Small-molecule boron compounds to use against interleukin-23

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) 2.13 to 6.07 0.9934 0.49 2 AN2887 0 3 AN2901 19* 4 AN2908 11 5 AN2909 0 6 AN2919 0 1 AN2728

Table 1 - Effect of having an oxygen, sulfide, sulfoxide, sulfone or nitrogen link between the aromatic ring in the main structure and the

remaining molecule. * - value displayed is an average of 2 values. § - value displayed is an average of 11 values. C.I. - Confidence Interval. The Anacor compound name, chemical structure IL-23 and PDE4 data are shown.

53§ 3.60*

Compounds Chemical Structure

IL-23 data O Confidential S Confidential MeO S Confidential MeO S O O Confidential Cl S Confidential Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) Table 1 - Effect of having an oxygen, sulfide, sulfoxide, sulfone or nitrogen link between the aromatic ring in the main structure and the

remaining molecule. * - value displayed is an average of 2 values. § - value displayed is an average of 11 values. C.I. - Confidence Interval. The Anacor compound name, chemical structure IL-23 and PDE4 data are shown.

Compounds Chemical Structure

IL-23 data 7 AN2920 0 8 AN2931 43 9 AN2936 32 10 AN3082 7 11 AN3108 0* 12 AN2889 0 13 AN2895 0 14 AN2902 16

Cl

S

O

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) Table 1 - Effect of having an oxygen, sulfide, sulfoxide, sulfone or nitrogen link between the aromatic ring in the main structure and the

remaining molecule. * - value displayed is an average of 2 values. § - value displayed is an average of 11 values. C.I. - Confidence Interval. The Anacor compound name, chemical structure IL-23 and PDE4 data are shown.

Compounds Chemical Structure

IL-23 data 15 AN3412 0 16 AN3443 0 17 AN3444 25 18 AN3454 0 19 AN2896 0 3.20 to 16.90 0.9814 0.414 20 AN3805 66 7.35 O H2N Confidential O HO Confidential O MeO Confidential Confidential Confidential Confidential O

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) 2.133 to 6.071 0.9934 0.49 >30 6 >30 AN2987 0

Table 2 - Effect of attaching a cyano-phenoxy in different positions of an aromatic ring. * - value displayed is an average of 2 values.

§ - value displayed is an average of 11 values. CBC - Can't Be Calculated; C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

AN2910 0 CBC

AN2888 0 CBC

Compounds Chemical Structure

IL-23 data AN2728 53§ 3.60* CBC Confidential O N Confidential O N+ C -Confidential O N Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) 86 6.42 50 6.81 80 1.46 84 0.57 94 0.1 1 2 3 4 5 AN2903 15*

Compounds Chemical Structure

IL-23 data

AN2861 17‡ CBC

AN2887 0

AN2893 49*

Table 3 - Effect of attaching different molecules in the "para" position of the phenoxy ring. ‡ - value displayed is an average of 4

results * - value displayed is an average of 2 values. C.I. - Confidence Interval, CBC - Can't Be Calculated. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

AN2892 18* Confidential

O

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) Compounds Chemical Structure

IL-23 data

Table 3 - Effect of attaching different molecules in the "para" position of the phenoxy ring. ‡ - value displayed is an average of 4

results * - value displayed is an average of 2 values. C.I. - Confidence Interval, CBC - Can't Be Calculated. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

106 0.29 7.66 1.26 1.26 >30 9 10 6 7 8 29 20 9 AN3650 AN3651 AN3652 CBC AN3649 6 AN3165 0 O O MeO Confidential Confidential Confidential Confidential Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) Compounds Chemical Structure

IL-23 data

Table 3 - Effect of attaching different molecules in the "para" position of the phenoxy ring. ‡ - value displayed is an average of 4

results * - value displayed is an average of 2 values. C.I. - Confidence Interval, CBC - Can't Be Calculated. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

3.23 to 33.44 0.9621 3.43 2.68 35.51 to 2896 0.9549 0.45 2.133 to 6.071 0.9934 0.49 53§ 3.60* 14 AN2728 13 11 12 320.7 10.39 AN3653 AN3654 AN3675 49 5 30 Confidential Confidential Confidential Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) 2.133 to 6.071 0.9934 0.49 16.57 to 74.87 0.9849 3.72 10.67 to 23.13 0.9957 4.4

Compounds Chemical Structure

IL-23 data

AN2728 53§ 3.60*

AN2876 28 35.22

Table 4 Effect of attaching a cyano group in different positions of an aromatic ring. * value displayed is an average of 2 values. §

-value displayed is an average of 11 -values. † - -value displayed is an average of 3 -values. C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

AN2906 10† 15.71 Confidential Confidential O CN O NC Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R 2 Graph %inhibition at 10µM IC50(µM) 0.6 to 1.3 >0.990 0.06 0.88 to 8.29 0.97 0.15 0.41 to 16.30 0.93 0.14 2.54 to 11.73 96 0.988 0.09 0.1 1 2 3 4

Table 5 - Effect of attaching another group in the "meta" position of the ring. * - value displayed is an average of 2 values. ¥ - value

displayed is an average of 5 results. C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

AN3142 64* 2.58

AN3141 79* 2.71

Compounds Chemical Structure

IL-23 data AN2898 82¥ 1.01* 5.46 5 62* AN3155 AN3163 24 NC O NC Confidential O NC Cl Confidential O NC Me Confidential O NC F3C Confidential O NC MeO O Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R 2 Graph %inhibition at 10µM IC50(µM) Table 5 - Effect of attaching another group in the "meta" position of the ring. * - value displayed is an average of 2 values. ¥ - value

displayed is an average of 5 results. C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

Compounds Chemical Structure

IL-23 data 79 0.55 to 1.06 0.9969 0.03 0.05 0.74 to 5.35 0.9748 0.03 0.66 to 1.56 0.9944 0.01 0.77 AN3169 AN3187 83* 6 7 8 AN3348 16 83* 9 77* 1.01 1.99 9 10 AN3398 AN3399 O NC HO O Confidential O NC MeO Confidential O NC O EtO O Confidential O O O O N Confidential O O N Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R 2 Graph %inhibition at 10µM IC50(µM) Table 5 - Effect of attaching another group in the "meta" position of the ring. * - value displayed is an average of 2 values. ¥ - value

displayed is an average of 5 results. C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

Compounds Chemical Structure

IL-23 data 0.43 0.84 AN3415 AN3437 11 12 57 37 NC O O N O O Confidential NC O O N O MeN PF6 Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) 0.37 to 6.30 97 0.95 0.082 2.90 to 14.09 0.9837 0.67 2.51 to 9.03 0.9899 0.17 0.5 0.09 5 1 2 3 4 1.52 0 AN3237

Compounds Chemical Structure

IL-23 data

AN3153 63*

AN3188 38 6.39

AN3228 0

Table 6 - Compounds whose substituent groups in the "ortho" position are carbon-linked * - value displayed is an average of 2

values.C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

AN3202 66* 4.77 O NC F Confidential O NC Me Confidential O NC O O HO Confidential O EtO2C OMe Confidential O NC Cl Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) Compounds Chemical Structure

IL-23 data

Table 6 - Compounds whose substituent groups in the "ortho" position are carbon-linked * - value displayed is an average of 2

values.C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

0.08 0.03 0.12 0.32 1.08 9 10 6 7 8 89 39 25 AN3382 AN3273 47 AN3276 AN3278 AN3249 O 7 EtO2C O N NC Confidential O EtO2C CF3 Confidential NC O CHO Confidential O NC HO Confidential O NC N HCl Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) Compounds Chemical Structure

IL-23 data

Table 6 - Compounds whose substituent groups in the "ortho" position are carbon-linked * - value displayed is an average of 2

values.C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

0.95 to 3.66 0.9878 0.36 0.53 0.14 2.42 to 9.60 0.9883 0.2 2.2 13 14 15 11 12 52 14 4.81 AN3440 AN3441 1.86 AN3405 AN3406 AN3438 80* 37 63 O NC N O HCl Confidential O NC N N 2HCl Confidential NC O N HO Confidential NC O N H O H Confidential NC O H2N HCl Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R 2 Graph %inhibition at 10µM IC50(µM) 0.25 to 0.98 0.9872 0.34 3.78 to 45.24 0.957 0.22 0.06 0.05 1.08 5 1 2 3 4 AN3228 0

Table 7 - Compounds whose substituent groups in the "ortho" position are oxygen-linked * - value displayed is an average of 2

values. C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

AN3221 29

AN3220 42* 13.07

Compounds Chemical Structure

IL-23 data AN3219 76* 0.49 17 AN3239 O OH NC Confidential O OMe NC Confidential O O NC O EtO Confidential O NC O O HO Confidential O NC O Me2N Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R 2 Graph %inhibition at 10µM IC50(µM) Table 7 - Compounds whose substituent groups in the "ortho" position are oxygen-linked * - value displayed is an average of 2

values. C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

Compounds Chemical Structure

IL-23 data 1.38 to 3.03 0.996 0.05 0.92 to 2.08 0.9968 0.05 2.63 to 5.50 0.9967 0.14 14.91 to 33.92 0.9953 0.21 9 6 7 8 AN3274 47 2.04 22.94 3.81 1.38 AN3275 88 AN3296 AN3297 82* 44* NC O O O O Confidential NC O O N HCl Confidential O NC O O N Confidential O NC O O N MeN HCl Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) 2.133 to 6.071 0.9934 0.49 1.58 to 6.63 0.9876 0.18

Compounds Chemical Structure

IL-23 data

AN2728 53§ 3.60*

AN2957 64* 3.24

Table 8 - Comparison between AN2728 and AN2957 (the pyridine analog of AN2728). § - value displayed is an average of 11 values.

* - value displayed is an average of 2 values. § - value displayed is an average of 11 values. C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

Confidential

N NC

O

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R 2 _Graph %inhibition at 10µM IC50(µM) 86 6.42 5 0.55 to 1.06 0.9969 0.03 0.24 to 0.73 >0.9910 0.02 5 1 2 3 4 0.40* 0 AN3165

Compounds Chemical Structure

IL-23 data

AN2861 17‡ CBC

AN3148 28

AN3317 95†

Table 9 - Compounds with and without the pyridine ring in their structure. Compounds are grouped being the first one the structure

containing the phenyl ring and the second one the structure containing the pyridine ring. ‡ - value displayed is an average of 4 values. † - value displayed is an average of 3 values. * - value displayed is an average of 2 values. C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

AN3187 83* 0.77 Confidential O N HO O Confidential O NC MeO Confidential O N NC MeO Confidential O O MeO _Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R 2 _Graph %inhibition at 10µM IC50(µM) Compounds Chemical Structure

IL-23 data

Table 9 - Compounds with and without the pyridine ring in their structure. Compounds are grouped being the first one the structure

containing the phenyl ring and the second one the structure containing the pyridine ring. ‡ - value displayed is an average of 4 values. † - value displayed is an average of 3 values. * - value displayed is an average of 2 values. C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

98 0.08 0.66 to 1.56 0.9944 0.01 0.22 to 0.68 0.9914 0.01 6 7 8 AN3827 95 AN3399 1.01 0.39 83* AN3171 32 O N O MeO _Confidential O O N Confidential Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R 2 _Graph %inhibition at 10µM IC50(µM) 0.24 to 0.73 >0.9910 0.02 0.22 to 0.57 0.9941 0.03 0.33 to 0.61 0.9975 0.01 0.53 to 1.20 0.9954 0.04 0.55 to 3.94 5 1 2 3 4 AN3783 87

Table 10 - Compounds with and without the pyridine ring in their structure and cyano in the "para" position. Derivatives of AN3317 and

itself are displayed. † - value displayed is an average of 3 values. * - value displayed is an average of 2 values. C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

AN3716 96 0.45

AN3715 96 0.35

Compounds Chemical Structure

IL-23 data AN3317 95† 0.40* 81 AN3828 0.80 1.48 O N NC MeO Confidential Confidential Confidential Confidential Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R 2 _Graph %inhibition at 10µM IC50(µM) Table 10 - Compounds with and without the pyridine ring in their structure and cyano in the "para" position. Derivatives of AN3317 and

itself are displayed. † - value displayed is an average of 3 values. * - value displayed is an average of 2 values. C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

Compounds Chemical Structure

IL-23 data 0.60 to 1.36 59 0.9951 0.07 0.36 to 0.61 0.9981 0.10 to 0.73 0.9734 0.02 3.86 to 16.39 62 0.9857 0.55 0.24 to 4.50 10 9 6 7 8 AN3851 93 0.91 7.95 AN3889 98 AN3826 AN3874 0.27 0.47 95 60 65* AN3251 1.05 Confidential Confidential Confidential Confidential NC EtO Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R 2 _Graph %inhibition at 10µM IC50(µM) Table 10 - Compounds with and without the pyridine ring in their structure and cyano in the "para" position. Derivatives of AN3317 and

itself are displayed. † - value displayed is an average of 3 values. * - value displayed is an average of 2 values. C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

Compounds Chemical Structure

IL-23 data 0.87 to 3.48 >0.9980 0.06 0.63 to 4.64 0.9733 0.05 11 12 AN3709 AN3710 81† 75* 1.83* 1.71 Confidential Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) 3.06 to 24.77 99 0.99 0.05 82 1.4 90 0.92 77 1.17 to 3.77 0.991 0.13 5 1 2 3 4 AN3161 8

Table11 - Compounds with the pyridine ring on their chemical structure and non-cyano groups in the "para" position. † - value

displayed is an average of 3 values. * - value displayed is an average of 2 values. CBC - Can't Be Calculated. C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

AN3160 10* CBC

AN3156 4* CBC

Compounds Chemical Structure

IL-23 data AN3137 44* 14.13 48 AN3181 2.1 O N EtO O Confidential O N Et2N O Confidential N O N H O Confidential N O HO _Confidential N O O O Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) Table11 - Compounds with the pyridine ring on their chemical structure and non-cyano groups in the "para" position. † - value

displayed is an average of 3 values. * - value displayed is an average of 2 values. CBC - Can't Be Calculated. C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

Compounds Chemical Structure

IL-23 data 0.09 0.04 0.47 1.37 0.1 9 10 6 7 8 AN3199 43 0 AN3223 24 AN3225 AN3229 0 21 AN3236 N O O O Confidential O N Cl EtO O Confidential O N OHC Confidential O N N O Confidencial N O MeO2C MeO2C Confidencial

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) Table11 - Compounds with the pyridine ring on their chemical structure and non-cyano groups in the "para" position. † - value

displayed is an average of 3 values. * - value displayed is an average of 2 values. CBC - Can't Be Calculated. C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

Compounds Chemical Structure

IL-23 data 0.06 11 AN3240 0 N O EtO2C EtO Confidencial

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) 1.07 1.7 0.12 <0.01 CBC

Compounds Chemical Structure

IL-23 data

Ibudilast 0 CBC

Rolipram 21* CBC

Roflumilast 39

Table 12 - Known and commercially available PDE4 inhibitors. CBC - Can't Be Calculated. * - value displayed is an average of 2

values. C.I. - Confidence Interval. The compound name, chemical structure and data for IL-23 and PDE4 are shown.

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) >100 0.17 to 8.26 0.9772 >100 AN3054 4¥ CBC

Table 13 - Anacor compounds with no PDE4 inhibition and reasonable IL-23 inhibition. ¥ - value displayed is an average of 5 values.

* - value displayed is an average of 2 values. CBC - Can't Be Calculated. C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

AN3056 45¥ 3.11

Compounds Chemical Structure

IL-23 data O H2N HCl Confidential O HCl H2N _Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) >100 Table 14 - Anacor compounds with no PDE4 inhibition and reasonable IL-23 inhibition. CBC - Can't Be Calculated. C.I. - Confidence

Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

AN3483 0

Compounds Chemical Structure

IL-23 data AN3465 19 85 AN3485 AN3482 0 AN3484 52 Confidential Confidential Confidential Confidential Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) 45 2.4 5 1 2 3 4 10 AN3011

Compounds Chemical Structure

IL-23 data

AN2679 9

AN2904 19

AN2954 19

Table 15 - Anacor compounds tested for IL-23 that are not displayed in the remaining tables. * - value displayed is an average of 2

values. CBC - Can't Be Calculated. C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

AN2946 29* CBC Confidential O Confidential O O N N N N Confidential N Confidential HO F Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) Compounds Chemical Structure

IL-23 data

Table 15 - Anacor compounds tested for IL-23 that are not displayed in the remaining tables. * - value displayed is an average of 2

values. CBC - Can't Be Calculated. C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

9 10 6 7 8 30* 0* 38 AN3128 AN3062 11 AN3100 AN3116 AN3018 40 F H N Confidential HO Confidential S F Confidential H N S O O MeO Confidential O N Confidential

PDE4 Data % inhibition at 10µM IC50 (µM) 95% C.I. R2 Graph %inhibition at 10µM IC50(µM) Compounds Chemical Structure

IL-23 data

Table 15 - Anacor compounds tested for IL-23 that are not displayed in the remaining tables. * - value displayed is an average of 2

values. CBC - Can't Be Calculated. C.I. - Confidence Interval. The Anacor compound name, partial chemical structure and data for IL-23 and PDE4 are shown.

2.92 to 20.02 100 0.98 0.121 0.93 to 12.15 102 0.968 0.1 0.15 0.64 0.06 13 14 15 11 12 58* 7.64 AN3235 4 3.37 AN3170 AN3416 AN3674 65 0 41 AN3168 O HN O O Confidential N EtO2C O Confidential Confidential O EtO2C MeO Confidential O MeO O H2N O Confidential