alkyl-carbonyl-amino,

    C1-6alkoxy-carbonyl-amino,

    C1-6alkoxy-carbonyl-amino-C1-6alkyl,

    benzyloxy,

    pyrrolidinyl which may be unsubstituted or substituted one or more times with C1-6alkyl or halo; or

    heteroaryl selected from pyrazolyl, pyrimidinyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, oxo or halo;

    Rm is:

    hydrogen;

    C1-6alkyl;

    cyano-C1-6alkyl;

    halo-C1-6alkyl;

    hydroxy-C1-6alkyl;

    C1-6alkoxy;

    C3-6cycloalkyl;

    C3-6cycloalkyl-C1-6alkyl;

    C1-6alkoxy-C1-6alkyl; hydroxy-C1-6alkyl

    amino-C1-6alkyl;

    heteroaryl selected from pyridinyl, indolyl, and indolinyl; each of which which may be unsubstituted or substituted one or more times with C1-6alkyl, halo, cyano, halo-C1-6alkyl, or C1-6alkyl-sulfonyl

    phenyl which which may be unsubstituted or substituted one or more times with C1-6alkyl,

    phenyl-C1-6alkyl wherein the phenyl portion thereof may be unsubstituted or substituted one or more times with C1-6alkyl, or

    heterocyclyl selected from azetidinyl, or oxetanyl, each of which which may be unsubstituted or substituted one or more times with C1-6alkyl, halo, cyano, or halo-C1-6alkyl,

    Rn is:

    hydrogen;

    C1-6alkyl;

    halo-C1-6alkyl;

    hydroxy-C1-6alkyl;

    hydroxy-C1-6alkoxy;

    C3-6cycloalkyl;

    C3-6cycloalkyl-C1-6alkyl;

    C1-6alkoxy,

    C1-6alkoxy-C1-6alkyl;

    hydroxy-C1-6alkyl,

    amino,

    N-C1-6alkyl-amino,

    N,N-di-C1-6alkyl-amino,

    amino-C1-6alkyl,

    N-C1-6alkyl-amino-C1-6alkyl,

    N,N-di-C1-6alkyl-amino-C1-6alkyl,

    amino-carbonyl-C1-6alkyl,

    N-C1-6alkyl-amino-carbonyl-C1-6alkyl,

    N,N-di-C1-6alkyl-amino-carbonyl-C1-6alkyl,

    amino-carbonyl-amino-C1-6alkyl,

    5-methylisoxazole-3-yl;

    cyano-C1-6alkyl;

    C1-6alkylsulfonyl;

    C1-6alkylcarbonyl-amino-C1-6alkyl, or

    C1-6alkylsulfonyl-C1-6alkyl; and

    Rp is:

    hydrogen;

    C1-6alkyl;

    halo-C1-6alkyl;

    hydroxy-C1-6alkyl;

    C1-6alkoxycarbonyl-C1-6alkyl; or

    cyano-C1-6alkyl;
    provided that when X is a bond, R1, R2 and R3 are hydrogen and R4 is C1-6alkyl, then Ar1 is 2,6-dihalophenyl.


     
    2. The compound of claim 1, wherein X is a bond.
     
    3. The compound of claims 1 or 2, wherein R1 is hydrogen.
     
    4. The compound of any of claim 1-3, wherein R3 is hydrogen.
     
    5. The compound of any of claim 1-4, wherein R4 is:

    halo-C1-6alkyl;

    halo;

    hydroxy;

    C1-6alkoxy;

    hydroxy-C1-6alkyl;

    C1-6alkoxy-C1-6alkyl;

    C1-6alkoxy-C1-6alkoxy-C1-6alkyl;

    cyano;

    cyano- C1-6alkyl;

    -(CRfRg)m-NRhRi;

    -(CRfRg)m-C(O)-NRjRk;

    -(CRfRg)m-C(O)-Rm;

    -(CRfRg)m-NRp-C(O)-Rn;

    -(CRfRg)m-O-C(O)-Rn;

    a six membered heteroaryl selected from pyridazin-2-yl, 1-methylpyridin-2-one-6-yl, pyridin-2-yl, and pyridin-3-yl,

    a five membered heteroaryl selected from oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and pyrazolyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, C1-6alkoxy, hydroxy-C1-6alkyl, C1-6alkoxy-C1-6alkyl, oxo, C3-6cycloalky, halo-C1-6alkyl, amino, N-C1-6alkyl-amin0, N,N-di-C1-6alkyl-amino amino-C1-6alkyl, cyano-C1-6alkyl, or C1-6alkoxycarbonyl;

    heteroaryl-C1-6alkyl, wherein the C1-6alkyl moity may be unsubstituted or substituted one or more times with hydroxy or C1-6alkoxy, and wherein the heteroaryl moiety is selected from pyrazolyl, oxadiazolyl and pyridinyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, hydroxy-C1-6alkyl, halo-C1-6alkyl, hydroxy, C1-6alkoxy, C1-6alkoxy-C1-6alkyl, amino-C1-6alkyl, or oxo;

    heteroaryloxy-C1-6alkyl, wherein the heteroaryl moiety is selected from oxadiazolyl, pyridinyl, and pyrazinyl, each of which may be unsubstituted or substituted one or more times with C1-6alkyl, hydroxy-C1-6alkyl, halo-C1-6alkyl, hydroxy, C1-6alkoxy, C1-6alkoxy-C1-6alkyl, amino-C1-6alkyl, or oxo;

    phenyl-C1-6alkoxy-C1-6alkyl wherein the phenyl moiety may be unsubstituted or substituted one or more times with C1-6alkoxy-carbonyl, carboxy, or aminocarbonyl;

    heterocyclyl selected from pyrrolidinyl, imidazolidinyl, oxazolidinyl, and 1,1-dioxoisothiazolidinyl, each of which may be unsubstituted or substituted one or more times with with C1-6alkyl, or oxo; or

    heterocyclyl-C1-6alkyl wherein the heterocyclyl moiety is selected from imidazolidinyl, morpholinyl, and azetidinyl each of which may be unsubstituted or substituted one or more times with C1-6alkyl, oxo, morpholinylethyl, or cyano.


     
    6. The compound of any of claims 1-5, wherein R5 is C1-6alkyl.
     
    7. The compound of any of claims 1-6, whereinR6 is C1-6alky.
     
    8. The compound of any of claims 1-7, wherein Ar1 is 2-halo-phenyl or 2,6-dihalo-phenyl.
     
    9. The compound of any of claims 1-8, wherein R7 is hydrogen.
     
    10. The compound of any of claims 1-9, wherein the compound is of formula II:

    and wherein:

    R8 is: hydrogen; or halo; and

    R9 is halo.


     
    11. A composition comprising:

    (a) a pharmaceutically acceptable carrier; and

    (b) a compound of any of claims 1-9.


     
    12. A compound of claim of any one of claim 1 to 9 for the treatment of rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, juvenile arthritis, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic, renal colic, diarrhea-dominant IBS, muscular sclerosis, Sjogren's disease, lupus, and pulmonary fibrosis.
     


    Ansprüche

    1. Verbindung der Formel I

    oder ein pharmazeutisches Salz davon,
    wobei:

    X:

    eine Bindung;

    -C1-6- Alkylen-;

    -NRa-;

    -NRa-C1-6-alkylen;

    -C1-6-Alkylen-NRa-;

    -O-; -O-C1-6-Alkylen-;

    -C1-6-Alkylen-O- oder

    -C1-6-Alkylen-O-C1-6-alkylen- ist;

    R1:

    Wasserstoff;

    C1-6-Alkyl oder

    Halogen-C1-6-alkyl ist;

    R2:

    Wasserstoff;

    C1-6-Alkyl;

    Oxo oder

    Halogen-C1-6-alkyl ist;

    R3:

    Wasserstoff;

    C1-6-Alkyl;

    Halogen;

    Hydroxy;

    C1-6-Alkoxy;

    -O-C(O)-Re;

    -CN;

    Carboxy;

    Oxo oder

    =CH2 ist;

    wobei die C1-6-Alkylreste jeweils unsubstituiert oder ein- oder mehrfach mit Halogen substituiert sein können;
    oder R2 und R3 zusammen mit den Atomen, an die sie gebunden sind, eine Doppelbindung bilden können;

    R4:

    C1-6-Alkyl;

    Halogen-C1-6-alkyl;

    Halogen;

    Hydroxy;

    Hydroxy-C1-6-alkyl;

    C1-6-Alkoxy-C1-6-alkyl;

    C1-6-Alkoxy-C1-6-alkoxy-C1-6-alkyl;

    Cyano;

    Cyano-C1-6-alkyl;

    Aminosulfonyl-C1-6-alkyl

    -(CRfRg)m-NRhRi;

    -(CRfRg)m-C(O)-NRjRk;

    -(CRfRg)m-C(O)-Rm;

    -(CRfRg)m-NRp-C(O)-Rn;

    -(CRfRg)m-O-C(O)-Rn ist;

    ein sechsgliedriges Heteroaryl ist, ausgewählt aus Pyridazin-2-yl, 1-Methylpyridin-2-on-6-yl, Pyridin-2-yl und Pyridin-3-yl,
    ein fünfgliedriges Heteroaryl ist, ausgewählt aus Oxazolyl, Isoxazolyl, Oxadiazolyl, Thiadiazolylimidazolyl, Triazolyl und Pyrazolyl, die jeweils unsubstituiert oder ein- oder mehrfach mit C1-6-Alkyl, C1-6-Alkoxy, Hydroxy-C1-6-alkyl, C1-6-Alkoxy-C1-6-alkyl, Oxo, C3-6-Cycloalkyl, Halogen-C1-6-alkyl, Amino, N-C1-6-Alkylamino, N,N-Di-C1-6-alkylamino, Amino-C1-6-alkyl, Cyano-C1-6-alkyl oder C1-6-Alkoxycarbonyl substituiert sein können;

    Heteroaryl-CH2- ist, wobei der Heteroarylrest ausgewählt ist aus Pyrazolyl und Oxadiazolyl, die jeweils unsubstituiert oder ein- oder mehrfach mit C1-6-Alkyl, Hydroxy-C1-6-alkyl, Halogen-C1-6-alkyl, Hydroxy, C1-6-Alkoxy, C1-6-Alkoxy-C1-6-alkyl, Amino-C1-6-alkyl oder Oxo substituiert sein können;

    Heteroaryloxy-CH2- ist, wobei der Heteroarylrest ausgewählt ist aus Oxadiazolyl, Pyridinyl und Pyrazinyl, die jeweils unsubstituiert oder ein- oder mehrfach mit C1-6-Alkyl, Hydroxy-C1-6-alkyl, Halogen-C1-6-alkyl, Hydroxy, C1-6-Alkoxy, C1-6-Alkoxy-C1-6-alkyl, Amino-C1-6-alkyl oder Oxo substituiert sein können;

    Phenyl-C1-6-alkoxy-CH2- ist, wobei der Phenylrest unsubstituiert oder ein- oder mehrfach mit C1-6-Alkoxycarbonyl, Carboxy oder Aminocarbonyl substituiert sein kann.

    Heterocyclyl ist, ausgewählt aus Pyrrolidinyl, Imidazolidinyl, Oxazolidinyl und 1,1-Dioxoisothiazolidinyl, die jeweils unsubstituiert oder ein- oder mehrfach mit C1-6-Alkyl oder Oxo substituiert sein können; oder

    Heterocyclyl-CH2- ist, wobei der Heterocyclylrest ausgewählt ist aus Imidazolidinyl, Morpholin-4-yl und Azetidinyl, die jeweils unsubstituiert oder ein- oder mehrfach mit C1-6-Alkyl, Oxo, Morpholinylethyl oder Cyano substituiert sein können;
    m 0 bis 2 beträgt;

    R5

    C1-6-Alkyl ist, das unsubstituiert oder ein- oder mehrfach mit Halogen substituiert sein kann;

    R6

    C1-6-Alkyl ist, das unsubstituiert oder ein- oder mehrfach mit Halogen oder C1-6-Alkylcarbonyloxy substituiert sein kann;
    oder R5 und R6 zusammen mit den Atomen, an die sie gebunden sind, einen drei- bis siebengliedrigen carbocyclischen Ring bilden können, der unsubstituiert oder ein- oder mehrfach mit Rx substituiert sein kann, und wobei ein Ringatom mit einem aus O, N und S ausgewählten Heteroatom substituiert sein kann;

    R7:

    Wasserstoff;

    C1-6-Alkyl;

    Halogen oder

    Halogen-C1-6-alkyl ist;

    Ar1:

    Aryl oder

    Heteroaryl ist, ausgewählt aus Pyridinyl, Pyrimidinyl, Pyridazinyl und Thienyl;
    wobei das Aryl und Heteroaryl jeweils unsubstituiert oder ein- oder mehrfach mit C1-6-Alkyl oder Halogen substituiert sein können;

    Re:

    C1-6-Alkyl oder

    C1-6-Alkoxy ist,

    die jeweils unsubstituiert oder ein- oder mehrfach mit Halogen substituiert sein können;

    Rf und Rg jeweils unabhängig:

    Wasserstoff oder

    C1-6-Alkyl sind;

    Rh:

    Wasserstoff;

    C1-6-Alkyl;

    C1-6-Alkoxy-C1-6-alkyl;

    Hydroxy-C1-6-alkyl;

    Amino-C1-6-alkyl;

    N-C1-6-Alkylamino-C1-6-alkyl;

    N,N-Di-C1-6-alkylamino-C1-6-alkyl oder

    Halogen-C1-6-alkyl ist;

    Ri:

    C1-6-Alkyl; C1-6-Alkoxy-C1-6-alkyl;

    Halogen-C1-6-alkyl;

    Hydroxy-C1-6-alkyl;

    C1-6-Alkylsulfonyl;

    C1-6-Alkylcarbonyl;

    Hydroxy-C1-6-alkoxy;

    Aminocarbonyl-C1-6-alkyl,

    Hydroxy-C1-6-alkylcarbonyl,

    Cyano-C1-6-alkyl;

    Oxetanyl;

    C1-6-Alkylsulfonyl;

    Halogen-C1-6-alkylsulfonyl oder
    Heteroaryl ist, ausgewählt aus Oxadiazolyl, Thiadiazolyl, Pyridinyl, Pyrimidinyl und Pyrazinyl, die jeweils unsubstituiert oder ein- oder mehrfach mit C1-6-Alkyl, Hydroxy-C1-6-alkyl, Oxo oder Halogen-C1-6-alkyl substituiert sein können;

    Rj:

    Wasserstoff;

    C1-6-Alkyl oder

    Benzyl ist

    Rk:

    Wasserstoff;

    C1-6-Alkyl;

    Halogen-C1-6-alkyl;

    Cyano-C1-6-alkyl;

    Hydroxy-C1-6-alkoxy;

    C1-6-Alkoxy;

    C3-6-Cycloalkyl;

    C3-6-Cycloalkyl-C1-6-alkyl;

    Heteroaryl, ausgewählt aus Oxadiazolyl oder Pyridinyl ist, die jeweils unsubstituiert oder ein- oder mehrfach mit C1-6-Alkyl, Cyano, C1-6-Alkylsulfonyl oder Halogen substituiert sein können;

    Phenyl ist, das unsubstituiert oder ein- oder mehrfach mit C1-6-Alkylsulfonyl substituiert sein kann; oder

    Benzyl ist, wobei sein Phenylanteil unsubstituiert oder ein- oder mehrfach mit C1-6-Alkyl, Halogen substituiert sein kann
    oder Rj und Rk zusammen mit den Atomen, an die sie gebunden sind, ein vier- bis siebengliedriges Heterocyclyl bilden können, das ausgewählt ist aus:

    Azetidinyl,

    Morpholinyl,

    Pyrrolidinyl,

    Azabicyclo[3.1.0]hexanyl,

    Piperidinyl,

    Piperazinyl,

    2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl,

    3-Azabicyclo[3.1.0]hexanyl,

    2-Azabicyclo[2.1.1]hexanyl,

    Tetrahydro-1H-furo[3,4-c]pyrrolyl

    2-Oxa-6-azaspiro[3.4]octanyl,

    5-Oxa-2-azaspiro[3.4]octanyl,

    2-Azabicyclo[3.1.0]hexanyl,

    2,5-Diazabicyclo[2.2.1]heptanyl,

    2-Azaspiro[3.3]heptanyl,

    7-Azabicyclo[2.2.1]heptanyl oder

    8-Azabicyclo[3.2.1]octanyl,

    die jeweils unsubstituiert oder ein- oder mehrfach substituiert sein können mit

    C1-6-Alkyl,

    Halogen,

    Amino,

    N-C1-6-Alkylamino,

    N-N-Di-C1-6-alkylamino,

    Hydroxy,

    C1-6-Alkoxycarbonyl,

    C1-6-Alkoxy,

    C1-6-Alkylsulfonyl,

    Hydroxy-C1-6-alkyl,

    C1-6-Alkoxy-C1-6-alkyl,

    Halogen-C1-6-alkyl,

    Cyano,

    Cyano-C1-6-alkyl,

    Aminocarbonyl,

    N-C1-6-Alkylaminocarbonyl,

    N,N-Di-C1-6-alkylaminocarbonyl,

    C1-6-Alkylcarbonylamino,

    C1-6-Alkoxycarbonylamino,

    C1-6-Alkoxycarbonylamino-C1-6-alkyl,

    Benzyloxy,

    Pyrrolidinyl, das unsubstituiert oder ein- oder mehrfach mit C1-6-Alkyl oder Halogen substituiert sein kann; oder

    Heteroaryl, ausgewählt aus Pyrazolyl, Pyrimidinyl, die jeweils ein- oder mehrfach mit C1-6-Alkyl, Oxo oder Halogen unsubstituiert oder substituiert sein können;

    Rm:

    Wasserstoff;

    C1-6-Alkyl;

    Cyano-C1-6-alkyl;

    Halogen-C1-6-alkyl;

    Hydroxy-C1-6-alkyl;

    C1-6-Alkoxy;

    C3-6-Cycloalkyl;

    C3-6-Cycloalkyl-C1-6-alkyl;

    C1-6-Alkoxy-C1-6-alkyl; Hydroxy-C1-6-alkyl;

    Amino-C1-6-alkyl;

    Heteroaryl ist, ausgewählt aus Pyridinyl, Indolyl und Indolinyl, die jeweils unsubstituiert oder ein- oder mehrfach mit C1-6-Alkyl, Halogen, Cyano, Halogen-C1-6-alkyl oder C1-6-Alkylsulfonyl substituiert sein können

    Phenyl ist, das unsubstituiert oder ein- oder mehrfach mit C1-6-Alkyl substituiert sein kann,

    Phenyl-C1-6-alkyl ist, wobei der Phenylanteil davon unsubstituiert oder ein- oder mehrfach mit C1-6-Alkyl substituiert sein kann, oder

    Heterocyclyl ist, ausgewählt aus Azetidinyl oder Oxetanyl, die jeweils unsubstituiert oder ein- oder mehrfach mit C1-6-Alkyl, Halogen, Cyano oder Halogen-C1-6-alkyl substituiert sein können,

    Rn:

    Wasserstoff;

    C1-6-Alkyl;

    Halogen-C1-6-alkyl;

    Hydroxy-C1-6-alkyl;

    Hydroxy-C1-6-alkoxy;

    C3-6-Cycloalkyl;

    C3-6-Cycloalkyl-C1-6-alkyl;

    C1-6-Alkoxy,

    C1-6-Alkoxy-C1-6-alkyl;

    Hydroxy-C1-6-alkyl,

    Amino,

    N-C1-6-Alkylamino,

    N,N-Di-C1-6-alkylamino,

    Amino-C1-6-alkyl,

    N-C1-6-Alkylamino-C1-6-alkyl,

    N,N-Di-C1-6-alkylamino-C1-6-alkyl,

    Aminocarbonyl-C1-6-alkyl,

    N-C1-6-Alkylaminocarbonyl-C1-6-alkyl,

    N,N-Di-C1-6-alkylaminocarbonyl-C1-6-alkyl,

    Aminocarbonylamino-C1-6-alkyl,

    5-Methylisoxazol-3-yl;

    Cyano-C1-6-alkyl;

    C1-6-Alkylsulfonyl;

    C1-6-Alkylcarbonylamino-C1-6-alkyl oder

    C1-6-Alkylsulfonyl-C1-6-alkyl ist und

    Rp:

    Wasserstoff;

    C1-6-Alkyl;

    Halogen-C1-6-alkyl;

    Hydroxy-C1-6-alkyl;

    C1-6-Alkoxycarbonyl-C1-6-alkyl oder

    Cyano-C1-6-alkyl ist;
    vorausgesetzt, dass dann, wenn X eine Bindung ist, R1, R2 und R3 Wasserstoff sind und R4 C1-6-Alkyl ist, Ar1 2,6-Dihalogenphenyl ist.


     
    2. Verbindung nach Anspruch 1, wobei X eine Bindung ist.
     
    3. Verbindung nach Anspruch 1 oder 2, wobei R1 Wasserstoff ist.
     
    4. Verbindung nach einem der Ansprüche 1-3, wobei R3 Wasserstoff ist.
     
    5. Verbindung nach einem der Ansprüche 1-4, wobei R4:

    Halogen-C1-6-alkyl;

    Halogen;

    Hydroxy;

    C1-6-Alkoxy;

    Hydroxy-C1-6-alkyl;

    C1-6-Alkoxy-C1-6-alkyl;

    C1-6-Alkoxy-C1-6-alkoxy-C1-6-alkyl;

    Cyano;

    Cyano-C1-6-alkyl;

    -(CRfRg)m-NRhRi;

    -(CRfRg)m-C(O)-NRjRk;

    -(CRfRg)m-C(O)-Rm;

    -(CRfRg)m-NRp-C(O)-Rn;

    -(CRfRg)m-O-C(O)-Rn ist;
    ein sechsgliedriges Heteroaryl ist, ausgewählt aus Pyridazin-2-yl, 1-Methylpyridin-2-on-6-yl, Pyridin-2-yl und Pyridin-3-yl,
    ein fünfgliedriges Heteroaryl ist, ausgewählt aus Oxazolyl, Isoxazolyl, Oxadiazolyl, Imidazolyl, Triazolyl und Pyrazolyl, die jeweils unsubstituiert oder ein- oder mehrfach mit C1-6-Alkyl, C1-6-Alkoxy, Hydroxy-C1-6-alkyl, C1-6-Alkoxy-C1-6-alkyl, Oxo, C3-6-Cycloalkyl, Halogen-C1-6-alkyl, Amino, N-C1-6-Alkylamino, N,N-Di-C1-6-alkylamino, Amino-C1-6-alkyl, Cyano-C1-6-alkyl oder C1-6-Alkoxycarbonyl substituiert sein können;
    Heteroaryl-C1-6-alkyl ist, wobei der C1-6-Alkylrest unsubstituiert oder ein- oder mehrfach mit Hydroxy oder C1-6-Alkoxy substituiert sein kann, und wobei der Heteroarylrest ausgewählt ist aus Pyrazolyl, Oxadiazolyl und Pyridinyl, die jeweils unsubstituiert oder ein- oder mehrfach mit C1-6-Alkyl, Hydroxy-C1-6-alkyl, Halogen-C1-6-alkyl, Hydroxy, C1-6-Alkoxy, C1-6-Alkoxy-C1-6-alkyl, Amino-C1-6-alkyl oder Oxo substituiert sein können;
    Heteroaryloxy-C1-6-alkyl ist, wobei der Heteroarylrest ausgewählt ist aus Oxadiazolyl, Pyridinyl und Pyrazinyl, die jeweils unsubstituiert oder ein- oder mehrfach mit C1-6-Alkyl, Hydroxy-C1-6-alkyl, Halogen-C1-6alkyl, Hydroxy, C1-6-Alkoxy, C1-6-Alkoxy-C1-6-alkyl, Amino-C1-6-alkyl oder Oxo substituiert sein können;
    Phenyl-C1-6-alkoxy-C1-6-alkyl ist, wobei der Phenylrest unsubstituiert oder ein- oder mehrfach mit C1-6-Alkoxycarbonyl, Carboxy oder Aminocarbonyl substituiert sein kann;
    Heterocyclyl ist, ausgewählt aus Pyrrolidinyl, Imidazolidinyl, Oxazolidinyl und 1,1-Dioxoisothiazolidinyl, die jeweils unsubstituiert oder ein- oder mehrfach mit C1-6-Alkyl oder Oxo substituiert sein können oder
    Heterocyclyl-C1-6-alkyl ist, wobei der Heterocyclylrest ausgewählt ist aus Imidazolidinyl, Morpholinyl und Azetidinyl, die jeweils unsubstituiert oder ein- oder mehrfach mit C1-6-Alkyl, Oxo, Morpholinylethyl oder Cyano substituiert sein können.


     
    6. Verbindung nach einem der Ansprüche 1-5, wobei R5 C1-6-Alkyl ist.
     
    7. Verbindung nach einem der Ansprüche 1-6, wobei R6 C1-6-Alkyl ist.
     
    8. Verbindung nach einem der Ansprüche 1-7, wobei Ar1 2-Halogenphenyl oder 2,6-Dihalogenphenyl ist.
     
    9. Verbindung nach einem der Ansprüche 1-8, wobei R7 Wasserstoff ist.
     
    10. Verbindung nach einem der Ansprüche 1-9, wobei die Verbindung nach der Formel II ist:

    und wobei:

    R8 Wasserstoff oder Halogen ist und

    R9 Halogen ist.


     
    11. Zusammensetzung, umfassend:

    (a) einen pharmazeutisch annehmbaren Träger und

    (b) eine Verbindung nach einem der Ansprüche 1-9.


     
    12. Verbindung nach einem der Ansprüche 1 bis 9 zur Behandlung von rheumatoider Arthritis, Osteoarthritis, psoriatischer Arthritis, septischer Arthritis, Spondyloarthropathien, Gichtarthritis, juveniler Arthritis, chronisch obstruktiver Lungenerkrankung (COPD), Asthma, Bronchospasmus, Reizdarmsyndrom (IBS), entzündlicher Darmerkrankung (IBD), Gallenkolik, Nierenkolik, diarrhoedominantem IBS, multipler Sklerose, Sjögren-Syndrom, Lupus und Lungenfibrose.
     


    Revendications

    1. Composé de formule I

    ou sel pharmaceutique de celui-ci,
    dans laquelle :

    X représente :

    une liaison ;

    -alkylène en C1-6- ;

    -NRa- ;

    -NRa-alkylène en C1-6- ;

    -alkylène en C1-6-NRa- ;

    -O- ; -O-alkylène en C1-6- ;

    -alkylène en C1-6-O- ; ou

    -alkylène en C1-6-O-alkylène en C1-6- ;

    R1 représente :

    un hydrogène ;

    un alkyle en C1-6 ; ou

    un halogénoalkyle en C1-6 ;

    R2 représente :

    un hydrogène ;

    un alkyle en C1-6 ;

    un oxo ; ou

    un halogénoalkyle en C1-6 ;

    R3 représente :

    un hydrogène ;

    un alkyle en C1-6 ;

    un halogène ;

    un hydroxy ;

    un alcoxy en C1-6 ;

    -O-C(O)-Re ;

    -CN ;

    un carboxy ;

    un oxo ; ou

    =CH2 ;

    chacun des fragments alkyle en C1-6 pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un halogène ;
    ou R2 et R3 pouvant former ensemble avec les atomes auxquels ils sont liés une double liaison ;

    R4 représente :

    un alkyle en C1-6 ;

    un halogénoalkyle en C1-6 ;

    un halogène ;

    un hydroxy ;

    un hydroxyalkyle en C1-6 ;

    un alcoxy en C1-6-alkyle en C1-6 ;

    un alcoxy en C1-6-alcoxy en C1-6-alkyle en C1-6 ;

    un cyano ;

    un cyanoalkyle en C1-6 ;

    un aminosulfonylalkyle en C1-6 ;

    -(CRfRg)m-NRhRi ;

    -(CRfRg)m-C(O)-NRjRk ;

    -(CRfRg)m-C(O)-Rm ;

    -(CRfRg)m-NRp-C(O)-Rn ;

    -(CRfRg)m-O-C(O)-Rn ;

    un hétéroaryle à six chaînons choisi parmi un pyridazin-2-yle, un 1-méthylpyridin-2-on-6-yle, un pyridin-2-yle et un pyridin-3-yle,

    un hétéroaryle à cinq chaînons choisi parmi un oxazolyle, un isoxazolyle, un oxadiazolyle, un thiadiazolyle, un imidazolyle, un triazolyle et un pyrazolyle, chacun de ceux-ci pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un alkyle en C1-6, un alcoxy en C1-6, un hydroxyalkyle en C1-6, un alcoxy en C1-6-alkyle en C1-6, un oxo, un cycloalkyle en C3-6, un halogénoalkyle en C1-6, un amino, un N-alkyle en C1-6-amino,
    un N,N-di-alkyle en C1-6-amino, un aminoalkyle en C1-6, un cyanoalkyle en C1-6 ou un alcoxy en C1-6-carbonyle ;

    un hétéroaryl-CH2-, ledit fragment hétéroaryle étant choisi parmi un pyrazolyle et un oxadiazolyle, chacun de ceux-ci pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un alkyle en C1-6, un hydroxyalkyle en C1-6, un halogénoalkyle en C1-6, un hydroxy, un alcoxy en C1-6, un alcoxy en C1-6-alkyle en C1-6, un aminoalkyle en C1-6 ou un oxo ;

    un hétéroaryloxy-CH2-, ledit fragment hétéroaryle étant choisi parmi un oxadiazolyle, un pyridinyle et un pyrazinyle, chacun de ceux-ci pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un alkyle en C1-6, un hydroxyalkyle en C1-6, un halogénoalkyle en C1-6, un hydroxy, un alcoxy en C1-6, un alcoxy en C1-6-alkyle en C1-6, un aminoalkyle en C1-6 ou un oxo ;

    un phényl-alcoxy en C1-6-CH2-, ledit fragment phényle pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un alcoxy en C1-6-carbonyle, un carboxy ou un aminocarbonyle ;

    un hétérocyclyle choisi parmi un pyrrolidinyle, un imidazolidinyle, un oxazolidinyle et un 1,1-dioxoisothiazolidinyle, chacun de ceux-ci pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un alkyle en C1-6 ou un oxo ; ou

    un hétérocyclyl-CH2-, ledit fragment hétérocyclyle étant choisi parmi un imidazolidinyle, un morpholin-4-yle et un azétidinyle, chacun de ceux-ci pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un alkyle en C1-6, un oxo, un morpholinyléthyle ou un cyano ;

    m est compris entre 0 et 2 ;

    R5 représente :

    un alkyle en C1-6 qui peut ne pas être substitué ou être substitué une ou plusieurs fois par un halogène ;

    R6 représente :

    un alkyle en C1-6 qui peut ne pas être substitué ou être substitué une ou plusieurs fois par un halogène ou un alkyle en C1-6-carbonyloxy ;
    ou R5 et R6 peuvent former ensemble avec les atomes auxquels ils sont liés un carbocycle ayant de trois à sept chaînons qui peut ne pas être substitué ou être substitué une ou plusieurs fois par Rx, et un atome du cycle pouvant être substitué par un hétéroatome choisi parmi O, N et S ;

    R7 représente :

    un hydrogène ;

    un alkyle en C1-6 ;

    un halogène ; ou

    un halogénoalkyle en C1-6 ;

    Ar1 représente :

    un aryle ; ou

    un hétéroaryle choisi parmi un pyridinyle, un pyrimidinyle, un pyridazinyle et un thiényle ;

    chacun desdits aryle et hétéroaryle pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un alkyle en C1-6 ou un halogène ;

    Re représente :

    un alkyle en C1-6 ; ou

    un alcoxy en C1-6 ;

    chacun de ceux-ci pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un halogène ;
    chacun des Rf et Rg représente indépendamment :

    un hydrogène ; ou

    un alkyle en C1-6 ;

    Rh représente :

    un hydrogène ;

    un alkyle en C1-6 ;

    un alcoxy en C1-6-alkyle en C1-6 ;

    un hydroxyalkyle en C1-6 ;

    un aminoalkyle en C1-6 ;

    un N-alkyle en C1-6-aminoalkyle en C1-6 ;

    un N,N-di-alkyle en C1-6-aminoalkyle en C1-6 ; ou

    un halogénoalkyle en C1-6 ;

    R1 représente :

    un alkyle en C1-6 ;

    un alcoxy en C1-6-alkyle en C1-6 ;

    un halogénoalkyle en C1-6 ;

    un hydroxyalkyle en C1-6 ;

    un alkyle en C1-6-sulfonyle ;

    un alkyle en C1-6-carbonyle ;

    un hydroxyalcoxy en C1-6 ;

    un aminocarbonylalkyle en C1-6 ;

    un hydroxyalkyle en C1-6-carbonyle ;

    un cyanoalkyle en C1-6 ;

    un oxétannyle ;

    un alkyle en C1-6-sulfonyle ;

    un halogénoalkyle en C1-6-sulfonyle ; ou

    un hétéroaryle choisi parmi un oxadiazolyle, un thiadiazolyle, un pyridinyle, un pyrimidinyle et un pyrazinyle, chacun de ceux-ci pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un alkyle en C1-6, un hydroxyalkyle en C1-6, un oxo ou un halogénoalkyle en C1-6 ;

    Rj représente :

    un hydrogène ;

    un alkyle en C1-6 ; ou

    un benzyle

    Rk représente :

    un hydrogène ;

    un alkyle en C1-6 ;

    un halogénoalkyle en C1-6 ;

    un cyanoalkyle en C1-6 ;

    un hydroxyalcoxy en C1-6 ;

    un alcoxy en C1-6 ;

    un cycloalkyle en C3-6 ;

    un cycloalkyle en C3-6-alkyle en C1-6 ;

    un hétéroaryle choisi parmi un oxadiazolyle ou un pyridinyle, chacun de ceux-ci pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un alkyle en C1-6, un cyano, un alkyle en C1-6-sulfonyle ou un halogène ;

    un phényle qui peut ne pas être substitué ou être substitué une ou plusieurs fois par un alkyle en C1-6-sulfonyle ; ou

    un benzyle, dont la partie phényle peut ne pas être substituée ou être substituée une ou plusieurs fois par un alkyle en C1-6, un halogène,

    ou Rj et Rk peuvent former ensemble avec les atomes auxquels ils sont liés un hétérocyclyle ayant de quatre à sept chaînons choisi parmi :

    un azétidinyle,

    un morpholinyle,

    un pyrrolidinyle,

    un azabicyclo[3.1.0]hexanyle,

    un pipéridinyle,

    un pipérazinyle,

    un 2-oxa-5-azabicyclo[2.2.1]heptan-5-yle,

    un 3-azabicyclo[3.1.0]hexanyle,

    un 2-azabicyclo[2.1.1]hexanyle,

    un tétrahydro-1H-furo[3,4-c]pyrrolyle,

    un 2-oxa-6-azaspiro[3.4]octanyle,

    un 5-oxa-2-azaspiro[3.4]octanyle,

    un 2-azabicyclo[3.1.0]hexanyle,

    un 2,5-diazabicyclo[2.2.1]heptanyle,

    un 2-azaspiro[3.3]heptanyle,

    un 7-azabicyclo[2.2.1]heptanyle, ou

    un 8-azabicyclo[3.2.1]octanyle,

    chacun de ceux-ci pouvant ne pas être substitué ou être substitué une ou plusieurs fois par

    un alkyle en C1-6,

    un halogène,

    un amino,

    un N-alkyle en C1-6-amino,

    un N,N-di-alkyle en C1-6-amino,

    un hydroxy,

    un alcoxy en C1-6-carbonyle,

    un alcoxy en C1-6,

    un alkyle en C1-6-sulfonyle,

    un hydroxyalkyle en C1-6,

    un alcoxy en C1-6-alkyle en C1-6,

    un halogénoalkyle en C1-6,

    un cyano,

    un cyanoalkyle en C1-6,

    un aminocarbonyle,

    un N-alkyle en C1-6-aminocarbonyle,

    un N,N-di-alkyle en C1-6-aminocarbonyle,

    un alkyle en C1-6-carbonylamino,

    un alcoxy en C1-6-carbonylamino,

    un alcoxy en C1-6-carbonylaminoalkyle en C1-6,

    un benzyloxy,

    un pyrrolidinyle qui peut ne pas être substitué ou être substitué une ou plusieurs fois par un alkyle en C1-6ou un halogène ; ou

    un hétéroaryle choisi parmi un pyrazolyle, un pyrimidinyle, chacun de ceux-ci pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un alkyle en C1-6, un oxo ou un halogène ;

    Rm représente :

    un hydrogène ;

    un alkyle en C1-6 ;

    un cyanoalkyle en C1-6 ;

    un halogénoalkyle en C1-6 ;

    un hydroxyalkyle en C1-6 ;

    un alcoxy en C1-6 ;

    un cycloalkyle en C3-6 ;

    un cycloalkyle en C3-6-alkyle en C1-6 ;

    un alcoxy en C1-6-alkyle en C1-6 ; un hydroxyalkyle en C1-6 ;

    un aminoalkyle en C1-6 ;

    un hétéroaryle choisi parmi un pyridinyle, un indolyle, et un indolinyle ; chacun de ceux-ci pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un alkyle en C1-6, un halogène, un cyano, un halogénoalkyle en C1-6, ou un alkyle en C1-6-sulfonyle ;

    un phényle qui peut ne pas être substitué ou être substitué une ou plusieurs fois par un alkyle en C1-6 ;

    un phényl-alkyle en C1-6, dont la partie phényle peut ne pas être substituée ou être substituée une ou plusieurs fois par un alkyle en C1-6 ; ou

    un hétérocyclyle choisi parmi un azétidinyle ou un oxétannyle, chacun de ceux-ci pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un alkyle en C1-6, un halogène, un cyano ou un halogénoalkyle en C1-6 ;

    Rn représente :

    un hydrogène ;

    un alkyle en C1-6 ;

    un halogénoalkyle en C1-6 ;

    un hydroxyalkyle en C1-6 ;

    un hydroxyalcoxy en C1-6 ;

    un cycloalkyle en C3-6 ;

    un cycloalkyle en C3-6-alkyle en C1-6 ;

    un alcoxy en C1-6 ;

    un alcoxy en C1-6-alkyle en C1-6 ;

    un hydroxyalkyle en C1-6 ;

    un amino ;

    un N-alkyle en C1-6-amino ;

    un N-N-di-alkyle en C1-6-amino ;

    un aminoalkyle en C1-6 ;

    un N-alkyle en C1-6-aminoalkyle en C1-6 ;

    un N,N-di-alkyle en C1-6-aminoalkyle en C1-6 ;

    un amino-carbonyl-alkyle en C1-6 ;

    un N-alkyle en C1-6-amino-carbonyl-alkyle en C1-6 ;

    un N,N-di-alkyle en C1-6-amino-carbonyl-alkyle en C1-6 ;

    un amino-carbonyl-aminoalkyle en C1-6 ;

    un 5-méthylisoxazol-3-yle ;

    un cyanoalkyle en C1-6 ;

    un alkyle en C1-6-sulfonyle ;

    un alkyle en C1-6-carbonyl-aminoalkyle en C1-6 ; ou

    un alkyle en C1-6-sulfonyl-alkyle en C1-6 ; et

    Rp représente :

    un hydrogène ;

    un alkyle en C1-6 ;

    un halogénoalkyle en C1-6 ;

    un hydroxyalkyle en C1-6 ;

    un alcoxy en C1-6-carbonyl-alkyle en C1-6 ; ou

    un cyanoalkyle en C1-6 ;
    à condition que lorsque X représente une liaison, R1, R2 et R3 représentent un hydrogène et R4 représente un alkyle en C1-6, alors Ar1 représente un 2,6-dihalogénophényle.


     
    2. Composé selon la revendication 1, dans lequel X représente une liaison.
     
    3. Composé selon les revendications 1 ou 2, dans lequel R1 représente un hydrogène.
     
    4. Composé selon l'une quelconque des revendications 1 à 3, dans lequel R3 représente un hydrogène.
     
    5. Composé selon l'une quelconque des revendications 1 à 4, dans lequel R4 représente :

    un halogénoalkyle en C1-6 ;

    un halogène ;

    un hydroxy ;

    un alcoxy en C1-6 ;

    un hydroxyalkyle en C1-6 ;

    un alcoxy en C1-6-alkyle en C1-6 ;

    un alcoxy en C1-6-alcoxy en C1-6-alkyle en C1-6 ;

    un cyano ;

    un cyano-alkyle en C1-6 ;

    -(CRfRg)m-NRhRi ;

    -(CRfRg)m-C(O)-NRjRk ;

    -(CRfRg)m-C(O)-Rm ;

    -(CRfRg)m-NRp-C(O)-Rn ;

    -(CRfRg)m-O-C(O)-Rn ;

    un hétéroaryle à six chaînons choisi parmi un pyridazin-2-yle,
    un 1-méthylpyridin-2-on-6-yle, un pyridin-2-yle et un pyridin-3-yle,

    un hétéroaryle à cinq chaînons choisi parmi un oxazolyle, un isoxazolyle, un oxadiazolyle, un imidazolyle, un triazolyle et un pyrazolyle, chacun de ceux-ci pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un alkyle en C1-6, un alcoxy en C1-6, un hydroxyalkyle en C1-6, un alcoxy en C1-6-alkyle en C1-6, un oxo, un cycloalkyle en C3-6, un halogénoalkyle en C1-6, un amino, un N-alkyle en C1-6-amino, un N,N-di-alkyle en C1-6-amino, un aminoalkyle en C1-6, un cyanoalkyle en C1-6 ou un alcoxy en C1-6-carbonyle ;

    un hétéroaryl-alkyle en C1-6, ledit fragment alkyle en C1-6 pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un hydroxy ou un alcoxy en C1-6, et ledit fragment hétéroaryle étant choisi parmi un pyrazolyle, un oxadiazolyle et un pyridinyle, chacun de ceux-ci pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un alkyle en C1-6, un hydroxyalkyle en C1-6, un halogénoalkyle en C1-6, un hydroxy, un alcoxy en C1-6, un alcoxy en C1-6-alkyle en C1-6, un aminoalkyle en C1-6 ou un oxo ;

    un hétéroaryloxy-alkyle en C1-6, ledit fragment hétéroaryle étant choisi parmi un oxadiazolyle, un pyridinyle et un pyrazinyle, chacun de ceux-ci pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un alkyle en C1-6, un hydroxy-alkyle en C1-6, un halogénoalkyle en C1-6, un hydroxy, un alcoxy en C1-6, un alcoxy en C1-6-alkyle en C1-6, un aminoalkyle en C1-6 ou un oxo ;

    un phényl-alcoxy en C1-6-alkyle en C1-6, ledit fragment phényle pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un alcoxy en C1-6-carbonyle, un carboxy ou un aminocarbonyle ;

    un hétérocyclyle choisi parmi un pyrrolidinyle, un imidazolidinyle, un oxazolidinyle et un 1,1-dioxoisothiazolidinyle, chacun de ceux-ci pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un alkyle en C1-6 ou un oxo ; ou

    un hétérocyclylalkyle en C1-6, ledit fragment hétérocyclyle étant choisi parmi un imidazolidinyle, un morpholinyle et un azétidinyle, chacun de ceux-ci pouvant ne pas être substitué ou être substitué une ou plusieurs fois par un alkyle en C1-6, un oxo, un morpholinyléthyle ou un cyano.


     
    6. Composé selon l'une quelconque des revendications 1 à 5, dans lequel R5 représente un alkyle en C1-6.
     
    7. Composé selon l'une quelconque des revendications 1 à 6, dans lequel R6 représente un alkyle en C1-6.
     
    8. Composé selon l'une quelconque des revendications 1 à 7, dans lequel Ar1 représente un 2-halogénophényle ou un 2,6-dihalogénophényle.
     
    9. Composé selon l'une quelconque des revendications 1 à 8, dans lequel R7 représente un hydrogène.
     
    10. Composé selon l'une quelconque des revendications 1 à 9, ledit composé étant de formule II :

    et dans laquelle :

    R8 représente : un hydrogène ; ou un halogène ; et

    R9 représente un halogène.


     
    11. Composition comprenant :

    (a) un excipient pharmaceutiquement acceptable ; et

    (b) un composé selon l'une quelconque des revendications 1 à 9.


     
    12. Composé selon l'une quelconque des revendications 1 à 9 pour le traitement de la polyarthrite rhumatoïde, de l'arthrose, de l'arthrite psoriasique, de l'arthrite septique, des spondylarthropathies, de l'arthrite goutteuse, de l'arthrite juvénile, d'une bronchopneumopathie chronique obstructive (BPCO), de l'asthme, d'un bronchospasme, du syndrome de l'intestin irritable (SII), d'une maladie inflammatoire de l'intestin (MII), de coliques biliaires, de coliques rénales, du SII à diarrhée dominante, d'une sclérose musculaire, de la maladie de Sjogren, d'un lupus et d'une fibrose pulmonaire.
     




    REFERENCES CITED IN THE DESCRIPTION



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    Patent documents cited in the description




    Non-patent literature cited in the description