SULFONE DERIVATIVES

Abstract

The present invention provides compounds of formula I

##STR00001##

wherein X.sup.1, X.sup.2, X.sup.3, X.sup.4, R.sup.1, R.sup.1a, R.sup.1b, R.sup.2′, R.sup.2″, R.sup.3′, R.sup.3″, R.sup.6 and R.sup.7 are as described herein, as well as pharmaceutically acceptable salts thereof. Further the present invention is concerned with the manufacture of the compounds of formula I, pharmaceutical compositions comprising them and their use as medicaments.

Claims

1. A compound of formula I ##STR00173## wherein X.sup.1 is either N or C X.sup.2 is either N or CR.sup.4 X.sup.3 is either N or CR.sup.5 X.sup.4 is either N or CH provided that no more than two of X.sup.1, X.sup.2 and X.sup.3 represent N; the dotted lines represent a single or double bond, to enable the six membered rings to be aromatic with the proviso that when X.sup.1 is N and X.sup.2 is C═O then the bond between X.sup.1 and X.sup.2, the bond between X.sup.2 and X.sup.3, the bonds a and c are single bonds and the bond between X.sup.3 and CR.sup.7 and b are double bonds; and with the proviso that when X.sup.1 is N and X.sup.2 is not C═O then the bond between X.sup.1 and X.sup.2, the bond between X.sup.3 and CR.sup.7, the bonds b and c are single bonds and the bond between X.sup.2 and X.sup.3 and the bond a are double bonds; R.sup.1 is —SO.sub.2R.sup.1a or —SOR.sup.1b; R.sup.1a and R.sup.1b are independently selected from (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, hydroxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, NR.sup.1′aR.sup.1′b oxetanyl, furanyl and pyranyl, wherein at least one of R.sup.1′a and R.sup.1′b is (C.sub.1-C.sub.6)alkyl and the other is H or (C.sub.1-C.sub.6)alkyl; or R.sup.2′ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.2″ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.3′ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.3″ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.4 is hydrogen, cyano, oxo, hydroxy, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, —CO.sub.2R.sup.4a, —CONR.sup.4bR.sup.4c, —SO.sub.2R.sup.4d, —SR.sup.4f, —SO(NR.sup.4h)R.sup.4g or —SO.sub.2(NR.sup.4i)R.sup.4j; R.sup.4a, R.sup.4b and R.sup.4c are independently selected from hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.4d, R.sup.4e and R.sup.4f are independently selected from (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.4h and R.sup.4g are independently selected from hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.4i and R.sup.4j are independently selected from hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.5 is hydrogen, halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.6 is halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, cyano, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkyl, oxetanyl or thiophenyl or —SO.sub.2R.sup.6a; R.sup.6a is (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl or halo(C.sub.1-C.sub.6) alkyl; and R.sup.7 is hydrogen, halogen, hydroxy, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo-(C.sub.1-C.sub.6)alkyl, halo-(C.sub.1-C.sub.6)alkoxy or NR.sup.7′aR.sup.7′b, wherein one of R.sup.7′a and R.sup.7′b is hydrogen and the other is hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, -(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-NHCO—(C.sub.1-C.sub.6)alkyl, —(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-NH.sub.2, —(C.sub.1-C.sub.6)alkyl-NHCO—(C.sub.1-C.sub.6)alkyl or -(C.sub.1-C.sub.6)alkyl-NH.sub.2; or pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, wherein the compound is of formula Ia ##STR00174## wherein X.sup.1 is either N or C; X.sup.3 is either N or CR.sup.5 the dotted line represents a double bond to enable the six membered rings to be aromatic with the proviso that when X.sup.1 is N and R.sup.4 is oxo then the bond is a single bond; R.sup.1 is —SO.sub.2R.sup.1a or —SOR.sup.1b; R.sup.1a and R.sup.1b are independently selected from (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, hydroxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, NR″ oxetanyl, furanyl and pyranyl, wherein at least one of R.sup.1′a and R.sup.1′b is (C.sub.1-C.sub.6)alkyl and the other is H or (C.sub.1-C.sub.6)alkyl; or R.sup.2′ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.2″ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.3′ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.3″ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.4 is hydrogen, cyano, oxo, hydroxy, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, —CO.sub.2R.sup.4a, —CONR.sup.4bR.sup.4c, —SO.sub.2R.sup.4d, —SR.sup.4f, —SO(NR.sup.4h)R.sup.4g or —SO.sub.2(NR.sub.4i)R.sub.4j; R.sup.4a, R.sup.4b and R.sup.4c are independently selected from hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.4d, R.sup.4e and R.sup.4f are independently selected from (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.4h and R.sup.4g are independently selected from hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.4i and R.sup.4j are independently selected from hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.6 is halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, cyano, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkyl, oxetanyl or thiophenyl or —SO.sub.2R.sup.6a; R.sup.6a is (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl or halo(C.sub.1-C.sub.6) alkyl; and R.sup.7 is hydrogen, halogen, hydroxy, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo-(C.sub.1-C.sub.6)alkyl, halo-(C.sub.1-C.sub.6)alkoxy or NR.sup.7′aR.sup.7′b, wherein one of R.sup.7′a and R.sup.7′b is hydrogen and the other is hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, —(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-NHCO—(C.sub.1-C.sub.6)alkyl, -(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-NH.sub.2, —(C.sub.1-C.sub.6)alkyl-NHCO—(C.sub.1-C.sub.6)alkyl or —(C.sub.1-C.sub.6)alkyl-NH.sub.2; or pharmaceutically acceptable salts thereof.

3. The compound according to claim 1, wherein the compound is of formula Ib ##STR00175## wherein X.sup.3 is either N or CR.sup.5 R.sup.1 is —SO.sub.2R.sup.1a or —SOR.sup.1b; R.sup.1a and R.sup.1b are independently selected from (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, hydroxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, NR.sup.1′aR.sup.1′b, oxetanyl, furanyl and pyranyl, wherein at least one of R.sup.1′a and R.sup.1′b is (C.sub.1-C.sub.6)alkyl and the other is H or (C.sub.1-C.sub.6)alkyl; or R.sup.2′ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.2″ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.3′ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.3″ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.4 is hydrogen, cyano, oxo, hydroxy, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, —CO.sub.2R.sup.4a, —CONR.sup.4bR.sup.4c, —SO.sub.2R.sup.4d, —SOR.sup.4e, —SR.sup.4f, —SO(NR.sup.4h)R.sup.4g or —SO.sub.2(NR.sup.4i)R.sup.4j; R.sup.4a, R.sup.4b and R.sup.4c are independently selected from hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.4d, R.sup.4e and R.sup.4f are independently selected from (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.4h and R.sup.4g are independently selected from hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.4i and R.sup.4j are independently selected from hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.5 is hydrogen, halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.6 is halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, cyano, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkyl, oxetanyl or thiophenyl or —SO.sub.2R.sup.6a; R.sup.6a is (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl or halo(C.sub.1-C.sub.6) alkyl; and R.sup.7 is hydrogen, halogen, hydroxy, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo-(C.sub.1-C.sub.6)alkyl, halo-(C.sub.1-C.sub.6)alkoxy or NR.sup.7′aR.sup.7′b, wherein one of R.sup.7′a and R.sup.7′b is hydrogen and the other is hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, —(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-NHCO—(C.sub.1-C.sub.6)alkyl, —(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-NH.sub.2, —(C.sub.1-C.sub.6)alkyl-NHCO—(C.sub.1-C.sub.6)alkyl or —(C.sub.1-C.sub.6)alkyl-NH.sub.2; or pharmaceutically acceptable salts thereof.

4. The compound according to claim 1, wherein the compound is of formula Ic ##STR00176## wherein R.sup.1 is —SO.sub.2R.sup.1a or —SOR.sup.1b; R.sup.1a and R.sup.1b are independently selected from (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, hydroxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, NR.sup.1′a oxetanyl, furanyl and pyranyl, wherein at least one of R.sup.1a and R.sup.1′b is (C.sub.1-C.sub.6)alkyl and the other is H or (C.sub.1-C.sub.6)alkyl; or R.sup.2′ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.2″ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.3′ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.3″ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.5 is hydrogen, halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.6 is halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, cyano, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkyl, oxetanyl or thiophenyl or —SO.sub.2R.sup.6a; R.sup.6′ is (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl or halo(C.sub.1-C.sub.6) alkyl; and R.sup.7 is hydrogen, halogen, hydroxy, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo-(C.sub.1-C.sub.6)alkyl, halo-(C.sub.1-C.sub.6)alkoxy or NR.sup.7′aT.sup.7′b, wherein one of R.sup.7′a and R.sup.7′b is hydrogen and the other is hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, —(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-NHCO—(C.sub.1-C.sub.6)alkyl, —(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-NH.sub.2, —(C.sub.1-C.sub.6)alkyl-NHCO—(C.sub.1-C.sub.6)alkyl or —(C.sub.1-C.sub.6)alkyl-NH.sub.2; or pharmaceutically acceptable salts thereof.

5. The compound according to claim 1, wherein the compound is of formula Id, ##STR00177## wherein R.sup.1 is —SO.sub.2R.sup.1a or —SOR.sup.1b; R.sup.1a and R.sup.1b are independently selected from (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, hydroxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, —, NR.sup.1′aR.sup.1′b, oxetanyl, furanyl and pyranyl, wherein at least one of R.sup.1′a and R.sup.1′b is (C.sub.1-C.sub.6)alkyl and the other is H or (C.sub.1-C.sub.6)alkyl; or R.sup.2′ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.2″ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.3′ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.3″ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.4 is hydrogen, cyano, oxo, hydroxy, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, —CO.sub.2R.sup.4a, —CONR.sup.4bR.sup.4c, —SO.sub.2R.sup.4d, —SR.sup.4f, —SO(NR.sup.4h)R.sup.4g or —SO.sub.2(NR.sup.4i)R.sup.4j; R.sup.4a, R.sup.4b and R.sup.4c are independently selected from hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.4d, R.sup.4e and R.sup.4f are independently selected from (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.4h and R.sup.4g are independently selected from hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.4i and R.sup.4j are independently selected from hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.5 is hydrogen, halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.6 is halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, cyano, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkyl, oxetanyl or thiophenyl or —SO.sub.2R.sup.6a; R.sup.6′ is (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl or halo(C.sub.1-C.sub.6) alkyl; and R.sup.7 is hydrogen, halogen, hydroxy, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo-(C.sub.1-C.sub.6)alkyl, halo-(C.sub.1-C.sub.6)alkoxy or NR.sup.7′aR.sup.7′b, wherein one of R.sup.7′a and R.sup.7′b is hydrogen and the other is hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, -(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-NHCO—(C.sub.1-C.sub.6)alkyl, —(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-NH.sub.2, —(C.sub.1-C.sub.6)alkyl-NHCO—(C.sub.1-C.sub.6)alkyl or —(C.sub.1-C.sub.6)alkyl-NH.sub.2; or pharmaceutically acceptable salts thereof.

6. The compound according to claim 1, wherein the compound is of formula Ie ##STR00178## wherein R.sup.1 is —SO.sub.2R.sup.1a or —SOR.sup.1b; R.sup.1a and R.sup.1b are independently selected from (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, hydroxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, NR.sup.1′aR.sup.1′b, oxetanyl, furanyl and pyranyl, wherein at least one of R.sup.1′a and R.sup.1′b is (C.sub.1-C.sub.6)alkyl and the other is H or (C.sub.1-C.sub.6)alkyl; or R.sup.2′ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.2″ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.3′ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.3″ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl or halo(C.sub.1-C.sub.6)alkoxy; R.sup.4 is hydrogen, cyano, oxo, hydroxy, halogen, —NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, —CO.sub.2R.sup.4a, —CONR.sup.4bR.sup.4c, —SO.sub.2R.sup.4d, —SO(NR.sup.4h)R.sup.4g or —SO.sub.2(NR.sup.4i)R.sup.4j; R.sup.4a, R.sup.4b and R.sup.4c are independently selected from hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.4d, R.sup.4e and R.sup.4f are independently selected from (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.4h and R.sup.4g are independently selected from hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.4i and R.sup.4j are independently selected from hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl and oxetanyl; R.sup.6 is halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, cyano, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkyl, oxetanyl or thiophenyl or —SO.sub.2R.sup.6a; R.sup.6a is (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl or halo(C.sub.1-C.sub.6) alkyl; and R.sup.7 is hydrogen, halogen, hydroxy, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo-(C.sub.1-C.sub.6)alkyl, halo-(C.sub.1-C.sub.6)alkoxy or NR.sup.7′aR.sup.7′b, wherein one of R.sup.7′a and R.sup.7′b is hydrogen and the other is hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, —(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-NHCO—(C.sub.1-C.sub.6)alkyl, —(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-NH.sub.2, —(C.sub.1-C.sub.6)alkyl-NHCO—(C.sub.1-C.sub.6)alkyl or -(C.sub.1-C.sub.6)alkyl-NH.sub.2; or pharmaceutically acceptable salts thereof.

7. The compound according to claim 1, wherein X.sup.4 is N.

8. The compound according to claim 1, wherein X.sup.1 is N or C, X.sup.2 is N or CR.sup.4 and X.sup.3 is N or CR.sup.5.

9. The compound according to claim 1, wherein R.sup.1 is —SO.sub.2R.sup.1a.

10. The compound according to claim 1, wherein R.sup.1a and R.sup.1b are independently selected from (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, hydroxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, NR.sup.1′aR.sup.1′b, oxetanyl, furanyl and pyranyl, wherein at least one of R.sup.1′a and R.sup.1′b is (C.sub.1-C.sub.6)alkyl and the other is H or (C.sub.1-C.sub.6)alkyl.

11. (canceled)

12. The compound according to claim 1, wherein R.sup.1a is selected from methyl, ethyl, propyl, i-propyl, i-butyl, cyclopropyl, ##STR00179## fluoromethyl, difluoromethyl, fluoro-ethanyl, difluoro-ethanyl, 1,2 difluoroethanyl, 1,1,2-trifluoroethanyl, 1,2,2-trifluoroethanyl, Hydroxymethyl, hydroxyethyl, metoxymethyl, methylaminyl (—NHCH.sub.3), dimethylaminyl (—N(CH.sub.3).sub.2) and oxetanyl.

13. (canceled)

14. (canceled)

15. The compound according to claim 1, wherein R.sup.1b is (C.sub.1-C.sub.6)alkyl, more particularly is (C.sub.1-C.sub.3)alkyl, most particularly methyl.

16. The compound according to claim 1, wherein if R.sup.2′ is other than hydrogen as defined according to claim 1, than R.sup.3′ is hydrogen, R.sup.2″ is hydrogen and R.sup.3″ is as defined according to claim 1.

17. The compound according to claim 1, wherein one of R.sup.2′ and R.sup.2″ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.2)alkyl, (C.sub.1-C.sub.2)alkoxy or halo(C.sub.1-C.sub.2)alkyl, while the other one is hydrogen.

18. (canceled)

19. (canceled)

20. (canceled)

21. The compound according to claim 1, wherein one of R.sup.3′ and R.sup.3″ is hydrogen, halogen, —NH.sub.2, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy or halo(C.sub.1-C.sub.3)alkyl, while the other one is hydrogen.

22. (canceled)

23. (canceled)

24. The compound according to claim 1, wherein both R.sup.3′ and R.sup.3″ are hydrogen.

25. The compound according to claim 1, wherein R.sup.4 is cyano, oxo, hydroxy, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy, halo(C.sub.1-C.sub.3)alkyl, halo(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.3)alkoxy-(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.4)cycloalkyl, —CONR.sup.4bR.sup.4c, —SO.sub.2R.sup.4d, —SOR.sup.4e, —SR.sup.4f or —SO(NR.sup.4h)R.sup.4g.

26. (canceled)

27. (canceled)

28. (canceled)

29. The compound according to claim 1, wherein R.sup.4a, R.sup.4b and R.sup.4c are independently selected from hydrogen, (C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.4)cycloalkyl, and oxetanyl.

30. (canceled)

31. (canceled)

32. The compound according to claim 1, wherein R.sup.4a is hydrogen.

33. (canceled)

34. The compound according to claim 1, wherein R.sup.4d, R.sup.4e and R.sup.4f are independently selected from (C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.4)cycloalkyl, and oxetanyl.

35. (canceled)

36. (canceled)

37. (canceled)

38. The compound according to claim 1, wherein R.sup.4d is methyl.

39. The compound according to claim 1, wherein R.sup.4h and R.sup.4g are independently selected from hydrogen and (C.sub.1-C.sub.6)alkyl.

40. (canceled)

41. (canceled)

42. (canceled)

43. The compound according to claim 1, wherein R.sup.4i ′ and R.sup.4j are independently selected from hydrogen and (C.sub.1-C.sub.6)alkyl.

44. (canceled)

45. (canceled)

46. (canceled)

47. The compound according to claim 1, wherein R.sup.5 is hydrogen, halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy or (C.sub.3-C.sub.6)cycloalkyl.

48. (canceled)

49. (canceled)

50. The compound according to claim 1, wherein R.sup.5 is hydrogen.

51. The compound according to claim 1, wherein R.sup.6 is halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, cyano, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkyl, thiophenyl, oxetanyl or —SO.sub.2R.sup.6a.

52. (canceled)

53. (canceled)

54. (canceled)

55. The compound according to claim 1, wherein R.sup.6a is (C.sub.1-C.sub.6)alkyl.

56. (canceled)

57. The compound according to claim 1, wherein R.sup.7 is hydrogen, halogen, hydroxy or (C.sub.1-C.sub.6)alkyl.

58. (canceled)

59. (canceled)

60. The compound according to claim 1, wherein one of R.sup.7′a and R.sup.7′b is hydrogen and the other is hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, —(C.sub.1-C.sub.3)alkyl-O—(C.sub.1-C.sub.3)alkyl-NHCO—(C.sub.1-C.sub.3)alkyl, —(C.sub.1-C.sub.3)alkyl-O—(C.sub.1-C.sub.3)alkyl-NH.sub.2, —(C.sub.1-C.sub.3)alkyl-NHCO—(C.sub.1-C.sub.3)alkyl or —(C.sub.1-C.sub.3)alkyl-NH.sub.2.

61. (canceled)

62. (canceled)

63. The compound according to claim 1, selected from the group consisting of: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-methoxy-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-chloro-4-(methylsulfonyl)phenyl)-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(4-(methylsulfonyl)-3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N,N,2-trimethylbenzenesulfonamide; 3-cyclopropyl-5-methoxy-4-(4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-4-(4-(cyclopropylsulfonyl)-3-methylphenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-chloro-4-(cyclopropylsulfonyl)phenyl)-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine; 2-chloro-4-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N,N-dimethylbenzenesulfonamide; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine; 4-(4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-(fluoromethyl)-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(oxetan-3-yl sulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-(3-methyl -4-(m ethyl sulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-methoxy-4-(3-methyl -4-(methyl sulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 5-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-2-(methylsulfonyl)aniline; 4-(3-methyl-4-(methyl sulfonyl)phenyl)-3-(methyl sulfonyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(methyl sulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(1,1-difluoroethyl)-4-(3-methyl -4-(m ethyl sulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-methyl-4-(methyl sulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile; 3-(difluoromethyl)-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine; 3-isopropyl-4-(3-methyl-4-(methyl sulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(4-ethyl sulfonyl-3-methyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(2-fluoro-5-methyl -4-methyl sulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(2,5-dimethyl -4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine hydrochloride; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile; 3-cyclopropyl-4-(3-methyl-4-methylsulfinyl-phenyl)-1H-pyrazolo[4,3-c]pyridine hydrochloride 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-ol 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-5-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine; 3-ethoxy-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[4,3-c]pyridine; 4-(4-cyclopropyl sulfonyl -3-methyl-phenyl)-3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-7-fluoro-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-(4-ethylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(oxetan-3-yl)-1H-pyrazolo[4,3-c]pyridine; 4-[4-(cyclopropylmethylsulfonyl)-3-methyl-phenyl]-3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-(3-methyl-4-propylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-[3-(difluoromethyl)-4-methyl sulfonyl-phenyl]-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-(4-isopropylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-[3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-4-yl]-N,2-dimethyl-benzenesulfonamide; 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile; 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile; 6-chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-[3-methyl-4-(oxetan-3-yl sulfonyl)phenyl]-1H-pyrazolo[4,3-c]pyridine; 2-[4-[3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-4-yl]-2-methyl-phenyl]sulfonylethanol 3-cyclopropyl-6-methoxy-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine 2,2,2-trifluoroacetic acid; 3-(difluoromethoxy)-4-[3-methyl-4-(1-methylcyclopropyl)sulfonyl-phenyl]-1H-pyrazolo[4,3-c]pyridine; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-cyclopropyl-N-methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyridazine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1H-indazole; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfinyl)-1H-indazole; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole; 3-(difluoromethoxy)-4-[4-(methoxymethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[4,3-c]pyridine formic acid; 5-methoxy-4-(3-methyl -4-(methyl sulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridine; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine; 3-(difluoromethoxy)-4-(3-methyl-4-methyl sulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one; 3-cyclopropyl-4-(3-methyl -4-methylsulfonylphenyl)-5-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one; 3,6-dicyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one; 3-cyclopropyl-5-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-N,N-dimethyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-cyclopropyl-5-(methoxymethyl)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3,5-dicyclopropyl-4-(3-methyl -4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine; N,3-dicyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile; 3-cyclopropyl-4-(4-ethylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethyl)-1H-indazole 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indole-5-carbonitrile; 3-cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-cyclopropyl-6-fluoro-N-methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carboxamide; 3-cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carboxamide; 6-chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1#H!-indazole-5-carbonitrile; 3-cyclopropyl-4-(2-fluoro-5-methyl -4-methyl sulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-b]pyridin-5-one; 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrrolo[3,2-b]pyridin-5-one; 4-[3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-4-yl]-2-(difluoromethyl)-N,N-dimethyl-benzenesulfonamide; 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole; 3-cyclopropyl-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1H-indazole; 3-cyclopropyl-4-[3-(difluoromethyl)-4-methylsulfonyl-phenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methyl sulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(difluoromethoxy)-4-[5-(difluoromethyl)-2-methyl-4-methylsulfinyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-[3-(difluoromethyl)-4-methylsulfonyl-phenyl]-5-methoxy-3-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-4-(3-(difluoromethyl)-4-(methyl sulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole; 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-cyclopropyl-4-(4-cyclopropyl sulfonyl-2-fluoro-5-methyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 4-(4-cyclopropyl sulfonyl -3-methyl-phenyl)-3-(difluoromethoxy)-5-methylsulfonyl-1H-indazole; 3-cyclopropyl-4-(2-fluoro-5-methyl -4-methyl sulfonyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl -4-methyl sulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(2-methoxyethyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methyl sulfonyl-phenyl)-5-(oxetan-3-ylsulfonyl)-1H-indazole; [3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazol-5-yl]-imino-methyl-oxo-sulfane; [3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazol-5-yl]-methyl-methylimino-oxo-λ.sup.6-sulfane; 3-cyclopropyl-N,N-dimethyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide; 3-cyclopropyl-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide; 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-5-(methylsulfonyl)-1H-indazole; 5-cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole; 3-(difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-5-methylsulfonyl-1H-indazole; and 4-(4-cyclopropyl sulfonyl -3-methyl-phenyl)-3-(difluoromethoxy)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide or pharmaceutically acceptable salts thereof.

64. The compound according to claim 1, selected from the group consisting of: 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one; 3-cyclopropyl-4-(4-ethylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethyl)-1H-indazole; 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole; 3-cyclopropyl-4-[4-(difluoromethyl sulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1H-indazole; 3-cyclopropyl-4-[3-(difluoromethyl)-4-methylsulfonyl-phenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; and 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide or pharmaceutically acceptable salts thereof.

65. A compound according to claim 1 for use as a therapeutically active substance.

66. Pharmaceutical compositions comprising compounds of formula I according to claim 1 or their pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.

67. (canceled)

68. Compounds of formula I according to claim 1 or their pharmaceutically acceptable salts for the use in the treatment, prevention and/or delay of progression of Lung Adenocarcinoma, Melanoma, Pancreatic Adenocarcinoma, Head and Neck Squamous Cell Carcinoma, Lung Squamous Cell Carcinoma, Esophageal Carcinoma, Glioblastmoa Multiforme, and Mesothelioma.

69. (canceled)

70. A method for the treatment or prevention of Lung Adenocarcinoma, Melanoma, Pancreatic Adenocarcinoma, Head and Neck Squamous Cell Carcinoma, Lung Squamous Cell Carcinoma, Esophageal Carcinoma, Glioblastmoa Multiforme, and Mesothelioma, which method comprises administering compounds of formula I according to claim 1 or their pharmaceutically acceptable salts as defined above to a subject.

71. (canceled)

72. The use of compounds of formula I according to claim 1 or their pharmaceutically acceptable salts for the treatment, prevention and/or delay of progression of Lung Adenocarcinoma, Melanoma, Pancreatic Adenocarcinoma, Head and Neck Squamous Cell Carcinoma, Lung Squamous Cell Carcinoma, Esophageal Carcinoma, Glioblastmoa Multiforme, and Mesothelioma.

73. (canceled)

74. The use of compounds of formula I according to claim 1 or their pharmaceutically acceptable salts for the preparation of medicaments for the treatment or prevention of Lung Adenocarcinoma, Melanoma, Pancreatic Adenocarcinoma, Head and Neck Squamous Cell Carcinoma, Lung Squamous Cell Carcinoma, Esophageal Carcinoma, Glioblastmoa Multiforme, and Mesothelioma.

75. (canceled)

76. (canceled)

Description

EXAMPLES

[0631]

TABLE-US-00003 Mol. Ex. weight From No. Structure Product Name found Intermediates Prep. 1 [00056] embedded image 3-cyclopropyl-4-(3- methyl-4- (methylsulfonyl) phenyl)-1H- pyrazolo[4,3- c]pyridine [M + H].sup.+ 328.1 4-chloro-3- cyclopropyl-1H- pyrazolo[4,3- c]pyridine (Intermediate 1) and (3-methyl-4- (methylsulfonyl) phenyl)boronic acid D 2 [00057] 3-cyclopropyl-4-(3- methoxy-4- (methylsulfonyl) phenyl)-1H- pyrazolo[4,3- c]pyridine [M + H].sup.+ 344.1 4-chloro-3- cyclopropyl-1H- pyrazolo[4,3- c]pyridine (Intermediate 1) and (4- Methanesulfonyl- 3- methoxyphenyl) boronic acid D 3 [00058] embedded image 4-(3-chloro-4- (methylsulfonyl) phenyl)-3- cyclopropyl- 1H-pyrazolo[4,3- c]pyridine [M + H, Cl].sup.+ 348.1 4-chloro-3- cyclopropyl-1H- pyrazolo[4,3- c]pyridine (Intermediate 1) and (3-Chloro-4- methanesulfonyl- phenyl)boronic acid D 4 [00059] 3-cyclopropyl-4-(4- (methylsulfonyl)-3- (trifluoromethyl) phenyl)-1H- pyrazolo[4,3- c]pyridine [M + H].sup.+ 382.1 4-chloro-3- cyclopropyl-1H- pyrazolo[4,3- c]pyridine (Intermediate 1) and [4- Methanesulfonyl- 3- (trifluoromethyl) phenyl]boronic acid D 5 [00060] embedded image 4-(3-cyclopropyl- 1H-pyrazolo[4,3- c]pyridin-4-yl)- N,N,2- trimethylbenzene- sulfonamide [M + H].sup.+ 357.1 4-chloro-3- cyclopropyl-1H- pyrazolo[4,3- c]pyridine (Intermediate 1) and N,N,2- trimethyl-4- (4,4,5,5- tetramethyl-1,3,2- dioxoborolan-2- yl)benzensulfona- mide D 6 [00061] 3-cyclopropyl-5- methoxy-4-(4- methylsulfonyl- phenyl)-1H- pyrazolo[3,4- c]pyridine [M + H].sup.+ 344.1 4-bromo-3- cyclopropyl-5- methoxy-1-((2- (trimethylsilyl) ethoxy)methyl)-1H- pyrazolo[3,4- c]pyridine (Intermediate 2) and 4- (methanesulfonyl) phenyl boronic acid D, J 7 [00062] embedded image 3-cyclopropyl-4-(4- (cyclopropylsulfonyl)- 3-methylphenyl)- 1H-pyrazolo[4,3- c]pyridine [M + H].sup.+ 354.1 4-chloro-3- cyclopropyl-1H- pyrazolo[4,3- c]pyridine (Intermediate 1) and 2-(4- (cyclopropyl- sulfonyl)-3- methylphenyl)- 4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 18) D 8 [00063] embedded image 4-(3-chloro-4- (cyclopropylsulfonyl) phenyl)-3- cyclopropyl-1H- pyrazolo[4,3- c]pyridine [M + H].sup.+ 374.1 4-chloro-3- cyclopropyl-1H- pyrazolo[4,3- c]pyridine (Intermediate 1) and 2-(4- (cyclopropyl- sulfonyl)-3- chlorophenyl)- 4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 19) D 9 [00064] embedded image 2-chloro-4-(3- cyclopropyl-1H- pyrazolo[4,3- c]pyridin-4-yl)-N,N- dimethylbenzene- sulfonamide [M + H].sup.+ 377.1 4-chloro-3- cyclopropyl-1H- pyrazolo[4,3- c]pyridine (Intermediate 1) and 2-chloro- N,N-dimethyl-4- (4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)benzenesul- fonamide (Intermediate 20) D 10 [00065] embedded image 4-(3-methyl-4- (methylsulfonyl) phenyl)-3- (trifluoromethyl)- 1H-pyrazolo[3,4- b]pyridine [M + H].sup.+ 356.1 4-chloro-3- (trifluoromethyl)- 1-((2- (trimethylsilyl) ethoxy)methyl)-1H- pyrazolo[4,3- c]pyridine (Intermediate 3) and (3-methyl-4- (methylsulfonyl) phenyl)boronic acid D, J 11 [00066] embedded image 4-(4- (methylsulfonyl) phenyl)-3- (trifluoromethyl)- 1H-pyrazolo[4,3- c]pyridine [M + H].sup.+ 342.0 4-chloro-3- (trifluoromethyl)- 1-((2- (trimethylsilyl) ethoxy)methyl)-1H- pyrazolo[4,3- c]pyridine (Intermediate 3) and 4- (methanesulfonyl) phenyl boronic acid D, J 12 [00067] 3-cyclopropyl-4-(3- (difluoromethyl)-4- (methylsulfonyl) phenyl)-1H- pyrazolo[4,3- c]pyridine [M + H].sup.+ 364.1 4-chloro-3- cyclopropyl-1H- pyrazolo[4,3- c]pyridine (Intermediate 1) and 2-(3- (difluoromethyl)- 4- (methylsulfonyl) phenyl)-4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 21) D 13 [00068] embedded image 3-cyclopropyl-4-(3- (fluoromethyl)-4- (methylsulfonyl) phenyl)-1H- pyrazolo[4,3- c]pyridine [M + H].sup.+ 346.1 4-chloro-3- cyclopropyl-1H- pyrazolo[4,3- c]pyridine (Intermediate 1) and 2-(3- (difluoromethyl)- 4- (methylsulfonyl) phenyl)-4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 22) D 14 [00069] embedded image 3-cyclopropyl-4-(3- methyl-4- (methylsulfonyl) phenyl)-1H-pyrrolo [3,2-c]pyridine [M + H].sup.+ 327.2 4-chloro-3- cyclopropyl-1- ((2- (trimethylsilyl) ethoxy)methyl)-1H- pyrrolo[3,2- c]pyridine (Intermediate 4) and (3-methyl-4- (methylsulfonyl) phenyl)boronic acid D, J 15 [00070] 3-cyclopropyl-4-(3- methyl-4-(oxetan-3- ylsulfonyl)phenyl)- 1H-pyrazolo[4,3- c]pyridine [M + H].sup.+ 370.2 4-chloro-3- cyclopropyl-1H- pyrazolo[4,3- c]pyridine (Intermediate 1) and 4,4,5,5- tetramethyl-2-(3- methyl-4-(oxetan- 3- ylsulfonyl)phenyl)- 1,3,2- dioxaborolane (Intermediate 23) D 16 [00071] embedded image 3-cyclopropyl-4-(3- methyl-4- (methylsulfonyl) phenyl)-1H- pyrazolo[3,4- c]pyridine-5- carbonitrile [M + H].sup.+ 353.1 4-bromo-3- cyclopropyl-1H- pyrazolo[3,4- c]pyridine-5- carbonitrile (Intermediate 5) and (3-methyl-4- (methylsulfonyl) phenyl)boronic acid D 17 [00072] 3-(1,1- difluoroethyl)-4-(3- methyl-4- (methylsulfonyl) phenyl)-1H- pyrazolo[4,3- c]pyridine [M + H].sup.+ 352.2 4-chloro-3-(1,1- difluoroethyl)- 1H-pyrazolo[4,3- c]pyridine (Intermediate 6) and (3-methyl-4- (methylsulfonyl) phenyl)boronic acid D 18 [00073] embedded image 3-(difluoromethyl)- 4-(3-methyl-4- methylsulfonyl- phenyl)-1H- pyraxolo[4,3- c]pyridine [M + H].sup.+ 338.1 2-[[4-chloro-3- (difluoromethyl) pyrazolo[4,3- c]pyridin-1- yl]methoxy]ethyl- trimethylsilane (Intermediate 7) and (3-methyl-4- (methylsulfonyl) phenyl)boronic acid D, J 19 [00074] embedded image 3-isopropyl-4-(3- methyl-4- (methylsulfonyl) phenyl)-1H- pyrazolo[4,3- c]pyridine [M + H].sup.+ 330.1 4-chloro-3- isopropyl-1H- pyrazolo[4,3- c]pyridine and (3- methyl-4- (methylsulfonyl) phenyl)boronic acid D 20 [00075] 3-cyclopropyl-4-(4- ethylsulfonyl-3- methyl-phenyl)-1H- pyrazolo[4,3- c]pyridine [M + H].sup.+ 314.9 4-chloro-3- cyclopropyl-1H- pyrazolo[4,3- c]pyridine (Intermediate 1) and 2-(4- ethylsulfonyl-3- methyl-phenyl)- 4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 24) D 21 [00076] embedded image 3-cyclopropyl-4-(2- fluoro-5-methyl-4- methylsulfonyl- phenyl)-1H- pyrazolo[4,3- c]pyridine [M + H].sup.+ 346.1 4-chloro-3- cyclopropyl-1H- pyrazolo[4,3- c]pyridine (Intermediate 1) and 2-(2-fluoro-5- methyl-4- methylsulfonyl- phenyl)-4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 25) D 22 [00077] embedded image 3-cyclopropyl-4- (2,5-dimethyl-4- methylsulfonyl- phenyl)-1H- pyrazolo[4,3- c]pyridine hydrochloride [M + H].sup.+ 342.1 4-chloro-3- cyclopropyl-1H- pyrazolo[4,3- c]pyridine (Intermediate 1) and 2-(2,5- dimethyl-4- methylsulfonyl- phenyl)-4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 26) D 23 [00078] embedded image 3-cyclopropyl-4-(3- methyl-4- methylsulfmyl- phenyl)-1H- pyrazolo[4,3- c]pyridine hydrochloride [M + H].sup.+ 312.2 4-chloro-3- cyclopropyl-1H- pyrazolo[4,3- c]pyridine (Intermediate 1) and 3-Methyl-4- (methylthio) phenylboronic acid D, G (1 eq) 24 [00079] 3-cyclopropyl-5- methoxy-4-(3- methyl-4- (methylsulfonyl) phenyl)-1H- pyrazolo[3,4- c]pyridine [M + H].sup.+ 358.3 4-bromo-3- cyclopropyl-5- methoxy-1-((2- (trimethylsilyl) ethoxy)methyl)-1H- pyrazolo[3,4- c]pyridine (Intermediate 2) and (3-methyl-4- (methylsulfonyl) phenyl)boronic acid D, J 25 [00080] embedded image 3- (difluoromethoxy)- 4-[4- (difluoromethyl- sulfonyl)-3-methyl- phenyl]-1H- pyrazolo[4,3- c]pyridine [M + H].sup.+ 390.1 4-chloro-3- (difluoromethoxy)- 1-trityl- pyrazolo[4,3- c]pyridine (Intermediate 8) and 2-[4- (difluoromethyl- sulfonyl)-3-methyl- phenyl]-4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 27) D, H 26 [00081] embedded image 4-(4- cyclopropylsulfonyl- 3-methyl-phenyl)-3- (difluoromethoxy)- 1H-pyrazolo[4,3- c]pyridine [M + H].sup.+ 380.1 4-chloro-3- (difluoromethoxy)- 1-trityl- pyrazolo[4,3- c]pyridine (Intermediate 8) and 2-(4- (cyclopropyl- sulfonyl)-3- methylphenyl)- 4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 18) D, H 27 [00082] embedded image 3- (difluoromethoxy)- 4-(4-ethylsulfonyl-3- methyl-phenyl)-1H- pyrazolo[4,3- c]pyridine [M + H].sup.+ 368.0 4-chloro-3- (difluoromethoxy)- 1-trityl- pyrazolo[4,3- c]pyridine (Intermediate 8) and 2-(4- ethylsulfonyl-3- methyl-phenyl)- 4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 24) D, H 28 [00083] embedded image 4-(3-methyl-4- methylsulfonyl- phenyl)-3-(oxetan-3- yl)-1H-pyrazolo[4,3- c]pyridine [M + H].sup.+ 344.0 4-chloro-3- (oxetan-3-yl)-1- tetrahydropyran- 2-yl-pyrazolo[4,3- c]pyridine (Intermediate 9) and (3-methyl-4- (methylsulfonyl) phenyl)boronic acid D, I1 29 [00084] 4-[4- (cyclopropylmethyl- sulfonyl)-3-methyl- phenyl]-3- (difluoromethoxy)- 1H-pyrazolo[4,3- c]pyridine [M + H].sup.+ 394.1 4-chloro-3- (difluoromethoxy)- 1-trityl- pyrazolo[4,3- c]pyridine (Intermediate 8) and 2-[4- (cyclopropyl- methylsulfonyl)-3- methyl-phenyl]- 4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 28) D, H 30 [00085] embedded image 3- (difluoromethoxy)- 4-[3- (difluoromethyl)-4- methylsulfonyl- phenyl]-1H- pyrazolo[4,3- c]pyridine [M + H].sup.+ 382.2 4-chloro-3- (difluoromethoxy)- 1-trityl- pyrazolo[4,3- c]pyridine (Intermediate 8) and 4,4,5,5- tetramethyl-2-(3- methyl-4- propylsulfonyl- phenyl)-1,3,2- dioxaborolane (Intermediate 29) D, H 31 [00086] embedded image 3- (difluoromethoxy)- 4-(4- isopropylsulfonyl-3- methyl-phenyl)-1H- pyrazolo[4,3- c]pyridine [M + H].sup.+ 390.1 4-chloro-3- (difluoromethoxy)- 1-trityl- pyrazolo[4,3- c]pyridine (Intermediate 8) and 2-(3- (difluoromethyl)- 4- (methylsulfonyl) phenyl)-4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 21) D, H 32 [00087] embedded image 4-(3-methyl-4- methylsulfonyl- phenyl)-3-(oxetan-3- yl)-1H-pyrazolo[4,3- c]pyridine [M + H].sup.+ 382.0 4-chloro-3- (difluoromethoxy)- 1-trityl- pyrazolo[4,3- c]pyridine (Intermediate 8) and 2-(4- isopropylsulfonyl- 3-methyl- phenyl)-4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 30) D, H 33 [00088] embedded image 4-[3- (difluoromethoxy)- 1H-pyrazolo[4,3- c]pyridin-4-yl]-N,2- dimethyl- benzenesulfonamide [M + H].sup.+ 369.0 4-chloro-3- (difluoromethoxy)- 1-trityl- pyrazolo[4,3- c]pyridine (Intermediate 8) and N,2- dimethyl-4- (4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)benzenesulfona- mide (Intermediate 30) D, H 34 [00089] embedded image 6-chloro-3- cyclopropyl-4-(3- methyl-4- methylsulfonylphenyl)- 1H-pyrazolo[4,3- c]pyridine [M + H].sup.+ 362.3 4,6-dichloro-3- cyclopropyl-1H- pyrazolo[4,3- c]pyridine (Intermediate 10) and (3-methyl-4- (methylsulfonyl) phenyl)boronic acid D 35 [00090] 3- (difluoromethoxy)- 4-[3-methyl-4- (oxetan-3- ylsulfonyl)phenyl]- 1H-pyrazolo[4,3- c]pyridine [M + H].sup.+ 396.1 4-chloro-3- (difluoromethoxy)- 1-trityl- pyrazolo[4,3- c]pyridine (Intermediate 8) and 4,4,5,5- tetramethyl-2-(3- methyl-4-(oxetan- 3- ylsulfonyl)phenyl)- 1,3,2- dioxaborolane (Intermediate 23) D, H 36 [00091] embedded image 2-[4-[3- (difluoromethoxy)- 1H-pyrazolo[4,3- c]pyridin-4-yl]-2- methyl- phenyl] sulfonylethanol [M + H].sup.+ 384.1 4-chloro-3- (difluoromethoxy)- 1-trityl- pyrazolo[4,3- c]pyridine (Intermediate 8) and tert-butyl- dimethyl-[2-[2- methyl-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl]sulfonyl- ethoxy]silane (Intermediate 32) D, H 37 [00092] embedded image 3- (difluoromethoxy)- 4-[3-methyl-4-(1- methylcyclopropyl) sulfonyl-phenyl]-1H- pyrazolo[4,3- c]pyridine [M + H].sup.+ 394.1 4-chloro-3- (difluoromethoxy)- 1-trityl- pyrazolo[4,3- c]pyridine (Intermediate 8) and 4,4,5,5- tetramethyl-2-[3- methyl-4-(1- methylcyclopropyl) sulfonyl- phenyl]-1,3,2- dioxaborolane (Intermediate 33) D, H 38 [00093] embedded image 3- (difluoromethoxy)- 4-[4- (methoxymethyl- sulfonyl)-3-methyl- phenyl]-1H- pyrazolo[4,3- c]pyridine [M + H].sup.+ 384.1 4-chloro-3- (difluoromethoxy)- 1-trityl- pyrazolo[4,3- c]pyridine (Intermediate 8) and 2-[4- (methoxymethyl- sulfonyl)-3- methyl-phenyl]- 4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 34) D, H 39 [00094] embedded image 5-methoxy-4-(3- methyl-4- (methylsulfonyl) phenyl)-3- (trifluoromethyl)- 1H-pyrazolo[3,4- c]pyridine [M + H].sup.+ 386.3 4-bromo-5- methoxy-3- (trifluoromethyl)- 2-((2- (trimethylsilyl) ethoxy)methyl)- 2H-pyrazolo[3,4- c]pyridine (Intermediate 11) and (3-methyl-4- (methylsulfonyl) phenyl)boronic acid D, J 40 [00095] embedded image 4-(3-methyl-4- (methylsulfonyl) phenyl)-3- (trifluoromethyl)- 1H-pyrrolo[3,2- c]pyridine [M + H].sup.+ 355.2 4-chloro-3- (trifluoromethyl)- 1-((2- (trimethylsilyl) ethoxy)methyl)-1H- pyrrolo[3,2- c]pyridine (Intermediate 12) and (3-methyl-4- (methylsulfonyl) phenyl)boronic acid D, J 41 [00096] embedded image 3-cyclopropyl-5- (methoxymethyl)-4- (3-methyl-4- (methylsulfonyl) phenyl)-1H- pyrazolo[3,4- c]pyridine [M + H].sup.+ 372.2 4-bromo-3- cyclopropyl-5- (methoxymethyl)- 1-(tetrahydro-2H- pyran-2-yl)-1H- pyrazolo[3,4- c]pyridine (Intermediate 13) and (3-methyl-4- (methylsulfonyl) phenyl)boronic acid D, I1 42 [00097] embedded image 3-cyclopropyl-4-(4- ethylsulfonyl-3- methyl-phenyl)-1H- pyrazolo[3,4- c]pyridine-5- carbonitrile [M + H].sup.+ 367.0 4-bromo-3- cyclopropyl-1H- pyrazolo[3,4- c]pyridine-5- carbonitrile (Intermediate 5) and -(4- ethylsulfonyl-3- methyl-phenyl)- 4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 24) D 43 [00098] embedded image 3-cyclopropvl-4-(4- cyclopropylsulfonyl- 3-methyl-phenyl)- 1H-pyrazolo[3,4- c]pyridine-5- carbonitrile [M + H].sup.+ 379.0 4-bromo-3- cyclopropyl-1H- pyrazolo[3,4- c]pyridine-5- carbonitrile (Intermediate 5) and 2-(4- (cyclopropyl- sulfonyl)-3- methylphenyl)- 4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 18) D 44 [00099] embedded image 4-(3-methyl-4- (methylsulfonyl) phenyl)-5- (methylsulfonyl)-3- (trifluoromethyl)- 1H-indazole [M + H].sup.+ 433.2 4-bromo-5- (methylsulfonyl)- 3- (trifluoromethyl)- 1-((2- (trimethylsilyl) ethoxy)methyl)-1H- indazole (Intermediate 14) and (3-methyl-4- (methylsulfonyl) phenyl)boronic acid D, J 45 [00100] embedded image 3-cyclopropyl-4-(3- methyl-4- methylsulfonylphenyl)- 1H-indole-5- carbonitrile [M + H].sup.+ 351.2 3-cyclopropyl-4- (3-methyl-4- (methylsulfonyl) phenyl)-2- (trimethylsilyl)-1- ((2- (trimethylsilyl) ethoxy)methyl)-1H- indole-5- carbonitrile (Intermediate 37) and (3-methyl-4- (methylsulfonyl) phenyl)boronic acid D, J2 46 [00101] embedded image 3-cyclopropyl-4-(4- cyclopropylsulfonyl- 3-methyl-phenyl)-N- methyl-1H- pyrazolo[3,4- c]pyridine-5- carboxamide [M + H].sup.+ 411.2 4-bromo-3- cyclopropyl-N- methyl-1H- pyrazolo[3,4- c]pyridine-5- carboxamide (Intermediate 15) and 2-(4- (cyclopropylsul- fonyl)-3- methylphenyl)- 4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 18) D 47 [00102] embedded image 3-cyclopropyl-4-(2- fluoro-5-methyl-4- methylsulfonyl- phenyl)-1H- pyrazolo[3,4- c]pyridine-5- carbonitrile [M + H].sup.+ 371.0 4-bromo-3- cyclopropyl-1H- pyrazolo[3,4- c]pyridine-5- carbonitrile (Intermediate 5) and 2-(2-fluoro-5- methyl-4- methylsulfonyl- phenyl)-4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 25) D 48 [00103] embedded image 4-[3- (difluoromethoxy)- 1H-pyrazolo[4,3- c]pyridin-4-yl]-2- (difluoromethvl)- N,N-dimethyl- benzenesulfonamide [M + H].sup.+ 419.1 4-chloro-3- (difluoromethoxy)- 1-trityl- pyrazolo[4,3- c]pyridine (Intermediate 8) and 2- (difluoromethyl)- N,N-dimethyl-4- (4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)benzenesulfona- mide(Intermediate 38) D, H 49 [00104] embedded image 3- (difluoromethoxy)- 4-(3-methyl-4- (methylsulfonyl) phenyl)-5- (methylsulfonyl)- 1H-indazole [M + H].sup.+ 430.1 4-bromo-3- (difluoromethoxy)- 5- (methylsulfonyl)- 1-trityl-1H- indazole (Intermediate 16) and (3-methyl-4- (methylsulfonyl) phenyl)boronic acid D, H 50 [00105] 3-cyclopropyl-4-[4- (difluoromethyl- sulfonyl)-3-methyl- phenyl]-1H- pyrazolo[3,4- c]pyridine-5- carbonitrile [M + H].sup.+ 389.0 4-bromo-3- cyclopropyl-1H- pyrazolo[3,4- c]pyridine-5- carbonitrile (Intermediate 5) and -[4- (difluoromethyl- sulfonyl)-3-methyl- phenyl]-4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 27) D 51 [00106] embedded image 3-cyclopropyl-4-[3- (difluoromethyl)-4- methylsulfonyl- phenyl]-N-methyl- 1H-pyrazolo[3,4- c]pyridine-5- carboxamide [M + H].sup.+ 421.2 4-bromo-3- cyclopropyl-N- methyl-1H- pyrazolo[3,4- c]pyridine-5- carboxamide (Intermediate 15) and 2-(3- (difluoromethyl)- 4- (methylsulfonyl) phenyl)-4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 21) D 52 [00107] embedded image 3- (difluoromethoxy)- 4-(3-methyl-4- methylsulfonyl- phenyl)-1H- pyrazolo[3,4- c]pyridine-5- carbonitrile [M + H].sup.+ 379.1 4-bromo-3- (difluoromethoxy)- 1-trityl- pyrazolo[3,4- c]pyridine-5- carbonitrile (Intermediate 17) and (3-methyl-4- (methylsulfonyl) phenyl)boronic acid D, H 53 [00108] embedded image 3- (difluoromethoxy)- 4-[5- (difluoromethyl)-2- methyl-4- methylsulfinyl- phenyl]-1H- pyrazolo[3,4- c]pyridine-5- carbonitrile [M + H].sup.+ 413.1 4-bromo-3- (difluoromethoxy)- 1-trityl- pyrazolo[3,4- c]pyridine-5- carbonitrile (Intermediate 17) and 4-bromo-3- (difluoromethoxy)- 1-trityl- pyrazolo[3,4- c]pyridine-5- carbonitrile (Intermediate 35) D, H 54 [00109] embedded image 4-[3- (difluoromethyl)-4- methylsulfonyl- phenyl]-5-methoxy- 3-(trifluoromethyl)- 1H-pyrazolo[3,4- c]pyridine [M + H].sup.+ 422.2 4-bromo-5- methoxy-3- (trifluoromethyl)- 2-((2- (trimethylsilyl) ethoxy)methyl)-2H- pyrazolo[3,4- c]pyridine (Intermediate 11) 2-(3- (difluoromethyl)- 4- (methylsulfonyl) phenyl)-4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 21) D, J 55 [00110] embedded image 4-(4- cyclopropylsulfonyl- 3-methyl-phenyl)-3- (difluoromethoxy)- 5-methylsulfonyl- 1H-indazole [M + H].sup.+ 457.1 4-bromo-3- (difluoromethoxy)- 5- methylsulfonyl-1- trityl-indazole (Intermediate 36) and 2-(4- (cyclopropyl- sulfonyl)-3- methylphenyl)- 4,4,5,5- tetramethyl-1,3,2- dioxaborolane (Intermediate 18) D, J

Example 56: 3-bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine

[0632] ##STR00111##

[0633] Step 1: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

[0634] 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (CAS: 1416713-66-0, US2014/128374 A1) is reacted with (3-methyl-4-(methylsulfonyl)phenyl)boronic acid (1.1 eq) at 100° C. using General procedure D. ([M+H].sup.+372.2).

[0635] Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine

[0636] 4-(3-Methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (step 1) (40 mg, 0.1 mmol) was dissolved in dioxane/DCM (2.0/0.5 ml) and HCl (50 μL, 4 N in dioxane, 0.2 mmol) was added. The reaction was stirred for 16 h after which time it was washed with saturated aqueous sodium hydrogen carbonate, water, brine, dried (Na.sub.2SO.sub.4) and concentrated to afford the title compound (23 mg, 67%) as an off-white solid. ([M+H].sup.+288.1).

[0637] Step 3: 3-bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine

[0638] 4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine (step 2) (23 mg, 0.1 mmol) was suspended in DCM (1.5 ml) and N-bromosuccinimide (14 mg, 0.1 mmol) was added. The reaction was stirred for 2 h after which time it was concentrated to dryness. Flash column chromatography (Ethyl acetate: n-Heptane 4:6-1:0) afforded the title compound (185 mg, 71%) as a white solid. ([M+H, Br].sup.+366.1).

Example 57 & 58: 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridinepyridine & 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine

[0639] ##STR00112##

[0640] Step 1: 4-chloro-1,2-dihydro-3H-pyrazolo[4,3-c]pyridin-3-one

[0641] Ethyl 2-chloro-4-fluoronicotinate was reacted with hydrazine hydrate (1 eq) and triethylamine (1 eq) in ethanol at 80° C. in accordance with General procedure C to afford the title compound. ([M+H,Cl].sup.+170.0).

[0642] Step 2: 4-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-ol

[0643] 4-chloro-1,2-dihydro-3H-pyrazolo[4,3-c]pyridin-3-one (20 mg, 0.1 mmol) in DMF (1 mL) was added sodium hydride (6 mg, 60% dispersion in mineral oi1,0.1 mmol) and triphenylmethyl chloride (33 mg, 0.1 mmol) at 0° C. under nitrogen atmosphere. The cooling bath was removed and the reaction stirred for 2 h on reaching ambient temperature. The reaction was quenched by addition of saturated aqueous ammonium chloride, repeatedly extracted with ethyl acetate and the combined organic extracts washed with brine and concentrated. Flash column chromatography (Ethyl acetate: n-Heptane 1:1) afforded the title compound (19 mg, 37%) as a light yellow solid. ([M+H].sup.+412.3).

[0644] Step 3: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-ol

[0645] The title compound ([M+H].sup.+546.2) was prepared from Suzuki coupling of 4-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-ol (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 100° C. in accordance with General procedure D.

[0646] Step 4: 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine & 3-methoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine

[0647] To a mixture of 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-ol (step 3) (51 mg, 0.1 mmol) and potassium carbonate (39 mg, 0.3 mmol) in DMF (1.5 mL) was added methyl 2-chloro-2,2-difluoroacetate (20 μL, 0.2 mmol). The reaction was stirred in a sealed tube at 80° C. for 30 min. The reaction was diluted with ethyl acetate washed with water, brine, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (Ethyl acetate: n-Heptane 0:1-1:4) afforded the titled compounds as a mixture (4:1) (27 mg, 35%) as a white solid. ([M+H].sup.+596.3 & 560.3).

[0648] Step 5: 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridinepyridine & 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine

[0649] The mixture of 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine and 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (step 4) is deprotected using General procedure H to afford the titled compounds, separate by preparative reversed phase HPLC. ([M+H].sup.+354.1 & 318.2).

Example 59: 5-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-2-(methylsulfonyl)aniline

[0650] ##STR00113##

[0651] Step 1: 3-cyclopropyl-4-(3-fluoro-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine

[0652] The title compound ([M+H].sup.+332.1) was prepared from Suzuki coupling of 4-chloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 1) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with cesium carbonate at 100° C. in accordance with General procedure D.

[0653] Step 2: 5-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-2-(methylsulfonyl)aniline

[0654] In a pressure tube was added 3-cyclopropyl-4-(3-fluoro-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine (step 1) (30 mg, 0.1 mmol) was condensed ammonia (approx 3 mL) at −78° C. Then the tube was tightly closed and then allowed to warm up to ambient temperature and stirred for 8 days. Evaporation of the ammonia and flash column chromatography (Ethyl acetate: n-Heptane 1:1-1:0) afforded the titled compound (6 mg, 21%) as a white solid. ([M+H].sup.+329.1).

Example 60: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylsulfonyl)-1H-pyrazolo[4,3-c]pyridine

[0655] ##STR00114##

[0656] Step 1: 3-bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

[0657] To a mixture of 3-bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine (Product 56) (648 mg, 1.8 mmol) in THF (20 ml) was added 3,4-dihydro-2H-pyran (1.6 ml, 17.7 mmol) and p-toluenesulfonic acid monohydrate (34 mg, 0.2 mmol) and the reaction mixture was stirred at 70° C. for 36 h. after which time it was concentrated in vacuo. The residue was redissolved with ethyl acetate and washed with water, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (DCM: MeOH 1:0-9:1) afforded the titled compound (689 mg, 78%) as a yellow solid. ([M+H].sup.+452.1).

[0658] Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

[0659] 3-bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (step 1) (102 mg, 0.2 mmol) was dissolved in DMSO (2.5 ml). 2-methyl-2 thiopsuedourea sulfate (63 mg, 0.2 mmol) and cesium carbonate (295 mg, 0.9 mmol) were added. The reaction mixture was heated to 100° C. for 15 h. The reaction mixture was allowed to cool down to RT, then silica gel was added. The suspension was concentrated in high vacuo. The crude mixture was purified by flash column chromatography (Ethyl acetate: n-Heptane 0:1-1:0) to afford the title compound (40 mg, 42% yield) as a light yellow gum. ([M+H].sup.+418.1).

[0660] Step 3: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

[0661] 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (step 2) was oxidised to the title compound using General procedure G. ([M+H].sup.+450.2).

[0662] Step 4: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylsulfonyl)-1H-pyrazolo[4,3-c]pyridine

[0663] 4-(3-Methyl-4-(methylsulfonyl)phenyl)-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (Step 3) was deprotected using General procedure Ito afford the title compound. ([M+H].sup.+366.0).

Example 61: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile

[0664] ##STR00115##

[0665] Step 1: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile

[0666] 3-Bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 60, step 1) (40 mg, 0.1 mmol), zinc cyanide (10 mg, 0.1 mmol) and tetrakistriphenylphosphine palladium (15 mg, 0.01 mmol) were suspended in DMF (1 ml) at ambient temperature. The reaction mixture was heated to 150° C. for 0.5 h in a microwave reactor. Silica gel was added to the reaction mixture and concentrated. The crude mixture was purified by flash column chromatography (Ethyl acetate: n-Heptane 0:1-1:0) to afford the title compound (16 mg, 44% yield) as a yellow solid. ([M+H].sup.+397.2).

[0667] Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile

[0668] 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile (step 1) was deprotected using General procedure Ito afford the title compound. ([M+H].sup.+313.1).

Example 62: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid

[0669] ##STR00116##

[0670] 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (Example 16) (20 mg, 0.1 mmol) was suspended in aqueous sodium hydroxide solution (0.5 ml, 6 M, 3.0 mmol) an the mixture was heated to 100° C. for 16 h. The reaction was cooled to ambient temperature, acidified with 37% HCl and concentrated. Purification by reversed phase preparative HPLC afforded the title compound (8 mg, 36% yield) as a white solid. ([M+H]+372.2).

Example 63: 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile

[0671] ##STR00117##

[0672] Step 1: 2-bromo-3-(cyclopropyl(hydroxy)methyl)-4-fluorobenzonitrile

[0673] 2-bromo-4-fluorobenzonitrile is treated with with LDA (1.3 eq) for 10 minutes before addition of cyclopropanecarbaldehyde (1.4 eq) in accordance with General procedure A. .sup.1H NMR (CHLOROFORM-d, 300 MHz) δ 7.62 (dd, 1H, J=5.2, 8.7 Hz), 7.1-7.2 (m, 1H), 4.4-4.6 (m, 1H), 2.4-2.6 (m, 1H), 1.5-1.6 (m, 1H), 0.7-0.8 (m, 1H), 0.5-0.6 (m, 3H)

[0674] Step 2: 2-bromo-3-(cyclopropanecarbonyl)-4-fluorobenzonitrile

[0675] 2-Bromo-3-(cyclopropyl(hydroxy)methyl)-4-fluorobenzonitrile was oxidised using General procudure B1 to afford the title compound. 1H NMR (CHLOROFORM-d, 300 MHz) δ 7.7-7.8 (m, 1H), 7.2-7.3 (m, 1H), 2.24 (dtt, 1H, J=1.0, 4.5, 7.8 Hz), 1.4-1.5 (m, 2H), 1.2-1.3 (m, 2H)

[0676] Step 3: 3-(cyclopropanecarbonyl)-4-fluoro-2-(3-methyl-4-methylsulfonylphenyl)benzonitrile

[0677] The title compound ([M+H].sup.+358.2) was prepared from Suzuki coupling of 2-bromo-3-(cyclopropanecarbonyl)-4-fluorobenzonitrile (Step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 90° C. in accordance with General procedure D.

[0678] Step 4: 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile

[0679] 3-(cyclopropanecarbonyl)-4-fluoro-2-(3-methyl-4-methylsulfonylphenyl)benzonitrile (step 3) was reacted with hydrazine hydrate (5 eq) in THF at ambient temperature in accordance with General procedure C to afford the title compound. ([M+H].sup.+352.3).

Example 64: 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-ol

[0680] ##STR00118##

[0681] Step 1: 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine

[0682] A mixture of N-bromosuccinimide (109 mg, 0.6 mmol), 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine (Example 1) (100 mg, 0.3 mmol) in DMF (2 mL) was stirred at 80° C. for 24 h. The reaction was directly purified by preparative reversed phase HPLC afforded the title compound (30 mg, 24%) as a green solid. ([M+H, Br].sup.+405.8).

[0683] Step 2: 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-ol

[0684] To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo [4,3-c]pyridine (step 3) (60 mg, 0.2 mmol), potassium hydroxide (33 mg, 0.6 mmol), Pd.sub.2(dba)2 (5 mg, 0.03 mmol,), tBuXPhos (4 mg, 0.01 mmol, 0.060 eq) in dioxane (1.5 mL) and water (1 mL) and the mixture stirred at 90° C. for 1 h under nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by preparative reversed phase HPLC afforded the title compound (6 mg, 10%) as a yellow solid. ([M+H].sup.+343.9)

Example 65: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-c]pyridine

[0685] ##STR00119##

[0686] Step 1: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-c]pyridine

[0687] 3-bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 60, step 1) is reacted with thiophene-3-boronic acid using potassium carbonate as base at 90° C. in accordance with General procedure D. ([M+H].sup.+454.2).

[0688] Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-c]pyridine

[0689] 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-c]pyridine (step 1) was deprotected using General procedure I2 to afford the title compound. ([M+H].sup.+370.2).

Example 66: 3-ethoxy-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine

[0690] ##STR00120##

[0691] Step 1: 3-ethoxy-4-(3-methyl-4-methylsulfonyl-phenyl)-1-trityl-pyrazolo[4,3-c]pyridine

[0692] To a solution of 4-(3-methyl-4-methylsulfonyl-phenyl)-1-trityl-pyrazolo[4,3-c]pyridin-3-ol (Example 57, step 3) (100 mg, 0.2 mmol) in acetonitrile (2 mL) was added cesium carbonate (120 mg, 0.4 mmol) and iodoethane (0.04 mL, 0.6 mmol) and the reaction mixture was stirred at 80° C. for 2 h. The reaction was filtered and concentrated. Purification by preparative-TLC (heptane: ethyl acetate 3:1) to afford the title compound (60 mg, 54%) as a white solid. ([M+H].sup.+574.3).

[0693] Step 2: 3-ethoxy-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine

[0694] 3-Ethoxy-4-(3-methyl-4-methylsulfonyl-phenyl)-1-trityl-pyrazolo[4,3-c]pyridine is deprotected using General procedure H to afford the titled compound. ([M+H].sup.+332.1).

Example 67: 3-cyclopropyl-7-fluoro-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine

[0695] ##STR00121##

[0696] Step 1: 2-bromo-4-chloro-5-fluoro-3-pyridyl)-cyclopropyl-methanol

[0697] 2-bromo-4-chloro-5-fluoro-pyridine was reacted with LDA (1.2 eq) for 30 minutes before addition of cyclopropanecarbaldehyde (1.4 eq) in accordance with General procedure A. ([M+H, Br].sup.+280.0)

[0698] Step 2: 2-bromo-4-chloro-5-fluoro-3-pyridyl)-cyclopropyl-methanone

[0699] 2-bromo-4-chloro-5-fluoro-3-pyridyl)-cyclopropyl-methanol was oxidised using General procedure B1 to afford the title compound. ([M+H, Br].sup.+278.0)

[0700] Step 3: [4-chloro-5-fluoro-2-(3-methyl-4-methylsulfonyl-phenyl)-3-pyridyl]-cyclopropyl-methanone

[0701] The title compound ([M+H].sup.+368.1) was prepared from Suzuki coupling 2-bromo-4-chloro-5-fluoro-3-pyridyl)-cyclopropyl-methanone (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 100° C. in accordance with General procedure D.

[0702] Step 4: 3-cyclopropyl-7-fluoro-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine

[0703] 4-chloro-5-fluoro-2-(3-methyl-4-methylsulfonyl-phenyl)-3-pyridyl]-cyclopropyl-methanone (step 3) was reacted with hydrazine hydrate (5 eq) in dioxane at 60° C. in accordance with General procedure C to afford the title compound. ([M+H].sup.+346.1).

Example 68 & 69: 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile & 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile

[0704] ##STR00122##

[0705] Step 1: ethyl 2-bromo-3-cyano-6-fluorobenzoate

[0706] 2-Bromo-4-fluorobenzonitrile was deprotonated with LDA (1.2 eq) for 0.5 h and reacted with ethyl chloroformate (1.2 eq) for 0.5 h in accordance with General procedure A to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.21 (dd, J=8.86, 5.64 Hz, 1 H) 7.70 (t, J=8.76 Hz, 1 H) 4.44 (q, J=7.05 Hz, 2 H) 1.34 (t, J=7.05 Hz, 3 H).

[0707] Step 2: 4-bromo-3-oxo-2,3-dihydro-1H-indazole-5-carbonitrile

[0708] Ethyl 2-bromo-3-cyano-6-fluorobenzoate (Step 1) was reacted with hydrazine hydrate (1 eq) and triethylamine (1 eq) in ethanol at 80° C. in accordance with General procedure C to afford the title compound. ([M+H, Br].sup.+240.0).

[0709] Step 3: 4-bromo-3-hydroxy-1-trityl-1H-indazole-5-carbonitrile

[0710] 4-bromo-3-oxo-2,3-dihydro-1H-indazole-5-carbonitrile (step 2) (180 mg, 0.8 mmol) in DMF (5 mL) was added sodium hydride (36 mg, 60% dispersion in mineral oil, 0.9 mmol) and triphenylmethyl chloride (232 mg, 0.8 mmol) at 0° C. under nitrogen atmosphere. The cooling bath was removed and the reaction stirred for 2 h on reaching ambient temperature. The reaction was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, brine, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (Ethyl acetate: n-Heptane 0:1-1:1) afforded the title compound (136 mg, 36%) as a white solid. ([M+Na].sup.+502.1).

[0711] Step 4: 3-hydroxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile

[0712] The title compound ([M−H].sup.−568.4) was prepared from Suzuki coupling of 4-bromo-3-hydroxy-1-trityl-1H-indazole-5-carbonitrile (step 3) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with cesium carbonate at 100° C. in accordance with General procedure D. Step 5: 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile & 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile

[0713] To a mixture of 3-hydroxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile (step 3) (49 mg, 0.1 mmol) and potassium carbonate (48 mg, 0.3 mmol) in DMF (1 mL) was added methyl 2-chloro-2,2-difluoroacetate (20 μL, 0.2 mmol). The reaction was stirred in a sealed tube at 80° C. for 50 min. The reaction was diluted with ethyl acerate washed with water, brine, dried (Na.sub.2SO.sub.4) and concentrated to afford the 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile & 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile as a crude mixture used directly.

[0714] The mixture of 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile & 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile (step 4) is deprotected using General procedure H to afford the titled compounds, separated by preparative reversed phase HPLC. ([M+H].sup.+342.2 & 378.2).

Example 70: 3-cyclopropyl-6-methoxy-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine

[0715] ##STR00123##

[0716] Step 1: cyclopropyl(2,4,6-trichloropyridin-3-yl)methanone

[0717] 2,4,6-Trichloropyridine was deprotonated with LDA (0.9 eq) for 1 h and reacted with cyclopropanecarbaldehyde (1.2 eq) for 1.5 h in accordance with General procedure A to afford crude cyclopropyl(2,4,6-trichloropyridin-3-yl)methanol which was directly oxidised was oxidised using General procedure B1 to afford the title compound. ([M+H, Cl].sup.+250.1)

[0718] Step 2: 4,6-dichloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine

[0719] Cyclopropyl(2,4,6-trichloropyridin-3-yl)methanone (step 1) was reacted with hydrazine hydrate (5 eq) in ethanol at ambient temperature in accordance with General procedure C to afford the title compound. ([M+H, Cl].sup.+228.1).

[0720] Step 3: 3-cyclopropyl-6-methoxy-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine

[0721] The title compound ([M+H, Cl].sup.+362.3) was prepared from Suzuki coupling of 4,6-dichloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 100° C. in accordance with General procedure D.

[0722] Step 4: 6-chloro-3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine

[0723] 6-chloro-3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine (step 3) (50 mg, 0.1 mmol) was SEM-protected using General procedure E2. The crude product was dissolved in 2 M sodium methoxide in MeOH (2 mL) and the reaction heated in a microwave to 130° C. for 30 minutes. The reaction mixture was concentrated, redissolved in trifluoroacetic acid (1 mL), ethylenediamine (0.1 ml, 1.4 mmol) was added and the mixture stirred for 1 h. The reaction was concentrated, the residue purified by reversed phase chromatography to afford the title compound (3 mg, 5%) as a white solid. ([M+H].sup.+358.2).

Example 71: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-c]pyridine

[0724] ##STR00124##

[0725] Step 1: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine

[0726] To a mixture of 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-ol (Example 57, step 3) (45 mg, 0.1 mmol) and potassium carbonate (35 mg, 0.3 mmol) in DMF (0.8 mL) was added 1-(trifluoromethyl)-113-benzo[d][1,2]iodaoxol-3(1H)-one (40 mg, 0.3 mmol). The reaction at ambient temperature for 16 h after which time a second portion of potassium carbonate (35 mg, 0.3 mmol) and 1-(trifluoromethyl)-113-benzo[d][1,2]iodaoxol-3(1H)-one (40 mg, 0.3 mmol) was added and the mixture stirred for a further 16 h. The reaction was diluted with ethyl acetate, washed with water, brine, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (Ethyl acetate: n-Heptane 0:1-1:4) afforded the titled compound (12 mg, 22%) as a colourless gum. ([M+H].sup.+614.4).

[0727] Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-c]pyridine

[0728] 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine (step 1) is deprotected using General procedure H to afford the title compound. ([M+H].sup.+372.2).

Example 72: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0729] ##STR00125##

[0730] Step 1: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid

[0731] To a solution of 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 62) (147 mg, 0.4 mmol) in dichloromethane (4 ml) was added 3,4-dihydro-2H-pyran (73 μl, 0.8 mmol) and p-toluenesulfonic acid monohydrate (15 mg, 0.1 mmol) and the reaction stirred for 7 h. Concentration of the reaction afforded the crude title compound (181 mg, quant) as a brown foam. ([M+H].sup.+456.3).

[0732] Step 2: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0733] To 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (45 mg, 0.1 mmol) in DMF (1 ml) was added TBTU (48 mg, 0.2 mmol) followed by triethylamine (41 μL, 0.3 mmol). After 0.5 h ammonium hydroxide (39 μL, 1 mmol) was added and the mixture stirred for 30 min. The reaction was concentrated, redissolved in HCl (0.5 ml, 4 N in dioxane, 2 mmol) and the reaction stirred for 6 h at 50° C. after which time the reaction was again concentrated to dryness. Purification by reversed phase HPLC afforded the title compound (3 mg, 8%) as an off-white solid. ([M+H].sup.+371.3).

Example 73: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0734] ##STR00126##

[0735] The title compound ([M+H].sup.+385.3) was prepared in analogy to Example 72 from 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 72, step 1) and methylamine hydrochloride.

Example 74: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyridazine

[0736] ##STR00127##

[0737] Step 1: methyl 3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylate

[0738] To a solution of methyl 3-cyclopropyl-1H-pyrazole-5-carboxylate (300 mg, 1.8 mmol) in dichloromethane (5 ml) was added 3,4-dihydro-2H-pyran (197 μl, 2.2 mmol) and p-toluenesulfonic acid monohydrate (35 mg, 0.2 mmol) and the reaction stirred for 1 h.

[0739] Concentration of the reaction and flash column chromatography (Heptane: ethyl acetate 3:7) afforded the title compound (374 mg, 82%) as a colourless oil. ([M+H].sup.+251.1).

[0740] Step 2: (3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methanol

[0741] To a solution of methyl 3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylate (step 1) (1.1 g, 4.6 mmol) in THF (34 ml) cooled to −78° C. under argon was added diisobutylaluminium hydride (9.11 ml, 1 M in THF, 9.1 mmol) and the mixture was stirred at this temperature for 30 min before coming to ambient temperature. The reaction was cooled again to −78° C. and water (0.3 ml) was added and the reaction again returned to ambient temperature, addition of Na.sub.2SO.sub.4 followed by filtration and concentrate afforded the title compound (670 mg, 63%) as a white solid. ([M+H].sup.+223.2).

[0742] Step 3: 3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole

[0743] To a solution of (3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methanol (step 2) (300 mg, 1.4 mmol) in DCM (5 ml) was added 3,4-dihydro-2H-pyran (136 μl, 1.6 mmol) and p-toluenesulfonic acid monohydrate (26 mg, 0.1 mmol) and the reaction stirred for 16 h. Addition of a few drops of triethylamine, concentration of the reaction and flash column chromatography (Heptane: ethyl acetate 1:1) afforded the title compound (354 mg, 66%) as a light yellow oil. ([M+H].sup.+307.1).

[0744] Step 4: 3-cyclopropyl-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole

[0745] To a solution of 3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole (step 3) (402 mg, 1.3 mmol) in dichloromethane (2.5 ml) was added N-iodosuccinimide (413 mg, 1.8 mmol) and the reaction was stirred at ambient temperature for 20 h. The reaction was diluted with dichloromethane, washed with 10% aqueous sodium thiosulfate, water, brine, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (Ethyl acetate: n-Heptane 1:3) afforded the titled compound (400 mg, 68%) as a light yellow oil. ([M+H].sup.+433.1).

[0746] Step 5: (3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanol

[0747] To an ice cold solution of 3-cyclopropyl-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole (step 4) (50 mg, 0.1 mmol) in THF (0.2 ml) under argon atmosphere was added isopropylmagnesium chloride-lithium chloride complex (98 μl, 1.3 M in THF, 0.1 mmol. The reaction was warmed to ambient temperature for 5 min and then cooled back down to 0° C. before quenching with a solution of 3-methyl (methylsulfonyl)benzaldehyde (28 mg, 0.1 mmol) dissolved in THF (0.1 ml) and the reaction subsequently stirred at ambient temperature for 30 minutes. The reaction was diluted with ethyl acetate, washed with saturated ammonium chloride, water, brine, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (Ethyl acetate: n-Heptane 1:9-4:1) afforded the titled compound (40 mg, 62%) as an off-white solid. ([M+H].sup.+505.4).

[0748] Step 6: (3-cyclopropyl-5-(hydroxymethyl)-1H-pyrazol-4-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanol

[0749] (3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanol (step 5) (41 mg, 0.1 mmol) was dissolved in HCl (1.0 ml, 4 N in dioxane, 4.1 mmol) and water (15 μl, 0.1 mmol) added. The reaction mixture was subsequently stirred at 45° C. for 5 min after which time it was concentrated to afford the crude title compound (40 mg, quant) as a light yellow gum. ([M+H].sup.+337.2).

[0750] Step 7: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyridazine

[0751] To a solution of (3-cyclopropyl-5-(hydroxymethyl)-1H-pyrazol-4-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanol (step 6) (30 mg, 0.1 mmol) in dichloromethane (0.4 ml) was added Dess-Martin periodinane (76 mg, 0.2 mmol) and the mixture was stirred at ambient temperature for 10 min. Hydrazine monohydrate (48 μl, 0.5 mmol) was then added and the reaction stirred for a further 16 h. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate, water, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (DCM: MeOH 1:0-1:9) afforded the title compound (3 mg, 9%) as a light yellow solid. ([M+H].sup.+329.2).

Example 75: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1H-indazole

[0752] ##STR00128##

[0753] Step 1: (2-bromo-6-fluoro-3-(methylthio)phenyl)(cyclopropyl)methanol

[0754] (2-bromo-4-fluorophenyl)(methyl)sulfane was reacted with LDA (1.1 eq) for 1 h before addition of cyclopropanecarbaldehyde (1.2 eq) in accordance with General procedure A. 1H NMR (300 MHz, DMSO-d6) δ ppm 6.98-7.11 (m, 1 H) 6.91-6.98 (m, 1 H) 5.25 (d, J=4.63 Hz, 1 H) 4.15 (ddd, J=8.66, 4.53, 1.31 Hz, 1 H) 2.24 (s, 3 H) 1.16-1.35 (m, 1 H) , 0.11-0.49 (m, 4 H)

[0755] Step 2: (2-bromo-6-fluoro-3-(methylthio)phenyl)(cyclopropyl)methanone

[0756] (2-bromo-6-fluoro-3-(methylthio)phenyl)(cyclopropyl)methanol (step 1) was oxidised using General procedure B1 to afford the title compound. ([M+H, Br].sup.+291.0)

[0757] Step 3: cyclopropyl(3-fluoro-3′-methyl-4′-(methylsulfonyl)-6-(methylthio)-[1,1′-biphenyl]-2-yl)methanone

[0758] The title compound ([M+H].sup.+379.2) was prepared from Suzuki coupling of 4,6-dichloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with cesium carbonate at 100° C. in accordance with General procedure D.

[0759] Step 4: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1H-indazole

[0760] Cyclopropyl(3-fluoro-3′-methyl-4′-(methylsulfonyl)-6-(methylthio)-[1,1′-biphenyl]-2-yl)methanone (step 2) was reacted with hydrazine hydrate (15 eq) in ethanol at150° C. (microwave) in accordance with General procedure C to afford the title compound. ([M+H].sup.+373.2).

Example 76: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfinyl)-1H-indazole

[0761] ##STR00129##

[0762] To an ice-cold solution of 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1H-indazole (Example 74) (23 mg, 0.1 mmol) in DCM (1 ml) was added a solution of m-chloroperbenzoic acid (124 μl, 0.5 M in DCM, 0.1 mmol) and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with DCM and washed with saturated aqueous sodium hydrogen carbonate, water, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (DCM: MeOH 1:0-1:9) afforded the title compound (15 mg, 59%) as a white solid. ([M+H].sup.+389.2).

Example 77: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole

[0763] ##STR00130##

[0764] To an ice-cold solution of 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1H-indazole (Example 74) (26 mg, 0.1 mmol) in DCM (1 ml) was added a solution of m-chlorperbenzoic acid (263 μl, 0.5 M in DCM, 0.1 mmol) and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with DCM and washed with saturated aqueous sodium hydrogen carbonate, water, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (DCM: MeOH 1:0-1:9) afforded the title compound (18 mg, 61%) as a white solid. ([M+H].sup.+405.2).

Example 78: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one

[0765] ##STR00131##

[0766] Step 1: 3-iodo-5-methoxy-1-trityl-pyrazolo[4,3-b]pyridine

[0767] To an ice cold solution of 3-iodo-5-methoxy-1H-pyrazolo[4,3-b]pyridine (WO2018/11628 A1) (1.0 g, 3.6 mmol) in DMF (20 mL) under argon atmosphere was added triphenylmethyl chloride (12.2 g, 4.4 mmol) and sodium hydride (175 mg, 60% dispersion in mineral oil, 4.4 mmol) and the reaction mixture was warmed to ambient temperature and stirred for 3 h. The reaction was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, brine, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (Ethyl acetate: n-Heptane 1:10) afforded the title compound (0.9 g, 46%) as a white solid. ([M+Na].sup.+518.0).

[0768] Step 2: 5-methoxy-1-trityl-pyrazolo[4,3-b]pyridin-3-ol

[0769] A mixture of 3-iodo-5-methoxy-1-trityl-pyrazolo[4,3-b]pyridine (step 1) (50 mg, 0.1 mmol), potassium hydroxide (16 mg, 0.3 mmol), t-BuBrettPhos (8 mg, 0.02 mmol,), t-BuBrettPhos Pd G3 (10 mg, 0.02 mmol) in dioxane (2 mL) and water (0.5 mL) was stirred at 80° C. for 18 h under nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by reversed phase preparative HPLC afforded the title compound (20 mg, 51%) as a white solid. ([M+Na].sup.+408.1)

[0770] Step 3: 3-(difluoromethoxy)-5-methoxy-1-trityl-pyrazolo[4,3-b]pyridine

[0771] A suspension of 5-methoxy-1-trityl-pyrazolo[4,3-b]pyridin-3-ol (step 2) (400 mg, 1.0 mmol), sodium 2-chloro-2,2-difluoroacetate (224 mg, 1.5 mmol), cesium carbonate (640 mg, 2.0 mmol) in acetonitrile (20 mL) was stirred at 50° C. for 2 h. The reaction mixture was filtered and concentrated.

[0772] Purification by reversed phase preparative HPLC afforded the title compound (400 mg, 89%) as a yellow solid. ([M+H].sup.+458.1)

[0773] Step 4: 3-(difluoromethoxy)-1,3a,4,7a-tetrahydropyrazolo[4,3-b]pyridin-5-one

[0774] 3-(difluoromethoxy)-5-methoxy-1-trityl-pyrazolo[4,3-b]pyridine (step 3) (300 mg, 0.7 mmol) was dissolved HCl (15 mL, 4N in dioxane, 60 mmol) and stirred at 80° C. for 3 h. The reaction mixture was concentrated to dryness and purified by reversed phase preparative HPLC to afford the title compound (100 mg, 75%) as a grey solid. ([M+H].sup.+202.1)

[0775] Step 5: 3-(difluoromethoxy)-1-tetrahydropyran-2-yl-4H-pyrazolo[4,3-b]pyridin-5-one

[0776] A mixture of 3-(difluoromethoxy)-1,4-dihydropyrazolo[4,3-b]pyridin-5-one (200 mg, 1.0 mmol), 3,4-dihydro-2H-pyran (0.14 mL, 1.5 mmol), p-toluenesulfonic acid monohydrate (86 mg, 0.5 mmol) in THF (5 mL) was stirred at 60° C. for 12 h after which time the reaction was concentrated. Purification by reversed phase preparative HPLC to afford the title compound (150 mg, 52%) as a white solid. ([M+H].sup.+286.0)

[0777] Step 6: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one

[0778] To a solution of 3-(difluoromethoxy)-1-tetrahydropyran-2-yl-4H-pyrazolo[4,3-b]pyridin-5-one (step 5) (100 mg, 0.4 mmol) in dichloromethane (3 mL) was added (3-methyl-4-methylsulfonyl-phenyl)boronic acid (150 mg, 0.7 mmol), pyridine (0.06 mL, 0.7 mmol), triethylamine (0.1 mL, 0.7 mmol) and copper (II) acetate (128 mg, 0.7 mmol) and the reaction was stirred at ambient temperature under air. After 12 h a further portion of (3-methyl-4-methylsulfonyl-phenyl)boronic acid (150 mg, 0.7 mmol) and triethylamine (0.1 mL, 0.7 mmol) was added and the mixture stirred for a further 16 h before the reaction was diluted with ethyl acetate, washed with water, brine, dried (Na.sub.2SO.sub.4) and concentrated. Preparative reversed phase HPLC afforded the title compound (70 mg, 44%) as a brown solid. ([M+H].sup.+454.1).

[0779] Step 5: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one

[0780] 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one (step 4) was deprotected using General procedure I1 to afford the title compound. ([M+H].sup.+370.1).

Example 79: 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-5-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridine

[0781] ##STR00132##

[0782] Step 1: (3-bromo-5-fluoro-2-(trifluoromethyl)pyridin-4-yl)(cyclopropyl)methanone

[0783] 3-bromo-5-fluoro-2-(trifluoromethyl)pyridine was reacted with LDA (1.1 eq) for 1 h before addition of cyclopropanecarbaldehyde (1.2 eq) in accordance with General procedure A to afford crude (3-bromo-5-fluoro-2-(trifluoromethyl)pyridin-4-yl)(cyclopropyl)methanol which was directly oxidised using General procedure B1 to afford the title compound. ([M+H, Br].sup.+312.1)

[0784] Step 2: cyclopropyl(5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)pyridin-4-yl)methanone

[0785] The title compound ([M+H].sup.+402.2) was prepared from Suzuki coupling of (3-bromo-5-fluoro-2-(trifluoromethyl)pyridin-4-yl)(cyclopropyl)methanone (step 1) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 100° C. in accordance with General procedure D.

[0786] Step 3: 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-5-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridine

[0787] 3 cyclopropyl(5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)pyridin-4-yl)methanone (step 2) was reacted with hydrazine hydrate (5 eq) in THF at ambient temperature in accordance with General procedure C to afford the title compound. ([M+H].sup.+396.2).

Example 80: 3-cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one

[0788] ##STR00133##

[0789] Step 1: 3-iodo-5-methoxy-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine

[0790] To solution of 3-iodo-5-methoxy-1H-pyrazolo[4,3-b]pyridine (WO2018/11628 A1) (1.6 g, 5.8 mmol) in dichloromethane (40 mL) was added 3,4-dihydro-2H-pyran (3.0 g, 35.6 mmol) and p-toluenesulfonic acid monohydrate (100.0 mg, 0.6 mmol) and the mixture was stirred at ambient temperature for 15 h. The reaction was diluted with DCM, washed with saturated aqueous sodium hydrogen carbonate, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (heptane: ethyl acetate 7:3) afforded the title compound (1.8 g, 82%) as a brown viscous oil. ([M+H].sup.+359.9).

[0791] Step 2: 3-cyclopropyl-5-methoxy-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine

[0792] The title compound ([M+H].sup.+274.0) was prepared from Suzuki coupling of 3-iodo-5-methoxy-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine (step 1) and cyclopropylboronic acid (8 eq) with potassium carbonate (4 eq) at 100° C. in accordance with General procedure D.

[0793] Step 3: 3-cyclopropyl-1-tetrahydropyran-2-yl-4H-pyrazolo[4,3-b]pyridin-5-one

[0794] To 3-cyclopropyl-5-methoxy-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine (step 2) (270 mg, 1.0 mmol) was dissolved in HCl (30 mL, 4N in dioxane, 120 mmol) and heated to 100° C. for 15 h. The mixture was concentrated and the residue redissolved in in DCM (9 mL) and DMF (3 mL). 4-dihydro-2H-pyran (80 mg, 1.0 mmol) and p-toluenesulfonic acid monohydrate (50 mg, 0.3 mmol) and the reaction stirred for 16 h. A second portion of 4-dihydro-2H-pyran (80 mg, 1.0 mmol) was added and the reaction stirred for a further 12 h. The reaction was diluted with DCM, washed with saturated aqueous sodium hydrogen carbonate, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (Ethyl acetate) afforded the title compound (170 mg, 62%) as a colourless viscous oil. ([M+H].sup.+260.3).

[0795] Step 4: 13-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one

[0796] To a solution of 3-(difluoromethoxy)-1-tetrahydropyran-2-yl-4H-pyrazolo[4,3-b]pyridin-5-one (step 3) (100 mg, 0.4 mmol) in DCM (3 mL) was added (3-methyl-4-methylsulfonyl-phenyl)boronic acid (150 mg, 0.7 mmol), pyridine (0.06 mL, 0.7 mmol), triethylamine (0.1 mL, 0.7 mmol) and copper (II) acetate (128 mg, 0.7 mmol) and the reaction was stirred at ambient temperature under air. After 12 h a further portion of (3-methyl-4-methylsulfonyl-phenyl)boronic acid (150 mg, 0.7 mmol) and triethylamine (0.1 mL, 0.7 mmol) was added and the mixture stirred for a further 16 h before a further portion of (3-methyl-4-methylsulfonyl-phenyl)boronic acid (150 mg, 0.7 mmol) and triethylamine (0.1 mL, 0.7 mmol) was added and the mixture stirred for a further 16 h the reaction was diluted with ethyl acetate, washed with water, brine, dried (Na.sub.2SO.sub.4) and concentrated. Purification by preparative TLC (ethyl acetate) afforded the title compound (90 mg, 50%) as a brown gum. ([M+H].sup.+428.1).

[0797] Step 5: 6-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one

[0798] To a solution of 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one (50 mg, 0.09 mmol) (step 4) in DMF (2.5 mL) was added N-bromosuccinimide (33 mg, 0.2 mmol). The reaction was stirred for 24 h after which time it was reaction was diluted with ethyl acetate, washed with water, brine, dried (Na.sub.2SO.sub.4) and concentrated. Purification by preparative TLC (heptane: ethyl acetate 1:1) afforded the title compound (40 mg, 68%) as a white solid. ([M+H, Br].sup.+506.0).

[0799] Step 6: 3-cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one

[0800] The title compound ([M+H]+422.1) was prepared from Suzuki coupling of 6-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one (step 5) and trimethylboroxine with potassium carbonate at 100° C. in accordance with General procedure D.

[0801] Step 7: 3-cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one

[0802] 3-cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one (Step 6) was deprotected using General procedure I1 to afford the title compound. ([M+H].sup.+358.1).

Example 81: 3,6-dicyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one

[0803] ##STR00134##

[0804] Step 1: 3,6-dicyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one

[0805] The title compound ([M+H].sup.+468.1) was prepared from Suzuki coupling of 6-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one (Example 81, step 5) and cyclopropylboronic acid (10eq) with potassium carbonate (4 eq) at 100° C. in accordance with General procedure D.

[0806] Step 2: 3-cyclopropyl-5-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine

[0807] 3,6-Dicyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one was deprotected using General procedure I1 to afford the title compound. ([M+H].sup.+384.2).

Example 82: 3-cyclopropyl-5-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine

[0808] ##STR00135##

[0809] Step 1: (3-bromo-2-(difluoromethoxy)-5-fluoropyridin-4-yl)(cyclopropyl)methanol

[0810] 3-bromo-2-(difluoromethoxy)-5-fluoropyridine was reacted with LDA (1.2 eq) for 1 h before addition of cyclopropanecarbaldehyde (3 eq) in accordance with General procedure A to afford the title compound. ([M+H, Br].sup.+312.1).

[0811] Step 2: (3-bromo-2-(difluoromethoxy)-5-fluoropyridin-4-yl)(cyclopropyl)methanone

[0812] (3-bromo-2-(difluoromethoxy)-5-fluoropyridin-4-yl)(cyclopropyl)methanol (step 1) was directly oxidised using General procedure B1 to afford the title compound. 1H NMR (CHLOROFORM-d, 300 MHz) δ 8.06 (s, 1H), 7.61 (s, 0.25 H), 7.37 (s, 0.5 H), 7.13 (s, 0.25 H), 2.23 (tt, 1H, J=4.2, 7.9 Hz), 1.4-1.5 (m, 2H), 1.24 (qd, 2H, J=3.8, 7.7 Hz)

[0813] Step 3: cyclopropyl(2-(difluoromethoxy)-5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)pyridin-4-yl)methanone

[0814] The title compound ([M+H].sup.+400.3) was prepared from Suzuki coupling of (3-bromo-2-(difluoromethoxy)-5-fluoropyridin-4-yl)(cyclopropyl)methanone (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 90° C. in accordance with General procedure D.

[0815] Step 4: 3-cyclopropyl-5-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine

[0816] Cyclopropyl(2-(difluoromethoxy)-5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)pyridin-4-yl)methanone (step 3) was reacted with hydrazine hydrate (5 eq) in THF at ambient temperature in accordance with General procedure C to afford the title compound. ([M+H].sup.+394.4).

Example 83: 3-cyclopropyl-N,N-dimethyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0817] ##STR00136##

[0818] The title compound ([M+H].sup.+399.3) was prepared in analogy to Exampe 72 from 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 72, step 1) and dimethylamine hydrochloride.

Example 84: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0819] ##STR00137##

[0820] The title compound ([M+H].sup.+425.4) was prepared in analogy to Exampe 72 from3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 72, step 1) and 3-oxetanamine.

Example 85: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0821] ##STR00138##

[0822] Step 1: 3-chloro-2-cyclopropyl-5-fluoropyridine

[0823] 2-bromo-3-chloro-5-fluoropyridine (300 mg, 1.4 mmol) , potassium cyclopropyltrifluoroborate (232 mg, 1.6 mmol), palladium (II) acetate (6 mg, 29 μmol,) and butyldi-1-adamantylphosphine (31 mg, 86 μmol) and cesium carbonate (1.4 g, 4.3 mmol) in a mixture of toluene (10 ml) and water (1.5 ml) was evacuated and sparged with argon. The reaction mixture was stirred for 2 h at 80° C. The reaction mixture was directly filtered over Dicalite®, washed with ethyl acetate and concentrated. Flash column chromatography (Ethyl acetate: n-Heptane 1:9) afforded the title compound (81 mg, 31%) as a colourless oil. ([M+H].sup.+172.0).

[0824] Step 2: (3-chloro-2-cyclopropyl-5-fluoropyridin-4-yl)(cyclopropyl)methanone 3-chloro-2-cyclopropyl-5-fluoropyridine was reacted with LDA (1.1 eq) for 1 h before addition of cyclopropanecarbaldehyde (1.2 eq) in accordance with General procedure A to afford crude (3-bromo-5-fluoro-2-(trifluoromethyl)pyridin-4-yl)(cyclopropyl)methanol which was directly oxidised using General procedure B 1 to afford the title compound. ([M+H, Cl].sup.+240.1)

[0825] Step 3: cyclopropyl(2-cyclopropyl-5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)pyridin-4-yl)methanone

[0826] The title compound ([M+H].sup.+374.2) was prepared from Suzuki coupling of (3-bromo-2 (3-chloro-2-cyclopropyl-5-fluoropyridin-4-yl)(cyclopropyl)methanone (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 120° C. in accordance with General procedure D.

[0827] Step 4: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0828] Cyclopropyl(2-cyclopropyl-5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)pyridin-4-yl)methanone (step 3) was reacted with hydrazine hydrate (100 eq) in THF at 170° C. (microwave) in accordance with General procedure C to afford the title compound. ([M+H].sup.+368.2).

Example 86: N,3-dicyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0829] ##STR00139##

[0830] The title compound ([M+H].sup.+425.4) was prepared in analogy to Example 72 from3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 72, step 1) and cyclopropylamine.

Example 87: 3-cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carboxamide

[0831] ##STR00140##

[0832] Step 1: 6-chloro-2,4-difluoro-3-(triethylsilyl)benzonitrile

[0833] To a solution of 2-chloro-4,6-difluorobenzonitrile (100 mg, 0.6 mmol) dissolved in THF (2 ml) under Ar and cooled to −78° C. was added LDA (0.3 ml, 0.7 mmol) and the mixture stirred for 5 min after which time chlorotrimethylsilane (0.1 ml, 0.6 mmol) was added and the reaction stirred for a further 30 min. The reaction was quenched by addition of saturated aqueous ammonium chloride, allowed to reach ambient temperature, extracted with ethyl acetate, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (heptane) afforded the title compound (127 mg, 73%) as a colourless oil. 1H NMR (CHLOROFORM-d, 300 MHz) δ 7.03 (dd, 1H, J=1.4, 8.1 Hz), 0.9-1.0 (m, 15H)

[0834] Step 2: 2-chloro-3-(cyclopropyl(hydroxy)methyl)-4,6-difluoro-5-(triethylsilyl)benzonitrile

[0835] 6-chloro-2,4-difluoro-3-(triethylsilyl)benzonitrile (step 1) was reacted with LDA (1.2 eq) for 0.25 h before addition of cyclopropanecarbaldehyde (1.3 eq) in accordance with General procedure A to afford the title compound. ([M+H, Cl].sup.+381.2).

[0836] Step 3: 2-chloro-3-(cyclopropanecarbonyl)-4,6-difluoro-5-(triethylsilyl)benzonitrile

[0837] 2-Chloro-3-(cyclopropyl(hydroxy)methyl)-4,6-difluoro-5-(triethylsilyl)benzonitrile (step 2) was oxidised using General procedure B1 to afford the title compound. 1H NMR (CHLOROFORM-d, 300 MHz) δ 2.22 (dtt, 1H, J=1.3, 4.5, 7.8 Hz), 1.37 (t, 2H, J=3.9 Hz), 1.1-1.2 (m, 2H), 0.9-1.0 (m, 15H)

[0838] Step 4: 6-(cyclopropanecarbonyl)-3,5-difluoro-3′-methyl-4′-(methylsulfonyl)-[1,1′-biphenyl]-2-carbonitrile

[0839] The title compound ([M+H].sup.+376.4) was prepared from Suzuki coupling of 2-chloro-3-(cyclopropanecarbonyl)-4,6-difluoro-5-(triethylsilyl)benzonitrile (step 3) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 120° C. in accordance with General procedure D.

[0840] Step 5: 3-cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carboxamide

[0841] 6-(cyclopropanecarbonyl)-3,5-difluoro-3′-methyl-4′-(methylsulfonyl)-[1,1′-biphenyl]-2-carbonitrile (step 4) was reacted with hydrazine hydrate (2 eq) in THF at ambient temperature in accordance with General procedure C to afford the title compound. ([M+H].sup.+370.2).

Example 88 & 89: 3-cyclopropyl-6-fluoro-N-methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carboxamide & 3-cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0842] ##STR00141##

[0843] 3-Cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile (Example 87) (20 mg, 54 μmol) was suspended in sodium hydroxide (3 ml, 3M in water, 9 mmol) and heated to 150° C. in a microwave for 4.5 h. The reaction was acidified with 6 N hydrochloric acid and extracted with ethyl acetate, the combined organic was dried (Na.sub.2SO.sub.4) and concentrated to afford crude mixture (1:1) of 3-cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide and 3-cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid. Reaction with methylamine hydrochloride prepared in analogy to Example 72 followed by reversed phase preparative HPLC afforded the two title compounds. ([M+H].sup.+402.3 & 388.2).

Example 90: 6-chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile

[0844] ##STR00142##

[0845] Step 1: 2,6-dichloro-3-(cyclopropyl(hydroxy)methyl)-4-fluorobenzonitrile

[0846] 2,6-dichloro-4-fluorobenzonitrile was reacted with LDA (1.0 eq) for 1 h before addition of cyclopropanecarbaldehyde (1.2 eq) in accordance with General procedure A to afford the title compound. ([M−H.sub.2O, 2Cl].sup.+242.1).

[0847] Step 2: 2,6-dichloro-3-(cyclopropanecarbonyl)-4-fluorobenzonitrile

[0848] 2,6-dichloro-3-(cyclopropyl(hydroxy)methyl)-4-fluorobenzonitrile (step 1) was oxidised using General procedure B1 to afford the title compound. ([M+H, 2Cl].sup.+258.1).

[0849] Step 3: 3-chloro-6-(cyclopropanecarbonyl)-5-fluoro-3′-methyl-4′-(methylsulfonyl)-[1,1′-biphenyl]-2-carbonitrile

[0850] The title compound ([M+H,Cl].sup.+392.2) was prepared from Suzuki coupling of 2-chloro-32,6-dichloro-3-(cyclopropanecarbonyl)-4-fluorobenzonitrile (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with cesium carbonate at 100° C. in accordance with General procedure D.

[0851] Step 4: 6-chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile

[0852] 3-chloro-6-(cyclopropanecarbonyl)-5-fluoro-3′-methyl-4′-(methylsulfonyl)-[1,1′-biphenyl]-2-carbonitrile (step 3) was reacted with hydrazine hydrate (15 eq) in THF at ambient temperature in accordance with General procedure C to afford the title compound. ([M+H,Cl].sup.+386.2).

Example 91: 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-b]pyridin-5-one

[0853] ##STR00143##

[0854] Step 1: 5-methoxy-3-(trifluoromethoxy)-1-trityl-pyrazolo[4,3-b]pyridine

[0855] To a solution of 5-methoxy-1-trityl-pyrazolo[4,3-b]pyridin-3-ol (Example 78, step 2) (430 mg, 1.1 mmol) in DMF (16 mL) was added potassium carbonate (438 mg, 3.2 mmol) and 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one (1001 mg, 3.2 mmol). The mixture was stirred at 25° C. for 16 h, after which time a second portion of potassium carbonate (438 mg, 3.2 mmol) and 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one (1001 mg, 3.2 mmol)was added and the reaction strired for a further 12 h. The reaction was diluted with water and repeatedly extracted with ethyl acetate. The combined organic was washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. Purification by preparative TLC (heptane: ethyl acetate 1:10) afforded the title compound (110 mg, 21%) as a white solid. ([M+H].sup.+476.1).

[0856] Step 2: 3-(trifluoromethoxy)-1-trityl-4H-pyrazolo[4,3-b]pyridin-5-one

[0857] A solution of 5-methoxy-3-(trifluoromethoxy)-1-trityl-pyrazolo[4,3-b]pyridine (step 1) (110 mg, 0.2 mmol) in 4 M HCl in dioxane (20.0 mL, 80 mmol) was stirred at 80° C. for 24 h. The reaction was concentrated and purification by preparative TLC (heptane: ethyl acetate 1:1 afforded the title compound (60 mg, 53%) as a white solid. ([M+H].sup.+462.1).

[0858] Step 3: 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(trifluoromethoxy)-1-trityl-pyrazolo[4,3-b]pyridin-5-one

[0859] To a solution of 3-(trifluoromethoxy)-1-trityl-4H-pyrazolo[4,3-b]pyridin-5-one (step 2) (55 mg, 0.1 mmol) in DCM (4 mL) was added (3-methyl-4-methylsulfonyl-phenyl)boronic acid (51 mg, 0.2 mmol), pyridine (0.02 mL, 0.2 mmol), triethylamine (0.03 mL, 0.2 mmol) and copper (II) acetate (43 mg, 0.2 mmol) and the reaction was stirred at ambient temperature under oxygen atmosphere (balloon). After 12 h a further portion of (3-methyl-4-methylsulfonyl-phenyl)boronic acid (51 mg, 0.2 mmol) pyridine (0.02 mL, 0.2 mmol), triethylamine (0.03 mL, 0.2 mmol) was added and the mixture stirred for a further 12 h before the reaction was diluted with ethyl acetate and filtered Purification by preparative TLC afforded the title compound (90 mg, 63%) as a white solid. ([M+H].sup.+630.1).

[0860] Step 4: 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-b]pyridin-5-one

[0861] 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(trifluoromethoxy)-1-trityl-pyrazolo[4,3-b]pyridin one was deprotected using General procedure I1 to afford the title compound. ([M+H].sup.+388.1).

Example 92: 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrrolo[3,2-b]pyridin-5-one

[0862] ##STR00144##

[0863] Step 1: 3-bromo-5-methoxy-1H-pyrrolo[3,2-b]pyridine

[0864] To a solution of 5-methoxy-1H-pyrrolo[3,2-b]pyridine (1.0 g, 6.75 mmol, 1 eq) in DMF (20 mL) was added N-bromosuccinimide (1.4 g, 7.1 mmol) at 25° C. and the reaction mixture was stirred at ambient temperature for 16 h. The reaction was diluted with water and repeatedly extracted with ethyl acetate. The combined organic was washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (Ethyl acetate: n-Heptane=0:1-1:8) afforded the title compound (1.2 g, 76%) as a white solid. ([M+H, Br].sup.+227.0).

[0865] Step 2: 2-[(3-bromo-5-methoxy-pyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane

[0866] 3-Bromo-5-methoxy-1H-pyrrolo[3,2-b]pyridine (step 1) was converted to the title compound employing General procedure E1 in THF. ([M+H, Br].sup.+b 357.1)

[0867] Step 3: 2-[(3-cyclopropyl-5-methoxy-pyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane

[0868] The title compound ([M+Hl].sup.+319.2) was prepared from Suzuki coupling of 2-[(3-bromo-5-methoxy-pyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (step 2) and cylcopropyl boronic acid (10 eq) with potassium carbonate (8 eq) at 100° C. in accordance with General procedure D.

[0869] Step 4: 3-cyclopropyl-1-(methoxymethyl)-4H-pyrrolo[3,2-b]pyridin-5-one

[0870] A solution of 2-[(3-cyclopropyl-5-methoxy-pyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (step 3) (320 mg, 1 mmol) in 4M HCl in dioxane (20.0 mL, 80 mmol) was stirred at 90° C. for 5 h. The reaction was concentrated and purification by preparative TLC (Heptane: ethyl acetate 1:1) afforded the title compound (140 mg, 58%) as an off-white solid. ([M+H].sup.+219.1).

[0871] Step 5: 3-cyclopropyl-1-(methoxymethyl)-4-(3-methyl-4-methylsulfonyl-phenyl)pyrrolo[3,2-b]pyridin-5-one

[0872] To a solution of 3-cyclopropyl-1-(methoxymethyl)-4H-pyrrolo[3,2-b]pyridin-5-one (step 4) (140 mg, 0.6 mmol) in dichloromethane (6 mL) was added (3-methyl-4-methylsulfonyl-phenyl)boronic acid (250 mg, 1.2 mmol), pyridine (0.09 mL, 1.2 mmol), triethylamine (0.16 mL, 1.2 mmol) and copper (II) acetate (212 mg, 1.2 mmol) and the reaction was stirred at ambient temperature under oxygen atmosphere (balloon). After 2 h a further portion of (3-methyl-4-methylsulfonyl-phenyl)boronic (3-methyl-4-methylsulfonyl-phenyl)boronic acid (250 mg, 1.2 mmol) and triethylamine (0.16 mL, 1.2 mmol) was added and the mixture stirred for a further 2 h before a third identical readdition of boronic acid and triethylamine added and the reaction stirred for a further 12 h. The reaction was then filtered and concentrated. Purification by preparative TLC (Heptane: ethyl acetate 1:1) afforded the title compound (170 mg, 68%) as a yellow solid. ([M+H].sup.+387.1).

[0873] Step 6: 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrrolo[3,2-b]pyridin-5-one

[0874] 3-Cyclopropyl-1-(methoxymethyl)-4-(3-methyl-4-methylsulfonyl-phenyl)pyrrolo[3,2-b]pyridin-5-one (step 5) was deprotected using General procedure J to afford the title compound. ([M+H].sup.+343.2).

Example 93: 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1H-indazole

[0875] ##STR00145##

[0876] Step 1: 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1-trityl-1H-indazol-3-ol

[0877] The title compound ([M−H].sup.−621.5) was prepared from Suzuki coupling of 4-bromo-5-(methylsulfonyl)-1-trityl-1H-indazol-3-ol (Intermediate 16, step 4) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 100° C. in accordance with General procedure D.

[0878] Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1-trityl-1H-indazole

[0879] To a solution of 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1-trityl-1H-indazol-3-ol (step 1) (206 mg, 0.3 mmol) in DMF (3 ml) was added potassium carbonate (137 mg, 1.0 mmol) and 1-(trifluoromethyl)-113-benzo[d][1,2]iodaoxol-3(1H)-one (165 mg, 0.5 mmol) and the mixture stirred 18 h at ambient temperature. The reaction was concentrated to dryness, suspended in ethyl acetate, washed with water, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (heptane:ethyl acetate 1:9-0:1) afforded the title compound (46 mg, 20%) as a white solid. ([M+NH.sub.4.sup.+].sup.+708.5)

[0880] Step 3: 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1H-indazole

[0881] 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1-trityl-1H-indazole (step 2) was deprotected using General procedure I1 to afford the title compound. ([M+H].sup.+449.2).

Example 94: 3-cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole

[0882] ##STR00146##

[0883] Step 1: cyclopropyl(3′-(difluoromethyl)-3-fluoro-4′-(methylsulfonyl)-6-(methylthio)-[1,1′-biphenyl]-2-yl)methanone

[0884] The title compound ([M+H].sup.+415.2) was prepared from Suzuki coupling of (2-bromo-6-fluoro-3-(methylthio)phenyl)(cyclopropyl)methanone (Example 75, step 2) and 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 21) with potassium carbonate at 100° C. in accordance with General procedure D. Step 2: cyclopropyl(3′-(difluoromethyl)-3-fluoro-4′,6-bis(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methanone

[0885] Cyclopropyl(3′-(difluoromethyl)-3-fluoro-4′-(methylsulfonyl)-6-(methylthio)-[1,1′-biphenyl]-2-yl)methanone (step 1) is converted to the title compound using General procedure G. ([M+H].sup.+447.3).

[0886] Step 3: 3-cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole

[0887] Cyclopropyl(3′-(difluoromethyl)-3-fluoro-4′,6-bis(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methanone (step 2) was reacted with hydrazine hydrate (2 eq) in THF at ambient temperature in accordance with General procedure C to afford the title compound. ([M+H].sup.+441.2).

Example 95: 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0888] ##STR00147##

[0889] Step 1: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid

[0890] A solution of 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (Example 52) (100 mg, 0.3 mmol) in water (4 mL) was added sodium hydroxide (1.0 mL, 6 N, 6 mmol) and the reaction heated to 100° C. for 10 h. The reaction mixture was cooled to 0° C. and acidified with concentrated aqueous HCl, extracted repeatedly with ethyl acetate, the combined organic dried (Na.sub.2SO.sub.4) and concentrated to afford the title compound

[0891] (100 mg, 95%) as yellow solid. ([M+H].sup.+398.0)

[0892] Step 2: 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0893] The title compound ([M+H].sup.+411.1) was prepared in analogy to Example 72 from 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (step 4) and methylamine hydrochloride.

Example 96: 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0894] ##STR00148##

[0895] Step 1: 1-bromo-4-cyclopropylsulfanyl-2-fluoro-5-methyl-benzene

[0896] To a stirred suspension of potassium tert-butoxide (61 mg, 0.5 mmol) in DMSO (1 mL) was added 4-bromo-5-fluoro-2-methyl-benzenethiol (CAS: 1208077-77-3) (100 mg, 0.5 mmol) and cyclopropyl bromide (164 mg, 1.4 mmol) and the reaction was heated to 100° C. for 12 h. The reaction was extracted repeatedly with ethyl acetate, the combined organic dried (Na.sub.2SO.sub.4) and concentrated, Purification by preparative TLC (heptane) afforded the title compound (60 mg, 51%) as a colourless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.29 (d, J=9.5 Hz, 1H), 7.27-7.24 (m, 1H), 2.18 (s, 3H), 2.13-2.06 (m, 1H), 1.19-1.13 (m, 2H), 0.75-0.67 (m, 2H)

[0897] Step 2: 1-bromo-4-cyclopropylsulfonyl-2-fluoro-5-methyl-benzene

[0898] 1-Bromo-4-cyclopropylsulfanyl-2-fluoro-5-methyl-benzene (step 1) is converted to the title compound using General procedure G. ([M+H].sup.+293.0).

[0899] Step 3: 2-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0900] 1-bromo-4-cyclopropylsulfonyl-2-fluoro-5-methyl-benzene (step 2) is converted to the title compound employing General procedure F. ([M+H].sup.+258.9).

[0901] Step 4: 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile

[0902] The title compound ([M+H].sup.+397.2) was prepared from Suzuki coupling of 4-bromo-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (Intermediate 17), 2-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (step 4) with potassium carbonate and, 1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (0.5 eq) at 120° C. in accordance with General procedure D.

[0903] Step 5: 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid

[0904] A solution of 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (step 4) (20 mg, 0.1 mmol) in water (0.2 mL) was added sodium hydroxide (0.05 mL, 6 N, 0.3 mmol) and the reaction heated to 100° C. for 38 h. The reaction mixture was cooled to 0° C. and acidified with concentrated aqueous HCl, extracted repeatedly with ethyl acetate, the combined organic dried (Na.sub.2SO.sub.4) and concentrated to afford the title compound (20 mg, 95%). ([M+H].sup.+416.1)

[0905] Step 6: 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0906] The title compound ([M+H].sup.+429.1) was prepared in analogy to Example 72 from 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (step 5) and methylamine hydrochloride.

Example 97: 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0907] ##STR00149##

[0908] Step 1: 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid

[0909] To a suspension of of 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (Example 47) (50 mg, 0.1 mmol) in water (0.6 mL) was added sodium hydroxide (0.1 mL, 0.8 mmol). The reaction mixture was stirred at 100° C. for 18 h. The reaction mixture was cooled to 0° C. and acidified with concentrated aqueous HCl, extracted repeatedly with ethyl acetate, the combined organic dried (Na.sub.2SO.sub.4) and concentrated. Purification by reversed phase preparative HPLC afforded the title compound (20 mg, 34%) as a grey foam. ([M+H].sup.+390.0)

[0910] Step 2: 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0911] The title compound ([M+H].sup.+403.1) was prepared in analogy to Example 72 from 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (step 1) and methylamine hydrochloride.

Example 98: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0912] ##STR00150##

[0913] A solution of 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-c]pyridine-5-carbonitrile (Example 52) (100 mg, 0.3 mmol) in ethanol (4 mL) was added sodium hydroxide (0.7 mL, 6 N, 0.3 mmol) and the reaction heated to 100° C. for 12 h. The reaction mixture was concentrated and the residue purified by reversed phase preparative HPLC to afford the title compound (28 mg, 26%) as white solid. ([M+H].sup.+397.1)

Example 99: N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]acetamide; Formic Acid Salt

[0914] ##STR00151##

[0915] Step 1: 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine

[0916] To a solution of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine (Example 64, step 1) (100 mg, 0.3 mmol) in THF (1 mL) was added p-toluenesulfonic acid monohydrate (13 mg, 0.1 mmol) and dihydropyran (0.07 mL, 0.7 mmol) and the reaction solution was stirred at 60° C. for 12 h. To the reaction mixture was added saturated sodium hydrogen carbonate solution and the mixture extracted with ethyl acetate, the combined organic was dried (Na.sub.2SO.sub.4) and concentrated. Purification by preparative TLC (heptane: ethyl acetate 1:1) afforded the title compound (60 mg, 50%) as a yellow oil. ([M+H, Br].sup.+490.0)

[0917] Step 2: N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]acetamide

[0918] To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine (step 1) (100 mg, 0.2 mmol) in 1,4-dioxane (5 mL) was added cesium carbonate (332 mg, 1.0 mmol), N-[2-(2-aminoethoxy)ethyl]acetamide (179 mg, 1.2 mmol), xantphos (14 mg, 0.02 mmol) and Pd(OAc).sub.2 (4.6 mg, 0.02 mmol) was stirred at 80° C. for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by reversed phase preparative HPLC afforded the title compound (40 mg, 34%) as a yellow solid. ([M+H].sup.+556.2)

[0919] Step 3: N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]acetamide; formic acid salt

[0920] N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]acetamide (step 2) was deprotected using General procedure I1 to afford the title compound. ([M+H].sup.+472.3).

Example 100: N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]propyl]acetamide; Formic Acid Salt

[0921] ##STR00152##

[0922] Step 1: N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]propyl]acetamide

[0923] To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine (Example 99, step 1) (100 mg, 0.2 mmol) in 1,4-dioxane (3 mL) was added cesium carbonate (332 mg, 1.0 mmol), N-(3-aminopropyl)acetamide (118 mg, 1.0 mmol), xantphos (14 mg, 0.02 mmol) and Pd(OAc).sub.2 (5 mg, 0.02 mmol) was stirred at 80° C. for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by reversed phase preparative HPLC afforded the title compound (60 mg, 56%) as a yellow solid. ([M+H].sup.+526.0)

[0924] Step 2: N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]propyl]acetamide; formic acid

[0925] N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]propyl]acetamide (step 1) was deprotected using General procedure I1 to afford the title compound. ([M+H].sup.+441.9).

Example 101: N-[2-(2-aminoethoxy)ethyl]-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-amine; Formic Acid

[0926] ##STR00153##

[0927] Step 1: tert-butyl N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]carbamate

[0928] To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine (Example 99, step 1) (120 mg, 0.2 mmol) in 1,4-dioxane (4 mL) was added cesium carbonate (399 mg, 1.2 mmol), N-Boc-2-(2-amino-ethoxy)-ethylamine (150 mg, 0.7 mmol), xantphos (17 mg, 0.03 mmol) and Pd(OAc).sub.2 (5 mg, 0.02 mmol) was stirred at 80° C. for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by reversed phase preparative HPLC afforded the title compound (98 mg, 62%) as a yellow solid. ([M+H].sup.+614.2)

[0929] Step 2: N-[2-(2-aminoethoxy)ethyl]-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-amine; formic acid salt

[0930] tert-butyl N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]carbamate (step 1) was deprotected using General procedure I1 to afford the title compound. ([M+H].sup.+430.1).

Example 102: N′-[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]butane-1,4-diamine

[0931] ##STR00154##

[0932] Step 1: tert-butyl N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]butyl]carbamate

[0933] To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine (Example 99, step 1) (130 mg, 0.3 mmol) in 1,4-dioxane (4 mL) was added cesium carbonate (432 mg, 1.3 mmol), N-Boc-1,4-diaminobutane (150 mg, 0.8 mmol), xantphos (18 mg, 0.03 mmol) and Pd(OAc).sub.2 (6 mg, 0.03 mmol) was stirred at 80° C. for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by reversed phase preparative HPLC afforded the title compound (90 mg, 56%) as a yellow solid. ([M+H].sup.+598.2)

[0934] Step 2: N′-[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]butane-1,4-diamine

[0935] tert-butyl N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]butyl]carbamate (step 1) was deprotected using General procedure I1 to afford the title compound. ([M+H].sup.+414.1).

Example 103: N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]butyl]acetamide

[0936] ##STR00155##

[0937] Step 1: N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]butyl]acetamide

[0938] To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine (Example 99, step 1) (80 mg, 0.2 mmol) in 1,4-dioxane (2 mL) was added cesium carbonate (266 mg, 0.8 mmol), N-(4-aminobutyl)acetamide (106 mg, 0.8 mmol), xantphos (11 mg, 0.02 mmol) and Pd(OAc).sub.2 (4 mg, 0.02 mmol) was stirred at 80° C. for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by reversed phase preparative HPLC afforded the title compound (60 mg, 68%) as a yellow solid. ([M+H].sup.+540.1)

[0939] Step 2: N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]butyl]acetamide

[0940] N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]butyl]acetamide (step 1) was deprotected using General procedure I1 to afford the title compound. ([M+H].sup.+499.9).

Example 104: N′-[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]propane-1,3-diamine

[0941] ##STR00156##

[0942] Step 1: tert-butyl N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]propyl]carbamate

[0943] To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine (Example 99, step 1) (100 mg, 0.2 mmol) in 1,4-dioxane (4 mL) was added cesium carbonate (332 mg, 1.0 mmol), N-Boc-1,3-diaminopropane (107 mg, 0.6 mmol), xantphos (14 mg, 0.02 mmol) and Pd(OAc).sub.2 (5 mg, 0.02 mmol) was stirred at 80° C. for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by reversed phase preparative HPLC afforded the title compound (50 mg, 42%) as a brown oil. ([M+H].sup.+584.4)

[0944] Step 2: N′-[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]propane-1,3-diamine

[0945] N tert-butyl N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]propyl]carbamate (step 1) was deprotected using General procedure I1 to afford the title compound. ([M+H].sup.+399.9).

Example 105: 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile

[0946] ##STR00157##

[0947] Step 1: 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile

[0948] The title compound ([M+formate].sup.−701.3) was prepared from Suzuki coupling of 4-bromo-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (Intermediate 17), 2-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (step 4) with potassium carbonate and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (0.05 eq) at 100° C. in accordance with General procedure D.

[0949] Step 2: 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile

[0950] 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile is deprotected using General procedure H to afford the titled compound ([M+H].sup.+415.2) after flash column chromatography.

Example 106: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0951] ##STR00158##

[0952] Step 1: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide

[0953] To a solution of 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (Example 105, step 1) (295 mg, 0.45 mmol) in dimethyl sulfoxide (3.5 mL) was added potassium carbonate (12.4 mg, 0.09 mmol) followed by dropwise addition of 35% aqueous hydrogen peroxide (153 μL, 10.23 mmol). The reaction was stirred for 16 h after which time it was diluted with water resulting in precipitation of product. The suspension was aged, filtered, the filter cake washed with water and dried to afford the title product compound (325 mg, quant) as an off-white powder. ([M+H].sup.+675.3)

[0954] Step 2: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0955] 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide is deprotected using General procedure H to afford the titled compound ([M+H]+433.2) after flash column chromatography.

Example 107: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0956] ##STR00159##

[0957] Step 1: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid

[0958] 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide (150 mg, 0.22 mmol) was dissolved in acetonitrile (5 mL) and heated to 80° C. tert-Butyl nitrite (132 μL, 1.11 mmol) was added and the mixture was stirred for 4 hr after which time the mixture was evaporated to dryness to afford the crude titled product (208 mg) as an orange foam, used in the next step without further purification. ([M+H]+434.2)

[0959] Step 2: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0960] The title compound ([M+H].sup.+489.2) was prepared in analogy to Example 72 from 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (step 1) and oxetan-3-ylamine.

Example 108: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0961] ##STR00160##

[0962] The title compound ([M+H].sup.+447.1) was prepared in analogy to Example 72 from 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example, 107 step 1) and methylamine hydrochloride.

Example 109: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(2-methoxyethyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0963] ##STR00161##

[0964] The title compound ([M+H].sup.+447.1) was prepared in analogy to Example 72 from 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 107, step 1) and 2-methoxyethylamine.

Example 110: 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0965] ##STR00162##

[0966] Step 1: 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid

[0967] To 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (Example 52) (238 mg, 0.6 mmol) was added 6 N sodium hydroxide (2.5 mL) and the reaction heated to 100° C. for 2.5 h after which time it was diluted with water (9 ml) and the heating continued for 36 h at 90° C. The reaction was cooled to 0° C. and acidifed with 25% hydrochloric acid and the product isolated by filtration to afford the title compound (92 mg, 30%) as a light brown solid. ([M+H].sup.+398.2)

[0968] Step 2: 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[0969] The title compound ([M+H].sup.+411.3) was prepared in analogy to Example 72 from 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (step 1) and methylamine hydrochloride.

Example 111: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-5-(oxetan-3-ylsulfonyl)-1H-indazole

[0970] ##STR00163##

[0971] Step 1: 3-(2-bromo-4-fluoro-phenyl)sulfanyloxetane

[0972] To a stirred suspension of 3-iodooxetane (10.4 g, 56.5 mmol) in DMF (30 mL) was added 2-bromo-4-fluorothiophenol (3.9 g, 18.8 mmol) and potassium tert-butoxide (2.5 g, 22.6 mmol) and the reaction heated to 100° C. for 5 h. The reaction was diluted with ethyl acetate washed with water, brine, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (Ethyl acetate: n-Heptane 1:10-1:3) afforded the title compound (4.1 g, 83%) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.37 (dd, J=2.7, 8.1 Hz, 1H), 7.12-7.07 (m, 1H), 7.05-6.98 (m, 1H), 5.06 (t, J=7.1 Hz, 2H), 4.68 (t, J=6.6 Hz, 2H), 4.49-4.41 (m, 1H)

[0973] Step 2: ethyl 2-bromo-6-fluoro-3-(oxetan-3-ylsulfanyl)benzoate

[0974] 3-(2-bromo-4-fluoro-phenyl)sulfanyloxetane (Step 1) was deprotonated with LDA (1.1 eq) for 30 minutes and reacted with ethyl chloroformate (1.2 eq) in accordance with General procedure A to afford the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.12-7.05 (m, 2H), 5.07 (t, J=7.1 Hz, 2H), 4.67 (t, J=6.6 Hz, 2H), 4.50-4.42 (m, 3H), 1.42 (t, J=7.1 Hz, 3H)

[0975] Step 3: ethyl 2-bromo-6-fluoro-3-(oxetan-3-ylsulfonyl)benzoate

[0976] To a solution of ethyl 2-bromo-6-fluoro-3-(oxetan-3-ylsulfanyl)benzoate (step 2) (4.1 g, 12.2 mmol) in dichloromethane (100 ml) was added mCPBA (6.2g, 30.6 mmol) and the reaction stirred at ambient temperature for 16 h. The reaction was then diluted with DCM, washed with 1 aq.sat. sodium hydrogencarbonate solution , dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (Ethyl acetate: n-Heptane 3:1-1:1) afforded the title compound (4.6 g, 87%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.31 (dd, J=5.6, 8.9 Hz, 1H), 7.33 (dd, J=7.6, 8.9 Hz, 1H), 5.03-4.96 (m, 3H), 4.89-4.83 (m, 2H), 4.49 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H)

[0977] Step 4: 4-bromo-5-(oxetan-3-ylsulfonyl)-1,2-dihydroindazol-3-one

[0978] To an ice-cold solution of ethyl 2-bromo-6-fluoro-3-(oxetan-3-ylsulfonyl)benzoate (step 3) (4.6 g, 12.5 mmol) in ethanol (40 ml) was added hydrazine monohydrate (689 μL, 13.9 mmol) followed by triethylamine (2.1 ml, 15.0 mmol) and the reaction brought to ambient temperature. It was then heated to 80° C. for 2 h after which time the reaction was concentrated to dryness. Reversed phase preparative HPLC afforded the title compound (2.8 g, 67%) was obtained as a light yellow solid. ([M+H, Br].sup.+335.0).

[0979] Step 5: 4-bromo-5-(oxetan-3-ylsulfonyl)-1-trityl-indazol-3-ol

[0980] To an ice cold solution of 4-bromo-5-(oxetan-3-ylsulfonyl)-1,2-dihydroindazol-3-one (step 4) (2.7 g, 8.1 mmol) in DMF (30 ml) was added trityl chloride (2.5 g, 8.9 mmol) followed by sodium hydride (389 mg, 60% dispersion in mineral oil, 9.7 mmol), the cooling bath was removed and the reaction stirred at ambient temperature for 1 h. The reaction was then diluted with ethyl acetate, washed with water, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (Ethyl acetate: n-Heptane 1:3-1:0) afforded the title compound (4.1 g, 65%) as a colourless solid. ([M+Na+, Br]+599.1).

[0981] Step 6: 4-bromo-3-(difluoromethoxy)-5-(oxetan-3-ylsulfonyl)-1-trityl-indazole

[0982] A mixture of 4-bromo-5-(oxetan-3-ylsulfonyl)-1-trityl-indazol-3-ol (step 5) (4.0 g, 5.21 mmol) in

[0983] DMF (40 mL) was added sodium chlorofluoroacetate (1.6 g, 10.4 mmol) and potassium carbonate (2.1 g, 15.6 mmol) was heated to 80° C. for 0.5 h. The reaction was diluted with ethyl acetate washed with water, brine, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (Ethyl acetate: n-Heptane 1:3-1:0) afforded the title compound (2.8 g, 86%) as a white solid. ([M+Na].sup.+649.1).

[0984] Step 7: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-5-(oxetan-3-ylsulfonyl)-1-trityl-indazole

[0985] The title compound ([M+Na+].sup.+737.4) was prepared from Suzuki coupling of 4-bromo-3-(difluoromethoxy)-5-(oxetan-3-ylsulfonyl)-1-trityl-indazole (step 6), (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (0.1 eq) at 100° C. in accordance with General procedure D.

[0986] Step 8: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-5-(oxetan-3-ylsulfonyl)-1H-indazole

[0987] 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-5-(oxetan-3-ylsulfonyl)-1-trityl-indazole (step 7) is deprotected using General procedure H to afford the titled compound ([M+H]+495.2) after flash column chromatography.

Example 112: p-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazol-5-yl]-imino-methyl-oxo-sulfane

[0988] ##STR00164##

[0989] Step 1: (6-(cyclopropanecarbonyl)-5-fluoro-3′-methyl-4′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)(imino)(methyl)-16-sulfanone

[0990] To a solution of yclopropyl(3-fluoro-3′-methyl-4′-(methylsulfonyl)-6-(methylthio)-[1,1′-biphenyl]-2-yl)methanone (Example 75, step 3) (250 mg, 661 μmol) in MeOH (3 ml) was added ammonium carbonate (95 mg, 991 μmol) and (diacetoxyiodo)benzene (532 mg, 1.65 mmol) The and the mixture stirred at ambient temperature for 1 h. The reaction was diluted with ethyl acetate washed with water, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (dichloromethane:MeOH 1:0-9:1) afforded the title compound (199 mg, 72%) as a white solid. ([M+H].sup.+410.2).

[0991] Step 2: [3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazol-5-yl]-imino-methyl-oxo-sulfane

[0992] To an solution of (6-(cyclopropanecarbonyl)-5-fluoro-3′-methyl-4′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)(imino)(methyl)-16-sulfanone (step 1) (15 mg, 36.6 μmol) in methanol (1 ml) was added hydrazine monohydrate (28 μL, 366 μmol) and the reaction heated to 65° C. for 16 h after which time the reaction was concentrated to dryness. Flash column chromatography (dichloromethane:MeOH 9:1) afforded the title compound (10 mg, 67%) as a white solid. ([M+H].sup.+404.1).

Example 113: [3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazol-5-yl]-methyl-methylimino-oxo-λ.SUP.6.-sulfane

[0993] ##STR00165##

[0994] Step 1: (6-(cyclopropanecarbonyl)-5-fluoro-3′-methyl-4′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)(methyl)(methylimino)-16-sulfanone

[0995] To a solution of (6-(cyclopropanecarbonyl)-5-fluoro-3′-methyl-4′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)(imino)(methyl)-16-sulfanone (50 mg, 122 μmol) in DMF (1 ml) was added sodium hydride (7.3 mg, 183 μmol) and iodomethane (10 μl, 159 μmol) and the reaction mixture was stirred at ambient temperature for 16 h. The reaction was diluted with ethyl acetate washed with water, dried (Na.sub.2SO.sub.4) and concentrated. Reversed phase preparative HPLC afforded the title compound (22 mg, 37%) as a white solid. ([M+H].sup.+424.2).

[0996] Step 2: [3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazol-5-yl]-methyl-methylimino-oxo-λ.sup.6-sulfane

[0997] To a solution of (6-(cyclopropanecarbonyl)-5-fluoro-3′-methyl-4′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)(methyl)(methylimino)-16-sulfanone (step 1) (22 mg, 52.7 μmol) in ethanol (0.4 ml) was added hydrazine monohydrate (156 μl, 316 μmol) followed by triethylamine (11 μl, 79 μmol) and the reaction stirred at ambient temperature for 16 h after which time the reaction was concentrated to dryness. Flash column chromatography (dichloromethane: MeOH 9:1) afforded the title compound (19 mg, 85%) as a white solid. ([M+H].sup.+418.2).

Example 114: 3-cyclopropyl-N,N-dimethyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide

[0998] ##STR00166##

[0999] Step 1: 2-bromo-4-fluoro-N,N-dimethyl-benzenesulfonamide

[1000] To a solution of 2-bromo-4-fluorobenzenesulfonyl chloride (2.0 g, 7.31 mmol) in dichloromethane (20 mL) was added diisopropylethylamine (2.8 mL, 21.9 mmol) and dimethylamine hydrochloride (1.1g, 14.6 mmol) and the reaction mixture stirred for 2 h at ambient temperature. The reaction was diluted with ethyl acetate, washed with 1M HCl and concentrated. Flash column chromatography (Ethyl acetate: n-Heptane 1:10-3:1) afforded the title compound (1.8 g, 83%) as a white solid. ([M+H, Br].sup.+282.0).

[1001] Step 2: 2-bromo-3-[cyclopropyl(hydroxy)methyl]-4-fluoro-N,N-dimethyl-benzenesulfonamide

[1002] 2-bromo-4-fluoro-N,N-dimethyl-benzenesulfonamide (step 1) was deprotonated with LDA (1.2 eq) for 0.5 h and reacted with cyclopropanecarboxaldehyde (1.5 eq) for 1 h in accordance with General procedure A to afford the title compound ([M+H (—OH), Br].sup.+334.0.

[1003] Step 3: 2-bromo-3-(cyclopropanecarbonyl)-4-fluoro-N,N-dimethyl-benzenesulfonamide

[1004] 2-bromo-3-[cyclopropyl(hydroxy)methyl]-4-fluoro-N,N-dimethyl-benzenesulfonamide (step 2) was oxidised using General procedure B2 to afford the title compound. ([M+H, Br].sup.+350.0.

[1005] Step 4: 4-bromo-3-cyclopropyl-N,N-dimethyl-1H-indazole-5-sulfonamide

[1006] To a solution of 2-bromo-3-(cyclopropanecarbonyl)-4-fluoro-N,N-dimethyl-benzenesulfonamide (step 3) (60 mg, 170 μmol) in ethanol (2 ml) was added hydrazine monohydrate (170 μl, 316 μmol) followed by triethylamine (30 μl, 210 μmol) and the reaction heated to 80° C. for 16 h after which time the reaction was concentrated to dryness. Reversed phase preparative HPLC afforded the title compound (40 mg, 67%) as a light yellow solid. ([M+H, Br].sup.+346.1).

[1007] Step 5: 3-cyclopropyl-N,N-dimethyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide

[1008] The title compound ([M+Na.sup.+].sup.+434.2) was prepared from Suzuki coupling of 4-bromo-3-cyclopropyl-N,N-dimethyl-1H-indazole-5-sulfonamide (step 4), (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (0.1 eq) at 100° C. in accordance with General procedure D.

Example 115: 3-cyclopropyl-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide

[1009] ##STR00167##

[1010] Step 1: 2-bromo-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-benzenesulfonamide

[1011] To a solution of 2-bromo-4-fluorobenzenesulfonyl chloride (2.0 g, 7.31 mmol) in dichloromethane (20 mL) was added diisopropylethylamine (1.6 mL, 14.6 mmol) and 4-methoxy-N-methylbenzylamine (1.7 g, 11.0 mmol) and the reaction mixture stirred for 2 h at ambient temperature. The reaction was diluted with ethyl acetate, washed with 1M HCl and concentrated. Flash column chromatography afforded the title compound (2.6 g, 92%) as a white solid. ([M+H, Br].sup.+412.1).

[1012] Step 2: 2-bromo-3-[cyclopropyl(hydroxy)methyl]-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-benzenesulfonamide

[1013] 2-bromo-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-benzenesulfonamide (step 1) was deprotonated with LDA (1.2 eq) for 0.5 h and reacted with cyclopropanecarboxaldehyde (1.5 eq) for 1 h in accordance with General procedure A to afford the title compound ([M+Na, Br].sup.+482.1.

[1014] Step 3: 2-bromo-3-(cyclopropanecarbonyl)-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-benzenesulfonamide

[1015] 2-bromo-3-[cyclopropyl(hydroxy)methyl]-4-fluoro-N,N-dimethyl-benzenesulfonamide (step 2) was oxidised using General procedure B2 to afford the title compound. ([M+H, Br].sup.+480.2.

[1016] Step 4: 4-bromo-3-cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-1H-indazole-5-sulfonamide

[1017] To a solution of 2-bromo-3-(cyclopropanecarbonyl)-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-benzenesulfonamide (step 3) (200 mg, 440 μmol) in ethanol (4 ml) was added hydrazine monohydrate (44 μl, 880 μmol) followed by triethylamine (70 μl, 530 μmol) and the reaction heated to 80° C. for 2 h after which time the reaction was concentrated to dryness . Reversed phase preparative HPLC afforded the title compound (200 mg, quant.) as a white solid. ([M+H, Br].sup.+450.0).

[1018] Step 5: 3-cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide

[1019] The title compound ([M+Na.sup.+].sup.+5402) was prepared from Suzuki coupling of 44-bromo-3-cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-1H-indazole-5-sulfonamide (step 4), (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (0.1 eq) at 100° C. in accordance with General procedure D.

[1020] Step 6: 3-cyclopropyl-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide

[1021] 3-cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide (step 5) is deprotected using General procedure H to afford the titled compound ([M+H]+420.0) after flash column chromatography.

Example 116: 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[1022] ##STR00168##

[1023] Step 1: 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile

[1024] The title compound ([M+Na].sup.+669.3) was prepared from Suzuki coupling of 4-bromo-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (Intermediate 17) and 2-(4-(cyclopropylsulfonyl)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 8) with potassium carbonate and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (0.05 eq) at 100° C. in accordance with General procedure D.

[1025] Step 2: 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide

[1026] To the solution of 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (step 1) (220.0 mg, 0.34 mmol) in ethanol (5 mL) was added 2 N aq. NaOH (0.85 mL, 1.7 mmol) ad the reaction heated to 100° C. for 6 h. The reaction was acidified by addition of 1N HCl, extracted with ethyl acetate and concentrated. Preparative tlc ((Ethyl acetate: n-Heptane 1:2) afforded the title compound (150 mg, 66%) as a yellow solid.

[1027] Step 3: 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[1028] 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide (step 2) is deprotected using General procedure H to afford the titled compound ([M+H]+423.2) after flash column chromatography.

Example 117: 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-5-(methylsulfonyl)-1H-indazole

[1029] ##STR00169##

[1030] The title compound ([M+Na].sup.+465.1) could be prepared in anaolgy to Example 49 by Suzuki coupling of 4-bromo-3-(difluoromethoxy)-5-(methylsulfonyl)-1-trityl-1H-indazole (intermediate 6) and 2-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 27) followed by deprotection using General procedure H.

Example 118: 5-cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole

[1031] ##STR00170##

[1032] Step 1: 2-bromo-1-cyclopropylsulfanyl-4-fluoro-benzene

[1033] To a stirred suspension of cyclopropyl bromide (6.1 g, 50.71 mmol) in DMF (50 mL) was added 2-bromo-4-fluorothiophenol (3.5 g, 16.9 mmol) and potassium tert-butoxide (2.2 g, 20.3 mmol) and the reaction heated to 100° C. for 12 h. The reaction was diluted with ethyl acetate washed with water, brine, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (n-Heptane) afforded the title compound (1.7 g, 41%) as a colourless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.50 (dd, J=5.6, 8.4 Hz, 1H), 7.30 (dd, J=2.0, 8.1 Hz, 1H), 7.06 (dt, J=1.9, 8.4 Hz, 1H), 2.20-2.11 (m, 1H), 1.16-1.10 (m, 2H), 0.79-0.71 (m, 2H)

[1034] Step 2: ethyl 2-bromo-3-cyclopropylsulfanyl-6-fluoro-benzoate

[1035] 2-bromo-1-cyclopropylsulfanyl-4-fluoro-benzene (Step 1) was deprotonated with LDA (1.1 eq) for 30 minutes and reacted with ethyl chloroformate (1.2 eq) in accordance with General procedure A to afford the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.56 (dd, J=5.5, 8.9 Hz, 1H), 7.12 (t, J=8.6 Hz, 1H), 4.45 (q, J=7.2 Hz, 2H), 2.14 (tt, J=4.4, 7.3 Hz, 1H), 1.41 (t, J=7.2 Hz, 3H), 1.18-1.13 (m, 2H), 0.77-0.71 (m, 2H)

[1036] Step 3: ethyl 2-bromo-3-cyclopropylsulfonyl-6-fluoro-benzoate

[1037] To a solution of ethyl 2-bromo-3-cyclopropylsulfanyl-6-fluoro-benzoate (step 2) (1.9 g, 5.95 mmol) in dichloromethane (40 ml) was added mCPBA (3.6 g, 17.9 mmol) and the reaction stirred at ambient temperature for 12 h. The reaction was then diluted with DCM, washed with 1 aq.sat. sodium hydrogencarbonate solution, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (Ethyl acetate: n-Heptane 1:5-1:3) afforded the title compound (2.0 g, 84%) as a white solid. ([M+H, Br]+353.0)

[1038] Step 4: 4-bromo-5-cyclopropylsulfonyl-1,2-dihydroindazol-3-one

[1039] To an ice-cold solution of ethyl 2-bromo-3-cyclopropylsulfonyl-6-fluoro-benzoate (step 3) (2.0 g, 5.69 mmol) in ethanol (20 ml) was added hydrazine monohydrate (1130 μL, 22.6 mmol) followed by triethylamine (0.79 ml, 5.69 mmol) and the reaction brought to ambient temperature. It was then heated to 80° C. for 2 h after which time the reaction was concentrated to dryness. Reversed phase preparative HPLC afforded the title compound (1.1 g, 58%) was obtained as an off-white solid. ([M+H, Br].sup.+316.8).

[1040] Step 5: 4-bromo-5-cyclopropylsulfonyl-1-trityl-indazol-3-ol

[1041] To an ice cold solution of 4-bromo-5-cyclopropylsulfonyl-1,2-dihydroindazol-3-one (step 4) (1.0 g, 3.15 mmol) in DMF (20 ml) was added trityl chloride (0.97 g, 3.47 mmol) followed by sodium hydride (151 mg, 60% dispersion in mineral oil, 3.78 mmol), the cooling bath was removed and the reaction stirred at ambient temperature for 2 h. The reaction was then diluted with ethyl acetate, washed with water, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (Ethyl acetate: n-Heptane 1:3-1:1) afforded the title compound (1.1 g, 52%) as a yellow solid. ([M+Na, Br].sup.+583.1).

[1042] Step 6: 4-bromo-5-cyclopropylsulfonyl-3-(difluoromethoxy)-1-trityl-indazole

[1043] A mixture of 4-bromo-5-cyclopropylsulfonyl-1-trityl-indazol-3-ol (step 5) (1.2 g, 2.06 mmol) in DMF (30 mL) was added sodium chlorofluoroacetate (0.63 g, 4.11 mmol) and potassium carbonate (0.85 g, 6.17 mmol) was heated to 80° C. for 0.5 h. The reaction was diluted with ethyl acetate washed with water, brine, dried (Na.sub.2SO.sub.4) and concentrated. Flash column chromatography (Ethyl acetate: n-Heptane 1:5-1:3) afforded the title compound (1.1 g, 83%) as a light yellow solid. ([M+Na].sup.+633.0).

[1044] Step 7: 5-cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1-trityl-indazole

[1045] The title compound ([M+Na.sup.+].sup.+721.1) was prepared from Suzuki coupling of 4-bromo-5-cyclopropylsulfonyl-3-(difluoromethoxy)-1-trityl-indazole (step 6), (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (0.1 eq) at 100° C. in accordance with General procedure D.

[1046] Step 8: 5-cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole

[1047] 5-cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1-trityl-indazole (step 7) is deprotected using General procedure H to afford the titled compound ([M+H]+457.2) after flash column chromatography.

Example 119: 3-(difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-5-methylsulfonyl-1H-indazole

[1048] ##STR00171##

[1049] Step 1: 3-(difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-5-methylsulfonyl-1-trityl-indazole

[1050] The title compound ([M+Na+]+713.2) was prepared from Suzuki coupling of 4-bromo-3-(difluoromethoxy)-5-methylsulfonyl-1-trityl-indazole (Intermediate 36), (2-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 25) with potassium carbonate and SPhos Pd G3 (0.1 eq) at 100° C. in accordance with General procedure D.

[1051] Step 2: 3-(difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-5-methylsulfonyl-1H-indazole

[1052] 3-(difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-5-methylsulfonyl-1-trityl-indazole (step 1) is deprotected using General procedure H to afford the titled compound ([M+H]+448.0) after flash column chromatography.

Example 120: 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

[1053] ##STR00172##

[1054] Step 1: 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide

[1055] To a solution of 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide (Example 116, step 2) (150.0 mg, 0.23 mmol) in DMF (1 mL) was added NaH (5.4 mg, 0.23 mmol) at 0° C. and the rection allowed to come to ambient temperature after which time iodomethane (32 mg, 0.23 mmol) was added and the mixture stirred for a furthr 2 h. The reaction was diluted with ethyl acetate washed with water, brine, dried (Na.sub.2SO.sub.4) and concentrated. Preparative tic (Ethyl acetate: n-Heptane 1:3) afforded the title compound (110 mg, 73%) as a white solid. ([M+H].sup.+679.2).

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