Octahydro-2-h-naphtho 1,2-f indole-4-carboxamide derivatives as selective glucocorticoid receptor modulators

Description of equivalent WO 2004026248 A2

0001TΓΓLE OF THE INVENTION

0002OCTAHYDRO-2-H-NAPHTHO[L,2-F] LNDOLE-4-CARBOXAMIDE DERIVATIVES AS SELECTIVE GLUCOCORTICOID RECEPTOR MODULATORS

BACKGROUND OF THE INVENTION

0004Intracellular receptors (IR's) are a class of structurally related proteins involved in the regulation of gene expression. The steroid hormone receptors are a subset of this superfamily whose natural ligands are typically comprised of endogenous steroids such as estradiol, progesterone, and cortisol. Man-made ligands to these receptors play an important role in human health and, of these receptors, the glucocorticoid receptor has an essential role in regulating human physiology and immune response. Steroids that interact with the glucocorticoid receptor have been shown to be potent antfinflammatory agents. The present invention is directed to a novel class of compounds that are selective glucocorticoid receptor modulators that have potent ani-inflammatory and immunosupresive activity and possess advantages over steroidal glucocorticoid ligands with respect to side effects, efficacy, toxicity and/or metabolism.

SUMMARY OF THE INVENTION

0006The present invention encompasses compounds of Formula I:

0007<img file="EP1542996A2_D0001.tif" />

0008I or pharmaceutically acceptable salts or hydrates thereof, which are useful as selective glucocorticoid receptor ligands for treating a variety of autoimmune and inflammatory diseases or conditions. Pharamaceutical compositions and methods of use are also included. DETAILED DESCRIPTION OF THE INVENTION

0009The present invention encompasses compounds of Formula I

0010<img file="EP1542996A2_D0002.tif" />

0011or a pharmaceutically acceptable salt or hydrate thereof, wherein:

0012n and m are each independently 0, 1 or 2;

0013J is selected from NRl or C(R1)(R2);

0014K is selected from NR3 or C(R3)(R4)_;

0015L is selected from NR5 or C(R5)(R6);

0016X is a bond, -C(O), -N(Rl4)-, -N(Rl4)-C(O)-, -C(O)-N(Rl4)-, -N(Rl4)-S(O)k-, -N(Rl4)-C(0)-NH- or -S(O)k-N(Rl );

0017k is 0, 1 or 2;

0018Rl and RlO are each independently selected from the group consisting of:

0019(1) Cι_6alkyl,

0020(2) C2-6alkenyl,

0021(3) C2-6akynyl,

0022(4) C3_6cycloalkyl,

0023(5) Cι_6alkoxy,

0024(6) Cι_6alkyl-S(O)k-, wherein k is 0, 1 or 2,

0025(7) aryl, (8) aryl Ci-6alkyl,

(9) HET,

0027(10) -Cι_6alkyl-HET,

0028(11) aryloxy,

0029(12) aroyloxy,

0030(13) aryl C2-6^alkenyl,

0031(14) aryl C2-6alkynyl,

0032(15) hydrogen,

0033(16) hydroxyl and

0034(17) cyano,

0035wherein items (1) to (6) above and the alkyl portions of items (8) and (10) above and the alkenyl portion of item (13) above and the alkynyl portion of item (14) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, oxo, OR13, N(Rl4)₂, C3_6cycloalkyl and Cι_6alkyl-S(O)k-, wherein k is 0, 1 or 2, and

0036wherein items (7), (9), (11) and (12) above and aryl portion of items (8), (13) and (14) above and the HET portion of item (10) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of:

0037(a) halo,

0038(b) ORB,

0039(c) N(R14)₂, (d) Cι_6alkyl,

0040(e) C2-6alkenyl,

0041(f) C2-6akynyl,

0042(g) Ci-6alkyl-S(O)k-, wherein k is 0, 1 or 2,

0043(h) aryl, (i) aryl-S(O)k-, wherein k is 0, 1 or 2,

0044(j) HET,

0045(k) aryl Ci-6alkyl,

0046(1) aroyl, (m) aryloxy, (n) aryl Cι_6alkoxy,

0047(o) CN and

0048(p) C3-6cycloalkyl, wherein items (d) to (g) and (p) above and the alkyl portions of item (k) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR1 and N(Rl4)₂, and

0049wherein items (h), (i), (j), (1) and (m) above and the aryl portions of items (k) and (n) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR13 and Ci-4alkyl,

0050R2, R3, R4_; R5 and R6 are each independently selected from the group consisting of:

0051(1) hydrogen,

0052(2) halo,

0053(3) Cι_6alkyl,

0054(4) C2-6alkenyl, (5) C₂-6akynyl,

0055(6) C3-6cycloalkyl,

0056(7) Ci-6alkoxy,

0057(8) Ci-6alkyl-S(O)k-, wherein k is 0, 1 or 2,

0058(9) aryl, (10) aryl Ci-6alkyl,

0059(11) HET and

0060(12) -Cι_6alkyl-HET, wherein items (3) to (8) above and the alkyl portions of items (10) and (12) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13, N(Rl4)₂ and Ci-6alkyl-S(0)k-, wherein k is 0, 1 or 2; and

0061wherein items (9) and (11) and the aryl portion of items (10) and the HET portion of item (12) are optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of:

0062(a) halo,

0063(b) OR13, (c) N(Rl4)₂,

0064(d) Ci-₆alkyl,

0065(e) C2-6alkenyl,

0066(f) C2-6akynyl and

0067(g) Ci_6alkyl-S(O)k-, wherein k is 0, 1 or 2, wherein items (d) to (g) above are optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR13 and N(Rl )2,

0068or Rl and R or R3 and R5 may be joined together to form a double bond;

0069R7 is selected from the group consisting of:

0070(1) hydrogen,

0071(2) OR13, (3) Ci_4alkyl₅

0072(4) aryl and

0073(5) aryl Ci-4alkyl, wherein item (3) above and the alkyl portion of item (5) above are optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR1 and N(Rl4)₂, and

0074wherein item (4) above and the aryl portion of item (5) above are optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of:

0075(a) halo,

0076(b) ORB,

0077(c) N(R14)₂,

0078(d) Ci-₆alkyl, (e) C2-6^alkenyl and (f) C2-6akynyl, wherein items (d) to (f) above are optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR1 and N(Rl )2;

0079each Yl , Y2 and Y3 are independently selected from the group consisting of:

0080(1) hydrogen,

(2) -O-R9,

0082(3) -S(0)k-R⁹, wherein k is 0, 1 or 2, (4) -C-W-R9, wherein W is O or S(O)k,

0083(5) -N(Rl5)2, <img file="EP1542996A2_D0003.tif" />

0084(7) -N(Rl5)-S(O)k-N(Rl5)₂,

0085(8) NO2, (9) -C(O)-Rl5,

0086(10) -C(O)O-Rl5,

(11) -CN,

0088(12) halo,

0089(13) -O-S(O)k-R¹⁵ and (14) Cι_4alkyl, optionally substituted with with from 1 to 6 halo groups,

0090with the proviso that when Y2 is hydrogen, Y3 is -C(O)-Rl5, Rl5 _1S Ci-6alkyl and X is -C(0) then l is not Ci-6alkyl, and

0091with the proviso that when Y2 is -C(O)-Rl5, Y3 is hydrogen, Rl5 is Ci_6alkyl and X is -C(O) then lO is not Ci-6alkyl, and

0092with the proviso that when Y2 and Y3 are both hydrogen, X is a bond and RlO _1S HET, then said HET is defined as a 5-membered aromatic or non-aromatic monocyclic ring containing 1-3 heteroatoms selected from O, S and N, R°> is selected from the group consisting of: hydrogen, Cι_6alkyl, Cι_ 6alkoxy, -Cι_6alkyl-C(O)OH and -Ci -6alkyl-C(O)O-Ci-6alkyl, wherein the Ci- 6alkyl portion is optionally mono, di or tri substituted with halo; or where R8 and carbon atom to which they are attached form the spiro

0093<img file="EP1542996A2_D0004.tif" />

0094R9 is selected from the group consisting of: hydrogen, Cι_i2alkyl and aryl, wherein Cι_i2alkyl and aryl are optionally substituted from one up to the maximum number of substituents with halo;

0095each Rl 1, Rl and Rl6 is independently selected from the group consisting of:

0096(1) hydrogen,

0097(2) halo,

0098(3) Cι_6alkyl,

0099(4) C2-6alkenyl,

0100(5) Ci-βalkoxy and

0101(6) hydroxy,

0102wherein items (3) to (5) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR12, N(Rl )2 and Cι_6alkyl-S(0)k-, wherein k is 0, 1 or

01032,

0104or Rl6 may additionally be hydrogen;

0105each Rl and Rl4 is independently selected from the group consisting of hydrogen and Ci-4alkyl, optionally substituted from one up to the maximum number of substitutable positions with halo; and

0106each Rl5 is independently selected from the group consisting of: hydrogen, Ci_6alkyl, aryl and Ci_i2alkoxycarbonyl, wherein said Cι_6alkyl and Cι_ 12alkoxycarbonyl are optionally substituted from one up to the maximum number of substituable positions with halo and said aryl is optionally substituted from one up to the maximum number of substituable positions with halo and Cι_4alkyl, optionally substituted with 1-3 halo groups.

0107In an alternative embodiment XRlO ma be CN.

0108The optional double bond shown in ring A of the compound of Formula I is depicted as a dotted line and means that the double bond may or may not be present. This is illustrated below for a sub-set of compounds within Formula I:

0109<img file="EP1542996A2_D0005.tif" /><img file="EP1542996A2_D0006.tif" /> not present in ring A

0110The substituent Rl2 in Formula I may or may not be present. When present, one or two Rl2 groups may occupy the positions illustrated below:

0111<img file="EP1542996A2_D0007.tif" />

0112Two Rl2 groups may also reside on the same carbon atom. The substituent Rl in Formula I may or may not be present. When present, one, two or three Rll groups may occupy the positions illustrated below:

0113<img file="EP1542996A2_D0008.tif" />

0114Two RU groups may also reside on the same carbon atom.

0115The optional double bonds show in ring D of the compound of Formula I may occupy the positions illustrated below:

0116<img file="EP1542996A2_D0009.tif" />

0117<img file="EP1542996A2_D0010.tif" />

0118An embodiment of the invention encompasses a genus of compounds of Formula I wherein:

0119JisNRl;

0120KisNR3;

0121LisC(R5)(R6);and

0122R3 and R5 are joined together to form a double bond.

0123An embodiment of the invention encompasses a genus of compounds of Formula I, herein identified as compounds of Formula la:

0124<img file="EP1542996A2_D0011.tif" />

0125la Within the genus of compounds of Formula la is the sub-genus of compounds wherein:

0126Rl is phenyl or pyridyl said phenyl or pyridyl or optionally mono or di- substituted with a substituent independently selected from the group consisting of: (a) halo,

0127(b) OCH₃,

0128(d) CH3,

0129(e) CN.

0130Within this sub-genus of compounds is the class of compounds wherein Rl is phenyl, optionally mono or di-substituted with halo.

0131Within the genus of compounds of Formula la are the compounds wherein Yi is hydrogen.

0132Also within the genus of compounds of Formula la are the compounds wherein Rl6 is hydrogen.

0133Also within the genus of compounds of Formula la are the compounds wherein R is methyl.

0134Also within the genus of compounds of Formula la are the compounds wherein Yi is hydrogen and Rl2 is hydrogen.

0135An embodiment of the invention encompasses compounds of Formula I and Formula la wherein: X is a bond, -C(O), -N(Rl4)-, -N(Rl4)-C(O)-, -C(O)-N(Rl4)-, -N(Rl4)-C(O)-NH- ; and Rl4 is hydrogen or methyl.

0136An embodiment of the invention encompasses compounds of Formula I and Formula la wherein: X is a bond, -C(O), -N(Rl4)-, -N(Rl4)-C(O)-, -C(O)-N(Rl4)-, -N(Rl4)-C(O)-NH- ; Yl is hydrogen;

0137Rl is phenyl, optionally mono or di-substituted with halo; R7 is methyl. Rll is hydrogen; Rl2 is hydrogen; Rl4 is hydrogen or methyl;

0138Rl6 is hydrogen; and

0139RlO are each independently selected from the group consisting of:

0140(1) Cι_4alkyl,

0141(2) C2-4aIkenyl,

0142(3) C2-4akynyl,

0143(4) C3_6cycloalkyl,

0144(5) Ci-4alkoxy,

0145(6) aryl,

0146(7) aryl Cι_4alkyl,

(8) HET,

0148(9) -Ci-4alkyl-HET, _,

0149(10) aryloxy,

0150(11) aroyloxy,

0151(12) aryl C2-4alkenyl,

0152(13) aryl C2-6alkynyl,

0153wherein items (1) to (5) above and the alkyl portions of items (7) and (9) above and the alkenyl portion of item (12) above and the alkynyl portion of item (13) above are optionally substituted with from one to three substituents independently selected from the group consisting of: halo, OR1 , N(Rl4)2, C3_6cycloalkyl and Cι_6alkyl-S(O)k-, wherein k is 0, 1 or 2, and

0154wherein items (6), (8), (10) and (11) above and aryl portion of items (7), (12) and (13) above and the HET portion of item (9) above are optionally substituted with from one to three substituents independently selected from the group consisting of:

0155(a) halo,

0156(b) OR13,

0157(c) N(R14)₂, (d) Cι_4alkyl,

0158(e) C2-4alkenyl,

0159(f) C2-4akynyl,

0160(g) aryl, (h) HET, (i) aryl Ci-6alkyl,

0161(j) aroyl,

0162(k) aryloxy,

0163(1) aryl Ci-galkoxy and (m) CN, wherein items (d) to (f) above and the alkyl portions of item (i) above are optionally substituted from with one to three substituents independently selected from the group consisting of: halo, OR13 and N( l )2, and

0164wherein items (g), (h), (j) and (k) above and the aryl portions of items (i) and (1) above are optionally substituted with from one to three substituents independently selected from the group consisting of: halo, OR13 and Cι_4alkyl,

0165Another embodiment of the invention encompasses a genus of compounds of Formula I, herein identified as compou nndds of Formula lb:

0166<img file="EP1542996A2_D0012.tif" />

0167lb wherein: m is O or l, n is O or 1,

0168Rl is phenyl, optionally mono or di-substituted with halo; RlO are each independently selected from the group consisting of: (1) Ci-6alkyl, (2) C2-6alkenyl,

0169(3) C2-6akynyl,

0170(4) C3-6cycloalkyl,

0171(5) Ci-6alkoxy,

0172(6) Ci-6alkyl-S(0)k-, wherein k is 0, 1 or 2, (7) aryl,

0173(8) aryl Ci-βalkyl,

(9) HET,

0175(10) -Ci-6alkyl-HET,

0176(11) aryloxy,

0177(12) aroyloxy,

0178(13) aryl C2-6alkenyl,

0179(14) aryl C2-6^alkynyl,

0180(15) hydrogen, and

0181(16) hydroxy

0182wherein items (1) to (6) above and the alkyl portions of items (8) and (10) above and the alkenyl portion of item (13) above and the alkynyl portion of item (14) above are optionally substituted with from one to three substituents independently selected from the group consisting of: halo, OR13, N(Rl4)2, C3_6cycloalkyl and Ci-6alkyl-S(O)k-, wherein k is 0, 1 or 2, and

0183wherein items (7), (9), (11) and (12) above and aryl portion of items (8), (13) and (14) above and the HET portion of item (10) above are optionally substituted with from one to three substituents independently selected from the group consisting of:

0184(a) halo,

0185(b) OR13,

0186(c) N(Rl4)₂,

0187(d) Ci-βalkyl, (e) C2-6alkenyl,

0188(f) C2-6akynyl,

0189(g) Cι_6alkyl-S(O)k-, wherein k is 0, 1 or 2,

0190(h) aryl,

0191(i) aryl-S(O)k-, wherein k is 0, 1 or 2, (j) HET,

0192(k) aryl Ci-βalkyl,

0193(1) aroyl,

0194(m) aryloxy,

0195(n) aryl Cι_6alkoxy and (o) CN, wherein items (d) to (g) above and the alkyl portions of item (k) above are optionally substituted from one to three substituents independently selected from the group consisting of: halo, OR13 and N(Rl4)2, and

0196wherein items (h), (i), (j), (1) and (m) above and the aryl portions of items (k) and (n) above are optionally substituted with from one to three substituents independently selected from the group consisting of: halo, OR13 and Cι_4alkyl, each R 3 and Rl is independently selected from the group consisting of hydrogen and Cι_4alkyl, optionally substituted from one to three halo groups; Rl6 and each Rl 1 are independently selected from the group consisting of:

0197(1) hydrogen,

0198(2) halo,

0199(3) methyl,

0200(4) methoxy, and (5) hydroxy;

0201Yl and Y2 are each selcected from the group consisting of:

0202(1) hydrogen,

0203(2) hydroxy,

0204(3) halo, (4) methyl,

0205(5) -NO₂,

(6) -CN,

0207(7) mono, di or tri halo substituted methyl,

0208X is a bond, -C(O), -N(Rl4)-, -N(Rl4)-C(O)-, -C(O)-N(Rl4)-, -N(Rl4)-S(O)k-, -N(Rl4)-C(O)-NH- or -S(O)k-N(Rl4);

0209Within Formula lb, there is the sub-genus of compounds wherein Yi, Rl 1 and Rl6 are each hydrogen.

0210Within Formula lb, there is a sub-genus of compounds herein identified as Formula Ic: <img file="EP1542996A2_D0013.tif" />

0211Ic wherein n is O or 1,

0212Rl is phenyl, optionally mono or di-substituted with halo;

0213RlO is selected from the group consisting of:

0214(1) Cι_6alkyl,

0215(2) C2-6alkenyl,

0216(3) C2-6akynyl,

0217(4) C3_6cycloalkyl,

0218(5) Cι_6alkoxy,

0219(6) Cι_6alkyl-S(O)k-, wherein k is 0, 1 or 2,

0220(7) aryl,

0221(8) aryl Ci-6alkyl,

(9) HET,

0223(10) -Ci-6alkyl-HET,

0224(11) aryloxy,

0225(12) aroyloxy,

0226(13) aryl C2-6alkenyl,

0227(14) aryl C2-6alkynyl,

0228(15) hydrogen, and

0229(16) hydroxy

0230wherein items (1) to (6) above and the alkyl portions of items (8) and (10) above and the alkenyl portion of item (13) above and the alkynyl portion of item (14) above are optionally substituted with from one to three substituents independently selected the group consisting of: halo, OR13, N(Rl4)2, C3_6cycloalkyl and Cι_6alkyl-S(O)k-, wherein k is 0, 1 or 2, and wherein items (7), (9), (11) and (12) above and aryl portion of items (8), (13) and (14) above and the HET portion of item (10) above are substituted with from one to three substituents independently selected from the group consisting of: (a) halo, (b) OR13,

0231(c) N(Rl4)₂,

0232(d) Cι_6alkyl,

0233(e) C2-6alkenyl,

0234(f) C2-6akynyl, (g) Ci-6alkyl-S(O)k-, wherein k is 0, 1 or 2,

0235(h) aryl,

0236(i) aryl-S(O)k-, wherein k is 0, 1 or 2,

0237(j) HET,

0238(k) aryl Ci-6alkyl, (1) aroyl,

0239(m) aryloxy,

0240(n) aryl Ci-βalkoxy and

0241(o) CN, wherein items (d) to (g) above and the alkyl portions of item (k) above are optionally substituted with from one to three substituents independently selected from the group consisting of: halo, OR13 and N(Rl4)2, and

0242wherein items (h), (i), (j), (1) and (m) above and the aryl portions of items (k) and (n) above are optionally substituted with from one to three substituents independently selected from the group consisting of: halo, OR13 and Cι_4alkyl, each Rl3 and Rl4 is independently selected from the group consisting of hydrogen and Ci-4alkyl, optionally substituted with from one up to three halo groups;

0243Rl and each Rl 1 are independently selected from the group consisting of: (1) hydrogen, (2) halo,

0244(3) methyl,

0245(4) methoxy, and

0246(5) hydroxy;

0247Yl and Y2 are each selcected from the group consisting of: (1) hydrogen, (2) hydroxy,

0248(3) halo,

0249(4) methyl,

0250(5) -NO₂, (6) -CN,

0251(6) mono, di or tri halo substituted methyl,

0252X is a bond, -C(O), -N(Rl4)-, -N(Rl4)-C(O)-, -C(O)-N(Rl4)-, -N(Rl4)-S(O)k-, -N(Rl4)-C(O)-NH- or -S(O)k-N(Rl4);

0253Within this sub-genus of Formula Ic there is a class of compounds wherein:

0254X is a bond, -C(O), -N(Rl4)-, -N(Rl4)-C(O)-, -C(O)-N(Rl4)-, -N(Rl4)-C(0)-NH- ; Rl3 and Rl4 are each independently selected from hydrogen or methyl; and RlO are each independently selected from the group consisting of:

0255(1) Ci-4alkyl,

0256(2) C2-4alkenyl,

0257(3) C2-4akynyl,

0258(4) C3-6cycloalkyl,

0259(5) Cχ-4alkoxy,

0260(6) aryl,

0261(7) aryl Cι_4alkyl,

(8) HET,

0263(9) -Ci-4alkyl-HET,

0264(10) aryloxy,

0265(11) aroyloxy,

0266(12) aryl C2-4alkenyl,

0267(13) aryl C2-6alkynyl,

0268wherein items (1) to (5) above and the alkyl portions of items (7) and (9) above and the alkenyl portion of item (12) above and the alkynyl portion of item (13) above are optionally substituted with from one to three substituents independently selected from the group consisting of: halo, OR13, N(Rl4)2, C3-6cycloalkyl and Ci_6alkyl-S(0)k-, wherein k is 0, 1 or 2, and wherein items (6), (8), (10) and (11) above and aryl portion of items (7), (12) and (13) above and the HET portion of item (9) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: (a) halo,

0269(b) OR13,

0270(c) N(Rl4)₂,

0271(d) Ci-4alkyl,

0272(e) C2-4alkenyl, (f) C₂-4akynyl,

0273(g) aryl,

0274(h) HET,

0275(i) aryl Ci-6alkyl,

0276(j) aroyl, (k) aryloxy,

0277(1) aryl Cι_6alkoxy and

0278(m) CN, wherein items (d) to (f) above and the alkyl portions of item (i) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR13 and N(Rl4)₂, and

0279wherein items (g), (h), (j) and (k) above and the aryl portions of items (i) and (1) above are optionally substituted with from one to three substituents independently selected independently selected from the group consisting of: halo, OR13 and Ci-4alkyl.

0280Within this class of compounds of Formula Ic is a sub-class of compounds wherein:

0281X is a bond, -C(O), -N(Rl4)-, -N(Rl4)-C(O)-, -C(O)-N(Rl4)-, -N(Rl4)-C(O)-NH- ; Rl3 and Rl are each independently from hydrogen or methyl; and RlO are each independently selected from the group consisting of:

0282(1) C3_6cycloalkyl,

0283(2) aryl,

0284(3) aryl Ci-4alkyl,

0285(4) HET, (5) -Cι_4alkyl-HET, (6) aryl C2-4alkenyl,

0286wherein item (1) above and the alkyl portions of items (3) and (5) above and the alkenyl portion of item (8) above are optionally substituted with from one to three substituents independently selected from the group consisting of: halo, OR13, N(Rl4)₂, and wherein the aryl portion of items (2), (3), (6) and the HET portion of item (4) and (5) above are optionally substituted with from one to three substituents independently selected from the group consisting of: (a) halo,

0287(b) OR13,

0288(c) N(Rl4)₂,

0289(d) Ci- alkyl,

0290(e) C2-4alkenyl, (f) C2-4akynyl,

0291(g) aryl,

0292(h) HET,

0293(i) aryl Cι_6alkyl,

0294(j) aroyl, (k) aryloxy,

0295(1) aryl Cι_6aIkoxy and

0296(m) CN, wherein items (d) to (f) above and the alkyl portions of item (i) above are optionally substituted with from one to three substituents independently selected from the group consisting of: halo, OR13 and N(Rl4)2, and

0297wherein items (g), (h), (j) and (k) above and the aryl portions of items (i) and (1) above are optionally substituted with from one to three substituents independently selected from the group consisting of: halo, OR 13 and Cι_4alkyl.

0298Within this subclass of compounds of Formula Ic are the compounds wherein: RlO are each independently selected from the group consisting of:

0299(1) C3_6cycloalkyl, (2) aryl,

0300(3) aryl Cι_4alkyl,

(4) HET,

0302(5) -Cι_4alkyl-HET,

0303(6) aryl C2-4alkenyl,

0304wherein item (1) above and the alkyl portions of items (3) and (5) above and the alkenyl portion of item (8) above' are optionally substituted with from to three substituents independently selected from the group consisting of: halo, OR13, N(Rl4)₂, and wherein the HET portion of item (4) and (5) are optionally substituted with from one to three substituents selected from the group consisting of Cι_4alkyl and aryl, and wherein the aryl portion of items (2), (3), (6) above are optionally substituted with from one to three substituents independently selected from the group consisting of:

0305(a) halo,

0306(b) OR13,

0307(c) N(R14)₂,

0308(d) Cι_₄alkyl, (e) C2-4alkenyl,

0309(f) C2-4akynyl,

0310(g) aryl, (h) HET,

0311(i) aryl Ci_6alkyl, (j) aroyl,

0312(k) aryloxy, (1) aryl Ci-6alkoxy and

0313(m) CN, wherein items (d) to (f) above and the alkyl portions of item (i) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR13 and N(Rl4) , and

0314wherein items (g), (h), (j) and (k) above and the aryl portions of items (i) and (1) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR13 and Ci^alkyl.

0315Another embodiment of the invention encompasses a compound of Formula la wherein Y2 is CF3. Within this embodiment RIO is selected from the group consisting of:

0316(1) phenyl,

0317(2) benzyl, and

0318(3) HET, wherein HET is a 5-membered aromatic or non-aromatic monocyclic ring containing 1-3 heteroatoms selected from O, S and N,

0319wherein groups (1) to (3) above are optionally substituted with 1 to 3 substituents independently selected from the group consisting of:

0320(a) halo,

0321(b) Ci_4alkyl, optionally substituted with hydroxy or 1 to 3 halo groups,

0322(c) Ci-4alkoxy, optionally substituted with 1 to 3 halo groups,

0323(d) NH₂,

0324(e) hydroxy, and

0325(e) phenyl or benzyl.

0326Another embodiment of the invention encompasses a compound of Formula la wherein Y2 is hydrogen, X is a bond and RlO is HET, wherein HET is a

03275-membered aromatic or non-aromatic monocyclic ring containing 1-3 heteroatoms selected from O, S and N. Within this embodiment HET is selected from oxazolyl and imidazolyl.

0328Another embodiment of the invention encompasses a compound of Formula Id

0329<img file="EP1542996A2_D0014.tif" />

0330Id

0331or a pharmaceutically acceptable salt thereof, wherein

0332RlO is a 5-membered aromatic or non-aromatic mono-cyclic ring containing 1-3 heteroatoms selected from O, S, and N, and

0333RlO is mono-substituted with phenyl, wherein phenyl is optionally substituted with 1- 3 substituents independently selected from halo, Ci_4alkyl and Ci_4alkoxy. Within this embodiment RlO is oxazolyl, oxadiazolyl or thiazolyl. Also within this embodiment RlO is oxazolyl.

0334Another embodiment of the invention encompasses a pharmaceutical composition comprising a compound of Formula I in combination with a pharmaceutically acceptable carrier.

0335Another embodiment of the invention encompasses a method for treating a glucocorticoid receptor mediated disease or condition in a mammalian patient in need of such treatment comprising administering the patient a compoud of Formula I in an amount that is effective for treating the glucocorticoid receptor mediated disease or condition.

0336Within this embodiment is encompassed the above method wherein the glucocorticoid receptor mediated disease or condition is selected from the group consisting of: tissue rejection, leukemias, lymphomas, Cushing's syndrome, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation/apoptosis, HPA axis suppression and regulation, hypercortisolemia, stroke and spinal cord injury, hypercalcemia, hypergylcemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia, Little's syndrome, obesity, metabolic syndrome, inflammatory bowel disease, systemic lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arteritis, rheumatoid arthritis, juvenile rheumatoid arthritis, uveitis, hay fever, allergic rhinitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, organ transplantation, hepatitis, cirrhosis, inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythematosus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, buflous pemphigoid, systemic lupus erythematosus, dermatomyositis, herpes gestationis, eosinophilic fasciitis, relapsing polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, type I reactive leprosy, capillary hemangiomas, contact dermatitis, atopic dermatitis, lichen planus, exfoliative dermatitus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform, cutaneous T-cell lymphoma, Human

0337Immunodeficiency Virus (HTV), cell apoptosis, cancer, Kaposi's sarcoma, retinitis pigmentosa, cognitive performance, memory and learning enhancement, depression, addiction, mood disorders, chronic fatigue syndrome, schizophrenia, sleep disorders, and anxiety. Another embodiment of the invention encompasses a method of selectively modulating the activation, repression, agonism and antagonism effects of the glucocorticoid receptor in a mammal comprising administering to the mammal a compound of Formula I in an amount that is effective to modulate the glucocorticoid receptor. Exemplifying the invention are the compounds of the Examples disclosed hereunder.

0338The invention is described using the following definitions unless otherwise indicated.

0339The term "halogen" or "halo" includes F, Cl, Br, and I. The term "alkyl" means linear or branched structures and combinations thereof, having the indicated number of carbon atoms. Thus, for example, Cι_6alkyl includes methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1- dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "alkoxy" means alkoxy groups of a straight, branched or cyclic configuration having the indicated number of carbon atoms. Ci-6aIkoxy, for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.

0340The term "alkylthio" means alkylthio groups having the indicated number of carbon atoms of a straight, branched or cyclic configuration. Ci_ όalkylthio, for example, includes methylthio, propylthio, isopropylthio, and the like.

0341The term "alkenyl" means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-to-carbon double bond, wherein hydrogen may be replaced by an additional carbon-to-carbon double bond. C2-6^alkenyl, for example, includes ethenyl, propenyl,

03421-methylethenyl, butenyl and the like.

0343The term "alkynyl" means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-to-carbon triple bond. C3-6alkynyl, for example, includes , propenyl, 1- methylethenyl, butenyl and the like.

0344The term "cycloalkyl" means mono-, bi- or tri-cyclic structures, optionally combined with linear or branched structures, the indicated number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl, 2-ethyl-l- bicyclo[4.4.0]decyl, and the like.

0345The term "aryl" is defined as a mono- or bi-cyclic aromatic ring system and includes, for example, phenyl, naphthyl, and the like.

0346The term "aralkyl" means an alkyl group as defined above of 1 to 6 carbon atoms with an aryl group as defined above substituted for one of the alkyl hydrogen atoms, for example, benzyl and the like.

0347The term "aryloxy" means an aryl group as defined above attached to a molecule by an oxygen atom (aryl-O) and includes, for example, phenoxy, naphthoxy and the like.

0348The term "aralkoxy" means an aralkyl group as defined above attached to a molecule by an oxygen atom (aralkyl-O) and includes, for example, benzyloxy, and the like.

0349The term "arylthio" is defined as an aryl group as defined above attached to a molecule by an sulfur atom (aryl-S) and includes, for example, thiophenyoxy, thionaphthoxy and the like. The term "aroyl" means an aryl group as defined above attached to a molecule by an carbonyl group (aryl-C(O)-) and includes, for example, benzoyl, naphthoyl and the like.

0350The term "aroyloxy" means an aroyl group as defined above attached to a molecule by an oxygen atom (aroyl-O) and includes, for example, benzoyloxy or benzoxy, naphthoyloxy and the like.

0351The term "HET" is defined as a 5- to 10-membered aromatic, partially aromatic or non-aromatic mono- or bicyclic ring, containing 1-4 heteroatoms selected from O, S and N, and optionally substituted with 1-2 oxo groups. Preferably, "HET" is a 5- or 6-membered aromatic or non-aromatic monocyclic ring containing 1-3 heteroatoms selected from O, S and N, for example, pyridine, pyrimidine, pyridazine, furan, thiophene, thiazole, oxazole, isooxazole and the like, or HET is a 9- or 10- membered aromatic or partially aromatic bicyclic ring containing 1-3 heteroatoms selected from O, S, and N, for example, benzofuran, benzothiophene, indole, pyranopyrrole, benzopyran, quionoline, benzocyclohexyl, naphtyridine and the like. "HET" also includes the following: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl. For all of the above definitions, each reference to a group is independent of all other references to the same group when referred to in the Specification. For example, if both Rl and R2 are HET, the definitions of HET are independent of each other and Rl and R2 may be different HET groups, for example furan and thiophene. The term "treating" encompasses not only treating a patient to relieve the patient of the signs and symptoms of the disease or condition but also prophylactically treating an asymptomatic patient to prevent the onset of the disease or condition or preventing, slowing or reversing the progression of the disease or condition. The term "amount effective for treating" is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.^' The term also encompasses the amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.

0352The following abbreviations have the indicated meanings:

0353AIBN = 2.2 -azobisisobutyronitrile

0354B.P. = benzoyl peroxide

0355Bn = benzyl

0356CC1₄ = carbon tetrachloride

0357D = -O(CH₂)3O-

0358DAST = diethylamine sulfur trifluoride

0359DCC = dicyclohexyl carbodiimide

0360DCI = l-(3-dimethylaminopropyl)-3-ethyl carbodiimide

0361DEAD = diethyl azodicarboxylate

0362DIBAL = diisobutyl aluminum hydride

0363DME = ethylene glycol dimethylether

0364DMAP = 4-(dimethylamino)pyridine

0365DMF = N,N-dimethylformamide

0366DMSO = dimethyl sulfoxide

0367Et3N = triethylamine

0368LDA = lithium diisopropylamide m-CPBA = metachloroperbenzoic acid

0369NBS = N-bromosuccinimide

0370NSAID = non-steroidal anti-inflammatory drug

0371PCC = pyridinium chlorochromate

0372PDC = pyridinium dichromate

0373Ph = phenyl 1,2-Ph = 1,2-benzenediyl

0374Pyr = pyridinediyl

0375Qn = 7-chloroquinolin-2-yl

0376Rs = -CH2SCH2CH2Ph r.t. = room temperature rac. = racemic

0377THF = tetrahydrofuran

0378THP n tetrahydropyran-2-yl

0379Alkvl group abbreviations

0380Me = methyl

0381Et = ethyl n-Pr = normal propyl i-Pr = isopropyl n-Bu = normal butyl i-Bu = isobutyl s-Bu = secondary butyl t-Bu = tertiary butyl c-Pr = cyclopropyl c-Bu = cyclobutyl c-Pen = cyclopentyl c-Hex = cyclohexyl

0382Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.

0383Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

0384The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

0385It will be understood that in the discussion of methods of treatment which follows, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.

0386The magnitude of prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature and the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to a variety of factors including the age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination and response of the individual patient. In general, the daily dose from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 10 mg per kg. On the other hand, it may be necessary to use dosages outside these limits in some cases. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain from about 0.5 mg to about 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain from about 1 mg to about 2 g of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg. For the treatment of glucocorticoid receptor mediated diseases the compound of Formula I may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non- toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrastemal injection or infusion techniques. In addition to the treatment of warmblooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compound of the invention is effective in the treatment of humans.

0387The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, solutions, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.

0388Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water-miscible solvents such as propylene glycol, PEGs and ethaήol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.

0389Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

0390Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.

0391The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

0392The compounds of Formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. For topical use, creams, ointments, gels, solutions or suspensions, etc., containing a compound of Formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.) Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.

0393The ability of the compounds of Formula I to selectively modulate glucocorticoid receptors makes them useful for treating, preventing or reversing the progression of a variety of inflammatory and autoimmune diseases and conditions. Thus, the compounds of the present invention are useful to treat, prevent or ameliorate the following diseases or conditions: inflammation, tissue rejection, auto-immunity, various malianancies, such as leukemias and lymphomas, Cushing's syndrome, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation/apoptosis, HP A axis suppression and regulation, hypercortisolemia, stroke and spinal cord injury, hypercalcemia, hypergylcemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia, Little's syndrome, -obesity and metabolic syndrome.

0394The compounds of the present invention are also useful for treating, preventing or reversing the progression of disease states involving systemic inflammation such as inflammatory bowel disease, systemic lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arteritis, rheumatoid arthritis, juvenile rheumatoid arthritis, uveitis, hay fever, allergic rhinitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, organ transplantation, hepatitis, and cirrhosis.

0395The compounds of the present invention are useful for treating, preventing or reversing the progression of a variety of topical diseases such as inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythematosus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, buflous pemphigoid, systemic lupus erythematosus, dermatomyositis, herpes gestationis, eosinophilic fasciitis, relapsing polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, type I reactive leprosy, capillary hemangiomas, contact dermatitis, atopic dermatitis, lichen planus, exfoliative dermatitus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform, cutaneous T-cell lymphoma.

0396The compounds of the present invention are also useful in treating, preventing or reversing the progression of disease states associated with Human Immunodeficiency Virus (HTV), cell apoptosis, and cancer including, but not limited to, Kaposi's sarcoma, immune system activation and modulation, desensitization of inflammatory responses, EL- 1 expression, natural killer cell development, lymphocytic leukemia, and treatment of retinitis pigmentosa. Cogitive and behavioral processes are also susceptible to glucocorticoid therapy where antagonists would potentially be useful in the treatment of processes such as cognitive performance, memory and learning enhancement, depression, addiction, mood disorders, chronic fatigue syndrome, schizophrenia,^' stroke, sleep disorders, and anxiety.

0397The invention also encompasses a method for treating a glucocorticoid receptor mediated disease comprising concomitantly administering to a patient in need of such treatment a compound of Formula I and one or additional more agents. For treating or preventing asthma or chronic obstructive pulmonary disease, the compounds of Formula I may be combined with one or more agents selected from the group consisting of: "θ-agonists (e.g., salmeterol), theophylline, anticholinergics (e.g., atropine and ipratropium bromide), cromolyn, nedocromil and leukotriene modifiers (e.g., montelukast). For treating or preventing inflammation, the compounds of Formula I may be combined with one or the following: a salicylate, including acetylsalicylic acid, a non-steroidal antiinflammatory drug, including indomethacin, sulindac, mefenamic, meclofenamic, tolfenamic, tolmetin, ketorolac, dicofenac, ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofin and oxaprozin, a TNF inhibitor, including etanercept and infliximab, an IL-1 receptor antagonist, a cytotoxic or immunosuppressive drug, including methotrexate, leflunomide, azathioprine and cyclosporine, a gold compound, hydroxychloroquine or sulfasalazine, penicillamine, darbufelone, and a p38 kinase inhibitor. The compound of Formula I may also be used in combination with bisphonates such as alendronate to treat a glucocorticoid mediated disease and simultaneously inhibit osteoclast-mediated bone resorption.

METHODS OF SYNTHESIS

0399Generally, compounds of the present invention may be synthesized by following the following synthetic scheme: <img file="EP1542996A2_D0015.tif" />

,NHNHP

0401base, acid <img file="EP1542996A2_D0016.tif" />

IV

0403<img file="EP1542996A2_D0017.tif" />

0404KH DS, aprotic solvent <img file="EP1542996A2_D0018.tif" />

VII

VI

0407<img file="EP1542996A2_D0019.tif" />

0408Acid, such as p-toluenesulfonic acid, is added to a solution of the Wieland-Miescher ketone i in ethylene glycol to give ketal ii. Ethyl formate and sodium hydride are added to ketal ii in an organic solvent such as anhydrous benzene to afford hydroxyketone iii. The hydroxyketone iii is dissolved in an appropriate acid such as glacial acetic acid and the appropriate hydrazine such as p-fluorophenylhyradzine hydrocloride and appropriate base such as sodium acetate is added to give pyrazole ketal iv. The pyrazole ketal iv is dissolved in an aprotic solvent such as THF and an aqeuous acid such as aqeuous 6N HCl is added to yield the ketone v.

04092-[N,N-Bis(trifluomethylsulphonyl)-amino]-5-chloropyridine is added to Potassium bis(trimethylsilyl amide) in an aprotic solvent such as THF to give the triflate vi. Diene vii is obtained by reaction of vi with vinyl tributyl tin and a palladium (0) source such as tetrakis(triphenylphosphine) palladium (0) in an aprotic solvent such as THF. Diels-Alder reaction in the presence of a Lewis acid in a non- polar solvent such as methylene chloride at low temperature yields the final product viii.

0410Methods for making compounds of Formula I outside the scope of formula viii are easily discernible by those having ordinary skill in the art in view of the above method and the examples set for the below. See, for example, Org. React. 4, 1, 1948; Org. React. 4, 60, 1958; Chem. Rev. 61, 537, 1961; Diels-Alder Reaction, Elsevier, London, 1965;l-4 Cycloadditions Reactions- The Diels-Alder Reaction in Heterocyclic Syntheses, Academic Press, New York, 1967; Angew Chem. Int. Ed. Engl. 19, 779, 1980; J. Am. Chem. Soc. 95, 4094, 1973.

0411The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:

0412(i) all operations were carried out at room or ambient temperature, that is, at a temperature in the range 18-25°C,

0413(ii) evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 pascals: 4.5-30 mm. Hg) with a bath temperature of up to 60°C,

0414(iii) the course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only;

0415(iv) melting points are uncorrected and d' indicates decomposition; the melting points given are those obtained for the materials prepared as described; polymorphism may result in isolation of materials with different melting points in some preparations;

0416(v) the structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data; (vi) yields are given for illustration only;

0417(vii) when given, NMR data is in the form of delta (5) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 500 MHz or 600 MHz using the indicated solvent; conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc.: in addition "Ar" signifies an aromatic signal;

0418(viii) chemical symbols have their usual meanings; the following abbreviations have also been used v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (litre(s)), mL (millilitres), g (gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq (equivalent(s)).

EXAMPLE 1

0420<img file="EP1542996A2_D0020.tif" />

0421Ethyl (3RARAaRΛ la5V8-(4-fluorophenylVl la-methyl-3-ftrifluorome hyl)- 3,4.4a,5,6.8,l l,lla-octahvdro-2H-naphthori.2- lindazole-4-carboxylate

0422<img file="EP1542996A2_D0021.tif" />

0423Step A: (8ai? -8a-hvdroxy-3,4,8.8a-tetrahvdronaDhthalene-1.6(2H H)-dione-l- ethylene ketal

0424(S) Wieland-Miescher ketone (5 g, 28.05 mmol) was dissolved in ethylene glycol (140 mL) and stirred at room temperature. Next, 4 A molecular sieves (~5 g) followed by p-toluenesulfonic acid (5.34g, 28.05 mmol) were added. After stirring at room temperature for 23 minutes, the reaction was poured slowly into a 2:1 mixture of ice water/sat. NaΗCO₃ (150 mL). The reaction was extracted with EtOAc (4 x 100 mL) and the combined organic layers were washed with brine (100 mL), dried over MgSO , filtered and concentrated in vacuo. The residue was purified by flash chromatography (0 to 40% EtOAc/hexanes) on silica gel to afford 5.77g (93%) of (8aR)-8a-hydroxy-3,4,8,8a-tetrahydronaρhthalene- l,6(2H,7H)-dione-l-ethylene ketal as a white solid. LCMS = 223; (M + 1)⁺. 1H NMR (CDCI₃, 500 MHz): 55.83 (br d, J= 1.8 Hz, IH), 4.43-3.94 (m, 4H), 2.49- 2.40 (m, 3H), 2.39-2.27 (m, 2H), 1.95-1.88 (m, IH), 1.84-1.78 (m, IH), 1.76-1.64 (m, 3H), 1.37 (s, 3H).

0425<img file="EP1542996A2_D0022.tif" />

0426Step B: f7E.8ay)-7-(hvΦoxymethyleneV8a-methyl-3A8.8a- tetrahvdronaphthalene- 1 ,6(2H7H)-dione- 1 -ethylene ketal

0427(8a/?)-8a-hydroxy-3,4,8,8a-tetrahydronaphthalene-l,6(2H,7H)- dione-1 -ethylene ketal (4.8 g, 21.62 mmol) was dissolved in 200 mL benzene and -50 mL benzene were distilled off atmospherically. The solution was cooled to - 40 °C and ethyl formate (7.36 mL, 86.48 mmol) was added, followed by sodium hydride (60% suspension in mineral oil; 3.46 g, 86.48 mmol). Next, 450 mL MeOΗ was added (bubbling evident) and the reaction was allowed to warm to room temperature. After stirring for 3 hours, the reaction was cooled to 0 °C and 50 mL Η₂O was added slowly. The biphasic system was shaken and the organic layer was washed with H₂O (3 x 50 mL). The combined aqueous layers were washed with diethyl ether (100 mL) and then acidified to pH 5.5-6 with sat. KH₂PO₄. The aqueous layer was extracted with ΕtOAc (5 x 200 mL). The combined extracts were dried over Na₂SO and concentrated in vacua to afford 5.04 g (93%) of (7E,8aS)-7-(hydroxymethylene)-8a~methyl-3,4,8,8a- tetrahydronaphthalene-l,6(2H,7H)-dione-l -ethylene ketal as an orange oil. LCMS = 251; (M + 1)⁺. This material was used without further purification.

0428<img file="EP1542996A2_D0023.tif" />

0429Step C: (4a )-l-(^"4-fluorophenylV4a-methyl- 4,4a.6.7.8-hexahvdro-5H- benzor |indazol-5-one-5-ethylene ketal (7E,8aS)-7-(hydroxymethylene)-8a-methyl-3,4,8,8a- tetrahydronaphthalene-l,6(2H,7H)-dione-l-ethylene ketal (4.1 g, 16.4 mmol) was dissolved in glacial acetic acid (40mL) and p-fluorophenylhyradzine hydrochloride (2.8 g, 17.22 mmol) and sodium acetate (1.41 g, 17.22 mmol) were added. After stirring at room temperature for 2 hours, the reaction was poured slowly into 10% NaΗCO₃ (1 L) and extracted with EtOAc (6 x 500 mL). The combined extracts were washed with brine (500 mL), dried over MgSO and concentrated in vacua. The cmde material was purified by flash chromatography (10% EtOAc/hexanes) on silica gel to afford 2.26 g (41%) of (4a5)-l-(4- fluorophenyI)-4a-methyl-l,4,4a,6,7,8-hexahydro-5H-benzo[ ]indazol-5-one-5- ethylene ketal as an orange solid. LCMS = 341 ; (M + 1)⁺. 1H NMR. (CDC1₃, 500 MHz): δ 7.47-7.44 (m, 2H), 7.43 (s, IH), 7.18-7.16 (d, 7 = 8.5 Hz, IH), 7.16-7.14 (d, 7= 8.7 Hz, IH), 6.22 (br d, 7= 2.2 Hz, IH), 4.11-4.01 (m, 4H), 3.20-3.16 (d, 7 = 15 7 Hz, IH), 2.54-2.51 (d, 7= 16 Hz, IH), 2.51-2.40 (m, IH), 2.34-2.28 (m, IH), 1.88-1.64 (m, 4H), 1.23 (s, 3H).

0430<img file="EP1542996A2_D0024.tif" />

0431Step D: (4a.S^')-l-(4-fluorophenyl)-4a-methyl- 4.4a.6.7,8-hexahvdro-5H- benzor lindazol-5-one The (4aS)-l-(4-fluorophenyl)-4a-methyl-l,4,4a,6,7,8-hexahydro- 5H-benzo[ ]indazol-5-one-5-ethylene ketal (2.26 g; 6.65 mmol) was dissolved in TΗF (65 mL) and 6N ΗC1 (4.43 mL, 26.6 mL) was added. The reaction was heated to 65 °C for 3.5 hours and then poured slowly into 10% NaΗCO₃ (150 mL). The mixture was extracted with EtOAc (4 x 250 mL) and the combined extracts washed with brine (2 x 200 mL), dried over MgSO and concentrated in vacuo to afford 1.97 g (100%) of (4aS)-l-(4-fluorophenyl)-4a-methyl-l,4,4a,6,7,8- hexahydro-5H-benzo[ ]indazol-5-one as a brown oil. LCMS = 297; (M + 1)⁺. 1H NMR (CDC1₃, 500 MHz): δ 7.50 (s, IH), 7.49-7.45 (m, 2H), 7.20-7.16 (m, 2H), 6.31 (br d, 7 = 2 Hz, 1 H), 2.96-2.88 (m, 2H), 2.72-2.62 (m, 2H), 2.59-2.53 (m, 2H), 2.14-2.80 (m, IH), 1.75-1,64 (qt, 7= 13.1 Hz, J = 4.3 Hz, IH), 1.27 (s, 3H).

0432<img file="EP1542996A2_D0025.tif" />

0433Step E: (4aSV 1 -(4-fluorophenyl V4a-mefhyl-4,4a.7.8-tetrahvdro- 1H- benzor lindazol-5-yl trifluoromethanesulfonate

0434(4aS)-l-(4-fluorophenyl)-4a-methyl-l,4,4a,6,7,8-hexahydro-5H- benzo[ ]indazol-5-one (0.44 g, 1.49 mmol) was dissolved in TΗF (30 mL) and cooled to 0 °C. Potassium hexamethyldisilazide (40.51 mL of a 0.5 M solution in toluene, 20.28 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 1.5 hours prior to addition of 2-[N,N- bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (7.96 g, 20.28 mmol). The reaction was stirred at room temperature for 18 hours and then quenched with sat. NΗ₄CI (50 mL) and H 0 (50 mL). The resultant mixture was extracted with EtOAc (4 x 200 mL) and the combined extracts were washed with H₂O (200 mL) and brine (200 mL), dried over MgSO and concentrated in vacuo. The residue was filtered through a plug of silica and then purified by flash chromatography (5 to 15% EtOAC/hexanes) on silica gel to afford 1 g (46%) of (4aS)-l-(4- fluorophenyl)-4a-methyl-4,4a,7,8-tetrahydro-lH-benzo[ ]indazol-5-yl trifluoromethanesulfonate as a yellow solid. LCMS = 429; (M + 1)⁺. 1H NMR (CDC , 500 MHz): δ 7.51 (s, IH), 7.50-7.46 (m, 2H), 7.21-7.19 (m, 2H), 6.33 (br d, 7= 1.6 Hz, 1 H), 5.93-5.91 (dd, 7 = 6.3 Hz, 7= 1.9 Hz, IH), 2.97-2.93 (d, 7 = 15.3 Hz, IH), 2.77-2.73 (d, 7= 15.3 Hz, IH), 2.54-2.38 (m, 3H), 2.34-2.25 (m, IH), 1.26 (s, 3H).

0435<img file="EP1542996A2_D0026.tif" />

0436Step F: (4aS)-l-(4-fluorophenyl -4a-methyl-5-vinyl-4.4a .8-tetrahvdro-lH- benzortlindazole

0437(4aS)-l-(4-fluorophenyl)-4a-methyl-4,4a,7,8-tetrahydro-lH- benzo[ ]indazol-5-yl trifluoromethanesulfonate (1 g, 2.34 mmol) was dissolved in TΗF (25 mL) and LiCl (298 mg, 7.02 mmol) and tetrakis(triphenylphosphine) palladium (0) (54 mg, 0.047 mmol) were added followed by tributyl(vinyl)tin (716 μL, 2.45 mmol). The reaction was refluxed under N₂ for 18 hours and then concentrated in vacuo. The residue was partitioned between EtOAc (50 mL) and 10% NEUOΗ (50 mL). The aqueous layer was extracted with EtOAc (50 mL) and the combined organic layers were washed with Η₂O (50mL) and brine (50 mL), dried over MgS0₄ and concentrated in vacuo. The product was purified by flash chromatography (5% EtOAc/hexanes) to afford 650 mg (91%) of (4aS)-l-(4- fluorophenyl)-4a-methyl-5-vinyl-4,4a,7 ,8-tetrahydro- lH-benzo [ indazole as an off-white solid. LCMS = 307; (M + 1)⁺. 1H NMR (CDC1₃, 500 MHz): 57.51- 7.47 (m, 2H), 7.45 (s, IH), 7.18-7.17 (d, 7= 8.4 Hz, IH), 7.17-7.16 (d, 7= 8.6 Hz, IH), 6.40-6.38 (d, 7 = 17.1 Hz, 7 = 10.8 Hz, IH), 6.24 (br d, 7 = 2 Hz, IH), 5.99- 5.97 (d, 7 = 5.3 Hz, IH), 5.44-5.40 (dd, 7= 17.1 Hz, 7= 1.6 Hz, IH), 5.08-5.06 (dd, 7 = 10.9 Hz, 7 = 1.8 Hz, IH), 2.92-2.89 (d, 7 = 15.5 Hz, IH), 2.54-2.51 (d, 7 = 15.5 Hz, IH), 2.48-2.42 (m, IH), 2.39-2.29 (m, 2H), 2.20-2.13 (m, IH), 1.16 (s, 3H).

0438<img file="EP1542996A2_D0027.tif" />

0439Step G: ethyl GRARAaRΛ laS>8-(4-fluorophenvD-l la-methyl-3- (trifluoromethyl -3.4.4a.5,6.8.11.11a-octahydro-2H-naphthon.2- lindazole-4- carboxylate

0440(4aS)-l-(4-fluorophenyl)-4a-methyl-5-vinyl-4,4a,7,8-tetrahydro- lH-benzo[ ]indazole (710 mg, 2.32 mmol) was dissolved in CΗ₂C1₂ (30 mL). Ethyl-4,4,4-trifluorocrotonate (381 μL; 2.55 mmol) was added, followed by dropwise addition of BC1₃ (5.8 mL of a 1.0 M solution in CH C1 , 5.8 mmol). The reaction was stirred at room temperature for 3 hours and then quenched with sat. NH₄CI. The reaction was partitioned between CH₂C1₂ (50 mL) and H₂O (50 mL) and the aqueous layer was extracted with CH₂C1₂ (2 x 50 mL). The combined organic layers were washed with IN HCl (50 mL) and brine (50 mL), dried over MgSO₄ and concentrated in vacuo. The residue was purified by flash chromatography (0 to 65% EtOAc/hexanes) on silica gel to afford 920 mg (84%) of the product as a mixture of 2 diastereomers. Separation by chiral HPLC (ChiralPak AD column; 15% isopropanol/heptane) gave 562 mg (61%) of ethyl (3i?,4i?,4ai?,l laS)-8-(4-fluoroρhenyl)-l la-methyl-3-(trifluoromethyl)- 3,4,4a,5,6,8,l 1,1 la-octahydro-2H-naphtho[l,2- ]indazole-4-carboxylate as a colorless solid. LCMS = 475; (M + 1)⁺. 1H NMR (CDC1₃, 500 MHz): δ 7.49- 7.45 (m, 2H), 7.43 (s, IH), 7.19-7.17 (d, 7= 8.5 Hz, IH), 7.17-7.15 (d, 7= 8.4 Hz, IH), 6.21 (br s, 1 H), 5.75 (br d, 7 = 5.9 Hz, IH), 4.22-4.18 (q, 7 = 7.1 Hz, 2H), 2.90-2.86 (d, 7= 15.8 Hz, IH), 2.81-2.74 (m, IH), 2.69-2.60 (m, IH), 2.53-2.47 (m, 2H), 2.44-2.22 (m, 4H), 1.97-1.89 (m, IH), 1.62-1.54 (m, IH), 1.30-1.27 (t, 7 = 7.1 Hz, 3H), 1.24 (s, 3H). EXAMPLE 2

0441<img file="EP1542996A2_D0028.tif" />

0442ORARAaR.11 a5 -8-(4-fluorophenylVJV-(4-methoxyρhenylV 11 a-methyl-3-

0443(trifluorornethyl)-3 ,4,4a,5 ,6.8,11.11 a-octahydro-2H-naphtho r 1 ,2- lindazole-4- carboxamide

0444<img file="EP1542996A2_D0029.tif" />

0445Step A: (3 RARAaR.11 aS)-8-f 4-fluorophenylV 11 a-methyl-3-f trifluoromethylV 3.4,4a.5.6.8,l 1,1 la-octahvdro-2H-naphthoπ,2- |indazole-4-carboxylic acid

0446Ethyl (32?,4i?,4aR, 11 aS)~8-(4-fluorophenyl)- 11 a-methyl-3- (trifluoromethyl)-3 ,4,4a,5 ,6,8,11,11 a-octahydro-2H-naphtho[l ,2- |indazole-4- carboxylate (106 mg, 0.224 mmol) was dissolved in 1:1:1 TΗF:MeOΗ:Η₂O (15 mL) and LiOH -H₂O (94 mg, 2.24 mmol) was added. The reaction was stirred at room temperature for 60 hours and then concentrated in vαcuo. The residue was dissolved in IN NaOH (15 mL) and washed with diethyl ether (15 mL). The aqueous layer was acidified to pH = 3 with IN HCl and extracted with EtOAc (4 x 25 mL). The combined extracts were dried over Na SO and concentrated in vαcuo to afford 99 mg (99%) of (3R,4#,4aR,llaS)-8-(4-fluorophenyl)-lla-methyl- 3-(trifluoromethyl)-3,4,4a,5,6,8, 11 , 1 la-octahydro-2H-naphtho[l ,2-jf]indazole-4- carboxylic acid as an off-white solid. LCMS = 447; (M + 1)⁺. 1H NMR (CDC1₃, 500 MHz): δ 7.49-7.46 (m, 2H), 7.44 (s, IH), 7.20-7.16 (m, 2H), 6.23 (br s, IH), 5.79-5.77 (br d, 7 = 5.7 Hz, IH), 2.90-2.85 (d, 7 = 15.8 Hz, IH), 2.83-2.76 (m, IH), 2.74-2.66 ( , IH), 2.58-2.53 (dd, 7= 11.1 Hz, 7= 9.1 Hz, IH) 2.54-2.51 (d, 7= 15.7 Hz, IH), 2.48-2.24 (m, 4H), 2.07-1.99 (m, IH), 1.67-1.59 (m, IH), 1.25 (s, 3H).

0447<img file="EP1542996A2_D0030.tif" />

0448Step B: (3R.4Jg.4aR.1 la -8-(4-fluorophenyl)-N-(4-methoxyphenyl^')-l la-methyl- 3-(trifluoromethyl)-3,4.4a.5.6.8.11.11a-octahvdro-2H-naphthori.2- lindazole-4- carboxamide

0449(3R,4R,4aZ?,lla5)-8-(4-fluorophenyl)-lla-methyl-3- (trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- |indazole-4- carboxylic acid (7 mg, 0.0157 mmol) was dissolved in CΗ₂C1₂ (2 mL) and O-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluoroρhosphate (12 mg, 0.0314 mmol), N,N-diisopropylethylamine (42.6 mL, 0.2355 mmol) mdp- anisidine (19.3 mg, 0.157 mmol) were added. The reaction was stirred at room temperature for 18 hours. The reaction was diluted with H₂O (5 mL) and shaken. The H₂O was decanted off; the organic layer was dried over MgSO₄ and concentrated in vacuo. The residue was purified by flash chromatography (0 to 25% EtOAc/hexanes) on silica gel to afford 7.7 mg (89%) of (3R,4R,4aR,l laS)-8- (4-fluorophenyl)-iV-(4-methoxyphenyl)-lla-methyl-3-(trifluoromethyl)- 3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2-j]indazole-4-carboxamide as an off-white solid. LCMS = 552 (M + 1)⁺. 1H NMR (CDC1₃, 500 MHz): δ 7.49- 7.45 (m, 2H), 7.43 (s, IH), 7.42-7.40 (m, 2H), 7.19-7.15 (m, 3H), 6.90-6.87 (m, 2H), 6.20 (br s, IH), 5.78-5.76 (br d, 7 = 6.2 Hz, IH), 3.81 (s, 3H), 2.99-2.93 (m, IH), 2.93-2.89 (d, 7 = 15.7 Hz, IH), 2.81-2.72 (m, IH), 2.57-2.53 (d, 7 = 15.8 Hz, IH), 2.30-2.25 (m, 4H), 2.25-2.20 (dd, 7= 11.2 Hz, 7= 9.4 Hz, IH), 2.13-2.05 (m, IH), 1.25 (s, 3H). The following compounds were synthesized by procedures analogous to that described in EXAMPLE 2:

0450<img file="EP1542996A2_D0031.tif" /><img file="EP1542996A2_D0032.tif" /><img file="EP1542996A2_D0033.tif" /><img file="EP1542996A2_D0034.tif" /><img file="EP1542996A2_D0035.tif" /><img file="EP1542996A2_D0036.tif" /><img file="EP1542996A2_D0037.tif" /><img file="EP1542996A2_D0038.tif" /><img file="EP1542996A2_D0039.tif" />

EXAMPLE 40

0452<img file="EP1542996A2_D0040.tif" />

0453(SR^ig aR.l la Vδ-^-fluorophenvD-lla-methvM-fS-phenyl-l.S -oxadiazol^-ylV 3-(trifluoromethyl)-3,4,4a,5.6.8,ll,lla-octahvdro-2H-naphthori,2- |indazole

0454To a solution of (3i?,4R,4aK,llaS)-8-(4-fluorophenyl)-lla-methyl-3- (trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- |indazole-4- carboxylic acid (90 mg, 0.2 mmol) prepared as in EXAMPLE 2 Step A in POCl₃ (2 mL) was added benzoic hydrazide (55 mg, 0.4 mmol), and the mixture was heated at 100 °C for 18h. The reaction mixture was cooled and poured into ice. It was made basic (~ pΗ 8) with cone. NΗ₄OΗ while cooling the mixture in ice/H O bath. Brine was added to the mixture and it was extracted with CH₂C1₂ three times. After drying over Na₂SO , it was filtered and concentrated under reduced pressure. The crude material was purified by preparative TLC eluting with 8% EtOAc/CH₂Cl₂ to obtain 53.7 mg of the title compound.

04551H NMR (CDCI₃, 500MHz): δ 8.03 (d, J = 6.9 Hz, 2H); 7.53-7.42 (m, 6H); 7.13 (t, J = 8.6 Hz, 2H); 6.18 (d, J = 1.4 Hz, IH); 5.85 (d, J = 6.0 Hz, IH); 3.26 (dd, J = 11, 9.8 Hz, IH); 3.0 (m, IH); 2.91 (d, J = 15.8 Hz, IH); 2.81 (m, IH); 2.55 (d, J = 15.8 Hz, IH); 2.5 (m, IH); 2.4 (m, 2H); 2.29 (m, IH); 1.85 (m, IH); 1.6 (m, IH); 1.27 (s, 3H). Mass spectrum (ESI): 547.1 (M+l).

EXAMPLE 41

0457<img file="EP1542996A2_D0041.tif" />

0458(3R.4R.4aR.lla^)-8-(4-fluorophenyl)-lla-methvI-4-(5-phenyl-l,3-oxazol-2-ylV3- (trifluoromethylV3.4,4a,5,6,8,ll,lla-octahvdro-2H-naphthori,2- 1indazole

0459<img file="EP1542996A2_D0042.tif" />

0460Step A: (3R.4J?.4aJ?.lla5V8-(4-fluorophenvD-lla-methyl-3-(trifluoromethvn- 3.4.4a.5.6.8.11.11a-octahvdro-2H-naphthon.2- lindazole-4-(2-oxo-2- phenylethyDcarboxamide The solution of (3R,4R,4aR, 11 a5)-8-(4-fluorophenyl)- 11 a-methyl-3-(trifluoromethyl)-3 ,4,4a,5 ,6, 8 ,11,11 a-octahydro-2H-naphtho[ 1 ,2- jf]indazole-4-carboxylic acid (40.8 mg, 0.091 mmol) in CΗ₂C1₂ (1.0 mL) was cooled down to 0 °C, and to this was added oxalyl chloride (70 μL, 2.0 M, 0.137 mmol) followed by 1 drop of DMF via pipet. The reaction mixture was stirred for 2h while slowly warming up to room temperature. The solvent was removed under reduced pressure, and the residue was co-evaporated two times with toluene. After drying under high vacuum, the acid chloride was dissolved in CH₂C1 (1.0 mL), and to this was added 2-aminoacetophenone hydrochloride (18 mg, 0.1 mmol) followed by Et₃N (28 μL, 0.2 mmol). The reaction mixture was stirred for 2h, then 10% aqueous NE OH was added. The aqueous layer was extracted with CH₂C1₂, and combined extracts were washed with brine and dried over Na₂SO₄. The crude material was purified by preparative TLC eluting with 1:2 acetone:hexane to obtain 42 mg of the title compound.

04611H NMR (CDC1₃, 500MHz): 57.97 (d, J = 7.6 Hz, 2H); 7.62-7.39 (m, 6H); 7.14 (t, J = 8.6 Hz, 2H); 6.82 (1 NH); 6.16 (s, IH); 5.73 (d, J = 6.0 Hz, IH); 4.91 (dd, J = 5, 19.9 Hz, IH); 4.68 (dd, J = 3.5, 19.9 Hz, IH); 2.86 (m, IH); 2.87 (d, J = 15.8 Hz, IH); 2.71 (m, IH); 2.5 (d, J = 15.8 Hz, IH); 2.44-2.21 (m, 5H); 2.01 (m, IH); 1.5 (m, IH); 1.22 (s, 3H). Mass spectrum (ESI): 564.2 (M+l).

0462Step B: (3R.4 g.4aR.llay)-8-(4-fluorophenyl)-lla-methyl-4-(5-ρhenyl-1.3-oxazol-2- yl)-3-(trifluoromethyl)-3,4,4a,5,6,8,l 1.1 la-octahvdro-2H-naphthon.2- 1indazole

0463The solution of (37?,4i?,4a2?,lla5)-8-(4-fluorophenyl)-lla-methyl-3- (trifluoromethyl)-3,4,4a,5,6,8,ll_>lla-octahydro-2H-naphtho[l,2-/]indazole-4-(2-oxo- 2-phenylethyl)carboxamide (17.4 mg, 0.031 mmol) in POCl₃ (0.5 mL) was heated at 100 °C for 3h and cooled to room temperature. The reaction mixture was poured into ice/Η₂O and made basic with cone. NH₄OH to pH 8 while cooling in ice bath (very exothermic). Brine was added and the aqueous layer was extracted with CH₂C1₂ three times. The combined organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude material was purified by preparative TLC eluting with 1:3 acetone:hexane system to obtain 12.2 mg of the title compound.

04641H NMR (CD₃OD, 500MHz): δ 7.65 (d, J = 7.3 Hz, 2H); 7.45-7.39 (m, 6H); 7.32 (m, IH); 7.22 (t, J = 8.7 Hz, 2H); 6.18 (s, IH); 5.89 (d, J = 5.7 Hz, IH); 3.08 (t, J = 10.6 Hz, IH); 2.97 (m, IH); 2.9 (d, J = 16 Hz, IH); 2.84 (m, IH); 2.6 (d, J = 16 Hz, IH); 2.49 (m, IH); 2.38 (m, 2H); 2.28 (m, IH); 1.7 (m, IH); 1.56 (m, IH); 1.24 (s, 3H). Mass spectrum (ESI): 546.2 (M+l). The following examples were synthesized by pocedures analogous to that described in EXAMPLE 41:

0465<img file="EP1542996A2_D0043.tif" /> EXAMPLE 42

0466<img file="EP1542996A2_D0044.tif" />

0467(3R.4R.4aR.lla5)-8-f4-fluorophenylVlla-methyl-4-(5-phenyl-1.3- hiazol-2-vn-3- (trifluoromethyl)-3,4.4a,5.6.8.11.11a-octahvdro-2H-naphthon.2- lindazole

0468To a solution of (3i?,4i?,4aR,lla5)-8-(4-fluorophenyl)-lla-methyl-3- (trifluoromethyl)-3 ,4,4a, ,6,8 , 11,1 la-octahydro-2H-naphtho [ 1 ,2- Jindazole-4-(2-oxo- 2-phenylethyl)carboxamide (25.4 mg, 0.045 mmol) in toluene (1 mL) was added

0469Lawesson's reagent (73 mg, 0.18 mmol), and the mixture was heated at 100 °C for 3h. The reaction mixture was cooled and the solvent was removed under reduced pressure. The crude material was purified by preparative TLC eluting with 1:3 acetone:hexane system to give 18.4 mg of the title compound. 1H NMR (CD₃OD, 500MHz): δ 7.98 (s, IH); 7.59 (d, J = 7.6 Hz, 2H);

04707.46-7.38 (m, 5H); 7.33 (t, J = 7.6 Hz, IH); 7.24 (t, J = 8.7 Hz, 2H); 6.19 (s, IH); 5.9 (d, J = 6.0 Hz, IH); 3.24 (dd, J = 9.6, 11 Hz, IH); 2.94 (m, IH); 2.94 (d, J = 15.9 Hz, IH); 2.83 (m, IH); 2.6 (d, J = 15.9 Hz, IH); 2.5 (m, IH); 2.38 (m, 2H); 2.29 (m, IH); 1.74 (m, IH); 1.59 (m, IH); 1.26 (s, 3H). Mass spectrum (ESI): 562.2 (M+l).

EXAMPLE 43

0472<img file="EP1542996A2_D0045.tif" /> (3i?.4i?,4aJ?.lla5')-8-(4-fluorophenylVlla-methyl-4-(3-phenyl-1.2.4-oxadiazol-5-ylV 3-(trifluoromethylV3.4.4a.5.6.8.11.11a-octahvdro-2H-naphthori.2-r1indazole A solution of (3R,4R,4aR laS)-8-(4-fluorophenyl)-l la-methyl-3-(trifluoromethyl)- 3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- |indazole-4-carboxylic acid (16.7 mg, 0.037 mmol) in CΗ₂C1 (0.5 mL) was cooled down to 0 °C, and to this was added oxalyl chloride (28 μL, 2.0 M, 0.056 mmol) followed by 1 drop of DMF via pipet. The reaction mixture was stirred for 2h while slowly warming up to room temperature. The solvent was removed under reduced pressure, and the residue was co-evaporated two times with toluene. After drying under high vacuum, the acid chloride was dissolved in THF (0.5 mL) and benzamide oxime (16 mg., 0.12 mmol) was added and the mixture was stirred at 65°C for 3 hours. The mixture was cooled to room temperature and BuψNF (40 μL of a 1.0 M solution in THF) was added. The reaction was stirred overnight. The mixture was heated to and maintained at 65°C for 6 h, and then stirred a room temperature overnight. More Bu+NF (40 μL of a 1.0 M solution in THF) was added and the reaction was heated to 65°C for 2 h. The mixture was cooled and was diluted with EtOAc. The organic layer was washed with H₂O and brine, then dried over Na SO₄. The crude material was purified by preparative TLC eluting with 1:3 acetone:hexane system to obtain 14.1 mg of the title compound.

04731H NMR (CDC1₃, 500MHz): δ 8.08 (dd, J = 1.6, 8.0 Hz, 2H); 7.49- 7.42 (m, 6H); 7.14 (t, J = 8.6 Hz, 2H); 6.19 (s, IH); 5.85 (d, J = 5.7 Hz, IH); 3.27 (dd, J = 9.6, 11.2 Hz, IH); 3.04 (m, IH); 2.93 (d, J = 15.8 Hz, IH); 2.56 (d, J = 15.8 Hz, IH); 2.51 (m, IH); 2.39 (m, 2H); 2.29 (m, IH); 1.78 (m, IH); 1.58 (m, IH); 1.27 (s, 3H). Mass spectrum (ESI): 547.2 (M+l). EXAMPLE 44

0474<img file="EP1542996A2_D0046.tif" />

0475(3^.4i?.4aJ?.lla5V8-(4-fluorophenylVlla-methyl-4-(5-phenyl-lH-imidazol-2-yl -3- (trifluoromethylV 3.4.4a.5.6.8.11.11 a-octahvdro-2H-naphtho r 1.2- lindazole To a solution of (3R,4R,4a ?,lla5)-8-(4-fluorophenyl)-lla-methyl-3-(trifluoromethyl)- 3 ,4,4a,5 ,6,8 , 11,11 a-octahydro-2H-naphtho[ 1 ,2- ]indazole-4-carbaldehyde (EXAMPLE 47) (12 mg, 0.028 mmol) in methanol (0.5 mL) was added phenyl glyoxal hydrate (11 mg, 0.084 mmol) and ammonium acetate (22 mg, 0.28 mmol). The mixture was heated at 65 °C for 4h. The reaction mixture was cooled down to room temperature and removed methanol under reduced pressure. The residue was dissolved in CΗ₂C1₂ and washed with saturated NaHCO₃, H₂O, and brine, respectively. The organic layer was dried over Na₂SO , then the crude material was purified by preparative TLC eluting with 1:2 EtOAc:hexane to give 5 mg of the title compound.

04761H NMR (CD₃OD, 500MHz): δ 7.63 (d, J = 7.5 Hz, 2H); 7.45-7.39 (m, 3H); 7.33 (t, J = 7.7 Hz, 2H); 7.29 (s, IH); 7.24-7.18 (m, 3H); 6.15 (s, IH); 5.88 (d, J = 6.0 Hz, IH); 2.95 (d, J = 16.2 Hz, IH); 2.93 (m, 2H); 2.83 (m, IH); 2.59 (d, J = 16.2 Hz, IH); 2.48 (m, IH); 2.36 (m, 2H); 2.27 (m, IH); 1.64 (m, IH); 1.50 (m, IH); 1.21 (s, 3H). Mass spectrum (ESI): 545.2 (M+l). EXAMPLE 45

0477<img file="EP1542996A2_D0047.tif" />

04783R.4R.4aR.11 a5)-8-f 4-fluorophenyl^')-l 1 a-methyl-4-(5-phenyl-l .3.4-thiadiazol-2-yl -3- (trifluoromethyl)-3,4.4a.5.6.8,ll.lla-octahvdro-2H-naphthon.2- lindazole

0479<img file="EP1542996A2_D0048.tif" />

0480Step A: (3RARAaRΛ la ViV-benzoyl-8-(4-fluorophenylVl la-methyl-3- (trifluoromethyl)-3 ,4,4a,5 ,6, 8 ,11,11 a-octahvdro-2H-naphtho f 1 ,2-f1indazole-4- carbohydrazide

0481The title compound was prepared according to the procedure described in EXAMPLE 41 Step A using benzoic hydrazide.

04821H NMR (CDC1₃, 500MHz): δ 10.1 (d, J = 5.5 Hz, IH); 9.89 (d, J = 5.5 Hz, IH); 7.8 (d, J = 7.1 Hz, 2H); 7.49-7.35 (m, 6H); 7.14 (t, J = 8.6 Hz, 2H); 6.12 (s, IH); 5.65 (d, J = 6.0 Hz, IH); 2.79 (d, J = 15.8 Hz, IH); 2.78 (m, IH); 2.63 (m, IH); 2.55 (dd, J = 9.4, 11.0 Hz, IH); 2.46 (d, J = 15.8 Hz, IH); 2.35 (m, IH); 2.31 (m, IH); 2.24 (m, 2H); 2.09 (m, IH); 2.0 (m, IH); 1.54 (m, IH); 1.15 (s, 3H).

0483Step B : (3R.4R.4aR.l la V8-(4-fluorophenylVlla-methyl-4-(5-phenyl-1.3.4- thiadiazol-2-yD-3-(trifluoromethylV3.4.4a.5.6.8.11.11a-octahvdro-2H-naphthori.2- flindazole The title compound was prepared according to the procedure described in EXAMPLE 42 starting from (3i?,4i?,4ai?,lla₁S)-iV-benzoyl-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2-y]indazole- 4-carbohydrazide.

04841H NMR (CDCI₃, 500MΗz): δ 7.94 (dd, J = 7.6, 2.0 Hz, 2H); 7.48- 7.42 (m, 6H); 7.14 (t, J = 8.6 Hz, 2H); 6.17 (d, J = 1.4 Hz, IH); 5.85 (d, J = 5.8 Hz, IH); 3.45 (dd, J = 10.4, 9.0 Hz, IH); 2.96 (m, IH); 2.92 (d, J = 15.8 Hz, IH); 2.84 (m, IH); 2.54 (d, J = 15.8 Hz, IH); 2.52 (m, IH); 2.44 (m, IH); 2.38 (m, IH); 2.35 (m, ^' IH); 2.26 (m, IH); 1.82 (m, IH); 1.62 (m, IH); 1.26 (s, 3H). Mass spectrum (ESI): 563.2 (M+l).

EXAMPLE 46

0486<img file="EP1542996A2_D0049.tif" />

0487(3J?.4J?,4aJ?.lla₁SV4-(4-benzyl-5-phenyl-4H-l,2,4-triazol-3-ylV8-(4-fluorophenylV lla-methyl-3-(trifluoromethylV3.4.4a.5.6.8.11.11a-octahvdro-2H-naphthori.2- flindazole

0488(3R,4R,4aR,lla5)-8-(4-fluorophenyl)-lla-methyl-4-(3-phenyl-l,2,4- oxadiazol-5-yl)-3-(trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- jindazole (EXAMPLE 43) (31.6 mg, 0.058 mmol) was dissolved in benzylamine (1 mL) in a sealed tube, and the mixture was heated at 150 °C for 13 days. It was cooled, loaded onto packed silica gel, and eluted with diethyl ether (50 mL) to remove benzyl amine followed by 5% MeOΗ/CΗ₂Cl to obtain the crude material. Further purification was done by a preparative TLC eluting with 3% MeOH/CH₂Cl₂ to obtain 3.6 mg of the title compound.

04891H NMR (CDCI₃, 500MHz): δ 7.61-6.99 (15 aromatic H's); 6.07 (s, IH); 5.75 (d, J = 5.9 Hz, IH); 5.34 (d, J = 16.7 Hz, IH); 5.07 (d, J = 16.7 Hz, IH); 3.21 (m, IH); 2.88 (d, J = 15.7 Hz, IH); 2.82 (m, IH); 2.75 (dd, J = 10.5, 8.9 Hz, IH); 2.52 (m, IH); 2.49 (d, J = 15.7 Hz, IH); 2.33 (m, IH); 2.06 (m, 2H); 1.38 (m, IH); 1.14 (s, 3H); 0.55 (m, IH). Mass spectrum (ESI): 636.4 (M+l).

0490<img file="EP1542996A2_D0050.tif" />

0491(3RARAaR, 11 aS)-8-(4-fluoroρhenyl 11 a-methyl-3-(trifluoromethylV 3,4,4a,5,6,8,ll,ll a-octahydro-2H-naphtho f 1 ,2- |indazole-4-carbaldehyde and r(3i?.4i?.4aJ?,lla5)-8-(4-fluorophenvD-lla-methyl-3-(trifluoromethylV 3.4.4a.5.6.8.11.11a-octahydro-2H-naphthon.2- indazol-4-yl1methanol

0492To a solution of ethyl (llaS)-8-(4-fluorophenyl)-lla-methyl-3- (trifluoromethyl)-3 ,4,4a,5 ,6 ,8 , 11 , 11 a-octahydro-2Η-naphtho [ 1 ,2-f] indazole-4- carboxylate (from EXAMPLE 1) (505 mg, 1.064 mmol) in CH₂C1₂ (15 mL) was added diisobutylaluminum hydride (2.13 mL of a IM solution in CH₂C1₂, 2.13 mmol) at -78 °C. The mixture stirred for 2 hours at -78°C and was quenched with

0493Rochelle's salt. The organic layer was extracted with water, brine, and dried over MgSO . The crude product was purified by liquid chromatography, 5% to 100% ethyl acetate in hexanes to yield (3i?,4i?,4ai?,lla5')-8-(4-fluorophenyl)-lla-methyl-3- (trifluoromethyl)-3 ,4,4a,5 ,6,8 , 11,11 a-octahydro-2H-naphtho [ 1 ,2-/]indazole-4- carbaldehyde (300 mg, 67 %) and [(3R,4R,4aR, 11 aS)-8-(4-fluoroρhenyl)- 11 a-methyl- 3-(trifluoromethyl)-3 ,4,4a,5 ,6, 8 ,11,11 a-octahydro-2H-naphtho [ 1 ,2-/jindazol-4- yl]methanol (108 mg, 24 %).

0494EXAMPLE 47: (3J?.4J?.4aJ?.lla5)-8-(4-fluorophenyl)-lla-methyl-3- (trifluoromethyl)-3 A4a,5.6.8.11.11 a-octahvdro-2H-naphtho [ 1 ,2- lindazole-4- carbaldehyde 1H NMR (CDCI₃, 500 MHz): δ 9.607 (s, IH), 7.458 (m, 2H), 7.408 (s, IH), 7.164 (m, 2H), 6.226 (s, IH), 5.764 (s, IH), 2.854 (d, J = 15.8 Hz, IH), 2.767-2.692 (m, 2H), 2.531-2.518 (m, IH), 2.484 (d, 15.8 Hz, IH), 2.410-2.039 (m, 4H), 1.927 (m, IH), 1.602 (m, IH), 1.233 (s, 3H). EXAMPLE 48: lY3fl.4fl.4aR.l lay>-8-(4-fluorophenyl)-l la-methyl-3-

0495(trifluoromethylV3.4.4a.5.6.8,ll.lla-octahvdro-2H-naphthon.2- lindazol-4- yllmethanol

04961H NMR (CDCI₃, 500 MHz): δ 7.451 (m, 2H), 7.395 (s, IH), 7.146 (t, J = 8.7 Hz, 2H), 6.190 (s, IH), 5.716 (s, IH), 3.845 (dd, J = 3.2, 11.7 Hz, IH), 3.660 (dd, J = 3.2, 11.7 Hz, IH), 2.813 (d, J = 15.6 Hz, IH), 2.551 (m, IH), 2.470 (m, IH), 2.398-2.246 (m, 5H), 2.057 (m, IH), 1.757 (m, IH), 1.520 (m, IH), 1.210 (s, 3H).

EXAMPLE 49

0498<img file="EP1542996A2_D0051.tif" />

0499(3fl.4fl.4afl,lla -8-(4-fluoroρhenylV4-(lH-imidazol-2-vn-lla-methyl-3- (trifluoromethyl)-3 ,4,4a,5 ,6,8,11,11 a-octahydro-2H-naphthor 1 ,2- lindazole

0500To a solution of (3fl,4fl,4afl,lla5)-8-(4-fluorophenyl)-lla-methyl-3- (trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- |indazole-4- carbaldehyde (EXAMPLE 47) (144 mg, 0.334 mmol) in methanol (6 mL) was added glyoxal (58.4 mg, 0.998 mmol) and ammonium acetate (528 mg, 6.68 mmol) at room temperature. The reaction mixture was heated to reflux for 4 days, then the solvent was removed under reduced pressure. The crude mixture was diluted with ethyl acetate and washed with NaΗCθ₃, H₂O, brine, and dried over MgS0 . After removal of the solvent, the crude product was purified twice by preparative thin layer chromatography eluting with 4% methanol in dichloromethane and then once by flash chromatography on silica gel using a gradient of 5% acetone in hexanes increasing to 100% acetone to give 54 mg of the title compound.

05011H NMR (CDC1₃, 500 MHz): δ 7.471 (m, 3H), 7.297 (t, J = 8.7 Hz, 2H), 6.209 (s, IH), 5.905 (d, J = 6.0 Hz, IH), 2.953 (t, J = 15.8 Hz, IH), 2.915 (m, 2H), 2.752 (m, IH), 2.643 (d, J = 15.8 Hz, IH), 2.273-2.518 (m, 4H), 1.601 (m, IH), 1.497 (m, IH), 1.278 (s, 3H).

EXAMPLE 50

0503<img file="EP1542996A2_D0052.tif" />

0504(3fl,4fl,4afl, 11 aSV 8-(4-fluorophenyl)-4-( lH-imidazol-2-ylV 11 a-methyl-3- (trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphthori,2-f|indazole

0505The title compound was prepared from (3fl,4fl,4afl,llaiS)-8-(4- fluorophenyι)-l la-methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,l 1,1 la-octahydro-2H- naphtho[l,2- |indazole-4-carbaldehyde (EXAMPLE 47) and pyruvic aldehyde according to the procedure described in EXAMPLE 49

05061H NMR (CDCI₃, 500 MHz): δ 7.476 (m, 3H), 7.297 (m, 3H), 6.269 (s, IH), 6.011 (d, J = 6.8 Hz, IH), 3.194 (t, J = 11.8 Hz, IH), 2.940 (d, J = 17.8 Hz, IH), 2.890 (m, 2H), 2.689 (d, J = 17.8 Hz, IH), 2.657 (m, IH), 2.477-2.39 (m, 6H), 1.692 (m, IH), 1.535 (m, IH), 1.313 (s, 3H).

EXAMPLE 51

0508<img file="EP1542996A2_D0053.tif" /> (3fl.4fl,4afl.lla V4-(lH-benzimidazol-2-ylV8-(4-fluorophenvn-lla-methyl-3- (trifluoromethylV3.4.4a.5.6.8.11.11a-octahvdro-2H-naphthoπ.2-flindazole

0509(3fl,4fl,4afl,lla5)-8-(4-fluorophenyl)-lla-methyl-3-(trifluoromethyl)- 3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- ]indazole-4-carbaldehyde (EXAMPLE 47) (15 mg, 0.035 mmol) and 1,2-phenylenediamine (10 mg) in nitrobenzene (0.4 mL) were heated to 150 °C for 4 hours. The nitrobenzene was evaporated and the crude residue^'was purified by preparative thin layer chromatography (1:1 EtOAc:hexane) to yield 3.2 mg of the title compound. 1H NMR (CDC1₃, 500 MHz): δ 7.575 (bs, IH), 7.473 (m, 3H), 7.410 (s, IH), 7.249 (m, 2H), 7.166 (t, J = 8.7 Hz, 2H), 6.153 (s, IH), 5.814 (d, J = 5.9 Hz, IH), 3.246 (m, IH), 3.030 (t, J = 11.0 Hz, IH), 2.853 (m, 2H), 2.521 (m, 2H), 2.383 (m, 2H), 2.258 (m, 2H), 1.790 (m, IH), 1.504 (m, IH), 1.275 (s, 3H).

EXAMPLE 52

0511<img file="EP1542996A2_D0054.tif" /> (3fl.4fl.4afl.llaS)-4-(1.3-benzoxazol-2-ylV8-(4-fluorophenyl)-lla-methyl-3- (trifluoromethyl)-3 ,4,4a,5.6, 8, 11,11 a-octahvdro-2H-naphtho I^" 1 ,2- lindazole The title compound was prepared from (3fl,4fl,4afl,l laS)-8-(4- fluorophenyl)-l la-methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,l 1,1 la-octahydro-2H- naphtho[l,2-/]indazole-4-carbaldehyde (EXAMPLE 47) and 2-aminophenol according to the procedure described in EXAMPLE 51. 1H NMR (CDCI₃, 500 MHz): δ 7.794 (m, IH), 7.715 (m, IH), 7.576 ( , IH), 7.466- 7.413 (m, 4H), 7.242 (t, J = 8.2 Hz, 2H), 6.119 (s, IH), 5.941 (d, J = 5.5 Hz, IH), 3.354 (m, 2H), 3.053 (m, 2H), 2.699 (d, J = 16.1 Hz, IH), 2.576 (m, IH), 2.482 (m, 2H), 2.365 (m, IH), 1.810 (m, IH), 1.732 (m, IH), 1.337 (s, 3H). EXAMPLE 53

0512<img file="EP1542996A2_D0055.tif" />

0513l-r(3fl.4fl.4afl,lla5 -8-(4-fluorophenylVlla-methyl-3-(trifluoromethylV 3,4,4a,5,6,8,ll,lla-octahvdro-2H-naphthon,2-flindazoI-4-ynmethanamine

0514<img file="EP1542996A2_D0056.tif" />

0515StepA: IY1 la5V8-(4-fluorophenyl l la-methyl-3-(trifluoromethylV 3.4.4a.5.6.8, 11.11 a-octahvdro-2H-naphthor 1.2- lindazol-4-vnmethyl methanesulfonate

0516To a solution of [(3fl,4fl,4afl,lla5)-8-(4-fluorophenyl)-lla-methyl-3- (trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- |indazol-4- yl]methanol from EXAMPLE 48 (17 mg, 0.039 mmol) in CΗ₂C1₂ (2 mL) at 0°C was added diisopropylethylamine (10.1 μL, 0.058 mmol) and methanesulfonyl chloride (36.4 μL, 0.047 mmol). After 2hrs at 0°C the reaction was diluted with ethyl acetate and washed with NaHCO₃, IN HCl, brine, and was dried with MgSO . The solvent was removed under reduced pressure to yield the title compound. 1H NMR (CDC1₃, 500 MHz): δ 7.515 (m, 2H), 7.444 (s, IH), 7.197 (t, J = 8.7 Hz, 2H), 6.248 (s, IH), 5.786 (s, IH), 4.359 (m, 2H), 3.035 (s, 3H), 2.864 (d, J = 15.7 Hz, IH), 2.580-2.309 (m, 7H), 2.141 (m, IH), 2.049 (m, IH), 1.565 (m, IH), 1.257 (s, 3H).

0517<img file="EP1542996A2_D0057.tif" />

0518Step B: (3fl.4fl.4afl,lla₁S -4-(azidomethylV8-(4-fluorophenyl)-lla-methvI-3- (trifluoromethyl)-3,4,4a,5,6,8.11.11a-octahvdro-2H-naphthon.2-flindazole

0519To a solution of [(lla_lS)-8-(4-fluoroρhenyl)-lla-methyl-3- (trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- ]indazol-4- yl]methyl methanesulfonate from Step A (120 mg, 0.234 mmol) in DMF (2.0 mL) was added sodium azide (20 mg, 0.375 mmol). The reaction mixture was heated to 50 °C for 4 hrs, cooled to RT, diluted with ethyl acetate. It was washed with Η₂O, brine, and dried over MgSO₄. After removal of the solvent, the crude product was purified by column chromatography eluting with 5 % to 100% ethyl acetate in hexane to yield 90 mg of the title compound. 1H NMR (CDC1₃, 500 MHz): δ 7.482 (m, 2H), 7.431 (s, IH), 7.179 (m, 2H), 6.237 (s, IH), 5.748 (m, IH), 3.654 (m, IH), 3.554 (m, IH), 2.838 (d, J = 15.8 Hz, IH), 2.222-2.504 (m, 6H), 2.066 (m, IH), 1.868 (m, IH), 1.521 (m, lH), 1.238 (s, 3H).

0520Ste C: 1 l(3fl.4fl,4afl.11 aSV 8-(4-fluorophenyl)- 11 a-methyl-3-(trifluoromethvn- 3,4,4a.5,6,8,ll,lla-octahydro-2H-naphthon,2- lindazol-4-vnmethanamine

0521To a solution of the intermediate from Step B (90 mg, 0.208 mmol) in TΗF/Η₂O (2.08/0.23 mL) was added triphenylphosphine (107.6 mg, 0.171 mmol) at room temperature. The reaction mixture was heated to 50 °C for 4 hours, cooled to RT and the solvent was removed under reduced pressure. The crude material was purified by preparative thin layer chromatography eluting was 5% 2M NH₃ in MeOH7CH₂Cl₂ to obtain 40 mg of the title compound. 1H NMR (CDCl _t 500 MHz): δ 7.968 (bs, 2H), 7.556 (s, IH), 7.450 (m, 3H), 7.217 (t, J = 8.2 Hz, 2 H), 6.118 (s, IH), 5.777 (s, IH), 3.052 (m, 2H), 2.854 (m, IH), 2.538 (m, IH), 2.429 (m, 3H), 2.252 (m, 3H), 2.037 (m, 2H), 1.487 (m, IH), 1.226 (s, 3H).

EXAMPLE 54

0523<img file="EP1542996A2_D0058.tif" />

05241- IY3fl.4fl.4afl, 11 aSV 8-(4-fluorophenyl)- 11 a-methyl-3-(trifluoromethyl)-

05253,4,4a,5,6.8.11.11a-octahvdro-2H-naphthon,2-/lindazoI-4-vn-N-(3- fluorobenzvDmethanamine

0526To a solution of (3fl,4fl,4afl,llaS)-8-(4-fluorophenyl)-lla-methyl-3- (trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- |indazole-4- carbaldehyde from EXAMPLE 47(11 mg, 0.0254 mmol) in 1,2-dichloroethane (0.5 mL) was added 3-fluorobenzylamine (4.80 mg, 0.381 mmol) at RT. After 2 hours, sodium triacetoxyborohydride (10.5 mg, 0.0381 mmol) was added and the reaction mixture was allowed to stir overnight. The reaction was quenched with NΗ₄CI, diluted with CH₂C1₂, and the organic layer was washed with H₂O, brine, and dried over MgS0 . The crude product was purified via HPLC to yield the title compound. 1H NMR (CDCI₃, 500 MHz): δ 7.473 (m, 2H), 7.398 (m, IH), 7.232 (m, IH), 7.169 (t, J = 8.2 Hz, 2H), 7.074 (m, 2H), 6.917 (t, J = 8.0 Hz, IH), 6.202 (s, IH), 5.676 (s, IH), 3.815 (m, IH), 3.743 (d, J = 13.5 Hz, IH), 2.760 (m, 2H), 2.503 (m, 3H), 2.379 (d, J = 13.5 Hz, IH), 2.232 (m, 4H), 1.860 (m, IH), 1.529 (m, 2H), 1.201 (s, 3H). EXAMPLE 55

0527<img file="EP1542996A2_D0059.tif" />

0528l-r(3fl.4fl,4afl,lla5 -8-(4-fluorophenyl lla-methyl-3-(trifluoromethvn-

05293 ,4,4a,5 ,6,8 , 11 , 11 a-octahvdro-2H-naphtho[ 1 ,2-f|indazol-4-yll -N-benzylmethanamine

0530The title compound was prepared from (3fl,4fl,4afl,l laS)-8-(4- fluorophenyl)-l la-methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,l 1,1 la-octahydro-2H- naphtho[l,2- |indazole-4-carbaldehyde from EXAMPLE 47 and benzylamine according to the procedure described in EXAMPLE 54.

05311H NMR (CDC1₃, 500 MHz): 5 7.483 (m, 2H), 7.410 (s, IH), 7.274 (m, 4H), 7.228 (m, IH), 7.173 (t, J = 8.5 Hz, 2H), 6.197 (s, IH), 5.666 (s, IH), 3.806 (m, 2H), 2.775 (m, 2H), 2.584 (m, 2H), 2.485 (m, IH), 2.338 (d, J = 15.6 Hz, IH), 2.247 (m, 4H), 1.870 (m, IH), 15.42 (m, IH), 1.201 (s, 3H).

EXAMPLE 56

0533<img file="EP1542996A2_D0060.tif" />

0534l-r(3fl.4fl,4afl.lla5)-8-(4-fluorophenyl)-lla-methyl-3-(trifluoromethylV

05353,4,4a,5,6,8,ll,lla-octahvdro-2H-naphthori,2- lindazol-4-yll-N-benzylmethanamine The title compound was prepared from (3fl,4fl,4afl, 11 a5)-8-(4- fluorophenyl)-lla-methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H- naphtho[l,2-/]indazole-4-carbaldehyde from EXAMPLE 47 and 3- (difluoromethoxy)benzylamine according to the procedure described in EXAMPLE 54. ^lΗ NMR (CDC1₃, 500 MHz): δ 7.472 (m, 2H), 7.405 (s, IH), 7.269 (m, IH), 7.170 (m, 3H), 7.096 (s, IH), 6.988 (d, J = 8.0 Hz, IH), 6.471 (t, J_HF = 74.2 Hz, IH), 6.203 (s, IH), 5.677 (s, IH), 3.815 (m, 2H), 2.778 ( , 2H), 2.570 (m, 3H), 2.347 (d, J = 15.8 Hz, IH), 2.264 (m, 4H), 1,852 (m, IH), 1.556 (m, IH).

EXAMPLE 57

0537<img file="EP1542996A2_D0061.tif" />

0538l-r(3fl.4fl.4afl,lla V8-(4-fluorophenylVlla-methyl-3-(trifluoromethyl)- 3,4,4a,5,6,8.11,lla-octahvdro-2H-naphthori,2-flindazol-4-yll-iV-benzylmethanamine The title compound was prepared from (3fl,4 ,4afl,llaS)-8-(4- fluorophenyl)-l 1 a-methyl-3-(trifluoromefhyl)-3,4,4a,5,6,8, 11,11 a-octahydro-2H- naphtho[l,2- lindazole-4-carbaldehyde from EXAMPLE 47 and aniline according to the procedure described in EXAMPLE 54. 1H NMR (CDC1₃, 500 MHz): δ 7.588 (s, IH), 7.456 (m, 2H), 7.215 (m, 4H), 6.914 (t, J = 8.1 Hz, IH), 6.806 (d, J = 6.806. 2H), 6.137 (s, IH), 5.772 (s, IH), 5.051 (bs, IH), 3.305 (m, 2H), 2.829 (d, J = 15.8 Hz, IH), 2.497 (m, IH), 2.436 (d, J = 15.8 Hz, IH), 2.365 (m, IH), 2.278 (m, IH), 2.156 (m, IH), 2.006 (m, IH), 1.662 (m, IH), 1.240 (s, 3H). EXAMPLE 58

0539<img file="EP1542996A2_D0062.tif" />

0540N-i IY3fl.4 .4afl,l la5V8-(4-fluorophenylVl la-methyI-3-ftrifluoromethyl)-

05413,4,4a,5,6,8,ll,l la-octahydro-2H-naphthori,2-flindazol-4-ynmethyl}-3-fluoroaniline

0542The title compound was prepared from (3fl,4fl,4afl,llaS)-8-(4- fluorophenyl)- 11 a-methyl-3-(trifluoromethyl)-3 ,4,4a,5 ,6,8 , 11,11 a-octahydro-2H- naphtho[l,2- ]indazole-4-carbaldehyde from EXAMPLE 47 and 3-fluoroaniline according to the procedure described in EXAMPLE 54. 1H NMR (CDC1₃, 500 MHz): δ 7.620 (s, IH), 7.438 (m, 2H) 7.198 (t, J = 6.4 Hz, 2H), 7.087 ( , IH), 6.388 (m ,2H), 6.311 ( , IH), 6.121 (s, IH), 5.771 (s, IH), 4.817 (bs, IH), 3.214 (d, J = 5.5 Hz, 2H), 2.778 (d, J = 15.8 Hz, IH), 2.453 (d, 15.8 Hz, IH), 2.408 (m, 2H), 2.352 (m, 2H), 2.297 (m, 2H), 2.095 (m, IH), 1.985 ( , IH), 1.683 (m, IH), 1.238 (s, 3H).

EXAMPLE 59

0544<img file="EP1542996A2_D0063.tif" />

0545N-i IY3fl,4fl.4afl,l laSV8-(4-fruorophenylV 1 la~methyl-4-ftrifluoromethyl)- 3.4.4a.5.6.8.11.11 a-octahvdro-2H-naphtho f 1.2-t1indazol-4-yllmethyl 1 -3- (difluoromethoxy) aniline The title compound was prepared from (3fl,4fl,4afl,l la5)-8-(4- fluorophenyl)-l la-methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H- naphtho[l,2- lindazole-4-carbaldehyde from EXAMPLE 47 and 4-difluoromethoxy anilineaccording to the procedure described EXAMPLE 54. 1H NMR (CDC1₃, 500 MHz): δ 7.861 (bs, IH), 7.681 (s, IH), 7.458 (m, 2H), 7.250 (t, J = 14.0 Hz, 2H), 7.160 (t, J = 8.0 Hz, IH), 6.634-6.336 (m, 3H), 6.129 (s, IH), 5.791 (s, IH), 3.265 (d, J = 4.6 Hz, 2H), 2.823 (d, J = 16.4 Hz, IH), 2.514-2.318 ( , 7H), 2.117 (m, IH), 2.022 (m, IH), 1.700 (m, IH), 1.266 (s, 3H).

EXAMPLE 60

0547<img file="EP1542996A2_D0064.tif" />

05483-(f r(3 ,4fl.4afl,l laS)-8-(4-fluorophenylH la-methyl-3-(trifluoromethyl)- 3,4,4a,5,6,8,ll,lla-octahvdro-2H-naphthori,2-f|indazol-4-yllmethyl}amino phenol The title compound was prepared from (3fl,4fl,4afl,lla₁S')-8-(4- fluorophenyl)- 11 a-methyl-3-(trifluoromethyl)-3 ,4,4a,5,6,8 , 11,11 a-octahydro-2H- naphtho[l,2- ]indazole-4-carbaldehyde from EXAMPLE 47 and 3-hydroxyaniline according to the procedure described in EXAMPLE 54. ^]Η NMR (CD₃OD, 500 MHz): δ 10.061 (s, IH), 7.477 (m, IH), 7.449 (s, IH), 7.249 (t, J = 12.8 Hz, 2H),

05497.117 (m, 2H), 6.915 (d, J = 8.0 Hz, IH), 6.558 (dd, J = 1.8 Hz, 8.0 Hz, IH), 6.221 (s,

0550IH), 5.860 (m, IH), 2.898 (d, J = 15.8 Hz, IH), 2.782 (m, IH), 2.689 ( , IH), 2.545

0551(m, 2H), 2.432 (m, 3H), 2.244 (m, 2H), 1.978 (m, IH), 1.602 (m, IH), 1.251 (s, IH). EXAMPLE 61

0552<img file="EP1542996A2_D0065.tif" />

0553(3fl,4fl,4afl.11 aS)-8-(4-fluorophenyl)- 11 a-methvI-3-(trifluoromethyl)- 3,4,4a.5,6,8.11 ,1 la-octahydro-2H-naphthori,2- |indazole-4-carboxamide

0554To a stirred solution of (3fl,4fl,4afl,lla5')-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2-_ι ]indazole- 4-carboxylic acid from EXAMPLE 2 Step A (45 mg, 0.10 mmol) in DMF (600 μl) was added benzotriazol-l-yloxy-tris(dimethylamino)phosρhonium hexafluorophosphate (66 mg, 0.15 mmol), 1-hydroxybenzotriazole hydrate (20 mg, 0.15 mmol), N,N-diisoproρyiethylamine (70 μl, 0.40 mmol), and NΗ4CI (11 mg, 0.20 mmol). The reaction mixture was stirred under N₂ at room temperature for 2 hours. It was then diluted with ethyl acetate and washed 2x with water followed by brine. The organic layer was dried over Na₂S0 and concentrated under reduced pressure. The product was purified by preparative thin-layer chromatography, eluting with 3:2 ethyl acetate-hexanes to yield 32 mg of the title compound. Mass spectrum (ESI) 446 (M+l). 1HNMR (500 MHz, CD₃OD): δ 1.26 (s, 3H); 1.59 (m, IH); 2.01 (m, IH); 2.24 ( , IH); 2.42 (m, 4H); 2.60 (V2 ABq, J=15.8 Hz, IH); 2.67 (m, 2H); 2.88 (V2 ABq, J=15.8 Hz, IH); 5.85 (br d, J=6.2 Hz, IH); 6.25 (s, IH); 7.28 (m, 2H); 7.44 (s, IH); 7.49 (m, 2H). EXAMPLE 62

0555<img file="EP1542996A2_D0066.tif" />

0556(3fl.4fl.4aff.1 laS)-8-(4-fluorophenviyi la-methyl-3-ftrifluoromethylV 3.4,4a,5,6,8.11,lla-octahvdro-2H-naphtho[l,2- |indazol-4-amine

0557To a stirred solution of 3fl,4fl,4afl,lla5)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- lindazole- 4-carboxamide from EXAMPLE 61 (268 mg, 0.602 mmol) in 1,4-dioxane (4.5 ml), under N₂, was added NaOCl (10-13%) (1.2 ml), 2N aqueous NaOΗ (2.1 ml), and water (2.1 ml). The reaction mixture was heated at 40°C for 1 hour. The reaction mixture was diluted with water and extracted 3x with ethyl acetate. The combined organic extracts were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure to yield 226 mg of the title compound. Mass spectrum (ESI) 418 (M+l).

05581H NMR (500 MHz, CD₃OD): δ 1.25 (s, 3H); 1.61 (m, IH); 2.32 (m, 7H); 2.52 (V2 ABq, J=15.8 Hz, IH); 2.88 (V2 ABq, J=15.8 Hz, IH); 2.95 (app t, J=8.0 Hz, IH); 5.81 (br d, J=6.0 Hz, IH); 6.25 (s, IH); 7.29 (m, 2H); 7.43 (s, IH); 7.49 (m, 2H).

EXAMPLE 63

0560<img file="EP1542996A2_D0067.tif" /> N-r(3fl.4fl.4a5.11a₁SV8-(4-fluorophenylVlla-methyl-3-(trifluoromethyl - 3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[^"l,2- lindazol-4-yl1-3-fluorobenzamide To a stirred solution of (3fl,4 ,4aS,llaS)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3,4,4a,5,6,8, 11,1 la-octahydro-2H-naphtho[l,2- ]indazol- 4-amine from EXAMPLE 62 (10 mg, 0.024 mmol) in methylene chloride (0.5 ml) was added diisopropylethylamine ( 8.4 μl, 0.048 mmol) followed by 3-fluorobenzoyl ^' chloride (4.4 μl, 0.036 mmol). The reaction mixture was stirred under N₂ at room temperature for 35 min. It was then concentrated under reduced pressure, diluted with ethyl acetate, and washed with saturated NaΗCO₃, 2N aqueous HCl, and brine. The organic layer was dried over Na₂SO , and concentrated under reduced pressure. The product was purified by preparative thin-layer chromatography, eluting with 95:5 dichloromethane-methanol to yield 8 mg of the title compound. Mass spectrum (ESI) 540 (M+l). 1H NMR (500 MHz, CD₃OD): δ 1.28 (s, 3H); 1.72 (m, IH); 2.03 (m, IH); 2.44 (m, 4H); 2.61 (! ₂ ABq, J=15.8 Hz, IH); 2.70 (m, 2H); 2.89 (V2 ABq, J=15.8 Hz, IH); 4.27 (app t, J=10.9 Hz, IH); 5.87 (br d, J=6.0 Hz, IH); 6.24 (s, IH); 7.29 (m, 3H); 7.44 (s, IH); 7.51 (m, 4H); 7.64 (br d, J=8.0 Hz, IH).

EXAMPLE 64

0562<img file="EP1542996A2_D0068.tif" />

0563N-r(3fl.4fl.4a .11a5)-8-(4-fluorophenylVlla-methyl-3-(trifluoromethvn- 3,4.4a,5,6,8,ll.lla-octahydro-2H-naphthori,2-/1indazol-4-yllbenzamide

0564The title compound was prepared from (3fl,4fl,4aS,llaS)-8~(4- fluorophenyl)-l la-methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,l 1,1 la-octahydro-2H- naphtho[l,2-/|indazol-4-amine from EXAMPLE 62 and benzoyl chloride according to the procedure described in EXAMPLE 63. Mass spectrum (ESI) 522 (M+l).

05651H NMR (500 MHz, CD₃OD): δ 1.28 (s, 3H); 1.73 (m, IH); 2.04 (m, IH); 2.43 (m,

05664H); 2.61 (V2 ABq, J=15.8 Hz, IH); 2.70 (m, 2H); 2.90 (V2 ABq, J=15.8 Hz, IH); 4.28

0567(app t, J=10.8 Hz, IH); 5.87 (br d, J=6.0 Hz, IH); 6.24 (s, IH); 7.28 (app t, J=8.7 Hz, 2H); 7.44 (s, IH); 7.48 (m, 4H); 7.55 (app t, J=7.1 Hz, IH); 7.81 (br d, J=7.5 Hz, 2H).

EXAMPLE 65

0569<img file="EP1542996A2_D0069.tif" />

0570JV-rr3fl.4fl.4aff.1 la5 -8-(4-fluorophenyl l la-methyl-3-ftrifluorornethviy

05713 ,4,4a,5 , 6 , 8 , 11.11 a-octahvdro-2H-naphtho I^" 1.2- l indazol-4-yll -3-chlorobenzamide The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4- fluorophenyl)-l la-methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,l 1,1 la-octahydro-2H- naphtho[l,2- ]indazol-4-amine from EXAMPLE 62 and 3-chlorobenzoyl chloride according to the procedure described in EXAMPLE 63. Triethylamine was used as the base.

0572Mass spectrum (ESI) 556 (M+l).

05731H NMR (500 MHz, CD₃OD): δ 1.24 (s, 3H); 1.68 (m, IH); 1.99 (m, IH); 2.36 ( , 3H); 2.48 (m, IH); 2.57 (V2 ABq, J=15.8 Hz, IH); 2.65 (m, 2H); 2.85 (V2 ABq, J=15.8

0574Hz, IH); 4.23 (app t, J=10.3 Hz, IH); 5.83 (br d, J=6.2 Hz, IH); 6.20 (s, IH); 7.24 (m,

05752H); 7.41 (s, IH); 7.44 (m, 3H); 7.53 (m, IH); 7.70 (br d, J=8.0 Hz, IH); 7.78 (app t,

0576J=1.7 Hz, IH). EXAMPLE 66

0577<img file="EP1542996A2_D0070.tif" />

0578iV-r(3fl,4fl.4aff.llaff)-8-(4-fluorophenylVlla-methyl-3-(trifluoromethyl -

05793.4,4a,5,6,8.11.11a-octahvdro-2H-naphthoπ.2-flindazol-4-vn-3-

0580(trifluoromethvDbenzamide

0581The title compound was prepared from (3fl,4fl,4aff,l laff)-8-(4- fluorophenyl)- 11 a-methyl-3-(trifluoromethyl)-3 ,4,4a,5 ,6, 8 ,11,11 a-octahydro-2H- naphtho[l,2- |indazol-4-amine from EXAMPLE 62 and 3-trifluoromethylbenzoyl chloride according to the procedure described in EXAMPLE 63. Triethylamine was used as the base.

0582Mass spectrum (ESI) 590 (M+l).

05831H NMR (500 MHz, CD₃OD): δ 1.25 (s, 3H); 1.69 ( , IH); 2.01 (m, IH); 2.36 ( , 3H); 2.49 (m, IH); 2.58 (V2 ABq, J=15.8 Hz, IH); 2.67 (m, 2H); 2.86 (V2 ABq, J=15.8

0584Hz, IH); 4.26 (app t, J=10.8 Hz, IH); 5.84 (br d, J=6.1 Hz, IH); 6.21 (s, IH); 7.24

0585(app t, J=8.7 Hz, 2H); 7.41 (s, IH); 7.45 (m, 2H); 7.67 (app t, J=7.7 Hz, IH); 7.83 (br d, J=7.7 Hz, IH); 8.04 (br d, J=7.8 Hz, IH); 8.09 (s,lH).

EXAMPLE 67

0587<img file="EP1542996A2_D0071.tif" /> N-[(3fl,4fl,4aff,llaff -8-(4-fluorophenyl -lla-methyl-3-(trifluoromethyl -

05883 ,4,4a,5 ,6, 8.11 , 11 a-octahydro-2H-naphtho r 1 ,2-flindazol-4-yll -4-fluorobenzamide

0589The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4- fluorophenyl)-l la-methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,l 1,1 la-octahydro-2H- naphtho[l,2- jindazol-4-amine from EXAMPLE 62 and 4-fluorobenzoyl chloride according to the procedure described in EXAMPLE 63. Mass spectrum (ESI) 540 (M+l).

EXAMPLE 68

0591<img file="EP1542996A2_D0072.tif" /> N-r(3fl,4fl,4aff , 11 aff)-8-(4-fluorophenvIV 11 a-methyl-3-(trifluoromethyl)- 3 ,4,4a,5 ,6,8 , 11,11 a-octahydro-2H-naphtho f 1 ,2-f1indazol-4-yll -3-methylbenzamide The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4- fluorophenyl)- 11 a-methyl-3-(trifluoromethyl)-3 ,4,4a,5 ,6,8,11,11 a-octahydro-2H- naphtho[l,2- indazol-4-amine from EXAMPLE 62 and 3-methylbenzoyl chloride according to the procedure described in EXAMPLE 63. Mass spectrum (ESI) 536 (M+l).

EXAMPLE 69

0593<img file="EP1542996A2_D0073.tif" /> iV-r(3fl,4fl.4aff.llaff)-8-(4-fluorophenylVlla-methyl-3-(trifluoromethyl - 3,4,4a,5,6,8,ll,lla-octahvdro-2H-naphthon,2- iindazol-4-yl]acetamide

0594The title compound was prepared from (3fl,4fl,4aS,llaS)-8-(4- fluorophenyl)- 11 a-methyl-3-(trifluoromethyl)-3 ,4,4a,5 ,6, 8, 11,11 a-octahydro-2H- naphtho[l,2- |indazol-4-amine from EXAMPLE 62 and acetyl chloride according to the procedure described in EXAMPLE 63. Mass spectrum (ESI) 460 (M+l).

EXAMPLE 70

0596<img file="EP1542996A2_D0074.tif" />

0597(3fl,4fl,4aff.llaff -N-benzyl-8-(4-fluorophenyl)-lla-methyl-3-(trifluoromethyl')- 3,4,4a,5,6,8,ll,lla-octahydro-2H-naphthori,2-flindazol-4-amine To a mixture of (3fl,4fl,4aff , 11 aff)-8-(4-fluorophenyl)- 11 a-methyl-3-

0598(trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- lindazol-4-amine from EXAMPLE 62 (15 mg, 0.036 mmol) in 1,2-dichloroethane (0.5 ml) was added benzaldehyde (5 μl, 0.047 mmol) followed by glacial acetic acid (2 μl, 0.036 mmol). After stirring under N₂ for 30 minutes at room temperature, sodium triacetoxyborohydride (15 mg, 0.072 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with 4 ml of 2N aqueous NaOΗ and extracted 3x with dichloromethane. The combined organic extracts were washed with brine, dried over Na₂S0 , and concentrated under reduced pressure. The product was purified by flash column chromatography on silica gel eluting with 10%- 100% ethyl acetate in hexanes, followed by a second purification by preparative thin-layer chromatography, eluting with 2:3 ethyl acetate-hexanes to yield 9 mg of the title compound. Mass spectrum (ESI) 508 (M+l). 1H NMR (500 MHz, CD₃OD): δ 1.22 (s, 3H); 1.55 (m, IH); 2.02 ( , IH); 2.27 (m, 3H); 2.47 (m, 2H); 2.49 (V2 ABq, J=15.8 Hz, IH); 2.59 (m, IH); 2.86 (V2 ABq, J=15.8 Hz, IH); 2.93 (app t, J=6.8 Hz, IH); 3.82(Abq, J=13.0 Hz, J=26.1 Hz, 2H); 5.77 (br s, IH); 6.23 (s, IH); 7.22 (m, IH); 7.29 (m, 4H); 7.34 (br d, J=7.5 Hz, 2H); 7.43 (s, IH); 7.49 (m, 2H).

EXAMPLE 71

0600<img file="EP1542996A2_D0075.tif" />

0601(3fl,4fl.4aff.llaff -N-(4-fluorobenzvD-8-(4-fluorophenvn-lla-methyl-3- (trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahvdro-2H-naphthori,2- |indazol-4-amine

0602The title compound was prepared from (3fl,4fl,4aff,llaS)-8-(4- fluorophenyl)-l la-methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,l 1,1 la-octahydro-2H- naphtho[l,2-jf|indazol-4-amine from EXAMPLE 62 and 4-fluorobenzaldehyde according to the procedure described in EXAMPLE 70. Mass spectrum (ESI) 526 (M+l).

06031HNMR (500 MHz, CD₃OD): δ 1.22 (s, 3H); 1.57 (m, IH); 2.04 (m, IH); 2.27 (m, 3H); 2.47 (m, 2H); 2.49 (V2 ABq, J=15.8 Hz, IH); 2.58 (m, IH); 2.85 (V2 ABq, J=15.8 Hz, IH); 2.91 (app t, J=7.3 Hz, IH); 3.81(Abq, J=13.0 Hz, J=25.8 Hz, 2H); 5.77 (br s, IH); 6.23 (s, IH); 7.02 (m, 2H); 7.28 (m, 2H); 7.36 (m, 2H); 7.43 (s, IH); 7.49 (m, ^' 2H).

EXAMPLE 72

0605<img file="EP1542996A2_D0076.tif" />

0606(3fl,4fl,4aff.1 laffj-N-f3-fluorobenzvD-8-f4-fluorophenyl -l la-methyl-3-

0607(trifluoromethyl)-3.4.4a.5 ,6.8.11 ,1 la-octahvdro-2H-naphthof 1 ,2- lindazol-4-amine

0608The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4- fluorophenyl)-l la-methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,l 1,1 la-octahydro-2H- naphtho[l,2- |indazol-4-amine from EXAMPLE 62 and 3-fluorobenzaldehyde according to the procedure described in EXAMPLE 70. Mass spectrum (ESI) 526 (M+l).

06091H NMR (500 MHz, CD₃OD): δ 1.22 (s, 3H); 1.58 (m, IH); 2.05(m, IH); 2.27 (m, 3H); 2.47 (m, 2H); 2.49 (V2 ABq, J=15.8 Hz, IH); 2.58 (m, IH); 2.86 (V2 ABq, J=15.8 Hz, IH); 2.92 (app t, J=5.9 Hz, IH); 3.84(Abq, J=14.0 Hz, J=25.0 Hz, 2H); 5.77 (br s, IH); 6.23 (s, IH); 6.94 (m, IH); 7.14 (m, 2H); 7.29 (m, 3H); 7.42 (s, IH); 7.48 (m, 2H).

EXAMPLE 73

0611<img file="EP1542996A2_D0077.tif" />

0612(3fl.4fl.4aff.llaff)-8-(4-fluorophenvn-lla-methyl-JV-(3-methylbenzyl)-3- (trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphthoπ,2-t1indazol-4-amine The title compound was prepared from (3fl,4fl,4aS,l laS)-8-(4- fluoroρhenyI)-l la-methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,l 1,1 la-octahydro-2H- naphtho[l,2- ]indazol-4-amine EXAMPLE 62 and 3-methylbenzaldehyde according to the procedure described in EXAMPLE 70. Mass spectrum (ESI) 521 (M+l).

06131H NMR (500 MHz, CD₃OD): δ 1.22 (s, 3H); 1.55 (m, IH); 1.99 (m, IH); 2.27 (m, ^' 3H); 2.30 (s, 3H); 2.47 (V₂ ABq, J=15.8 Hz, IH); 2.48 (m, 2H); 2.59 (m, IH); 2.84 (V2 ABq, J=15.8 Hz, IH); 2.94 (app t, J=5.5 Hz, IH); 3.78 (Abq, J=12.8 Hz, J=32.0 Hz, 2H); 5.77 (br s, IH); 6.22 (s, IH); 7.04 (br d, J=7.6 Hz, IH); 7.12 (br d, J=7.7 Hz, IH); 7.18 (m, 2H); 7.28 (app t, J=8.5 Hz, 2H); 7.43 (s, IH); 7.49 (m, 2H).

EXAMPLE 74

0615<img file="EP1542996A2_D0078.tif" />

0616(3fl,4fl.4afl.llaff -8-(4-fluorophenyl)-lla-methyl-3-(trifluoromethylV 3.4.4a.5,6,8.U.lla-octahydro-2H-naphthori,2- 1indazole-4-carbonitrile

0617To a solution of £3fl,4fl,4afl,llaff)-8-(4-fluorophenyl)-lla-methyl-3- (trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- ]indazole-4- carboxamide from EXAMPLE 61 (20 mg) in DMF (200 μl) was added cyanuric chloride (8mg). The reaction mixture was stirred under N₂ at room temperature for 1.75 hours. It was then diluted with water and extracted 3x with ethyl acetate. The combined organic layers were washed with brine, dried over Na SO₄, and concentrated under reduced pressure. The product was purified by flash column chromatography on silica gel eluting with 10%- 100% ethyl acetate in hexanes to yield 13 mg of the title compound. Mass spectrum (ESI) 428 (M+l). ^lH NMR (500 MHz, CD₃OD): δ 1.26 (s, 3H); 1.72 (m, IH); 2.29 (m, 3H); 2.45 (m, 2H); 2.59 (V2 ABq, J=15.8 Hz, IH); 2.87 (m, 4H); 5.87 (br d, J=6.0 Hz, IH); 6.30 (s, IH); 7.29 (m, 2H); 7.44 (s, IH); 7.49 (m, 2H).

EXAMPLE 75

0619<img file="EP1542996A2_D0079.tif" />

0620JV-r(3fl.4fl,4aff,llaffV8-(4-fluorophenyl')-lla-methyl-3-(trifluoromethylV 3 ,4.4a.5,6.8.11.11 a-octahvdro-2H-naphtholT ,2-flindazol-4-yl1-4- fluorobenzenesulfonamide

0621To a mixture of (3fl,4fl,4aff,llaff)-8-(4-fluorophenyl)-lla-methyl-3- (trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- Iindazol-4-amine from EXAMPLE 62 (15 mg, 0.036 mmol) in TΗF (0.5 ml) was added 4- fluorobenzenesulfonyl chloride (11 mg, 0.054 mmol) followed by diisopropylethylamine (9 μl, 0.054 mmol). After stirring under N₂ at room temperature for ea. 2 hours, the solvent was removed under reduced pressure. The product was purified by preparative thin-layer chromatography, eluting with 95:5 dichloromethane-methanol to yield 12 mg of the title compound. Mass spectrum (ESI) 576 (M+l).

06221H NMR (500 MHz, CD₃OD): δ 1.20 (s, 3H); 1.52 (m, IH); 1.76 (m, IH); 2.24 (m, 4H); 2.48 (V2 ABq, J=15.8 Hz, IH); 2.50 (m, 2H); 2.71 (¥2 ABq, J=15.8 Hz, IH); 3.60 (app t, J=8.0 Hz, IH); 5.78 (br s, IH); 6.17 (s, IH); 7.23 (app t, J=8.7 Hz, 2H); 7.29 (app t, J=8.7 Hz, 2H); 7.43 (s, IH); 7.48 (m, 2H); 7.89 (m, 2H). EXAMPLE 76

0623<img file="EP1542996A2_D0080.tif" />

0624N-r(3fl,4fl,4aff.llaffV8-(4-fluorophenyl -lla-methyl-3-(trifluoromethyl -

06253,4,4a,5,6,8,ll,lla-octahvdro-2H-naphthori,2- lindazol-4-yl1benzenesulfonamide

0626The title compound was prepared from (3fl,4fl,4aff,l laff)-8-(4- fluorophenyl)-lla-methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H- naphtho[l,2-j^&lt;]indazol-4-amine from EXAMPLE 62 and benzenesulfonyl chloride according to the procedure described in EXAMPLE 75. Mass spectrum (ESI) 558 (M+l).

EXAMPLE 77

0628<img file="EP1542996A2_D0081.tif" />

0629iV-r(3fl,4fl,4aff.llaffV8-f4-fluorophenvn-lla-methyl-3-(trifluoromethylV 3,4,4a,5,6,8,ll,lla-octahvdro-2H-naphthon,2-f1indazoI-4-yllmethanesulfonamide The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4- fluorophenyl)- 11 a-methyl-3-(trifluoromethyl)-3 ,4,4a,5 ,6 ,8 , 11,11 a-octahydro-2H- naphtho[l,2- ]indazol-4-amine from EXAMPLE 62 and mefhanesulfonyl chloride according to the procedure described in EXAMPLE 75. Mass spectrum (ESI) 496 (M+l). EXAMPLE 78

0630<img file="EP1542996A2_D0082.tif" />

0631JV-r(3fl.4fl,4aff,llaff -8-(4-fluorophenyl -lla-methyl-3-rtrifluoromethyl)- 3.4,4a,5,6,8.11.11a-octahvdro-2H-naphthofl.2-flindazol-4-vn-N'-phenylurea

0632To a solution of (3fl,4fl,4aff,llaff)-8-(4-fluorophenyl)-lla-methyl-3- (trifluoromethyl)-3 ,4,4a,5,6,8,ll,ll a-octahydro-2H-naphtho [ 1 ,2- |indazol-4-amine from EXAMPLE 62 (15 mg, 0.036 mmol) in dichloromethane (0.5 ml) was added phenyl isocyanate (4.1 μl, 0.038 mmol). After stirring under N₂ at room temperature for 3 hours, the solvent was removed under reduced pressure. The product was purified by flash column chromatography on silica gel eluting with 1%-100% methanol in dichloromethane, followed by a second purification by preparative thin- layer chromatography, eluting with 95:5 dichloromethane-methanol to yield 13 mg of the title compound.

0633Mass spectrum (ESI) 537 (M+l).

06341H NMR (500 MHz, CD₃OD): δ 1.27 (s, 3H); 1.72 (m, IH); 2.10 (m, IH); 2.41 (m, 4H); 2.59 (m, 2H); 2.59 (^l/₂ ABq, J=15.8 Hz, IH); 2.89 (^l/₂ ABq, J=15.8 Hz, IH); 3.93 (app t, J=9.6 Hz, IH); 5.83 (br d, J=5.3 Hz, IH); 6.25 (s, IH); 6.99 (app t, J=6.9 Hz, IH); 7.27 (m, 4H); 7.34 (br d, J=8.3 Hz, 2H); 7.44 (s, IH); 7.49 (m, 2H).

EXAMPLE 79

0636<img file="EP1542996A2_D0083.tif" />

0637iV-r(3fl.4fl.4aff.llaffV8-(4-fluorophenyl)-lla-methyl-3-(trifluoromethyl -

06383,4.4a.5,6,8.11,lla-octahvdro-2H-naphthoπ,2- 1indazol-4-vn-N'-(3- fluorophenyDurea

0639The title compound was prepared from (3fl,4fl,4aff,llaS)-8-(4- fluorophenyl)- 11 a-methyl-3-(trifluoromethyl)-3 ,4,4a,5 ,6,8 , 11 , 11 a-octahydro-2H- naphtho[l ,2- |indazol-4-amine from EXAMPLE 62 and 3-fluorophenylisocyanate according to the procedure described in EXAMPLE 78.

0640Mass spectrum (ESI) 555 (M+l).

06411H ΝMR (500 MHz, CD₃OD): δ 1.27 (s, 3H); 1.71 (m, IH); 2.09 (m, IH); 2.41 (m,

06424H); 2.57 (m, 2H); 2.59 QA ABq, J=15.8 Hz, IH); 2.88 Q i ABq, J=15.8 Hz, IH); 3.93 (app t, J=9.6 Hz, IH); 5.83 (br d, J=6.0 Hz, IH); 6.24 (s, IH); 6.69 (m, IH); 7.02 (br d, J=8.3 Hz, IH); 7.23 (dd, J=8.2 Hz, J=14.8 Hz, IH); 7.28 (app t, J=8.4 Hz, 2H);

06437.33 (m,lH); 7.44 (s, IH); 7.49 (m, 2H).

EXAMPLE 80

0645<img file="EP1542996A2_D0084.tif" /> N-r(3fl,4fl.4aff.lla,;V8-(4-fluorophenyl -lla-methyl-3-(trifluoromethyl -

06463,4,4a,5,6,8.11.11a-octahvdro-2H-naphthon.2-r1indazol-4-yl1-N'-f4- fluorophenvDurea

0647The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4- fluorophenyl)-lla-methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H- naphtho[ 1 ,2- ]indazol-4-amine from EXAMPLE 62 and 4-fluoroρhenylisocyanate according to the procedure described in EXAMPLE 78. Mass spectrum (ESI) 555 (M+l):

06481H NMR (500 MHz, CD₃OD): δ 1.26 (s, 3H); 1.71 (m, IH); 2.09 (m, IH); 2.41 (m, 4H); 2.57 (m, 2H); 2.59 (V2 ABq, J=15.8 Hz, IH); 2.88 (V2 ABq, J=15.8 Hz, IH); 3.92 (app t, J=9.9 Hz, IH); 5.82 (br d, J=5.7 Hz, IH); 6.24 (s, IH); 7.00 (app t, J=8.9 Hz, 2H); 7.28 (app t, J=9.0 Hz, 2H); 7.33 (m, 2H); 7.44 (s, IH); 7.49 (m, 2H).

EXAMPLE 81

0650<img file="EP1542996A2_D0085.tif" />

0651N-r(3fl.4fl,4aff,l laffV8-(4-fluorophenyl)-lla-methyl-3-(trifluoromethyl - 3.4.4a.5,6.8,ll.lla-octahvdro-2H-naρhthori,2-flindazol-4-yll-N'-(^'3- methylphenyDurea

0652The title compound was prepared from (3fl,4fl,4aS,llaff)-8-(4- fluorophenyl)-lla-methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H- naphtho[l,2- ]indazol-4-amine from EXAMPLE 62 and 3-methylphenylisocyanate according to the procedure described in EXAMPLE 78. Mass spectrum (ESI) 551 (M+l).

06531H NMR (500 MHz, CD3OD): δ 1.26 (s, 3H); 1.71 (m, IH); 2.09 (m, IH); 2.30 (s, 3H); 2.42 (m, 4H); 2.57 (m, 2H); 2.58 (V2 ABq, J=15.8 Hz, IH); 2.88 (V2 ABq, J=15.8 Hz, IH); 3.92 (app t, J=10.0 Hz, IH); 5.82 (br d, J=5.7 Hz, IH); 6.24 (s, IH); 6.82 (app t, J=3.2 Hz, IH); 7.13 (br d, J=4.8 Hz, 2H); 7.19 (s, IH); 7.28 (app t, J=8.7 Hz, 2H); 7.44 (s, IH); 7.49 (m, 2H).

EXAMPLES 82 AND 83

0655<img file="EP1542996A2_D0086.tif" />

0656Dimethyl (3R.4S.4aR.l laS)-8-(4-fluorophenyl)-l la-methyl-3.4.4a.5.6.8.11.1 la- octahydro-2H-naphtholT.2-r1indazole-3,4-dicarboxylate and dimethyl (3ff.4fl.4aff,llaff)-8-(4-fluorophenvn-lla-methyl-3.4.4a.5.6.8.11.11a-octahvdro-2H- naphtho I^" 1 ,2-f|indazole-3 ,4-dicarboxylate To a solution of lOO mg of (4aff)-l-(4-fluorophenyl)-4a-methyl-5- vinyl-4,4a,7,8-tetrahydro-lH-benzo[ ]indazole prepared as in EXAMPLE 1 Step F in 2 mL of CΗ₂C1₂ was added 39 mg of maleic anhydride, then 0.7 mL of a 1.0 M solution of BC1₃ in CH₂C1₂. The mixture was stirred at room temperature for 2 h, then concentrated. The residue was dissolved in 3 mL of 2:1 benzene-MeOH and excess TMSCH₂N₂ was added. The mixture was stirred overnight, then quenched with trifluoroacetic acid and concentrated. Preparative TLC, eluting with 1:1 hexanes- EtOAc, provided 92 mg of the title compounds as approximately a 2:1 mixture. Further purification by HPLC on Chiralcel OJ, eluting with 20% ethanol-heptane, provided two clean diastereomers: 29 mg of dimethyl (3R,4S,4aR,llaS)-8-(4- fluorophenyl)-l la-methyl-3,4,4a,5,6,8,l 1,1 la-octahydro-2H-naphtho[l,2- ]indazole- 3,4-dicarboxylate and 14.5 mg of dimethyl (3S,4fl,4aS,llaS)-8-(4-fluorophenyl)-lla- methyl-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- ]indazo3e-3,4-dicarboxylate. Mass spectrum (ESI) 451 (M+l). 1H NMR (500 MHz, CD₃CN) diagnostic peaks only: EXAMPLE 82 Dimethyl (3R,4S,4aR,l laS)-8-(4-fluorophenyl)-l la-methyl-

06573,4,4a,5,6,8,ll,l la-octahydro-2H-naρhtho[l,2- ]indazole-3 ,4-dicarboxylate: δ 3.13 (dd, J=4 Hz, 6 Hz, IH, ff₄), 2.98 (ddd, J=4 Hz, 7.5 Hz, 7.5 Hz, IH, H₃) 2.69-2.79 (m,

06582Η, Η4a, Ηιι).

0659EXAMPLE 83 Dimethyl (3ff,4fl,4aff,llaff)-8-(4-fluorophenyl)-l la-methyl- 3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- ]indazole-3,4-dicarboxylate: δ 3.22 (dd, J=4 Ηz, 6 Ηz, 1Η, H₄), 3.01 (d, J=15 Ηz, 1Η, H_π), 2.78-2.87 (m, 2Η, H₃, H _a).

EXAMPLES 84, 85 AND 86

0661<img file="EP1542996A2_D0087.tif" />

0662Dimethyl (3ff.4ff.4afl.l laff 8-(4-fluorophenyl)-l la-methyl-3.4.4a.5,6,8.11.1 la- octahvdro-2H-naphtholT.2- 1mdazole-3.4-dicarboxylate: dimethyl (3ff.4ff.4aff.l laffV 8-(4-fluorophenvD- 1 la-methyl-3.4.4a.5.6.8.11.11 a-octahvdro-2H-naphthor 1.2- flindazoIe-3.4-dicarboxylate: and dimethyl (3fl.4fl,4afl.llaffV8-(4-fluorophenvD-lla- methyl-3 ,4,4a,5 ,6,8.11,11 a-octahvdro-2H-naphthor 1 ,2-flindazole-3 ,4-dicarboxylate The title compounds were prepared from (4aff)-l-(4-fluorophenyl)-4a- methyl-5-vinyl-4,4a,7,8-tetrahydro-lH-benzo[^]indazole EXAMPLE 1 Step F and dimethyl fumarate according to the procedure described in EXAMPLE 82. Purification by ΗPLC on Chiralpak AD, eluting with 15% ethanol-heptane provided three clean diastereomers. Mass spectrum (ESI) 451 (M+l). 1H NMR (500 MHz,

0663C₆D₆) diagnostic peaks only:

0664EXAMPLE 84 Dimethyl (3S,4ff,4afl,llaff)-8-(4-fluorophenyl)-lla-methyl-

06653,4,4a,5,6,8,ll,lla-octahydro-2H-naρhtho[l,2- |indazole-3,4-dicarboxylate: δ 3.19

0666(dd, J=6 Hz, 12 Hz, IH, H₄), 2.95 (ddd, J=5.5 Ηz, 11.5 Ηz, 12 Ηz, 1Η, H₃) 2.84 (m, lΗ, H_4a).

0667EXAMPLE 85 Dimethyl (3ff,45,4aS,llaff)-8-(4-fluorophenyl)-lla-methyl- 3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- jindazole-3,4-dicarboxylate: δ 3.00 (ddd, J=5 Ηz, 10.5 Ηz, 11 Ηz, 1Η, H₃), 2.73 (d, J=15 Ηz, 1Η, H_π), 2.66 (m, 2Η, H_u,

0668EXAMPLE 86 Dimethyl (3fl,4fl,4afl,llaff)-8-(4-fluorophenyl)-lla-methyl- 3,4,4a,5,6,8,l l,lla-octahydro-2H-naphtho[l,2- ]indazole-3,4-dicarboxylate: δ 2.95 (ddd, J=6 Ηz, 9.5 Ηz, 10.5 Ηz, 1Η, H₃), 2.78 (dd, J=9.5 Ηz, 11 Ηz, 1Η, H ), 2.67 (m, lΗ, H_n).

EXAMPLES 87, 88, 89, AND 90

0670<img file="EP1542996A2_D0088.tif" />

0671Methyl (4aff .11 affV 8-(4-fluorophenyl)- 11 a-methyl-4-(trifluorometh yl)-

06723 ,4,4a,5 ,6, 8 ,11,11 a-octahvdro-2H-naphthof 1 ,2- lindazole-4-carboxylate and methyl (4afl.llaff)-8-r4-fluorophenyl)-lla-methyl-4-(^'trifluoromethyl)-3.4.4a,5.6,8,ll.lla- octahydro-2H-naphthor 1 ,2- |indazole-4-carboxylate

0673The title compounds were prepared from (4aff)-l-(4-fluorophenyl)-4a- methyl-5-vinyl-4,4a,7,8-tetrahydro-lH-benzo[flindazole EXAMPLE 1 Step F and trifluoromefhyl acrylic acid according to the procedure described in EXAMPLE 82. Purification by ΗPLC on Chiralcel OJ, eluting with 10% ethanol-heptane, provided four clean diastereomers, two with 4aff stereochemistry and two with 4afl stereochemistry. Mass spectrum (ESI) 447 (M+l). 1H NMR (600 MHz, C₆D₆) diagnostic peaks only:

0674EXAMPLE 87 Methyl (4aff,llaS)-8-(4-fluorophenyl)-lla-methyl-4-(trifluoromethyl)- 3,4,4a,5,6,8,l 1,1 la-octahydro-2H-naphtho[l,2-/]indazoIe-4-carboxylate, diastereomer 1: δ 3.09 (br t, J=9.6 Ηz, 1Η, H_4a), 2.91 (d, J=15.6 Ηz, 1Η, H_n), 2.25 (dd, J=5 Ηz, 12 Ηz, 1Η, H₃) 2.17, (d, J=15.6 Ηz, 1Η, Hπ), 2-09 (m, 1Η, H₂), 2.01 (m, 1Η, H₃), 1.83- 1.94 (m, 2Η, H₂, Η₆).

0675EXAMPLE 88 Methyl (4aS,llaS)-8-(4-fluorophenyl)-lla-methyl-4-(trifluoromethyl)- 3,4,4a,5,6,8,l 1 ,1 la-octahydro-2H-naphtho[l,2-/]indazole-4-carboxylate, diastereomer 2: δ 3.52 (dd, J=6.5 Ηz, 9.5 Ηz, 1Η, H_4a), 3.18 (d, J=15.6 Ηz, 1Η, H_π), 2.33-2.42 (m, 2Η, H₂, H₃), 2.21 (d, J=15.6 Ηz, 1Η, H_π), 2.03 (m, 1Η, H₆).

0676EXAMPLE 89 Methyl (4afl,l laff)-8-(4-fluorophenyl)-l la-methyl-4-

0677(trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- |indazole-4- carboxylate, diastereomer 1: δ 3.45 (br d, J=13.5 Ηz, 1Η, H _a), 2.86 (d, J=15 Ηz, 1Η, Hπ), 2.46 (m, 1Η, H₆), 2.39 (d, J=15 Ηz, 1Η, H_π), 2.12-2.33 (m, 3Η, H₂, H₃, He).

0678EXAMPLE 90 Methyl (4afl,l laff)-8-(4-fluorophenyl)-l la-methyl-4-

0679(trifluoromethyl)-3 ,4,4a,5 ,6,8 , 11,11 a-octahydro-2H-naphtho [1 ,2- ]indazole-4- carboxylate, diastereomer 2: δ 2.90 (br d, J=12.5 Ηz, 1Η, H_4a), 2.86 (d, J=15.5 Ηz, 1Η, H_n), 2.55 (d, J=15.5 Ηz, 1Η, H_n), 2.26 ( , 1Η, H₆), 2.01-2.20 (m, 3Η, H₂, H₃,

0680H₃). ^'

EXAMPLES 91 AND 92

0682<img file="EP1542996A2_D0089.tif" />

0683Methyl (4fl.4afl.llaff -8-(4-fluorophenyl -lla-methyl-3,4,4a.5.6.8.11.11a-octahvdro-

06842H-naphthon.2- lindazole-4-carboxylate and methyl (4ff.4aff.llaff -8-(4- fluorophenyl)- 1 la-methyl-3,4,4a.5,6,8,l 1,1 la-octahydro-2H-naphthori,2- |indazole-

06854-carboxylate

0686The title compounds were prepared from (4aff)-l-(4-fluorophenyl)-4a- methyl-5-vinyl-4,4a,7,8-tetrahydro-lH-benzo[ ]indazole from EXAMPLE 1 Step F and methyl acrylate according to the procedure described in EXAMPLE 82. Purification by ΗPLC on Chiralcel OJ, eluting with 5% ethanol-heptane provided two clean diastereomers. Mass spectrum (ESI) 393 (M+l). 1H NMR (C₆D₆) diagnostic peaks only:

0687EXAMPLE 91 Methyl (4fl,4afl,l laff)-8-(4-fluorophenyl)-lla-methyl-

06883,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- lindazole-4-carboxylate (500 MHz): δ 2.83 (m, IH, H_4a), 2.72 (d, J=16 Ηz, 1Η, H_π), 2.50 (ddd, J=2.5 Ηz, 5.5 Ηz, 12.5 Ηz,

06891Η, H₄).

0690EXAMPLE 92 Methyl (4ff,4aff,l laS)-8-(4-fluorophenyl)-lla-methyl- 3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- ]indazole-4-carboxylate (600 MHz): δ 2.91 (d, J=16 Hz, IH, Hπ), 2.76 (m, 1Η, H_4a), 2.63 (ddd, J=3 Ηz, 6 Ηz, 12.5 Ηz, 1Η, H₄). EXAMPLES 93 AND 94

0691<img file="EP1542996A2_D0090.tif" />

0692DimethvU3fl.4fl.4aff.llaff)-8-r4-fluorophenyl)-lla-methyl-4-(trifluoromethyl)- 3 ,4,4a,5 ,6, 8 ,11,11 a-octahydro-2H-naphtho \ 1 ,2-ιΗindazole-3 ,4-dicarboxylate and dimethyl (3ff.4ff,4afl.l laff)-8-(4-fluorophenylVl la-methyl-4-(trifluoromethylV 3,4,4a,5 ,6,8,11,11 a-octahydro-2H-naphtho[T ,2-flindazole-3 ,4-dicarboxylate

0693To a suspension of LiClO (532 mg) in 0.5 mL of Et₂O was added 100 mg of (4aff)-l-(4-fluorophenyl)-4a-methyl-5-vinyl-4,4a,7,8-tetrahydro-lH- benzo[/]indazole from EXAMPLE 1 Step F in 0.5 mL of Et₂O, then 60 mg of trifluoromethylmaleic anhydride. The mixture, which gradually became homogeneous, was stirred at room temperature overnight (20h), then poured into 5 mL NaΗCO₃ and extracted with 3 5 mL EtOAc. The combined organics were washed with brine, dried (Na₂SO ), and concentrated. The residue was dissolved in 3 mL of 2:1 benzene-MeOH and excess TMSCH₂N₂ was added. The mixture was stirred overnight, then quenched with trifluoroacetic acid and concentrated. Preparative TLC, eluting with 3:1 hexanes-EtOAc, provided 14 mg of dimethyl (3S,4S,4afl,llaff)-8-(4-fluorophenyl)-lla-methyl-4-(trifluoromethyl)- 3 ,4,4a,5 ,6,8 , 11,11 a-octahydro-2H-naphtho[ 1 ,2-/]indazole-3 ,4- dicarboxylate,EXAMPLE 94, and 60 mg of a 10 to 1 mixture of dimethyl (3fl,4fl,4aff , 11 aff)-8-(4-fluorophenyl)- 11 a-methyl-4-(trifluoromethyl)- 3,4,4a,5,6,8, 11,11 a-octahydro-2H-naphtho[l ,2-/|indazole-3 ,4-dicarboxylate and dimethyl (3ff,4ff,4afl, 11 aff)-8-(4-fluoroρhenyl)- 11 a-methyl-3-(trifluoromethyl)- 3,4,4a,5,6,8,ll,l la-octahydro-2H-naphtho[l,2- ]indazole-3,4-dicarboxylate. Part of this mixture was used in Example 103 and 104 and the remainder was further purified by ΗPLC on Chiralcel OJ, eluting with 10% ethanol-heptane to give the title compound of Example 93. Mass spectrum (ESI) 519 (M+l). 1H NMR (500 MHz) diagnostic peaks only:

0694EXAMPLE 93 Dimethyl (3fl,4fl,4aS,llaff)-8-(4-fluorophenyl)-lla-methyl-4- (trifluoromethyl)-3 ,4,4a,5 ,6,8, 11,11 a-octahydro-2H-naphtho [ 1 ,2- ]indazole-3 ,4- dicarboxylate (CDC1₃): δ 3.08 (dd, J=6 Ηz, 9 Ηz, 1Η, H₃), 2.93 (br t, J=9.5 Ηz, 1Η,

0695H4a).

0696EXAMPLE 94 Dimethyl (3ff,4ff,4afl,llaff)-8-(4-fluorophenyl)-lla-methyl-4- (trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2-/]indazole-3,4- dicarboxylate (C₆D₆): δ 2.99 (dd, J=6.5 Ηz, 11.5 Ηz, 1Η, H₃), 2.81 (br d, J=11.5 Ηz, 1Η, H_4a).

0697<img file="EP1542996A2_D0091.tif" />

0698(4afl.llaffV8-(4-Fluorophenyl)-lla-methyl-3.4.4a,5,6.8.11,lla-octahvdro-2H- naphthon,2-f|indazole-4-(2,2-dimethyl-l,3-dioxane-4,6-dione and (4aff,llaff)-8-(4- fluorophenyl)-lla-methyl-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphthori,2-f|indazole- 4-(2,2-dimethyl-l,3-dioxane-4,6-dione)

0699To a solution of 100 mg of (4aff)-l-(4-fluorophenyl)-4a-methyl-5- vinyl-4,4a,7,8-tetrahydro-lH-benzo[/]indazole from EXAMPLE 1 Step F, 47 mg of 2,2-dimethyl-l,3-dioxane-4,6-dione, and 4 mg of L-proline in 1 mL of CΗ₃CN was added 32 μL of a 37% aqueous solution of formaldehyde. The mixture was stirred at room temperature for 1 h; then an additional 5 mg of 2,2-dimethyl-l,3-dioxane-4,6- dione and 5 μL of formaldehyde were added. After 5 min, a white precipitate formed and the mixture was quenched by addition of ice, then filtered, washing solids with cold water. The solid precipitate was dried under vacuum to yield 129 mg of a 10:1 mixture of the title compounds. Recrystallization (2 crops) from t-butyl methyl ether provided 93 mg of (4afl,l laff)-8-(4-fluorophenyl)-lla-methyl-3,4,4a,5,6,8,ll,lla- octahydro-2H-naphtho[l,2- |indazole-4-(2,2-dimethyl-l,3-dioxane-4,6-dione). Preparative TLC of the filtrate, eluting with 1:1 hexanes-EtOAc, provided an additional 18 mg of the major diastereomer, and 10 mg of (4aff,llaff)-8-(4- fluorophenyl)-l la-methyl-3,4,4a,5,6,8,l 1,1 la-octahydro-2H-naphtho[l,2- |indazole- 4-(2,2-dimethyl-l,3-dioxane-4,6-dione). Mass spectrum (ESI) 463 (M+l). 1H NMR (500 MHz, CDC1₃) diagnostic peaks only:

0700EXAMPLE 95 (4afl,llaff)-8-(4-fluorophenyl)-lla-methyl-3,4,4a,5,6,8,ll, 11a- octahydro-2H-naphtho[l,2- ]indazole-4-(2,2-dimethyl-l,3-dioxane-4,6-dione): δ 5.86 (m, 1Η, H_4a).

0701EXAMPLE 96(4aS,l laff)-8-(4-fluorophenyl)-l la-methyl-3,4,4a,5,6,8,l 1,1 la- octahydro-2H-naphtho[l,2- jindazole-4-(2,2-dimethyl-l,3-dioxane-4,6-dione): δ 3.33 (br d, J=12.6 Ηz, 1Η, H_4a).

EXAMPLES 97 AND 98

0703<img file="EP1542996A2_D0092.tif" />

0704Methyl (4fl.4afl.11 aff )-8-(4-fluorophenvn- 11 a-methyl-3 ,4,4a,5 ,6,8, 11,11 a-octahvdro- 2H-naphthon.2- lindazole-4-carboxylate and methyl (4ff.4afl,llaff -8-(4- fluorophenyl)- 11 a-methyl-3.4,4a,5,6,8,U.ll a-octahydro-2H-naphtho \ 1 ,2- l indazole-

07054-carboxylate

0706To a solution of 890 mg of (4afl,llaS)-8-(4-fluorophenyl)-lla-methyl-

07073,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2-/]indazole-4-(2,2-dimethyl-l,3- dioxane-4,6-dione from EXAMPLE 95 in 10 mL of DMSO was added 200 μL of water, then 81 mg of LiOΗ. The mixture was heated to 120C for 4 h, then cooled, poured into 20 mL of IN ΗC1 and extracted with 3 X 20 mL of Et₂O. The combined organics were washed with 10 mL of brine, dried (Na₂SO ), and concentrated. The residue was dissolved in 5 mL of benzene and 0.5 mL of MeOH and treated with 1.5 mL of 2.0 M TMSCH₂N₂, then quenched with trifluoroacetic acid and concentrated. Flash chromatography (Biotage Horizon system, 40S cartridge) with a gradient of 2% EtOAc in hexanes to 100% EtOAc provided 650 mg of the title compounds as a 1.6:1 mixture of diastereomers. Further purification of a 140 mg aliquot of the mixture by HPLC on Chiralpak AD, eluting with 50% isopropanol-heptane, provided 76 mg of methyl (4fl,4afl,llaff)-8-(4-fluorophenyl)-lla-methyl-3,4,4a,5,6,8,ll,lla-octahydro- 2H-naphtho[l,2-jT|indazole-4-carboxylate and 46 mg of methyl (4ff,4afl,llaff)-8-(4- fluorophenyl)- 11 a-methyl-3 ,4,4a,5 ,6, 8, 11,11 a-octahydro-2H-naphtho[ 1 ,2- ]indazole- 4-carboxylate. Mass spectrum (ESI) 393 (M+l). 1H NMR (500 MHz, C₆D₆) diagnostic peaks only:

0708EXAMPLE 97 Methyl (4fl,4afl,llaS)-8-(4-fluorophenyl)-lla-methyl- 3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- indazole-4-carboxylate: see EXAMPLE 91

0709EXAMPLE 98 Methyl (4ff,4afl,llaff)-8-(4-fluorophenyl)-lla-methyl- 3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- ]indazole-4-carboxylate: δ 3.08 (d, J=16 Ηz, 1Η, H_n), 2.91 (m, 1Η, H_4a), 2.31 (m, 1Η, H₄).

EXAMPLES 99 AND 100

0711<img file="EP1542996A2_D0093.tif" />

0712(4fl.4afl.11 aff -8-(4-Fluoroρhenviy 11 a-methyl-4-(5-phenyl- 1 ,3-oxazol-2-vD- 3.4.4a.5.6.8.11.11a-octahvdro-2H-naphthon,2-r1indazole and (4ff.4afl.llaffV8-r4- fluorophenyl -lla-methyl-4-(5-phenyl-1.3-oxazol-2-yl -3,4,4a,5,6,8,ll,lla- octahvdro-2H-naphtho r 1 , 2-flindazole Step A: (4afl.11 aff)-8-(4-Fluorophenyl V 11 a-methyl-3 ,4,4a,5.6.8.11.11 a-octahvdro- 2H-naphtho|T ,2-flindazole-4-carboxylic acid

0713To a solution of 25 mg of a ca. 1 : 1 mixture of methyl (4fl,4afl,l laff)-8- (4-fluorophenyl)-lla-methyl-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- Jindazole-4-carboxylate and methyl (4ff,4afl,l laff)-8-(4-fluorophenyl)-l la-methyl- 3,4,4a,5 ,6,8, 11,11 a-octahydro-2H-naphtho[ 1 ,2- ]indazole-4-carboxylate (EXAMPLES 97 and 98 ) in 1.5 mL of 1:1:1 TΗF-MeOΗ-Η₂O was added LiOH. The mixture was stirred overnight (18 h) at 45° C.^'then cooled, diluted with 10 mL of 1 N HCl, and extracted with 3 X 10 mL of EtOAc. The combined organics were dried (Na₂SO₄) and concentrated to yield 21 mg of the title compound as a ca. 1:1 mixture of diastereomers. Mass spectrum (ESI) 379 (M+l).

0714Step B: (4afl.11 affV 8-(4-FluorophenylV 11 a-methyl-3 ,4.4a,5 ,6,8, 11,11 a-octahvdro- 2H-naphtholT ,2-flindazole-4- iV-f2-oxo-2-phenylethyl)carboxamide To a 0° C solution of 45 mg of (4afl,llaff)-8-(4-fluorophenyl)-lla- methyl-3,4,4a,5,6,8,l 1 ,1 la-octahydro-2H-naphtho[l ,2-/]indazole-4-carboxylic acid (a ca. 1:1 mixture of diastereomers, EXAMPLE 99, Step A) in 1 mL of CΗ₂C1 was added oxalyl chloride (90 μL of a 2.0 M solution in CH₂C1₂), then DMF (5 μL). The mixture was stirred at 0° C until gas evolution ceased; then the bath was removed and stirring was continued for 30 min, at which point LC/MS analysis showed no starting material. The mixture was concentrated, then co-concentrated twice with 10 mL toluene, then redissolved in 1 mL of CH₂C1₂. 2-Aminoacetophenone (22 mg) and . Et₃N (36 μL) were added and the mixture was stirred overnight at room temperature. The mixture was diluted with 10 mL of 10% aq NH₄OH, and extracted with 3 X 10 mL of CH₂C1₂. The combined organics were washed with 10 mL of brine, dried (Na₂SO₄) and concentrated. Preparative TLC, eluting with 1:1 hexanes-EtOAc provided 40 mg of the title compound as a ca. 1:1 mixture of diastereomers. Mass spectrum (ESI) 496 (M+l).

0715Ste C: (4fl,4afl,llaff -8-(4-fluorophenyl)-lla-Methyl-4-(5-phenyl-l,3-oxazol-2-vD- 3.4,4a.5.6.8,ll,lla-octahvdro-2H-naphthon,2-r1indazole and (4ff,4afl,llaffV8-(4- fluorophenyl)- 11 a-methyl-4-(5 -phenyl- 1 ,3-oxazol-2-yl)-3 ,4,4a,5,6,8, 11,11a- octahvdro-2H-naphtho|T.2-flindazoIe

0716A solution of 38 mg of (4afl,llaff)-8-(4-fluorophenyl)-l la-methyl- 3,4,4a,5,6,8,ll,l la-octahydro-2H-naphtho[l,2- |indazole-4- V-(2-oxo-2- phenylethyl)carboxamide (a ca. 1:1 mixture of diastereomers, EXAMPLE 99, Step B) in 1 mL of phosphorus oxychloride was heated to reflux and stirred at this temperature for 30 min, then quenched by careful addition of ice. The mixture was basified with cone. NH OH (exothermic), diluted with 5 mL of H₂O and extracted with 3 X 10 mL of CH₂C1₂. The combined organics were washed with 10 mL of brine, dried (Na₂SO₄) and concentrated. Preparative TLC, eluting with 2:1 hexanes- EtOAc provided 10 mg of each of the title compounds. Mass spectrum (ESI) 496 (M+l). 1H NMR (600 MHz, C₆D₆) diagnostic peaks only:

0717EXAMPLE 99 (4fl,4afl,llaS)-8-(4-fluorophenyl)-l la-methyl-4-(5-phenyl-l,3-oxazol- 2-yl)-3 ,4,4a,5, 6,8,11,1 la-octahydro-2H-naphtho[l,2- |indazole: δ 3.06 (m, H₄), 3.00 (m, 1Η, H _a), 2.78 (d, J=16 Ηz, 1 Η, H_n), 2.19 (d, J=16 Ηz, 1 Η, H_n), 2.12 (m, 1 Η, H₃), 1.86-2.06 (m, 4 Η, H₂, H₂, H₃, He).

0718EXAMPLE 100 (4ff,4afl,l laff)-8-(4-fluorophenyl)-l la-methyl-4-(5-phenyl-l,3- oxazol-2-yl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- ]indazole: δ 3.23 (d,

0719J=16 Ηz, 1 Η, H_n), 3.15 (m, H_4a), 2.85 (m, 1Η, H₄), 2.30(d, J=16 Ηz, 1 Η, Hπ), 2.12 (m, 1 Η, H₃), 1.86-2.16 (m, 5 Η, H₂, H₂, H₃, H₆, H₆).

EXAMPLES 101 AND 102

0721<img file="EP1542996A2_D0094.tif" />

0722(4fl.4afl.llaff -8-(4-fluorophenvD-lla-MethvI-4-(5-methyl-lH-imidazol-2-vn-

07233,4,4a.5,6,8.11,lla-octahvdro-2H-naphthoπ.2-t1indazoϊe and (4ff,4afl.llaff)-8-(4- fluorophenvD-1 la-methyl-4-(5-methyl-lH-imidazol-2-vn-3.4.4a,5,6,8,l 1,1 la- octahvdro-2H-naphthor 1 ,2-f|indazole

0724Step A: (4afl,llaff)-8-(4-Fluorophenyl)-lla-methyl-3.4.4a.5.6.8.11.11a-octahydro-

07252H-naphtho|^" 1 ,2- |indazole-4-carbaldehvde To a 0°C solution of 105 mg of a ca. 1:1 mixture of methyl (4fl,4afl,l laff)-8-(4-fluorophenyl)-l la-methyl-3,4,4a,5,6,8,l 1,1 la-octahydro-2H- naphtho[l,2-/]indazole-4-carboxylate and methyl (4ff,4afl,llaff)-8-(4-fluorophenyl)- 11 a-methyl-3 ,4,4a,5 ,6,8 , 11,11 a-octahydro-2H-naphtho [ 1 ,2- ]indazole-4-carboxylate (EXAMPLES 97 and 98 ) in 3 mL of THE was added 0.3 mL of a 1.0 M solution of LiAlH₄in THF dropwise. The mixture was stirred 15 min at 0°C; then the bath was removed and the mixture was stirred 30 min while warming to room temperature, at which point TLC showed no starting material. To the mixture was added 11 μL of H₂O, then 11 μL of 15% aq NaOH, then 33 μL of H₂O. The mixture was stirred 30 min, then filtered and concentrated. The residue was dissolved in 1 mL of CH₂C1₂. To 0.31 mL of a 2.0 M solution of oxalyl chloride in 2 mL of CH₂C1₂ at -78°C was added 36 μL of DMSO. The mixture was stirred 5 min at -78°C; then the solution of alcohol in 1 mL CH₂C1₂ was added dropwise and stirring was continued for 15 min. Et N (0.14 mL) was added and the mixture was stirred 10 min at -78°C, then allowed to warm to room temperature. The mixture was poured into 10 mL of saturated

0726NaHCO₃ and extracted with 15 mL of EtOAc. The organic extract was washed with 10 mL each of 1 N NaHSO , saturated NaHCO₃, and brine, then dried (Na₂SO ) and concentrated to yield 67 mg of the title compound as a ca. 1:1 mixture of diastereomers. Mass spectrum (ESI) 363 (M+l).

0727Step B: (4fl,4afl.llaff)-8-(4-fluorophenyl)-lla-Methyl-4-r5-methyl-lH-imidazol-2- yl)-3.4.4a,5,6,8,l 1,1 la-octahvdro-2H-naphthoπ,2- lindazole and (4ff,4afl,l laff)-8-(4- fluorophenyl)-lla-methyl-4-(5-methyl-lH-imidazol-2-yI)-3,4,4a,5,6,8,ll,lla- octahvdro-2H-naphthon,2-f1indazole To a 0° C solution of 87 mg of (4afl,l laS)-8-(4-fluorophenyl)-l la- methyl-3,4,4a,5,6,8,l 1,1 la-octahydro-2H-naphtho[l,2- ]indazole-4-carbaldehyde (a ca. 1:1 mixture of diastereomers), from Step A in 3 mL of MeOΗ was added ammonium acetate (185 mg) and methyl glyoxal (0.13 mL of a 40% aqueous solution). The mixture was heated to reflux and stirred at this temperature overnight. The mixture was cooled and concentrated, then dissolved in minimal CΗ₂Cl₂-MeOΗ and purified by preparative TLC, eluting with 9:1 CH₂Cl₂-MeOH to provide 14 mg of (4fl,4afl,llaff)-8-(4-fluorophenyl)-lla-methyl-4-(5-methyl-lH-imidazol-2-yl)- 3,4,4a,5,6,8,ll,l la-octahydro-2H-naphtho[l,2- lindazole and 12 mg of (4ff,4afl,llaff)-8-(4-fluorophenyl)-lla-methyl-4-(5-methyl-lH-imidazol-2-yl)- 3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- lindazole. Mass spectrum (ESI) 415 (M+l). 1H NMR (500 MHz, CD₃OD) diagnostic peaks only: EXAMPLE 101 (4fl,4afl,llaff)-8-(4-fluorophenyl)-lla-methyl-4-(5-methyl-lH- imidazol-2-yl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- iindazole: δ 3.13 (m, 1Η, H₄), 2.97 (d, J=15.5 Ηz, 1 Η, Hπ), 2.80 ( , 1Η, H_4a), 2.43 (d, J=15.5 Ηz, 1 Η, Hn).

0728EXAMPLE 102 (4ff,4afl,llaS)-8-(4-fluorophenyl)-l 1 a-methyl-4-(5 -methyl- 1H- imidazol-2-yl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- lindazole: δ 2.92 (d, J=16 Ηz, 1 Η, Hπ), 2.70-2.80 (m, 2Η, H_4a, H₄), 2.51 (d, J=16 Ηz, 1 Η, H_π).

EXAMPLES 103 AND 104

0730<img file="EP1542996A2_D0095.tif" />

0731Dimethyl (3fl.4fl,4aff ,6afl.11 aff)-8-(4-fluorophenyl)- 11 a-methyl-4-(trifluoromethviy 3 ,4,4a,5 ,6,6a,7,8 , 11 , 11 a-decahydro-2H-naphtho I^" 1 ,2-flindazole-3 ,4-dicarboxylate and dimethyl (3ff.4ff.4afl,6afl! laff)-8-(4-fluorophenyl Η la-methyl-3-ftrifluoromethvD- 3,4,4a,5,6,6a.7,8,ll,lla-decahvdro-2H-naphthon,2- |indazole-3,4-dicarboxylate

0732To a solution of 20 mg of a ca. 10:1 mix of dimethyl (3fl,4fl,4aff , 11 aff)-8-(4-fluorophenyl)- 11 a-methyl-4-(trifluoromethyl)- 3,4,4a,5,6,8,l 1,1 la-octahydro-2H-naphtho[l,2-/]indazole-3,4-dicarboxylate and dimethyl (3ff,4ff,4afl,l laff)-8-(4-fluorophenyl)-l la-methyl-3-(trifluoromethyl)- 3,4,4a,5,6,8,l 1,1 la-octahydro-2H-naphtho[l,2- ]indazole-3 ,4-dicarboxylate ( see EXAMPLE 93 ) in 1 mL of EtOAc was added 10 mg of PtO₂ (Adam's catalyst). The mixture was flushed with N₂, then flushed with Η and stirred 3 h under an H₂ balloon, at which point LC/MS analysis showed no starting material. The mixture was filtered through Celite, washing liberally with MeOH, then concentrated. Preparative TLC, eluting with 3:1 hexanes-EtOAc, provided 15.9 mg of dimethyl

0733(3fl,4fl,4aff,6afl,llaff)-8-(4-fluorophenyl)-lla-methyl-4-(trifluoromethyl)-

07343,4,4a,5 ,6,6a,7,8, 11 , 1 la-decahydro-2H-naphtho[ 1 ,2-/]indazole-3 ,4-dicarboxylate and

07351.2 mg of dimethyl (3ff,4ff,4afl,6afl,l laff)-8-(4-fluorophenyl)-lla-methyl-3-

0736(trifluoromethyl)-3,4,4a,5,6,6a,7,8,ll,lla-decahydro-2H-naphtho[l,2-jπindazole-3,4- dicarboxylate. Mass spectrum (ESI) 521 (M+l). 1H NMR (500 MHz, CDC1₃) diagnostic peaks only:

0737EXAMPLE 103 Dimethyl (3fl,4fl,4aff,6afl,llaff)-8-(4-fluorophenyl)-lla-methyl-4-

0738(trifluoromethyl)-3,4,4a,5,6,6a,7,8,ll,lla-decahydro-2H-naρhtho[l,2 /]indazole-3,4- dicarboxylate: 3.04 (dd, J=6 Ηz, 17 Ηz, 1Η, H₇), 2.78-2.95 (m, 4Η, H₂, H₃, H_4a, H_n),

07392.34-2.46 (m, 2Η, H₇, H₂), 1.68 (m, 1Η, H_6a).

0740EXAMPLE 104 Dimethyl (3ff,4ff,4afl,6afl,llaS)-8-(4-fluorophenyl)-lla-methyl-3- (trifluoromethyl)-3,4,4a,5,6,6a,7,8,ll,lla-decahydro-2H-naphtho[l,2- |indazole-3,4- dicarboxylate: δ 3.59 (d, J=6.5 Ηz, 1Η, H₄), 3.27 (br d, J=19 Ηz, 1Η, H₂), 3.06 (dd, J=6.5 Ηz, 17 Ηz, 1Η, H₇), 2.75-2.85 (m, 2Η, H_4a, H_π), 2.60 (dd, J5.5 Ηz, 19.5 Ηz, 1Η, H₂), 2.41 (d, J= 16.5 Ηz, 1Η, H₇), 1.69 (m, 1Η, H_6a).

EXAMPLE 105

0742<img file="EP1542996A2_D0096.tif" />

0743Methyl (3fl.4fl.4afl.6afl, 1 laff -8-(4-fluorophenyl)-l la-methyl-3-(trifluoromethylV 3,4,4a,5,6,6a,7,8,ll,lla-decahvdro-2H-naphthori,2- |indazoIe-4-carboxylate The title compound was prepared from methyl (3fl,4fl,4afl,llaff)-8-(4- fluorophenyl)- 11 a-methyl-3-(trifluoromethyl)-3 ,4,4a,5 ,6,8,11,11 a-octahydro-2H- naphtho[l,2- ]indazole-4-carboxylate (EXAMPLE 1) according to the procedure described in EXAMPLE 103. Final purification by ΗPLC on Chiralpak AD, eluting with 10% ethanol-heptane provided the title compound. Mass spectrum (ESI) 477 (M+l). 1H NMR (500 MHz, CDC1₃) diagnostic peaks only: δ 3.04 (dd, J=6 Hz, 17 Hz, IH, H_η), 2.93 (d, J=16 Hz, IH, Hπ), 2.73 (m, 1Η, H_4a), 2.57 (m, 1Η, H₃), 2.36- 2.46 (m, 2Η, H₇, H₂), 2.33 (dd, J=10.5 Ηz, 11.5 Ηz, 1Η, H₄), 1.66 (m, 1Η, H_6a).

EXAMPLE 109

0745<img file="EP1542996A2_D0097.tif" />

0746(3fl,4fl,4afl.llaff)-8-r4-fluoropheny])-lla-methyl-3-ftrifluoromethyl)- 3.4.4a.5,6.8.11.11a-octahvdro-2H-naphthoπ.2-r1indazole-4-(2-oxo-2- phenylethvDcarboxamide

0747A solution of (3fl,4fl,4afl,llaff)-8-(4-fluorophenyl)-lla-methyl-3- (trifluoromethyl)-3 ,4,4a,5 ,6, 8 , 11 , 11 a-octahydro-2H-naphtho [ 1 ,2-fl indazole-4- carboxylic acid (40.8 mg, 0.091 mmol) in CΗ₂C1₂ (1.0 mL) was cooled down to 0 °C, and to this was added oxalyl chloride (70 μL, 2.0 M, 0.137 mmol) followed by 1 drop of DMF via pipet. The reaction mixture was stirred for 2h while slowly warming up to room temperature. The solvent was removed under leduced pressure, and the residue was co-evaporated two times with toluene. After drying under high vacuum, the acid chloride was dissolved in CH C1₂ (1.0 mL), and to this was added 2- aminoacetophenone hydrochloride (18 mg, 0.1 mmol) followed by Et₃N (28 μL, 0.2 mmol). The reaction mixture was stirred for 2h, then 10% aqueous NFLOH was added. The aqueous layer was extracted with CH₂C1₂, and combined extracts were washed with brine and dried over Na₂SO . The crude material was purified by preparative TLC eluting with 1 :2 acetone:hexane to obtain 42 mg of the title compound.

0748Η NMR (CDCI3, 500MHz): δ 7.97 (d, J = 7.6 Hz, 2H); 7.62-7.39 (m, 6H); 7.14 (t, J = 8.6 Hz, 2H); 6.82 (1 NH); 6.16 (s, IH); 5.73 (d, J = 6.0 Hz, IH); 4.91 (dd, J = 5, 19.9 Hz, IH); 4.68 (dd, J = 3.5, 19.9 Hz, IH); 2.86 (m, IH); 2.87 (d, J = 15.8 Hz, IH); 2.71 (m, IH); 2.5 (d, J = 15.8 Hz, IH); 2.44-2.21 (m, 5H); 2.01 (m, IH); 1.5 (m, IH); 1.22 (s, 3H). Mass spectrum (ESI): 564.2 (M+l).

0749The following examples were synthesized by procedures analogous to that described in EXAMPLE 109:

0750<img file="EP1542996A2_D0098.tif" /> EXAMPLE 118

0751<img file="EP1542996A2_D0099.tif" />

07523-fluoro-N-r(3fl,4fl,4aff, 1 laff)-8-f4-fluorophenylV 1 la-methyl-3-(trifluoromethylV 3,4,4a,5,6,8,ll,lla-octahydro-2H-naphthori,2- lindazol-4-yll-4-methoxybenzamide

0753The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,l 1,1 la-octahydro-2H-naphtho[l,2-/]indazol- 4-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE 63. Mass spectrum (ESI) 570 (M+l).

EXAMPLE 119

0755<img file="EP1542996A2_D0100.tif" />

0756N-r(3fl.4fl.4aff.llaff)-8-(4-fluorophenyl)-lla-methyl-3-(trifluoromethyl)- 3,4,4a,5,6,8,ll,lla-octahydro-2H-naphthori,2- |indazol-4-vnheptanamide

0757The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- ]indazol- 4-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE

075863.

0759Mass spectrum (ESI) 530 (M+l).

EXAMPLE 120

0761<img file="EP1542996A2_D0101.tif" />

0762N-r(3fl,4fl,4aff,llaff)-8-(4-fluorophenyl)-l la-methyl-3-(trifluoromethyl)- 3 ,4,4a,5 ,6,8 , 11,11 a-octahvdro-2H-naphtho I^" 1 ,2- |indazol-4-yll-2-methylpropanamide

0763The title compound was prepared from (3fl,4fl,4aff,llaS)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3 ,4,4a,5 ,6,8,11,11 a-octahydro-2H-naphtho[ 1 ,2- ]indazol-

07644-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE

076563.

0766Mass spectrum (ESI) 488 (M+l).

EXAMPLE 121

0768<img file="EP1542996A2_D0102.tif" />

0769N-IY3fl.4fl,4aff.11 aff)-8-(4-fluorophenvD-l 1 a-methyl-3-(trifluoromethvn-

07703 ,4,4a,5 ,6.8.11.11 a-octahydro-2H-naphtho I^" 1 ,2- lindazol-4-yll-3-methylbutanamide The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,ll,l la-octahydro-2H-naphtho[l,2- ]indazol-

07714-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE

077263.

0773The product was purified by flash column chromatography on silica gel eluting with

07741%-100% methanol in dichloromethane.

0775Mass spectrum (ESI) 502 (M+l).

EXAMPLE 122

0777<img file="EP1542996A2_D0103.tif" />

0778N-r(3fl,4fl,4aff.llaff)-8-(4-fluorophenvn-lla-methyl-3-(trifluoromethylV 3 ,4,4a,5 ,6, 8, 11,11 a-octahvdro-2H-naρhthor 1 ,2-r1indazol-4- yllcyclopentanecarboxamide

0779The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3 ,4,4a,5,6, 8, 11,11 a-octahydro-2H-naphtho[ 1 ,2- ]indazol- 4-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE 63.

0780The product was purified by preparative thin-layer chromatography, eluting with 97.5:2.5 dichloromethane-methanol. Mass spectrum (ESI) 514 (M+l). EXAMPLE 123

0781<img file="EP1542996A2_D0104.tif" />

0782N- rf 3fl,4fl,4aff .11 aff V8-f 4-fluorophenylV 11 a-me hyl-3-(trifluoromethyl V 3,4,4a,5,6,8.11.11a-octahvdro-2H-naphthori.2- lindazol-4-yl1nicotinamide

0783The title compound was prepared from (3fl,4fl,4aff,llaS)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- |indazol- 4-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE 63. Mass spectrum (ESI) 523 (M+l).

EXAMPLE 124

0785<img file="EP1542996A2_D0105.tif" />

0786N-r(3fl,4fl,4aff,llaffV8-(4-fluorophenylVlla-methyl-3-(trifluoromethyl)- 3,4,4a.5,6,8,ll,lla-octahydro-2H-naphthon,2-flindazol-4-yllthiophene-2- carboxamide

0787The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4-fluorophenyl)-l la- methyl -3-(trifluoromethyl)-3 ,4 ,4a,5 ,6,8,11,11 a-octahydro-2H-naphtho[l ,2- )indazol- 4-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE

078863.

0789Mass spectrum (ESI) 528 (M+l).

EXAMPLE 125

0791<img file="EP1542996A2_D0106.tif" />

0792Phenyl IT 3fl.4fl.4aff.11 aS)-8-(4-fluαrophenvIV 11 a-methyl-3-(trifluoromethyl)- 3,4,4a.5.6,8, 11,11 a-octahvdro-2H-naphtho ) 1 ,2-r1indazol-4-yl1 carbamate

0793The title compound was prepared from (3fl,4fl,4aff,llaS)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- ]indazol- 4-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE 63.

0794Mass spectrum (ESI) 538 (M+l).

EXAMPLE 126

0796<img file="EP1542996A2_D0107.tif" />

0797Isopropyi r(3fl,4fl,4aff,llaffV8-(4-fluorophenyl -lla-methyl-3-(trifluoromethylV 3,4,4a,5,6,8.11,lla-octahydro-2H-naphthoπ,2-f|indazol-4-yllcarbamate The title compound was prepared from (3fl,4fl,4aS,llaff)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- ]indazol-

07984-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE

079963.

0800The product was purified by preparative thin-layer chromatography, eluting with

080197.5:2.5 dichloromethane-methanol.

0802Mass spectrum (ESI) 504 (M+l).

EXAMPLE 127

0804<img file="EP1542996A2_D0108.tif" />

0805Ethyl IY3fl.4fl.4aff,l laff)-8-(4-fluorophenyl)-l la-methyl-3-(trifluoromethyl - 3,4,4a,5,6,8.11,lla-octahvdro-2H-naphthon,2-/1indazol-4-yncarbamate

0806The title compound was prepared from (3A,4A,4aff,llaff)-8-(4-fluorophenyI)-lla- methyl-3-(trifluoromethyl)-3 ,4,4a,5,6,8 , 11,11 a-octahydro-2H-naphtho [1 ,2- ]indazol- 4-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE 63. The product was purified by preparative thin-layer chromatography, elutmg with 97.5:2.5 dichloromethane-methanol. Mass spectrum (ESI) 490 (M+l).

EXAMPLE 128

0808<img file="EP1542996A2_D0109.tif" />

0809methyl lY3fl.4fl,4aff.l laffV8-f4-fJuorophenyl)-l la-methyl-3-(trifluoromethyl)- 3 ,4,4a,5 ,6, 8.11 , 11 a-octahydro-2H-naphtho 1 ,2- lindazol-4-yl1carbamate

0810The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2 ]indazol- 4-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE 63.

0811The product was purified by preparative thin-layer chromatography, eluting with 75:25 dichloromethane-methanol.

0812Mass spectrum (ESI) 476 (M+l).

EXAMPLE 129

0814<img file="EP1542996A2_D0110.tif" />

0815(3fl,4fl.4aff.llaff)-N-(3-fluoro-4-methoxybenzyl)-8-(4-fluorophenyl -lla-methyl-3- (trifIuoromethyI)-3,4,4a,5,6,8,ll,lla-octahvdro-2H-naphthori,2- |indazol-4-amine The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3 ,4,4a,5 ,6, 8 ,11,11 a-octahydro-2H-naphtho [ 1 ,2- ]indazol-

08164-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE

081770.

0818The product was purified by preparative thin-layer chromatography, eluting with

081997.5:2.5 dichloromethane-methanol .

0820Mass spectrum (ESI) 556 (M+l).

EXAMPLE 130

0822<img file="EP1542996A2_D0111.tif" />

0823(3fl,4fl,4aff , 11 aff V 8-(4-fluorophenylV 11 a-methyl-N-(pyridin-2-ylmethyl -3- (trifluoromethylV3 ,4,4a,5 ,6 , 8 , 11 , 11 a-octahydro-2H-naphtho r 1 ,2-flindazol-4-amine

0824The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- lindazol- 4-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE 70.

0825The product was purified by preparative thin-layer chromatography, eluting with 97.5:2.5 dichloromethane-methanol. Mass spectrum (ESI) 509 (M+l).

0826Ill EXAMPLE 131

0827<img file="EP1542996A2_D0112.tif" />

0828(3fl,4fl,4aff,llaffV8-(4-fluorophenyl -lla-methvI-N-(pyridin-3-ylmethyl)-3-

0829(trifluoromethviy 3 ,4,4a,5,6,8,ll,ll a-octahydro-2H-naphtho f 1 ,2- l indazol-4-amine

0830The title compound was prepared from (3A,4fl,4aff,llaff)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3 ,4,4a,5 ,6,8 , 11,11 a-octahydro-2H-naphtho[ 1 ,2- |indazol- 4-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE 70.

0831The product was purified by preparative thin-layer chromatography, eluting with 97.5 : 2.5 dichloromethane-methanol . Mass spectrum (ESI) 509 (M+l).

EXAMPLE 132

0833<img file="EP1542996A2_D0113.tif" />

0834(3fl.4fl.4aff, 11 aff - 8-(4-fluoroρhenyl)- 11 a-methyl-N-(pyridin-4-ylmethyl)-3-

0835(trifluoromethyl)-3 ,4,4a,5 ,6,8 , 11,11 a-octahydro-2H-naphtho \ 1 ,2-f|indazol-4-amine

0836The title compound was prepared from (3fl,4fl,4aS,llaff)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahydro-2H-naphtho[l,2- ]indazol- 4-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE 70.

0837The product was purified by preparative thin-layer chromatography, eluting with 95:5 dichloromethane-methanol. Mass spectrum (ESI) 509 (M+l).

EXAMPLE 133

0839<img file="EP1542996A2_D0114.tif" />

0840(3fl,4fl.4aff,llaff -N-(cvclohexylmethyl)-8-(4-fluorophenyl -lla-methyl-3- (trifluoromethyl)-3,4,4a,5,6,8,ll,lla-octahvdro-2H-naphthon,2- |indazol-4-amine

0841The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,l 1,1 la-octahydro-2H-naphtho[l,2-/|indazol-

08424-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE

084370.

0844The product was purified by preparative thin-layer chromatography, eluting with

084597.5:2.5 dichloromethane-methanol. Mass spectrum (ESI) 514 (M+l).

EXAMPLE 134

0847<img file="EP1542996A2_D0115.tif" /> (3fl.4fl.4aff .11 aff)-iv^~-cvclohexyl-8-(4-fluorophenylV 11 a-methyl-3-f faifluoromethylV 3,4,4a,5,6, 8, 11.11 a-octahydro-2H-naphthol^' 1 ,2-/^~1indazol-4-amine

0848The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4-fluoroρhenyl)-lla- methyl-3-(trifluoromethyl)-3 ,4,4a,5 ,6,8, 11 , 11 a-octahydro-2H-naρhtho[ 1 ,2- |indazol- 4-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE 70.

0849The product was purified by preparative thin-layer chromatography, eluting with 97.5:2.5 dichloromethane-methanol. Mass spectrum (ESI) 500 (M+l).

EXAMPLE 135

0851<img file="EP1542996A2_D0116.tif" />

0852(3fl.4fl.4aff.11 aff)-N-cyclopentyl-8-(4-fluoroρhenviy 11 a-methyl-3-(trifluoromethyl)- 3 ,4,4a,5 ,6, 8, 11,11 a-octahydro-2H-naphthof 1 ,2- lindazol-4-amine

0853The title compound was prepared from (3fl,4fl,4aff,llaS)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3 ,4,4a,5 ,6,8 , 11,11 a-octahydro-2H-naphtho[ 1 ,2-/|indazol- 4-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE 70. The product was purified by preparative thin-layer chromatography, eluting with 97.5:2.5 dichloromethane-methanol. Mass spectrum (ESI) 486 (M+l). EXAMPLE 136

0854<img file="EP1542996A2_D0117.tif" />

0855(3fl,4fl.4aff,llaff)-iV-cvclobutyl-8-r4-fluorophenylVlla-methyl-3-(trifluoromethyl)- 3,4,4a,5,6.8,ll,lla-octahydro-2H-naphtho[l,2- 1indazol-4-amine

0856The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,ll_Jlla-octahydro-2H-naphtho[l,2- ]indazol-

08574-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE

085870.

0859The product was purified by preparative thin-layer chromatography, eluting with

086097.5:2.5 dichloromethane-methanol .

0861Mass spectrum (ESI) 472 (M+l).

EXAMPLE 137

0863<img file="EP1542996A2_D0118.tif" />

0864(3fl,4fl,4aff.llaffV8-(4-fluorophenyl)-iV-isopropyl-lla-methyl-3-(trifluoromethylV 3,4,4a,5,6.8,l 1,1 la-octahydro-2H-naphthori,2- lindazol-4-amine

0865The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,ll,l la-octahydro-2H-naphtho[l,2- ]indazol- 4-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE 70.

0866The product was purified by preparative thin-layer chromatography, eluting with 97.5:2.5 dichloromethane-methanol. Mass spectrum (ESI) 460 (M+l).

EXAMPLE 138

0868<img file="EP1542996A2_D0119.tif" />

0869iV-r(3fl,4fl,4aff,llaff^')-8-(4-fluoroρhenylVlla-methyl-3-(trifluoromethvn- 3,4,4a,5,6,8,ll,lla-octahvdro-2H-naphthon,2- 1indazol-4-yl1-N'-methylurea

0870The title compound was prepared from (3fl,4fl,4aS,llaS)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3 ,4,4a,5,6,8 , 11,11 a-octahydro-2H-naphtho [ 1 ,2- |indazol- 4-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE 78. Mass spectrum (ESI) 475 (M+l).

EXAMPLE 139

0872<img file="EP1542996A2_D0120.tif" /> N-ethyl-N- f (3fl.4fl.4aff .11 aff V8-(4-fluorophenvI)- 11 a-methyl-3-(trifluoromethyl)- 3,4,4a,5 ,6,8,11,11 a-octahvdro-2H-naphthor 1 ,2- |indazol-4-yl1urea

0873The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4-fluorophenyl)-lla- methyl-3-(trifluoromethyl)-3,4,4a,5,6,8,ll,l la-octahydro-2H-naphtho[l,2- |indazol- 4-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE 78. Mass spectrum (ESI) 489 (M+l):

EXAMPLE 140

0875<img file="EP1542996A2_D0121.tif" />

0876N-IY3fl,4fl.4aff , 11 aff)-8-(4-fluorophenyl - 11 a-methyl-3-(trifluoromethyl)- 3.4.4a,5,6,8,ll,lla-octahydro-2H-naphthori,2- lindazol-4-yll-N^,-isopropylurea

0877The title compound was prepared from (3fl,4fl,4aff,llaff)-8-(4-fluorophenyl)-lla- methyl-3 -(trifluoromethyl)-3 ,4,4a,5,6,8,ll,ll a-octahydro-2H-naphtho [ 1 ,2-f\ indazol- 4-amine (EXAMPLE 62) by a procedure analogous to that described in EXAMPLE 78.

0878Mass spectrum (ESI) 503 (M+l).

BIOLOGICAL ASSAYS

0880The activity of the compounds of the present invention as modulators of the glucocorticoid receptor can be evaluated using the following assays:

0881Ligand Binding Assays

0882For the hGRI ligand binding assay, cytosols were prepared from recombinant baculovirus expressed receptors. Frozen cell pellets were dounce homogenized in ice cold PO4 buffer (lOmM KPO4, 20mM sodium molybdate, ImM EDTA, 5mM DTT and complete protease inhibitor tablets from Boehringer

0883Mannheim) with a "B" plunger. The homogenates were centrifuged at 35,000 x g for 1 h at 4°C in a JA-20 rotor. The IC50_S were determined by incubating the cytosols at a final concentration of 2.5nM [1,2,4,6,7- H] Dexamethasone in the presence of increasing concentrations (10-11 to 10-6) of cold dexamethasone or the ligands at 4°C for 24 h. Bound and free were separated by a gel filtration assay, (Geissler et al„ personal communication). Half of the reaction was added to a gel filtration plate (MILLIPORE) containing sephadex G-25 beads that was previously equilibrated with KPO4 buffer containing lmg/ml BSA and centrifuged at 1000 x g for 5 min.. The reaction plate was centrifuged at 1000 x g for 5 min. and the reactions were collected in a second 96-well plate and scintillation cocktail was added and counted in (Wallac) double coincidence beta counter. The IC50s were calculated using a 4-parameter fit program.

0884The IC50 of representative compounds of the invention are in the range of l nM to 3.0 μM.