`
`VI
`
`Cluster Analysis and
`the Design of Congener Sets
`
`V1-l POSSIBILITIES OF MOLECULAR
`MODIFICATION
`
`As the study of structure-activity relationships develops
`and especially as work in the biomedicinal chemical field
`gains momentum, the need to deal with many more vari-
`ables becomes pressing. From an economic standpoint,
`the probelm of ruling out
`irrelevant parameters and
`focusing on the relevant ones early in a structure-
`activity study is one of extreme importance. This pro-
`blem is both crucial and complex and deserves much
`more systematic attention than has been customarily
`allotted to it in the past.
`the number of deriva-
`that
`it has been pointed out’
`tives that can be made from a set of N substituents
`
`where m is the number of nonsyrnmctric positions on
`the parent compound is Nm; for example, if one were
`making derivatives of quinoline using the 166 well-chap
`
`it
`it‘ we made only one-billionth of the possibilities,
`would amount
`to one million molecules; yet relatively
`few drug modification programs make as many as a
`thousand derivatives.
`
`A general formula for calculating the possibilities is
`
`k _
`
`X
`
`ii!
`kl(r1 - k)?
`
`In this expression, X is the number of substituents to be
`considered,
`:1
`is
`the total number of nonsymmetric
`positions on the parent molecule, andk is the number of
`substitucnts to be placed on the parent compound at
`one time. With this forniifla we can consider simpler and
`more varied cases. For example, using only 100 substitu-
`ents from the 2000 of Appendix I and considering only
`three out of the seven possible positions on quinoline
`leads to 35,000,000 analogs. With 100 substituents and
`only two positions, one still has to face 210,000 possibil-
`ities. Even considcring only 20 substituents, two at a
`time, means 8400 possibilities. No wonder
`that me
`too” drugs are always being developed.
`
`in all possible com-
`actetized substituents of Table V1-l
`binations, this would amount to 1667 or approximately
`3.5 X 10”‘ molecules. Of" course. 16613 a small fraction
`of the almost 2000 substituents in Appendix I. What
`constitutes a reasonable sample of 10”’ congeners? Even
`48
`
`VI-2 THE COLLINEARITY PROBLEM
`
`Since the Cost oi'rnodii'ying a patent structure is so great
`and since the possibilities are so enormous, one wants to
`
`EXHIBIT
`
`Ex. 1018
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:25)
`Sun-Amneal-IPR2016-01104- Ex. 1018, p. 1 of 16
`
`
`
`Table VI-1 Well-Characterized” Aromatic Substituentsb
`
`H-
`
`H-
`
`Accpt
`
`Donor
`
`MR
`
`.9‘
`
`R
`
`0.86
`0.71
`0.14
`0.05
`1.23
`1.12
`-3.46
`- 1.20
`-0.28
`0.46
`0.00
`-0.67
`0.39
`-0.55
`-1.23
`-1.34
`-1.82
`-0.88
`-0.65
`0.41
`0.88
`1.04
`0.55
`1.44
`-0.57
`1.15
`0.41
`-4.36
`-1.04
`-0.26
`-0.65
`-0.32
`0.79
`0.17
`1.50
`-0.98
`— 1.49
`-0.38
`0.56
`-1.30
`- 1.40
`-0.02
`—- 1.03
`- 1.58
`- 1.63
`-0.88
`0.61
`0.74
`-0.47
`*1.18
`1.68
`0.40
`0.08
`-0.57
`
`0
`0
`0
`1
`0
`0
`1
`1
`1
`0
`0
`1
`0
`1
`1
`1
`1
`1
`1
`0
`0
`1
`1
`0
`1
`1
`1
`1
`1
`1
`1
`1
`0
`0
`0
`1
`1
`1
`0
`1
`1
`1
`1
`1
`1
`1
`0
`0
`1
`1
`0
`0
`1
`1
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`1
`1
`1
`1
`1
`1
`1
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`1
`0
`1
`0‘
`0
`0
`1
`1
`1
`0
`1
`1
`0
`1
`0
`0
`0
`0
`0
`1
`1
`0
`0
`1
`0
`
`8.88
`6.03
`0.92
`8.65
`9.89
`13.94
`63.5.1
`5.20
`7.36
`10.20
`1.03
`2.85
`9.22
`11.04
`5.42
`7.22
`12.28
`8.44
`23.16
`18.35
`5.02
`7.86
`12.86
`13.81
`6.33
`17.24
`13.40
`6.05
`18.33
`10.14
`6.88
`6.93
`13.39
`10.49
`18.60
`10.31
`9.81
`10.28
`5.65
`13.72
`22.19
`7.87
`7.19
`13.70
`13.49
`16.99
`13.82
`17.03
`10.33
`18.17
`9.23
`9.55
`14.30
`10.11
`
`0.44
`0.41
`0.43
`0.75
`0.57
`0.40
`0.63
`0.50
`0.67
`0.30
`0.00
`0.29
`0.28
`-0.07
`0.02
`0.06
`0.41
`0.17
`0.58
`0.23
`0.38
`0.38
`0.73
`0.35
`0.51
`0.51
`0.36
`-0.15
`0.52
`0.26
`0.31
`0.33
`0.10
`0.10
`0.09
`0.25
`0.24
`0.25
`-0.04
`0.04
`0.23
`0.26
`0.00
`0.52
`0.54
`0.39
`0.20
`0.13
`-0.11
`0.25
`0.44
`0.19
`0.36
`0.21
`
`-0.17
`-0.15
`-0.34
`0.22
`0.15
`-O. 19
`0.20
`0.45
`0.16
`-0. 13
`0.00
`-0.64
`-0.11
`0.18
`-0.68
`-0.40
`0.19
`-0.71
`0.07
`I-0.08
`0.19
`0.00
`0.26
`0.18
`0.19
`-0.09
`0.19
`0.13
`0.02
`-0.18-
`0.13
`0.15
`0.05
`0.03
`0.03
`-0.23
`0.14
`-0.13
`-0.13
`-0.28
`-0.05
`-0.51
`0.00
`0.01
`0.22
`0.00
`-0.18
`-0.12
`-0.74
`-0.20
`0.11
`0.05
`-0.21
`-0.18
`
`0.39
`0.37
`0.34
`0.80
`0.61
`0.35
`0.68
`0.62
`0.71
`0.27
`0.00
`0.12
`0.25
`-0.01
`-0.16
`-0.04
`0.46
`-0.02
`0.60
`0.21
`0.43
`0.38
`0.79
`0.40
`0.56
`0.48
`0.41
`-0.10
`0.52
`0.21
`0.35
`0.37
`0.12
`0.11
`0.10
`0.19
`0.28
`0.22
`-0.07
`-0.03
`0.22
`0.12
`0.00
`0.52
`0.60
`0.39
`0.15
`0.10
`-0.30
`0.20
`0.47
`0.21
`0.30
`0.16
`
`I
`
`0.23
`0.23
`0.06
`0.91
`0.68
`O. 18
`0.78
`0.91
`0.78
`0.15
`0.00
`-0.37
`0.15
`0.12
`-0.66
`-0.34
`0.57
`-0.55
`0.61
`0.13
`0.54
`0.35
`0.93
`0.50
`0.66
`0.38
`0.52
`0.00
`0.50
`0.06
`0.42
`0.45
`0.14
`0.12
`0.11
`0.00
`0.36
`0.10
`-0:17
`-0.24
`0.16
`-0.27
`0.00
`0.49
`0.72
`0.36
`0.00
`0.00
`-0.84
`0.03
`0.52
`0.23
`0.12
`0.01
`49
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:21)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:25)
`Sun-Amneal-IPR2016-01104- Ex. 1018, p. 2 of 16
`
`Br
`Cl
`
`F S
`
`02 F
`SF5
`
`I I
`
`02
`NO
`
`NNN
`
`H O
`
`H
`SH
`
`B(OH)2
`NH2
`NHOH
`
`SO2NH2
`NHNH2
`S-C1-1—Tetrazo1y1
`N=CCl2
`CF3
`OCF3
`SO2CF3
`SCF3
`CN
`NCS
`SCN
`
`CO2’
`1-Tetrazolyl
`NHCN
`CHO
`
`COQH
`CH2BI'
`CH2 C1
`CH2 I
`NHCHO
`
`CONH2
`CH=NOH
`
`CH3
`NHCONH2
`NHC=S(NH;)
`OCH3
`CH2OH
`SOCH3
`SO2CH3
`OSO2CH3
`SCH3
`SCCH3
`NHCH3
`NHSO2CH3
`CF; CF3
`CECH
`
`NHCOCF3
`CH2CN
`
`
`
`Table VI-1 Well-Characterized” Aromatic Substituentsb (Continued)
`
`H-
`
`H-
`
`17
`
`Accpt
`
`Donor
`
`MR
`
`.9‘
`
`CH=CHNO2-(trans)
`C1-I=CH2
`N1-1C=O(CH2C1)
`COCH3
`SCOCH3
`OCOCH3
`CO2CH3
`NHCOCH3
`NHCO2CH3*
`C=0(NHCH3)
`CH=NOC1-13
`NHC=S(C1-I3)
`CH=NNHC=S(NH2)
`CH2CH3
`CH=NNHC0NHNH2
`CH2 OCH3
`OCHQCH3
`SOC1H5 *
`SC2H5
`SeC2H5 *
`NHC2H5
`SO2C2H5*
`N(CH3 )2
`NHSO2C2H5*
`P(CH3 )2
`PO(OCH3 )2
`C(OH)(CF3)2
`CH=CHCN
`
`Cyclopropyl
`COC2H5*
`SCOC2 H5 *
`CO2C2H5
`OCOC,H5*
`CH,CH2CO2H
`NHCO2C21-15
`CONHC2H5*
`NHCOC2115 *
`CH=NOC2H5*
`N1-1C=S(C2H5)*
`CH(CH3 )2
`C3115
`NHC:S(NHCgH5)
`OCH(CH3)2
`OC3H-,
`CHQOCQHS *
`SOC3H7*
`SO2C3H7*
`SC31-17*
`SeC3H7*
`NHC3H7*
`
`131-IS02C3H-,*
`N(CH3)3
`Si(CH3 )3
`CH=C(CN)2
`50
`
`0.1 1
`0.82
`-0.50
`-0.55
`0.10
`-0.64
`-0.01
`-0.97
`-0.37
`-1.27
`0.40
`-0.42
`-0.27
`1.02
`-1.32
`-0.78
`0.38
`-1.04
`1.07
`1.28
`0.08
`-1.09
`0.18
`-0.64
`0.44
`- 1.18
`1.28
`-0.17
`
`1.14
`0.06
`0.64
`0.51
`-0. 10
`-0.29
`0.17
`-0.73
`-0.43
`0.94
`0.12
`1.53
`1.55
`-0.71
`0.85
`1.05
`-0.24
`-0.50
`-0.55
`1.61
`1.82
`0.62
`
`-0.10
`"$.96
`2.59
`0.05
`
`1
`0
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`0
`1
`1
`1
`1
`0
`0
`1
`1
`1
`1
`0
`1
`1
`1
`
`0
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`0
`0
`1
`1
`1
`1
`1
`1
`0
`0
`1
`
`1
`0
`0
`1
`
`0
`0
`I
`0
`0
`O
`O
`1
`1
`1
`0
`1
`1
`0
`1
`0
`0
`0
`0
`0
`1
`0
`0
`1
`0
`0
`1
`0
`
`O
`0
`0
`0
`0
`1
`1
`1
`1
`0
`1
`O
`0
`1
`O
`0
`O
`O
`0
`0
`0
`1
`
`1
`0
`0
`0
`
`16.42
`10.99
`19.77
`11.18
`18.42
`12.47
`12.87
`14.93
`16.53
`14.57
`14.93
`23.40
`29.92
`10.30
`24.86
`12.07
`12.47
`18.35
`18.42
`21.68
`14.98
`18:14
`15.55
`22.82
`21.19
`21.87
`15.18
`16.23
`13.53
`15.83
`23.07
`17.47
`17.12
`16.52
`21.18
`19.22
`19.58
`19.58
`28.05
`14.96
`14.96
`31.66
`17.06
`17.06
`16.72
`23.00
`22.79
`23.07
`26.33
`19.63
`27.47
`21.20
`24.96
`21.53
`
`0.33
`0.07
`0.23
`0.32
`0.36
`0.41
`0.33
`0.28
`0.14
`0.34
`0.39
`0.27
`0.46
`-0.05
`0.23
`0.01
`0.22
`0.52
`0.23
`0.13
`-0.11
`0.54
`0.10
`0.25
`"008
`-0.37
`0.28
`0.26
`-0.03
`0.32
`0.36
`0.33
`0.41
`-0.02
`0.14
`0.34
`0.28
`0.39
`0.27
`-0.05
`-0.06
`0.38
`0.30
`0.22
`0.01
`0.52
`0.54
`0 23
`0.13
`‘0.11
`0.25
`0.89
`-0.04
`0.58
`
`(R
`
`-0.05
`*0.08
`-0.25
`0.20
`0.11
`-0.07
`0.15
`“0.26
`‘0.28
`0.05
`-0.06
`“0.13
`‘0.02
`I ‘0.10
`‘0.05
`0.02
`-0.44
`0.01
`-0.18
`-0.12
`-0.51
`0.22
`*0.92
`-0.20
`0.39
`0.19
`0.05
`‘0.07
`"‘0.19
`0.20
`0.11
`0.15
`-0.07
`“0.05
`‘0.28
`0.05
`*0.26
`*0.06
`"0.13
`-0.10
`-0.08
`-0.28
`-0.72
`-0.45
`0.02
`0.01
`0.22
`-0.18
`-0.12
`-0.51
`-0.20
`0.00
`-0.04
`0.30
`
`am
`
`0.32
`0.05
`0.17
`0.38
`0.39
`0.39
`0.37
`0.21
`0.07
`0.35
`0.37
`0.24
`0.45
`-0.07
`0.22
`0.02
`0.10
`0.52
`0.18
`0.10
`‘0.24
`0.60
`-0.15
`0.20
`0.03
`0.42
`0.29
`0.24
`-0.07
`0.38
`0.39
`0.37
`0.39
`‘0.03
`0.07
`0.35
`0.21
`0.37
`0.24
`-0.07
`-0.07
`0.30
`0.10
`0.10
`0.02
`0.52
`0.60
`0.15
`0.10
`-0.24
`0.20
`0.88
`-0.04
`0.66
`
`0.26
`-0.02
`-0.03
`0.50
`0.44
`0.31
`0.45
`0.00
`-0.15
`0.36
`0.30
`0.12
`0.40
`-0.15
`0.16
`0.03
`-0.24
`0.49
`0.03
`0.00
`-0.61
`0.72
`-0.83
`0.03
`0.31
`0.53
`0.30
`0.17
`-0.21
`0.50
`0.44
`0.45
`
`0.31
`-0.07
`-0.15
`0.36
`0.00
`0.30
`0.12
`-0.15
`-0.13
`0.07
`-0.45
`-0.25
`0.03
`0.49
`0.72
`0.00
`0.00
`-0.61
`0.03
`0.82
`-0.07
`0.84
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:22)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:25)
`Sun-Amneal-IPR2016-01104- Ex. 1018, p. 3 of 16
`
`
`
`
`
`E1
`
`-
`
`f
`%
`
`i
`
`5
`
`Table VI-1 Well-Characterized” Aromatic Substituentsb (Continued)
`
`.
`
`;
`§
`%
`§
`;
`1
`§
`1
`f
`E
`1
`1
`=
`1
`.1
`
`I
`1-
`.1
`
`
`71 J__ .Accpt Donor MR 9 (R Om op
`
`
`
`
`
`
`1
`0
`1-Pyrryl
`0.95
`21.85
`0.50
`-0.09
`0.47
`0.37
`i
`2-Thienyl
`1.61
`0
`0
`24.04
`0.10
`0.04
`0.09
`0.05
`3-Thicnyl
`1.81
`0
`0
`24.04
`0.04
`-0.06
`0.03
`-0.02
`CH=CHCOCH3
`-0.06
`1
`0
`21.10
`0.28
`-0.27
`0.21
`-0.01
`CH=CHCO2CH3*
`0.32
`1
`0
`22.56
`0.24
`-0.19
`0.19
`0.03
`COC3H-,*
`0.53
`1
`0
`20.48
`0.32
`0.20
`0.38
`0.50
`SCOC3H-,*
`1.18
`1
`0
`27.72
`0.36
`0.11
`0.39
`0.44
`OCOC3H7*
`0.44
`1
`0
`21.77
`0.41
`-0.07
`0.39
`0.31
`C02C3H7*
`1.07
`1
`0
`22.17
`0.33
`0.15
`0.37
`0.45
`(CH2)3CO2H*
`0.25
`1
`1
`21.17
`-0.02
`-0.05
`-0.03
`-0.07
`CONHC3H7*
`-0.19
`1
`1
`23.87
`0.34
`-0.05
`0.35
`0.36
`NHCOC3H»,*
`0.11
`1
`1
`24.23
`0.28
`-0.26
`0.21
`0.00
`NHC=OCH(CH3)2
`-0.18
`1
`1
`24.23
`0.18
`-0.26
`0.11
`-0.10
`NHCO2C3H7*
`0.71
`1
`1
`25.83
`0.14
`-0.28
`0.07
`-0.15
`CH=NOC3H7*
`1.48
`1
`0
`24.23
`0.39
`-0.06
`0.37
`0.30
`NH‘C=S(C_-.,H7)*
`0.66
`1
`1
`32.70
`0.27
`-0.13
`0.24
`0.12
`C4H9
`2.13
`0
`0
`19.61
`-0.06
`-0.11
`-0.08
`-0.16
`C(CH3)3
`1.98
`0
`0
`19.62
`-0.07
`-0.13
`-0.10
`-0.20
`0124119
`1.55
`1
`0
`21.66
`0.25
`-0.55
`0.10
`-0.32
`CI-I2OC3H7*
`0.30
`1
`0
`21.37
`0.01
`0.02
`0.02
`0.03
`N(C2H5)2 ,
`1.18
`1
`0
`24.85
`0.01
`-0.91
`-0.23
`-0.90
`NHC4H9*
`1.16
`1
`1
`24.26
`-0.28
`-0.25
`-0.34
`-0.51
`P(C2H5)2 *
`1.52
`0
`0
`30.49
`-0.08
`0.39
`0.03
`0.31
`PO(OC2H5)2*
`-0.10
`1
`0
`31.16
`0.37
`0.19
`0.42
`0.53
`CH2Si(CH3)3
`2.00
`0
`0
`29.61
`-0.15
`-0.07
`-0.16
`-0.21
`CH=CHC0C2H5*
`0.48
`1
`0
`25.75
`0.28
`-0.27
`0.21
`-0.01
`CH=CHCO2C2H5
`0.86
`1
`0
`27.21
`0.24
`-0.19
`0.19
`0.03
`CH=NOC4H9*
`2.02
`1
`0
`28.88
`0.39
`-0.06
`0.37
`0.30
`C5Hu*
`2.67
`0
`0
`24.26
`-0.06
`-0.08
`-0.08
`-0.16
`CH2OC4H9*
`0.84
`1
`0
`26.02
`0.01
`0.02
`0.02
`0.03
`C61-I5
`1.96
`0
`0
`25.36
`0.08
`-0.08
`0.06
`-0.01
`N=NC5H5
`1.69
`0
`0
`31.31
`0.28
`0.13
`0.32
`0.39
`OC6H5
`2.08
`1
`0
`27.68
`0.34
`-0.35
`0.25
`—o_o3
`SO2C6H5
`0.27
`1
`0
`33.20
`0.56
`0.18
`0.61
`0.70
`0S02C6Hs
`0.93
`1
`0
`36.70
`0.36
`0.00
`0.36
`0.33
`NHC6H5
`1.37
`1
`1
`30.04
`-0.02
`-0.38
`-0.12
`-0.40
`NHSO2C5H5
`0.45
`1
`1
`37.88
`0.21
`-0.18
`0.16
`0.01
`2,5-di-Me-1-pyny1
`1.95
`1
`0
`31.15
`0.52
`-0.10
`0.49
`0.38
`CH=CHCOC3H7*
`1.02
`1
`0
`30.40
`0.28
`-0.27
`0.21
`—--0.01
`cH=cHco2c3H7=«=
`1.40
`1
`0
`31.86
`0.24
`-0.19
`0.19
`0.03
`Cyclohexyl
`2.51
`0
`0
`26.69
`-0.13
`-0.10
`-0.15
`-0.22
`2-Benzthjazolyl
`2.13
`1
`0
`38.88
`0.25
`0.06
`0.27
`0.29
`COC6H5
`1.05
`1
`0
`30.33
`0.30
`0.16
`0.34
`0.43
`co,c.,,115
`1.46
`1
`0
`32.31
`0.33
`0.13
`0.37
`0.44
`0COC6H5
`1.46
`1
`0
`32.33
`0.23
`-0.08
`0.21
`0.13
`N-'=CHC6H5
`-0.29
`1
`0
`33.01
`0.09
`-0.63
`-0.08
`-0.55
`cH=Nc6H5
`-0.29
`1
`0
`33.01
`0.31
`0.13
`0.35
`0.42
`NHCQC6HS
`0.49
`1
`1
`34.64
`0.09
`-0.27
`0.02
`-0. 19
`c112c6H5
`2.01
`0
`0
`30.01
`-0.08
`-0.01
`-0.08
`-0.09
`CH2OC6H5
`1.66
`1
`0
`32.19
`0.02
`0.02
`0.03
`0.04
`CECC6H5
`2.65
`0
`0
`33.21
`0.12
`0.05
`0.14
`0.16
`CH=NNI—[C0C6}-[5
`0.43
`1
`1
`42.37
`0.33
`0.20
`0.39
`0.51
`CH2Si(C2H.=.)3*
`3.26
`0
`0
`43.56
`-0 15
`-0.07
`-0.16
`-0.21
`cH=cHc6H5_(t,ans)
`2.68
`0
`0
`34.17
`0.06
`-0.12
`0.03
`-0.07
`51
`
`
`
`K
`6
`
`*
`
`i:
`1
`1
`
`jg
`
`;;
`-
`
` a mvmm.m—1.~.....
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:23)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:25)
`Sun-Amneal-IPR2016-01104- Ex. 1018, p. 4 of 16
`
`
`
`Table V1-1 Well-Characterized” Aromatic Substituents” (Continued)
`
`C]-[=CHCQC6HS
`FeH0¢eny1
`N(CsHs)2
`P=O(C5H5)2
`
`11
`
`0.95
`2.46
`3.61
`0.70
`
`H-
`
`H-
`
`Accpt
`
`Donor
`
`MR
`
`9
`
`(R
`
`am
`
`op
`
`1
`0
`1
`1
`
`0
`0
`0
`0
`
`40.25
`48.24
`54.95
`59.29
`
`0.22
`-0.15
`0.07
`0.31
`
`-0.15
`-0.04
`-0.29
`0.24
`
`0.18
`-0.15
`0.00
`0.38
`
`0.05
`-0.18
`-0.22
`0.53
`
`“By we11»characterized, we mean that the set of eight constants is known for each substituent; we do not mean to
`imply that all of the constants are of the highest accuracy.
`8 Substituents are ordered first by number of C, then by number of H, and the remaining elements alphabetically.
`
`TableVI-2 Well-Characterized” Aliphatic Substituents
`
`Br
`C1
`
`F
`I
`N02
`H
`OH
`SH
`
`NH;
`CBr3
`CC13
`CF3
`CN
`SCN
`
`C02‘
`CO2H
`CH2Br
`CH2C1
`CH2I
`CONH2
`CH=NOH
`
`CH3
`NHCONH;
`OCH3
`CHQOH
`SOCH3
`OSO2CH3
`SCH3
`NHCH3
`CFQCF3
`CECH
`
`~
`
`CH2CN
`CH=CHNO2-trans
`CH=C1-I2
`COCH3
`OCOCH3
`CO;CH3
`NHCOCH3
`C=O(NHCH3)
`52
`
`-
`
`Fr
`
`0.20
`0.06
`
`-0.38
`0.59
`-1.16
`0.23
`-1.64
`-0.23
`
`— 1.54
`2.03
`1.61
`0.29
`-1.27
`-0.48
`
`—5.19
`-1.11
`0.74
`0.60
`1.13
`-2. 18
`-1.02
`
`0.77
`-2.90
`-1.54
`-1.10
`-2.24
`-1.34
`-0.02
`-1.38
`1.34
`0.01
`
`-0.73
`-0.63
`0.88
`- 1.13
`-0.72
`-0.72
`-1.94
`-1.94
`
`H-Accpt
`
`H-Donor
`
`0
`0
`
`0
`0
`1
`0
`1
`0
`
`1
`0
`0
`0
`1
`1
`
`1
`1
`0
`0
`0
`1
`1
`
`0
`1
`1
`1
`1
`1
`0
`1
`0
`0
`
`1
`1
`0
`1
`1
`1
`1
`1
`
`0
`0
`
`0
`0
`0
`0
`1
`1
`
`1
`0
`0
`0
`0
`0
`
`0
`1
`O
`0
`0
`1
`1
`
`0
`1
`0
`1
`0
`0
`0
`1
`0
`1
`
`0
`0
`0
`0
`0
`0
`1
`1
`
`A/IR
`
`8.80
`5.93
`
`1.05‘
`13.76
`6.71
`1.03
`2.55
`8.76
`
`4.37
`28.81
`20.12
`5.02
`5.39
`13.40
`
`5.15
`6.03
`13.39
`10.49
`18.60
`9.81
`10.28
`
`5.65
`13.72
`7.33
`7.19
`13.70
`16.99
`13.33
`9.11
`9.23
`8.25
`
`10.11
`16.42
`9.79
`10.29
`11.85
`11.85
`13.71
`13.39
`
`W
`
`0.44
`0.41
`
`0.43
`0.40
`0.67
`0.00
`0.29
`0.28
`
`0.02
`0.27
`0.31
`0.38
`0.51
`0.36
`
`-0.15
`0.33
`0.10
`0.10
`0.09
`0.24
`0.25
`
`-0.04
`0.04
`0.26
`0.00
`0.52
`0.39
`0.20
`'0.1l
`0.44
`0.19
`
`0.21
`0.33
`0.07
`0.32
`0.41
`0.33
`0.28
`0.34
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:24)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:25)
`
`
`
`
`. Table VI-2 Well-Characterized‘ Aliphatic Substituents (Continued)
`
`CH2CH3
`OCH2CH3
`CH2OCH3
`SOC2I-I5 *
`SCZHS
`CH2Si(CH3)3
`NHCZH5
`N(CH3 )2
`CH=CHCN
`
`Cyclopropyl
`COC2H5*
`CO2 CZH5
`OCOC2H5 *
`EtCO2H
`NHCO2C2H5
`CONHC2H5 *
`NHCOC2H5 *
`CH(CH3)2
`C3H7
`OCH(CH3)2
`OC3H7
`CH2OC2 H5 *
`
`NHC3H7*
`Si(CH3)3
`2-Thienyl
`3-Thienyl
`CH:-CHCOCH3
`CH=CHCO2 CH3 *
`COC3H7*
`
`CO2C3H7*
`(CH2 )3 C02H*
`NHCOC3H7*
`CONHC3H7*
`C4H9
`C(CH3 )3
`OC4H9
`CH2OC3H7*
`A NHC4H9*
`N(C2 H5 )2
`H5 *
`CH=CHC02C2 H5
`C5H11 *
`CH2OC4H9 *
`
`OC6H5
`
`NHC6 H5
`2-Benzthiazolyl
`CH=CHC0C3H-, *
`CH=CHC02C3H-,*
`COC5H5
`CO2 C51-[5
`
`Fr
`
`1.43
`-0.51
`-0.23
`-1.70
`0.52
`3.62
`-0.84
`-0.64
`-0.74
`1.49
`-0.59
`-0.18
`-0.18
`-0.03
`-1.40
`-1.40
`-1.40
`1284
`1.97
`-0.10
`0.03
`0.03
`-1.16
`1.06
`-0.30
`2.96
`1.58
`1.58
`-0.13
`0.28
`-0.05
`0.36
`0.36
`0.51
`-0.86
`-0.86
`2.51
`2.22
`0.57
`0.57
`0.24
`0.16
`0.41
`0.82
`3.10
`1.11
`1.90
`1.22
`-0.39
`0.75
`1.78
`0.95
`1.36
`0.69
`0.60
`
`H-Accpt
`
`H-Donor
`
`MR
`
`0
`1
`1
`1
`0
`0
`1
`1
`1
`0
`1
`1
`1
`1
`1
`1
`1
`0
`0
`1
`1
`1
`1
`0
`1
`0
`0
`0
`1
`1
`1
`1
`1
`1
`1
`1
`0
`0
`1
`1
`1
`1
`1
`1
`0
`1
`0
`1
`1
`1
`1
`1
`1
`1
`1
`
`0
`0
`0
`0
`0
`0
`1
`11
`0
`0
`0
`0
`0
`1
`1
`1
`1
`0
`0
`0
`0
`0
`0
`0
`1
`0
`0
`0
`0
`0
`0
`0
`0
`1
`1
`1
`0
`0
`0
`0
`1
`0
`0
`0
`0
`0
`0
`0
`0
`1
`0
`0
`15
`0
`0
`
`10.30
`11.93
`12.07
`18.35
`17.93
`29.61
`13.76
`14.14
`15.33
`13.53
`14.65
`16.76
`17.12
`16.52
`19.96
`18.04
`18.36
`. 14.96
`14.96
`16.52
`16.52
`16.72
`23.00
`22.58
`18.41
`24.96
`24.04
`24.04
`19.92
`21.85
`19.30
`21.77
`21.46
`21.17
`23.01
`22.69
`19.61
`19.62
`21.12
`21.37
`23.06
`23.44
`24.57
`26.03
`24.26
`26.02
`25.36
`27.02
`33.20
`28.50
`38.88
`29.22
`26.50
`29.96
`31.60
`
`70.05
`0.22
`0.01
`0.52
`0.23
`-0.15
`-0.11
`0.10
`0.26
`-0.03
`0.32
`0.33
`0.41
`—0.02
`0.14
`0.34
`0.28
`-0.05
`-0.06
`0.30
`0.22
`0.01
`0.52
`0.23
`-0.11
`-0.04
`0.10
`0.04
`0.28
`0.24
`0.32
`0.41
`0.33
`-0.02
`0.28
`0.34
`-0.06
`-0.07
`0.25
`0.01
`"0.28
`0.01
`0.28
`0.24
`-0.06
`0.01
`0.08
`0.34
`0.56
`-0.02
`0.25
`0.28
`0.24
`0.30
`0.33
`53
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:25)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:25)
`Sun-Amneal-IPR2016-01104- Ex. 1018, p. 6 of 16
`
`
`
`54
`
`Cluster Analysis and the Design of Congener Sets
`
`Table V1-2 Well-Characterized" Aliphatic Substituents (Continued)
`
`Fr
`
`1.22
`-0.03
`2.44
`1.71
`4.82
`2.72
`1.81
`2.43
`2.43
`
`.
`
`OCOC5H5
`NHCOC6H5
`CH2C6H5
`CH2OC6H5
`CH2Si(C2H5)3*
`CH=CHC5H5-(trans)
`CH=CHCOC6H5
`Ferrocenyl
`N(C5H5)2
`
`“See footnote a, Table VI-1.
`
`H-Accpt
`
`H-Donor
`
`1
`l
`0
`1
`0
`0
`1
`O
`l
`
`0
`1
`0
`0
`0
`0
`0
`0
`0
`
`MR
`
`32.33
`34.28
`30.01
`31.77
`43.56
`32.97
`39.05
`48.24
`53.55
`
`.?
`
`0.23
`0.09
`-0.08
`0.02
`-0.15
`0.06
`0.22
`-0.15
`0.07
`
`gain the maximum amount of information possible from
`each derivative that
`is to be tested in some standard
`
`system. This means that at any given point in time, one
`wants to consider all of the known variables that cause
`
`change in activity of the parent molecule when a sub-
`stituent change is made. For quantitative work, we are
`limited to those variables that can be defined in numer-
`
`ical terms. Four such parameters, 17, MR, 9 and (R, are
`well characterized and have been shown to be relevant in
`
`many biomedicinal QSAR. The problem of selecting a
`set of substituents that would be independent with re-
`spect to these four variables is illustrated in Tables VI-3
`and VI-4.2
`
`Table VI-3 Two Sets of Substituents for Compound
`Modification
`
`Set A
`
`Set B
`
`CH3
`NO;
`COCH3
`CECH
`SCH3
`
`NHCGH5
`OCH, CI-I2CH3
`SO2CH2CH2CH3
`I
`CH2 Cl
`
`CH3
`CF3
`F
`CN
`N02
`
`CHZCI-I3
`NHCOCH3
`CONH2
`SOZNH2
`OCF3
`
`Table VI—4 Squared Correlation Matrices for Substitu-
`ents of Table V1-3”
`
`Set A
`
`Set B
`
`(R
`
`37 MR
`
`11
`
`(R
`
`9
`
`MR
`
`11
`0.94 0.30 0.32
`(R
`1
`0.32
`0.38
`1
`0.09 9
`1
`MR
`
`1 0.09 0.08
`1
`0.15
`1
`
`0.26
`0.03
`0.03
`1
`
`11
`
`1
`
`7!
`(R
`37
`MR
`
`“The figures are r2 for the correlation between variables.
`
`From an inspection of these two sets, even knowing
`the values of 11’, W,
`(R, and MR, it is not possible to
`decide which is the better set as far as independence
`among the four variables is concerned. However, it can
`easily be done by formulating the correlation matrices
`for the two sets of substituents as in Table VI-4. One
`
`sees immediately from the correlation matrix that 11 and
`(R are almost completely collinear in Set A; either of
`these two vectors would give almost the same result in
`a correlation equation. Hence, one cannot be sure
`whether the correct variable is 1r or (R or if. indeed both
`
`variables are involved. All of the other variables except
`9 and MR show significant collinearity. Selecting data
`Set A would mean that one would have to make more
`
`derivatives if either 7r or (R turned up in the correlation
`equation to resolve their relative importance. Only 11 and
`MR show significant collinearity in data Set B, and this
`is not serious for most purposes. Although 10 substitu-
`ents would not be enough to work in a system where
`four variables are influencing a given process, they do
`illustrate the collinearity problem.
`Since only a tiny fraction of the almost infinite num-
`ber of possibilities can be studied in drug modification,
`we cannot afford redundancy. Testing two congeners
`that have essentially the same physicochemical pro-
`perties is most likely to be less valuable than testing two
`with different properties. One often sees sets of con-
`geners in the literature where all of the normal alkyl
`groups from methyl to decyl have been made and tested.
`While this may give one useful information on optimum
`lipophilicity, it also may not. The variables 7r and MR for
`such substituents are prefectly collinear so that hydro-
`phobicity and bulk tolerance effects cannot be resolved
`with such a set of congeners. Of course, such a data set
`would reveal nothing about
`the electronic effect of
`substituents.
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:26)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:25)
`Sun-Amneal-IPR2016-01104- Ex. 1018, p. 7 of 16
`
`
`
`VI-3 Cluster Analysis
`
`55
`
`
`
`
`
`
`‘».E1+511
`fl3
`El
`
`
`
`Amalgamationdistance
`
`at
`
`4-
`
`rear
`
`an
`
`«-4-
`
`1»
`
`1-06»
`
`4:
`
`«-4:
`
`«Q 2 ii are
`
`41»
`
`4|‘
`
`I-
`
`ABCDEFGHIJKLIMNOPOIRSTUWWXYZAA
`Substituents
`Figure Vl-1
`
`VI-3 CLUSTER ANALYSIS
`
`The problem of selecting a set of substituents with in-
`dependence among several parameters has concerned
`medicinal chemists for some time. Meyer and Hemmi3
`pointed out in 1935 that one could not gain information
`about the relative role of physicochemical properties of
`narcotics from the study of sets of homologous series.
`The alkyl groups are completely collinear with respect to
`many parameters.
`Craig“ first emphasized the importance of plotting 11 vs
`or to obtain a set of substituents with minimal collinear-
`ity and, at the same time, good coverage of substituent
`space, Wooton et a1.5 have developed a sophisticated
`algorithm for substituent selection.
`Hierarchical clustering can greatly assist in the proper
`selection of substituents from the ever-growing number
`available. Most computer centers have available the
`UCLA biomed BMDP2M, BMDPIM, or the Xerox Data
`Systems CLUSANL programs. The clustering in this
`chapter has been done with the Xerox program.
`
`In this program, the parameters X’ can be placed on
`the same scale via eq VI-1. X in this expression is the
`mean value of a given parameter and S,- is the standard
`
`=Xl'Ic—fz'
`SI
`
`Xzk
`
`(VI- 1 )
`
`deviation. This equation defines the deviation of each
`point from the group average X,- in units of the standard
`deviation. If we have N substituents, each with K para-
`meters,
`then the Euclidian distance between them is
`given by
`
`K
`1
`d,~,- = lk§1(Xi‘k — AW] *2 211- 1, 2. . .N (VI-2)
`
`In hierarchical clustering, all interpoint distances in K
`space are calculated via eq VI-2, and the two closest
`points are clustered into a pseudo point (see Figure
`VI-I). In Figure VI—l ,R and S are the two points closest
`to each other; the pseudo point is formed from these
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:27)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:25)
`Sun-Amneal-lPR2016-01104- Ex. 1018, p. 8 of 16
`
`
`
`56
`
`two and is then clustered with T; this group of three is
`then clustered withP and Q. Note that H is so isolated in
`data space that
`it does not enter a cluster until
`the
`penultimate group. At the bottom of the graph all points
`are distinct units in data space; at the top, all have been
`forced into a single cluster.
`The composition of the clusters that one obtains
`depends entirely on the parameters that are used in eq
`
`VI-2 to obtain the d,-]-. If one uses parameters not pertin-
`ent
`to the data set for which substituents are being
`selected, this will not result in a well-balanced group of
`congeners on which to base the QSAR. For this reason,
`in the case of substituents for use in an aromatic system
`we have clustered only on 1r, 37 , <R,MR, and H-bonding;
`these are established variables that can be shown to be
`
`reasonably independent. The parameters am and up have
`been shown to be strongly related? This can be seen
`from the correlation matrix of Table VI-9 for all 166
`aromatic substituents.
`
`If steric effects are involved, it is assumed that MR will
`approximate the
`steric properties of substituents.‘
`Since at the present time we do not have a set of hydro-
`gen-bonding parameters, we have assigned hydrogen
`bond acceptors a value of 1, hydrogen bond donors a
`value of 1 (at present there are no substituents acting
`only as donors), and other substituents a value of 0. We
`believe that
`the inclusion of hydrogen bonding gives
`better balanced sets of clusters.
`
`The aliphatic constants of Table VI-2 have been
`clustered on the same variables (Table VI-6), except that
`(R has not been included. These constants refer to
`
`systems where resonance is not present.
`The 166 “aromatic” substituents of Table VI-l have
`
`been forced into three sets of clusters containing 20, 10,
`and 5 substituents, respectively. Note that in the‘“20”
`set the clusters vary in size from 2 to 16 members. Those
`substituents closest
`to each other in six-dimensional
`
`space are forced into clusters; hence, when choosing a
`set of substituents, one should, insofar as possible, select
`one substituent from each cluster. Some substituents
`
`turn out to be rather strange from the point of view of
`synthesis, metabolic stability, or chemical reactivity; for
`this reason, one may need to take two substituents from
`the same cluster.
`
`When one forces 166 substituents into 20 clusters, it
`means of necessity that the substituents in a particular
`set may not appear similar from the traditional view-
`point of organic chemistry. For example,
`in the “5”
`cluster set of Table VI-5 we find H and cyclopropyl to-
`gether. If, instead of forcing 166 substituents into five
`clusters, we had compressed them to a lesser degree into
`60, then a single cluster with H and Me would result; the
`
`Cluster Analysis and the Design of Congener Sets
`
`similarity is obviously much closer. At the “60” cluster
`level, 15 substituents are so far removed from the others
`
`in data space that they “cluster” alone [e.g., F , I02,
`CO2", N(CH3)3] .
`0
`One does not assume by selecting one substituent
`from each group that a set of substituents perfectly
`orthogonal with respect to each vector will be obtained.
`The next imperative step is to form a correlation matrix
`as in Table V1-4. The collinearity between two variables
`will often be unacceptably high; a plot of the values of
`one variable against the other helps one choose new sub-
`stituents to break up this feature.
`For example, a chemist selects a substituent from each
`cluster in the “l0” cluster set of aromatic substituents
`giving the following groups: Br, N02, N(CH3)3, OH,
`SOZNH2, OCF3, NCS, NHCOC5H5, OCH3, C4H9. The
`correlation matrix is given in Table VI-7. This is not a
`satisfactory set because of the high collinearity between
`1: and .9‘ and between H-acceptor and MR.
`Discussing this set with medicinal chemists brings out a
`number of further objections. The N02 group is so read-
`ily reduced in biological systems that it would be more
`appropriate to substitute it with CN from the same
`cluster. The N(CH3)3 group bears a charge. It is well
`known from studies in physical organic chemistry that
`charged substituents behave poorly when mixed in sets
`of neutral groups. In the initial phases of study, one
`would not expect the charged group to behave in the
`same fashion as neutral substituents. Several such groups
`could be introduced later via an indicator variable. The
`
`only other substituent in this cluster is 102, which is not
`selected because little is known of its behavior
`in
`biologic systems. I:I(CH3)3 is replaced with H from the
`first and largest cluster. The NCS group is so highly
`active chemically that it might not behave as a true
`congener and is replaced with OC6H5. The new set is
`then: Br, H, CN, OH, SO2NH2, OCF3, OC5H5,
`NHCOC6H5, OCH3, C4H9. This affords the correlation
`matrix of Table VI-8.
`Table VI-8 shows that although ‘there is still some
`collinearity between certain variables,
`it has been re-
`duced to a reasonable level. Also, the new set of sub-
`stituents contains a good spread in values of the various.
`parameters:
`7: (-1.82 to 2.13), 9(-0.06 to 0.44,
`(R
`(—0.64 to 0.19), andMR (0.10 to 3.46).
`The hydrogen bonding parameters are of course the
`most poorly defined. Nevertheless,
`inspection of the
`clustering of the aromatic substituents at the 10 set level
`shows that
`they do cluster hydrogen—bonding groups
`well. Most of the nonhydrogen bonders are clustered
`into groups I and 8. The acceptors fall into clusters 2, 6,
`and 7. The substituents that are both donors and
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:28)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:25)
`Sun-Amneal-IPR2016-01104- Ex. 1018, p. 9 of 16
`
`
`
`Table VI-5a Aromatic Constants-Twenty Cluster Sets
`
`4
`U!
`6
`
`NNN
`SCF3
`N0
`so2c,H5 *
`SOC;H5 *
`
`CH=CH;_
`I-IC(CH3 )2
`S(C2 H5)
`
`(CH;)3CO2H*
`CH=NOH
`
`C0NHC2H5 *
`CH=NOCI-I3
`COC2 fls *
`COC3 H7*
`
`0C0C3H7*
`CH=CHCO;CH3*
`OCOCGH5
`3-Thienyl
`3i.(CH3J3
`C4H9 ’
`CON}-lC3H»7"‘
`NHSO2C;H5 *
`NHC=S(C2H5)*
`NHSO1C5H5
`
`OC3H-,
`
`NHC4H9*
`CH1OC4Hg*
`
`SO¢C6H5
`
`cr=,c1=3
`CN
`s02C3H7*
`SOCH3
`
`CH2Cl
`C3117
`SC3H7*
`
`NHCOCF1
`
`C0211
`OCOC2H5 *
`CHO
`SCOC;H5 *
`
`CH=NOC3H-1*
`CH=CHCOC2 H5 *
`oc6H5
`C5115
`CsH11*
`C(CH3)3
`NHC=S(NHC2 H5)
`NIICO,CH3*
`NI-ISO2C3H7*
`NHCOC,«,H5
`
`NHC5 H5
`CH2 OC5H5
`
`CH=CHCOC5l-15
`P=O(C6H5)2
`
`I C
`
`F3
`S02 (CF3)
`SOC3 H7 *
`]-Tetrazolyl
`
`CH2 Br
`Cyclopropyl
`Se(CH3)
`
`NHNH2
`Etco, H
`NHCN
`NHCOCH3
`C=O(NHCH3 )
`Cl-I=CHNO2 (tr)
`CO1CH3
`CO2C2H5
`
`C]
`SF5
`No,
`5-C1-1-tetrazolyl
`P0(OCH3);
`OCOCH3
`CH3
`CH2 CH3
`SCH3
`
`NH,
`CI-[;OH
`NHCONH;
`NHSO2CH3
`CONH;
`CHZCN
`SCN>
`SCOCH3
`
`Pyrryl
`2,5-di-Me-Pyrry1*
`CH=CHCOC3H-, "
`2-Thienyl
`CECC5H5
`CH2 Si(CI-I3 )3
`CI-l=NNHCONHNH;
`NHCOC; H5 *
`NHC=OCH(CH3),
`€(0H)(CFa)2
`
`cH=Noc,H5*
`CH=CHCOCH3
`CH=CHC0;C3H7*
`5B(C3H7)*
`CI-1=CHC5H5 (tr)
`CH;C6H5
`CH=NNHC=S(NH2)
`NHC=S(CH3)
`NI-ICO2C3H-,*
`NI-IC=S(C34H-,)*
`
`OCHZCH3
`N(C2Hs )2
`NH(C-3H5)
`CH20C2H5 *
`P(C2Hs)2*
`COC5I-I5
`P0(0C2H5 )2 *
`Ferrocenyl
`
`co,
`
`OCH(CH3);*
`N=CHC6H5
`NI-IC3H7*
`CH;OC3 H-,*
`
`COQC6 H5
`CH=Nc6H5
`N(C£-H5 )2
`
`fi<cH3>s
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:19)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:25)
`Sun-Amneal-|PR2016-01104- Ex. 1018, p. 10 of 16
`
`1 10 members = Br
`SH
`2 17 members = SO2F
`SO;CH3
`CH=C(CN)2
`OSOZCH3
`3 16 members = H
`C‘=‘CH
`N=CCl2
`Se(C2H5)*
`V
`3 members = OH
`4 members = B(0H)2
`8 members = NH(OH)
`r NHCHO
`\l
`5 members = S0z(NI-I2)
`8 16 members = OCF3
`CH=CHCN
`COCH3
`C0gC3H7*
`9 15 members = NCS
`CH=NOC4H9*
`CI-I=CHCO1C,I-I5
`10 15 members = CI-I21
`N=NC6I-[5
`Cyclohexyl
`ll 21 members = NHC=S(NH2)
`NHC=O(CH2C1)
`NHco,c,H5
`NHC0C3H-,"
`CI-I=NNHC0C6H5
`8 members = OCH,
`N(CHa)z
`5 members = NI-[CH3
`13
`5 members = CH; OCH3
`14
`2 members = P(CH3)2
`15
`16 10 members = SCOC3H7*
`2-Benzthiazolyl
`3 members = CH;Si(C2H5 )3*
`3 single-
`member = 102
`groups
`
`12
`
`17
`18
`|
`20
`
`[.9
`
`
`
`89
`
`Table VI-Sb Aromatic Constants-«Ten Cluster Sets
`
`F C
`
`F3CF3
`CHzCl
`C3H7
`SC3H7*
`
`CN
`S02C3H7*
`SOCH3
`
`NH(C2Hs)
`
`NH(0H)
`NHCHO
`C=O(NHCH3)
`
`OCOCZH5 *
`CHO
`SCOC;H5 "‘
`CH2OC4Hg*
`
`CH=NOC3H7*
`CH=CHC0C2 H5 *
`OC5H5
`CH=CHCOC6H5
`P=0(C6H5 )1
`CaHs
`CsH1I*
`C(CH3)3
`N(Cc~Hs )2
`NHC=S(NHC1H5)
`NHCOZCH3 *
`NHso,c3H7*
`NHCOCGHS
`
`OC4 H9 *
`
`NNN
`SCF3
`CH=CH2
`CH(CH3 )2
`S(C2 H5)
`
`NO
`S02C2H5*
`S0C2H5*
`
`NHCH3
`
`(CH, ),co2 H*
`NHCOCF3
`CONH2
`
`CH=NOCH3
`coc,H5 *
`COC-_.,H-,*
`cH,oc3H7
`
`OCOC3 H-7 *
`CH=CHO2 CH 3 *
`OCOCGH5
`OSO2C(, H5
`S02 C5H5
`3-Thienyl
`Si(CH3)3
`C4H9
`Ferrocenyl
`CONHC3H7 *
`NHS 02 C; H5 *
`NHC=S(C2 H5 )"‘
`NHSO; C5 H5
`
`I C
`
`F3 '
`CH; Br
`Cyclopropyl
`Se(CH3)
`
`SO; (CF3)
`SOC3H-, *
`l-Tetrazolyl
`
`NHNH3
`NHC5 H5
`Etco, H
`CH=NOH
`S02 (NH2)
`CO2-
`CH=CHNO2 -(tr)
`C01CH3
`C0; C1 H5
`CH; OC2 H5 *
`
`C1
`SF5
`CH3
`CH1 CH3
`SCH3
`
`_
`N02
`5-C1-1-tetrazolyl
`P0(OCH3 )1
`QCOCH3
`N(CH3)3
`NH;
`NHC4 H9 *
`CH2OH
`NHCN
`NHCOCH3
`CO; H
`CH; CN
`SCN
`SCOCH3
`CH; OCH3
`
`Pyrryl
`2,5-di—Me-Pyrry1*
`CH=CHC0C3 H7 *
`COC6I-15
`P0(0C2 H5 )2 *
`2-Thienyl
`C'=‘CC6H5
`CH; Si(CH3 )3
`P(C2H5 )2 *
`CH=NNHCONHNH2
`NHCOC; H5 *
`NHC=OCH(CH3)2
`C(0H)(CF3)2
`
`CH=N0C;H5*
`CH=CH0CH3
`CH'—'CHC02 C3 H7 *
`C01CgH5
`CH=NC.-,H5
`S€(C3H7)*
`CH=CHC6H5 (tr)
`CH;C5H5
`CH2 3i(C2 H5 )3 *
`CN=NNHC=S(NI-I2)
`NHC=’-S(CH3)
`NHC0-;C3H7*
`NHC=S(C3H7)*
`
`0CH(CH3)2*
`oc1-1,cH3
`N(C2 H5 )2
`N=CHC6H5
`of1L6»
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:20)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:25)
`
`OC3 H7
`
`1 26 members = Br
`SH
`
`HC
`
`3
`4
`
`10
`
`ECH
`N=CCl2
`Se(C2Hs)*
`2 17 members = S02F
`S0; CH3
`CH=C(CN)2
`OSO; CH3
`2 members = IO;
`8 members = OH
`NHC3H~,*
`5 18 members = B(0H)2
`NHCONH2
`NHSO; CH3
`CONHC2 H5 *
`6 21 members = OCF3
`CH=CHCN
`COCH3
`CO2C3H-,*
`CH1 0C6H5
`7 25 members = NCS
`CH=NOC4 H9 *
`CH=CHC02C2H5
`SCOC3I-17*
`2-Benzthiazolyl
`8 20 members = CH2I
`N=NC6l-I5
`Cyclohexyl
`P(CH3)2
`9 2] members = NHC=S(NH;)
`NHC= O(CH; Cl)
`NHC02 C; H5
`NHCOC3 H7 *
`CH=NNHCOC6H5
`8 members = OCH3
`N(CHa)2
`
`
`
`Tabl