US2014179681A1PendingUtilityA1
Methods and compositions of targeted drug development
Est. expiryJan 6, 2030(~3.5 yrs left)· nominal 20-yr term from priority
Inventors:Joseph P. ErricoBenjamin MugrageIgnatius TurchiMatthew SillsJeffrey D. HerronNicholas J. LodatoJane OngCorey PineWilliam John FeaverJohn AlloccoPam Wines
A61P 35/00A61P 9/00A61P 43/00C07D 403/12A61K 45/06C07D 417/14C07D 409/06C07D 285/135C07D 209/08A61K 31/47C07D 239/42C07D 239/52G16B 15/00A61K 31/4709C07D 295/26C07D 207/48C07D 405/06C07D 401/12A61P 17/02A61P 17/06C07D 405/14C07C 335/26C07D 215/26C07D 401/14C07D 307/54A61K 31/496C07D 409/14A61P 17/08C07D 239/47A61P 17/00A61P 17/12G16B 15/30G06F 19/16
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Claims
Abstract
Provided herein are compounds having anti-proliferative effect. Also provided are compounds that can modulate the activity of multi-domain proteins comprising a dimerization arm and interdomain tether, such as EGFR, where an untethered, extended conformation is the active state and a tethered conformation is the inactive state, resulting in an autoinhibited configuration. Also provided are methods and pharmacophores for identifying such compounds. Other aspects provide methods or therapeutic treatment for proliferative diseases, disorders, or conditions, such as those associated with EGFR.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having a formula of:
or a stereoisomer or pharmaceutically acceptable salt thereof;
wherein,
R 101 is selected from the group consisting of:
(i) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(ii) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(iii) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(a) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(b) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(c) heteroaryl containing from 1 to 4 N, O, or S atoms;
R 102 is hydrogen;
R 103 is selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(iii) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iv) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(v) halogen;
R 104 and R 105 are independently selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(iii) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(iv) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
R 106 is selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(iii) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(a) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(b) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(c) heteroaryl containing from 1 to 4 N, O, or S atoms;
(d) aryl comprising a phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
(e) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(1) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(2) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(f) trifluoromethyl;
(g) trifluoromethoxy;
(h) difluoromethoxy;
(i) 3,4-methylenedioxy;
(j) 2,3-methylenedioxy;
(k) nitro; and
(l) halogen; and
(iv) C-1 to C-3 substituted alkyl having at least one substitution group selected from the group consisting of:
(a) carboxyl —COOR 10 where R 10 is selected from the group consisting of:
(1) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(2) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(b) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(1) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(2) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(3) aryl having phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
(4) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(A) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(B) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(5) trifluoromethyl;
(6) trifluoromethoxy;
(7) difluoromethoxy;
(8) 3,4-methylenedioxy;
(9) 2,3-methylenedioxy;
(10) nitro; and
(11) halogen; and
(c) aryloxy (—OAr);
R 107 is selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(iii) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iv) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(a) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(b) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(c) aryl comprising a phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
(d) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(1) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(2) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(e) trifluoromethyl;
(f) trifluoromethoxy;
(g) difluoromethoxy;
(h) 3,4-methylenedioxy;
(i) 2,3-methylenedioxy;
(j) nitro; and
(k) halogen; and
(v) C-1 to C-3 substituted alkyl having at least one substitution group selected from the group consisting of:
(a) carboxyl —COOR 10 where R 10 is selected from the group consisting of:
(1) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(2) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(b) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(1) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(2) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(3) aryl having phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
(4) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(A) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(B) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(5) trifluoromethyl;
(6) trifluoromethoxy;
(7) difluoromethoxy;
(8) 3,4-methylenedioxy;
(9) 2,3-methylenedioxy;
(10) nitro; and
(11) halogen; and
(c) aryloxy (—OAr); and
Formula (25) excludes a compound of Formula (24):
or a stereoisomer or pharmaceutically acceptable salt thereof;
wherein,
R 108 is selected from the group consisting of:
(i) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(ii) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iii) C-1 to C-3 substituted alkyl having at least one substitution group selected from the group consisting of:
(a) carboxyl —COOR 10 where R 10 is selected from the group consisting of:
(1) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(2) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(b) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(1) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(2) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(3) aryl having phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
(4) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(A) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(B) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(5) trifluoromethyl;
(6) trifluoromethoxy;
(7) difluoromethoxy;
(8) 3,4-methylenedioxy;
(9) 2,3-methylenedioxy;
(10) nitro; and
(11) halogen; and
(c) aryloxy (—OAr);
(iv) aryl comprising a phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
(v) amino; and
(vi) hydroxyl;
R 109 is hydrogen;
R 110 and R 111 are independently selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(iii) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iv) C-1 to C-3 substituted alkyl having at least one substitution group selected from the group consisting of:
(a) carboxyl —COOR 10 where R 10 is selected from the group consisting of:
(1) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(2) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(b) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(1) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(2) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(3) aryl having phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
(4) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(A) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(B) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(5) trifluoromethyl;
(6) trifluoromethoxy;
(7) difluoromethoxy;
(8) 3,4-methylenedioxy;
(9) 2,3-methylenedioxy;
(10) nitro; and
(11) halogen; and
(c) aryloxy (—OAr);
(v) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(vi) halogen;
R 112 is selected from the group consisting of: hydrogen and straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
R 113 is selected from the group consisting of:
(i) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(ii) trifluoromethyl;
(iii) aryl comprising a phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms; and
(iv) amino;
R 114 is selected from the group consisting of:
(i) hydrogen;
(ii) acyl —COR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(iii) carboxyl —COOR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
R 115 is selected from the group consisting of:
(i) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(ii) trifluoromethyl; and
(iii) aryl comprising a phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms; and
Formula (27) excludes a compound of Formula (24):
or a stereoisomer or pharmaceutically acceptable salt thereof;
wherein
n is 1 or 2;
R 116 is selected from the group consisting of:
(i) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(ii) aryl comprising a phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
R 117 of is hydrogen;
R 118 is selected from the group consisting of:
(i) hydrogen,
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(ii) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(iii) halogen;
R 119 is selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(iii) aryl comprising a phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
R 120 is selected from the group consisting of:
(i) hydrogen,
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(iii) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
R 121 is selected from the group consisting of: hydrogen and aryl comprising a phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms; and
Formula (28) excludes a compound of Formula (24):
2 . The compound of claim 1 , wherein
(A) the compound is according to Formula (25) (10381-like Type D) and at least one of the following features is satisfied R 101 is selected from the group consisting of methyl and phenyl; R 103 is selected from the group consisting of methyl, ethyl, chloro, methoxy, and ethoxy; R 104 is selected from the group consisting of hydrogen, methyl, and methoxy; R 105 is selected from the group consisting of hydrogen, methyl, methoxy, and ethoxy; R 106 is selected from the group consisting of methyl and phenyl; or the compound is selected from the group consisting of
(B) the compound is according to Formula (27) (10381-like Type E) and at least one of the following features is satisfied
R 108 is selected from the group consisting of: methyl, phenyl, and hydroxyl;
R 110 and R 111 are independently selected from the group consisting of: hydrogen, methyl, methoxy, and chloro;
R 112 is methyl;
R 113 is selected from the group consisting of: methyl, phenyl, and amino;
R 115 is selected from the group consisting of: methyl, phenyl, and trifluoromethyl;
the compound is selected from the group consisting of
or
(C) the compound is according to Formula (28) (10381-like Type F) and at least one of the following features is satisfied
n is 2 and the compound has a formula of:
or the compound is
3 . The compound of claim 1 that inhibits EGFR activity comprising:
eight or more of functional groups F(IV)1, F(IV)2, F(IV)3, F(IV)4, F(IV)5, F(IV)6, F(IV)7, F(IV)8, F(IV)9, and F(IV)10 of a Scheme IV 10381-like pharmacophore;
wherein
functional group F(IV)1 accepts a hydrogen bond from receptor side chain OH of Thr239 of SEQ ID NO: 1 and has coordinates of r=49.686, θ (theta)=113.993, and φ (phi)=−17.014 and a spherical radius of about 1.2 Å;
functional group F(IV)2 accepts a hydrogen bond from receptor side chain OH of Thr239 of SEQ ID NO: 1 and has coordinates of r=48.071, θ (theta)=115.388, and φ (phi)=−16.211 and a spherical radius of about 1.6 Å;
functional group F(IV)3 forms a hydrophobic contact with a side chain of receptor Met576 and imidazolidine ring of Pro242 of SEQ ID NO: 1 and has coordinates of r=50.781, θ (theta)=113.121, and φ (phi)=−17.520 and a spherical radius of about 1.2 Å;
functional group F(IV)4 forms a hydrophobic contact with a side chain of receptor Met576 and imidazolidine ring of Pro242 of SEQ ID NO: 1 and has coordinates of r=52.021, θ (theta)=114.264, and φ (phi)=−15.878 and a spherical radius of about 1.5 Å;
functional group F(IV)5 forms a hydrophobic contact with a side chain of receptor Met576 and imidazolidine ring of Pro242 of SEQ ID NO: 1 and has coordinates of r=50.322, θ (theta)=111.253, and φ (phi)=−15.426 and a spherical radius of about 1.2 Å;
functional group F(IV)6 forms a hydrophobic contact with a side chain of receptor Met576 and imidazolidine ring of Pro242 of SEQ ID NO: 1 and has coordinates of r=51.575, θ (theta)=112.433, and φ (phi)=−13.827 and a spherical radius of about 1.5 Å;
functional group F(IV)7 forms a hydrophobic contact with a side chain of receptor Leu243 and a side chain of Thr239 of SEQ ID NO: 1 and has coordinates of r=47.767, θ (theta)=112.521, and φ (phi)=−10.196 and a spherical radius of about 1.2 Å;
functional group F(IV)8 donates a hydrogen bond to a backbone carbonyl of His280 of SEQ ID NO: 1 and has coordinates of r=45.184, θ (theta)=112.328, and φ (phi)=−8.875 and a spherical radius of about 1.2 Å;
functional group F(IV)9 forms a hydrophobic contact with a side chain of receptor Met244 and Leu243 of SEQ ID NO: 1 and has coordinates of r=49.512, θ (theta)=108.007, and φ (phi)=−8.504 and a spherical radius of about 1.2 Å;
functional group F(IV)10 forms a hydrophobic contact with a side chain of receptor Met244 of SEQ ID NO: 1 and has coordinates of r=50.431, θ (theta)=104.985, and φ (phi)=−7.420 and a spherical radius of about 1.8 Å; and
the compound substantially maintains a non-extended tether inactive configuration of EGFR or substantially prevents stabilization of an extended tether active configuration of EGFR.
4 . A compound having a formula of:
or a stereoisomer or pharmaceutically acceptable salt thereof;
wherein,
R 23 and R 27 are hydrogen;
R 24 and R 26 are independently selected from the group consisting of:
(i) hydrogen;
(ii) C-1 to C-6 lower alkyl;
(iii) alkoxy —OR 10 where R 10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(iv) halogen;
R 25 is selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(iii) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iv) C-1 to C-3 substituted alkyl having at least one substitution group selected from the group consisting of
(a) carboxyl —COOR 10 where R 10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(b) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of: straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; aryl having phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms; alkoxy —OR 10 where R 10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; trifluoromethyl; trifluoromethoxy; difluoromethoxy; 3,4-methylenedioxy; 2,3-methylenedioxy; nitro; and halogen; and
(c) aryloxy (—OAr);
(v) alkoxy —OR 10 where R 10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(vi) halogen;
R 28 is selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(iii) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(a) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(b) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(c) halogen.
R 29 is selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(iii) hydroxy;
(iv) alkoxy —OR 10 where R 10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(v) halogen;
R 30 is selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(iii) alkoxy —OR 10 where R 10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iv) trifluoromethyl; and
(v) halogen;
R 31 is selected from the group consisting of:
(i) hydrogen;
(ii) hydroxy;
(iii) alkoxy —OR 10 where R 10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iv) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(v) trifluoromethyl; and
(vi) halogen; and
R 32 is selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(iii) hydroxy;
(iv) trifluoromethyl; and
(v) halogen; and
Formula (13) excludes the compound of Formula (12):
or a stereoisomer or pharmaceutically acceptable salt thereof;
wherein,
R 33 is selected from the group consisting of:
(i) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(ii) C-1 to C-3 substituted alkyl having at least one substitution group selected from the group consisting of:
(a) carboxyl —COOR 10 where R 10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(b) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of: straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; aryl having phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms; alkoxy —OR 10 where R 10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; trifluoromethyl; trifluoromethoxy; difluoromethoxy; 3,4-methylenedioxy; 2,3-methylenedioxy; nitro; and halogen; and
(c) aryloxy (—OAr); and
(iii) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(a) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(b) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(c) aryl having phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
(d) alkoxy —OR 10 where R 10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(e) trifluoromethyl;
(f) trifluoromethoxy;
(g) difluoromethoxy;
(h) 3,4-methylenedioxy;
(i) 2,3-methylenedioxy;
(j) nitro; and
(k) halogen;
R 34 is hydrogen;
R 35 is selected from the group consisting of:
(i) hydrogen;
(ii) hydroxy;
(iii) alkoxy —OR 10 where R 10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iv) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(v) trifluoromethyl; and
(vi) halogen;
R 36 is selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(iii) hydroxy;
(iv) alkoxy —OR 10 where R 10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(v) trifluoromethyl; and
(vi) halogen; and
R 37 is hydrogen; and
Formula (14) excludes a compound of Formula (12):
or a stereoisomer or pharmaceutically acceptable salt thereof;
wherein,
n is 1 or 2;
X 2 and X 3 are independently selected from the group consisting of: carbon, oxygen, nitrogen, and sulfur;
R 38 is hydrogen;
R 39 is selected from the group consisting of:
(i) hydrogen;
(ii) C-1 to C-6 lower alkyl;
(iii) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(iv) halogen;
R 40 is hydrogen;
R 41 is selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(iii) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(a) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(b) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(c) aryl having phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
(d) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(1) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(2) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(e) trifluoromethyl;
(f) trifluoromethoxy;
(g) difluoromethoxy;
(h) 3,4-methylenedioxy;
(i) 2,3-methylenedioxy;
(j) nitro; and
(k) halogen;
R 42 is selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(iii) hydroxy;
(iv) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(v) halogen;
R 43 is selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(iii) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iv) trifluoromethyl; and
(v) halogen;
R 44 is selected from the group consisting of:
(i) hydrogen;
(ii) hydroxy;
(iii) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iv) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(v) trifluoromethyl; and
(vi) halogen;
R 45 is selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(iii) hydroxy;
(iv) trifluoromethyl; and
(v) halogen; and
Formula (15) excludes the compound of Formula (12):
or a stereoisomer or pharmaceutically acceptable salt thereof;
wherein,
n is 1 or 2;
X 4 and X 5 are independently selected from the group consisting of: carbon, oxygen, nitrogen and sulfur;
R 46 and R 50 are hydrogen;
R 47 and R 49 are independently selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(iii) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iv) halogen; and
(v) R 47 and R 49 form a 5 or 6 membered cycloalkyl ring;
R 48 is selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(iii) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iv) C-1 to C-3 substituted alkyl having at least one substitution group selected from the group consisting of:
(a) carboxyl —COOR 10 where R 10 is selected from the group consisting of:
(1) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(2) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(b) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(1) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(2) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(3) aryl having phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
(4) alkoxy —OR 10 where R 10 is selected from the group consisting of: (A) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and (B) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(5) trifluoromethyl;
(6) trifluoromethoxy;
(7) difluoromethoxy;
(8) 3,4-methylenedioxy;
(9) 2,3-methylenedioxy;
(10) nitro; and
(11) halogen; and
(c) aryloxy (—OAr);
(v) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(vi) halogen; and
(vii) R 48 forms a 5 or 6 membered cycloalkyl ring with R 47 ;
R 51 is selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(iii) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(a) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(b) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(c) aryl having phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
(d) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(1) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(2) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(e) trifluoromethyl;
(f) trifluoromethoxy;
(g) difluoromethoxy;
(h) 3,4-methylenedioxy;
(i) 2,3-methylenedioxy;
(j) nitro; and
(k) halogen;
R 52 is selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(iii) hydroxy;
(iv) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(v) halogen;
R 53 is selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(iii) hydroxy;
(iv) trifluoromethyl; and
(v) halogen; and
Formula (16) excludes the compound of Formula (12):
5 . The compound of claim 4 , wherein
(A) the compound is according to Formula (13) (1734-like Type P) and one or more of the following features are satisfied: R 24 and R 26 are independently selected from the group consisting of: hydrogen and alkoxy; R 25 is selected from the group consisting of: hydrogen or alkoxy —OR 10 ; R 28 is selected from the group consisting of: hydrogen or aryl; R 28 is hydrogen; R 30 is straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; R 31 is selected from the group consisting of: hydroxy or alkoxy —OR 10 ; R 32 is hydrogen; or the compound is selected from the group consisting of
(B) the compound is according to Formula (14) (1734-like Type Q) and one or more of the following features are satisfied:
R 35 is straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
R 36 is selected from the group consisting of:
(i) hydroxy and
(ii) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; or
the compound is
(C) the compound is according to Formula (15) (1734-like Type R) and one or more of the following features are satisfied:
n is 1;
X 2 and X 3 are independently selected from the group consisting of: oxygen or carbon;
R 42 is hydrogen;
R 43 is straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
R 44 is selected from the group consisting of
(i) hydroxy and
(ii) alkoxy —OR 10 where R 10 is selected from the group consisting of
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
R 45 is hydrogen; or
the compound is
or
(D) the compound is according to Formula (16) (1734-like Type S) and one or more of the following features are satisfied:
n is 1;
X 4 and X 5 are independently selected from the group consisting of oxygen and carbon;
R 48 is selected from the group consisting of hydrogen or straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
R 47 and R 48 form a 5 membered cycloalkyl ring;
R 51 is selected from the group consisting of
(i) hydrogen and
(ii) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(a) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation,
(b) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom,
(c) aryl having phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms,
(d) alkoxy —OR 10 where R 10 is selected from the group consisting of
(1) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation, and
(2) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom,
(e) trifluoromethyl,
(f) trifluoromethoxy,
(g) difluoromethoxy,
(h) 3,4-methylenedioxy,
(i) 2,3-methylenedioxy,
(j) nitro, and
(k) halogen;
R 52 is hydrogen; or
the compound is selected from the group consisting of
6 . The compound of claim 4 that inhibits EGFR activity, the compound comprising:
five or more of functional groups F(II)1, F(II)2, F(II)3, F(II)4, F(II)5, F(II)6, F(II)7, F(II)8, and F(II)9 of a Scheme II 1734-like pharmacophore;
wherein
functional group F(II)1 donates an H-bond or forms a salt bridge to a carboxylate side chain of receptor Asp553 of SEQ ID NO: 1 and has coordinates of r=56.363, θ (theta)=94.368, and φ (phi)=−17.752 and a spherical radius of about 1.2 Å;
functional group F(II)2 is a donor and has coordinates of r=53.290, θ (theta)=101.494, and φ (phi)=−23.244 and a spherical radius of about 1.0 Å;
functional group F(II)3 forms a hydrophobic contact with a side chain of receptor Val568, imidazolidine side chain of receptor Pro552 and with a side chain of Met253 of SEQ ID NO: 1 and has coordinates of r=53.726, θ (theta)=97.830, and φ (phi)=−18.377 and a spherical radius of about 1.7 Å;
functional group F(II)4 forms a hydrophobic contact with side chain of receptor Val575, Met253, and with an imidazolidine ring of receptor Pro552 of SEQ ID NO: 1 and has coordinates of r=53.647, θ (theta)=103.844, and φ (phi)=−20.990 and a spherical radius of about 1.4 Å;
functional group F(II)5 donates an H-bond to a side chain hydroxyl of Thr570 of SEQ ID NO: 1 and has coordinates of r=51.093, θ (theta)=104.261, and φ (phi)=−25.552 and a spherical radius of about 1.2 Å;
functional group F(II)6 is a donor having directionality of F4 with respect to a backbone carbonyl of receptor Thr570 of SEQ ID NO: 1 and has coordinates of r=52.340, θ (theta)=103.980, and φ (phi)=−27.461 and a spherical radius of about 1.5 Å;
functional group F(II)7 accepts an H-bond from a receptor backbone NH of Ala573 of SEQ ID NO: 1 and has coordinates of r=51.383, θ (theta)=106.455, and φ (phi)=−24.319 and a spherical radius of about 1.2 Å;
functional group F(II)8 is an acceptor having directionality of F7 with respect to the backbone NH of receptor Ala573 of SEQ ID NO: 1 and has coordinates of r=52.861, θ (theta)=107.691, and φ (phi)=−25.448 and a spherical radius of about 1.5 Å;
functional group F(II)9 donates an H-bond to a backbone carbonyl of Asp563 and forms a salt bridge to a side chain carboxylate of receptor Asp563 of SEQ ID NO: 1 and has coordinates of r=57.688, θ (theta)=99.198, and φ (phi)=−21.588 and a spherical radius of about 1.2 Å; and
the compound substantially maintains a non-extended tether inactive configuration of EGFR or substantially prevents stabilization of an extended tether active configuration of EGFR.
7 . A compound having a formula of:
or a stereoisomer or pharmaceutically acceptable salt thereof;
wherein,
R 54 is selected from the group consisting of:
(i) a 5 or 6 membered heterocyclic containing from 1 to 4 N, O, or S atoms or any combination of those atoms with carbon atoms to form a heterocyclic aromatic ring optionally substituted with from 1 to 3 groups selected from:
(a) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(b) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(c) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(1) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(2) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(d) trifluoromethyl,
(e) trifluoromethoxy,
(f) substituted amino,
(g) nitro; and
(h) halogen;
R 55 is selected from the group consisting of: hydrogen and straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
R 56 , R 57 , R 58 , and R 59 are hydrogen;
R 60 is selected from the group consisting of:
(i) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(ii) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(iii) C-1 to C-3 substituted alkyl having at least one substitution group selected from the group consisting of:
(a) carboxyl —COOR 10 where R 10 is selected from the group consisting of:
(1) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(2) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(b) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(1) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(2) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(3) aryl having phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
(4) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(A) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(B) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(5) trifluoromethyl;
(6) trifluoromethoxy;
(7) difluoromethoxy;
(8) 3,4-methylenedioxy;
(9) 2,3-methylenedioxy;
(10) nitro; and
(11) halogen; and
(c) aryloxy (—OAr); and
Formula (18) excludes a compound of Formula (17):
or a stereoisomer or pharmaceutically acceptable salt thereof;
wherein,
R 61 , R 62 , and R 64 are independently selected from the group consisting of: hydrogen and straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
R 63 and R 65 are independently selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(iii) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; R 66 is selected from the group consisting of: hydrogen and straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
R 67 , R 68 , R 69 , and R 70 are hydrogen;
R 71 is selected from the group consisting of:
(i) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(ii) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iii) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(a) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(b) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(c) aryl having phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
(d) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(1) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(2) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(e) trifluoromethyl;
(f) trifluoromethoxy;
(g) difluoromethoxy;
(h) 3,4-methylenedioxy;
(i) 2,3-methylenedioxy;
(j) nitro; and
(k) halogen;
(iv) C-1 to C-3 substituted alkyl having at least one substitution group selected from the group consisting of:
(a) carboxyl —COOR 10 where R 10 is selected from the group consisting of:
(1) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(2) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(b) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(1) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(2) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(3) aryl having phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
(4) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(A) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(B) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(5) trifluoromethyl;
(6) trifluoromethoxy;
(7) difluoromethoxy;
(8) 3,4-methylenedioxy;
(9) 2,3-methylenedioxy;
(10) nitro; and
(11) halogen; and
(c) aryloxy (—OAr);
(v) heteroaryl containing a heterocyclic ring containing from 1 to 4 N, O, or S atoms optionally substituted with one or more groups selected from the group consisting of:
(a) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(b) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(c) aryl having phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
(d) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(1) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(2) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(e) trifluoromethyl;
(f) trifluoromethoxy;
(g) nitro; and
(h) halogen; and
Formula (19) excludes a compound of Formula (17):
or a stereoisomer or pharmaceutically acceptable salt thereof;
wherein, R 72 is selected from the group consisting of: hydrogen and straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
R 73 is selected from the group consisting of:
(i) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(ii) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iii) C-1 to C-3 substituted alkyl having at least one substitution group selected from the group consisting of:
(a) carboxyl —COOR 10 where R 10 is selected from the group consisting of:
(1) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(2) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(b) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(1) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(2) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(3) aryl having phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
(4) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(A) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(B) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(5) trifluoromethyl;
(6) trifluoromethoxy;
(7) difluoromethoxy;
(8) 3,4-methylenedioxy;
(9) 2,3-methylenedioxy;
(10) nitro; and
(11) halogen; and
(c) aryloxy (—OAr); and
(iv) acyl —COR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
R 74 , R 75 , R 76 , and R 77 are hydrogen; and
R 78 is selected from the group consisting of:
(i) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(ii) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iii) C-1 to C-3 substituted alkyl having at least one substitution group selected from the group consisting of:
(a) carboxyl —COOR 10 where R 10 is selected from the group consisting of:
(1) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(2) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(b) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(1) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(2) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(3) aryl having phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
(4) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(A) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(B) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(5) trifluoromethyl;
(6) trifluoromethoxy;
(7) difluoromethoxy;
(8) 3,4-methylenedioxy;
(9) 2,3-methylenedioxy;
(10) nitro; and
(11) halogen; and
(c) aryloxy (—OAr); and
Formula (20) excludes a compound of Formula (17):
or a stereoisomer or pharmaceutically acceptable salt thereof;
wherein,
n is 1 or 2;
R 79 , R 81 , R 82 , R 83 , R 84 , R 85 , and R 86 are hydrogen;
R 80 is selected from the group consisting of:
(i) hydrogen,
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(iii) alkoxy —OR 10 where R 10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iv) halogen; and
(v) trifluoromethyl;
R 87 is selected from the group consisting of:
(i) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(ii) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iii) C-1 to C-3 substituted alkyl having at least one substitution group selected from the group consisting of:
(a) carboxyl —COOR 10 where R 10 is selected from the group consisting of:
(1) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(2) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(b) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(1) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; \
(2) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(3) aryl having phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
(4) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(A) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(B) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(5) trifluoromethyl;
(6) trifluoromethoxy;
(7) difluoromethoxy;
(8) 3,4-methylenedioxy;
(9) 2,3-methylenedioxy;
(10) nitro; and
(11) halogen; and
(c) aryloxy (—OAr); and
(iii) aryl comprising a phenyl or heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms; and
Formula (21) excludes a compound of Formula (17):
or a stereoisomer or pharmaceutically acceptable salt thereof;
wherein,
n is 3, 4, or 5;
R 88 is selected from the group consisting of: hydrogen and straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
R 89 , R 90 , R 91 , R 83 , and R 92 are hydrogen;
R 93 is selected from the group consisting of:
(i) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(ii) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iii) C-1 to C-3 substituted alkyl having at least one substitution group selected from the group consisting of:
(a) carboxyl —COOR 10 where R 10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(b) aryl having an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups selected from the group consisting of:
(1) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(2) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(3) aryl having phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
(4) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(A) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(B) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(5) trifluoromethyl;
(6) trifluoromethoxy;
(7) difluoromethoxy;
(8) 3,4-methylenedioxy;
(9) 2,3-methylenedioxy;
(10) nitro; and
(11) halogen; and
(c) aryloxy (—OAr); and
(iv) aryl comprising a phenyl or heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms; and
Formula (22) excludes a compound of Formula (17):
or a stereoisomer or pharmaceutically acceptable salt thereof;
wherein,
R 94 is a 5 or 6 membered heterocyclic aromatic ring containing from 1 to 4 N, O, or S atoms or any combination of those atoms with carbon atoms optionally substituted with from 1 to 3 of groups selected from:
(i) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(ii) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iii) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iv) trifluoromethyl;
(v) trifluoromethoxy;
(vi) substituted amino;
(vii) nitro; and
(viii) halogen; R 95 is selected from the group consisting of: hydrogen and straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
R 96 , R 97 , R 98 , and R 99 are hydrogen;
R 100 is aryl comprising a phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms; and
Formula (23) excludes a compound of Formula (17):
8 . The compound of claim 7 , wherein
(A) the compound is according to Formula (18) (1886-like Type J) and one or more of the following features are satisfied: R 54 is selected from the group consisting of: 4,6-dimethyl-2-pyrimidine; 2,6-dimethoxy-4-pyrimidine; 6-methoxy-4-pyrimidine; 5-ethyl-2-(1,3,4-Thiadiazole); 5-methyl-3-Isoxazole; 3-methoxy-6-pyridazinamine, 2-thiazole; and 2-methoxy-3-pyrazine. R 55 is selected from the group consisting of hydrogen and methyl; the compound is selected from the group consisting of:
(B) the compound according to Formula (19) (1886-like Type K) is
(C) the compound according to Formula (20) (1886-like Type L) is selected from the group consisting of:
(D) the compound according to Formula (21) (1886-like Type M) is
(E) the compound of Formula (22) (1886-like Type N) is selected from the group consisting of:
or
(F) the compound of Formula (23) (1886-like Type O) is selected from the group consisting of:
9 . The compound of claim 7 that inhibits EGFR activity comprising:
at least seven or more of functional groups F(III)1, F(III)2, F(III)3, F(III)4, F(III)5, F(III)6, F(III)7, F(III)8, and F(III)9 of a Scheme III 1886-like pharmacophore;
wherein
functional group F(III)1 donates a hydrogen bond to a side chain carbonyl of receptor Gln408 and accepts a hydrogen bond from the side chain NH 2 of receptor Gln384 of SEQ ID NO: 1 and has coordinates of r=81.552, θ (theta)=41.243, and φ (phi)=45.369 and a spherical radius of about 1.2 Å;
functional group F(III)2 accepts a hydrogen bond from a side chain OH of receptor Ser440 of SEQ ID NO: 1 and has coordinates of r=87.287, θ (theta)=40.739, and φ (phi)=51.781 and a spherical radius of about 1.2 Å;
functional group F(III)3 accepts a hydrogen bond from a side chain OH of receptor Ser440 of SEQ ID NO: 1 and has coordinates of r=86.320, θ (theta)=41.915, and φ (phi)=52.323 and a spherical radius of about 1.5 Å;
functional group F(III)4 forms a favorable coulombic interaction with an imidazole side chain of receptor His409 of SEQ ID NO: 1 and has coordinates of r=85.870, θ (theta)=38.463, and φ (phi)=41.650 and a spherical radius of about 1.2 Å;
functional group F(III)5 forms a favorable coulombic interaction with an imidazole side chain of receptor His409 of SEQ ID NO: 1 and has coordinates of r=82.241, θ (theta)=37.431, and φ (phi)=44.151 and a spherical radius of about 1.5 Å;
functional group F(III)6 accepts a hydrogen bond from, or forms a salt bridge to, NH 3+ of receptor Lys465 of SEQ ID NO: 1 and has coordinates of r=88.009, θ (theta)=37.822, and φ (phi)=54.903 and a spherical radius of about 1.2 Å;
functional group F(III)7 accepts a hydrogen bond from, or forms a salt bridge to, NH 3+ of receptor Lys465 of SEQ ID NO: 1 and has coordinates of r=86.513, θ (theta)=36.889, and φ (phi)=54.484 and a spherical radius of about 1.5 Å;
functional group F(III)8 donates a hydrogen bond to a side chain carbonyl of receptor Gln408 of SEQ ID NO: 1 and has coordinates of r=81.552, θ (theta)=41.243, and φ (phi)=45.369 and a spherical radius of about 1.2 Å;
functional group F(III)9 donates a hydrogen bond to a side chain carbonyl of receptor Gln408 of SEQ ID NO: 1 and has coordinates of r=79.652, θ (theta)=40.928, and φ (phi)=44.528 and a spherical radius of about 1.6 Å; and
the compound substantially maintains a non-extended tether inactive configuration of EGFR or substantially prevents stabilization of an extended tether active configuration of EGFR.
10 . A compound having a formula of:
or a stereoisomer or pharmaceutically acceptable salt thereof;
wherein,
R 122 and R 126 are independently selected from the group consisting of:
(i) hydrogen,
(ii) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iii) trifluoromethyl; and
(iv) halogen;
R 123 and R 125 are independently selected from the group consisting of:
(i) hydrogen;
(ii) trifluoromethyl;
(iii) halogen;
(iv) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(v) acyl —COR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(vi) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
R 124 is selected from the group consisting of:
(i) hydrogen;
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
(iii) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iv) acyl —COR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(v) halogen;
R 127 and R 131 are independently selected from the group consisting of:
(i) hydrogen,
(ii) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(iii) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
R 128 and R 130 are independently selected from the group consisting of: hydrogen and halogen;
R 129 is selected from the group consisting of:
(i) hydrogen;
(ii) halogen;
(iii) alkoxy —OR 10 where R 10 is selected from the group consisting of:
(a) a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
(b) a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(iv) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
R 132 is selected from the group consisting of: hydrogen and straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
Formula (32) excludes a compound of Formula (31):
or a stereoisomer or pharmaceutically acceptable salt thereof;
wherein
n is 1 or 2;
R 133 and R 137 are independently selected from the group consisting of: hydrogen; halogen; and straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
R 134 and R 136 are independently selected from the group consisting of: hydrogen; trifluoromethyl; and halogen;
R 135 selected from the group consisting of: hydrogen and halogen;
R 138 , R 140 , and R 141 are hydrogen;
R 139 is selected from the group consisting of: hydrogen and halogen;
R 142 is selected from the group consisting of: hydrogen and straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; and
Formula (33) excludes a compound of Formula (31):
11 . The compound of claim 10 , wherein
(A) the compound is according to Formula (32) (11091-like Type H) and one or more of the following features are satisfied: R 122 and R 126 are independently selected from the group consisting of hydrogen; trifluoromethyl; methoxy; and chloro; R 122 or R 126 is hydrogen; R 123 and R 125 are independently selected from the group consisting of halogen and trifluoromethyl; R 124 selected from the group consisting of halogen and straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; R 127 and R 131 are independently selected from the group consisting of hydrogen, methyl, and methoxy; R 128 and R 130 are independently selected from the group consisting of hydrogen and chloro; R 129 is selected from the group consisting of hydrogen; chloro; methoxy; and methyl. R 132 of Formula (32) is selected from the group consisting of hydrogen; methyl; and ethyl; or the compound is selected from the group consisting of:
or
(B) the compound is according to Formula (33) (11091-like Type I) and one or more of the following features are satisfied:
R 133 and R 137 are independently selected from the group consisting of: hydrogen; methyl; and chloro.
R 134 and R 136 are independently selected from the group consisting of: hydrogen; trifluoromethyl; and chloro.
R 135 is chloro.
R 139 is selected from the group consisting of: fluoro and hydrogen.
R 142 is selected from the group consisting of: hydrogen or methyl and
the compound is selected from the group consisting of
12 . The compound of claim 10 that inhibits EGFR activity comprising:
at least nine or more of functional groups F(V)1, F(V)2, F(V)3, F(V)4, F(V)5, F(V)6, F(V)7, F(V)8, F(V)9, F(V)10, and F(V)11 of a Scheme V 11091-like pharmacophore;
wherein
functional group F(V)1 accepts a hydrogen bond from a side chain amino of receptor Lys465 of SEQ ID NO: 1 and has coordinates of r=85.329, θ (theta)=34.962, and φ (phi)=53.394 and a spherical radius of about 1.2 Å;
functional group F(V)2 accepts a hydrogen bond from a side chain amino of receptor Lys465 of SEQ ID NO: 1 and has coordinates of r=87.180, θ (theta)=35.618, and φ (phi)=53.267 and a spherical radius of about 1.5 Å;
functional group F(V)3 accepts a hydrogen bond from a side chain amino of receptor Lys465 of SEQ ID NO: 1 and has coordinates of r=86.349, θ (theta)=34.560, and φ (phi)=55.424 and a spherical radius of about 1.5 Å;
functional group F(V)4 donates a hydrogen bond to a side chain carbonyl of receptor Gln411 of SEQ ID NO: 1 and has coordinates of r=83.958, θ (theta)=35.296, and φ (phi)=51.296 and a spherical radius of about 1.2 Å;
functional group F(V)5 donates a hydrogen bond to a side chain carbonyl of receptor Gln411 of SEQ ID NO: 1 and has coordinates of r=82.060, θ (theta)=34.984, and φ (phi)=50.365 and a spherical radius of about 1.5 Å;
functional group F(V)6 donates a hydrogen bond to a side chain nitrogen of receptor Gln411 of SEQ ID NO: 1 and has coordinates of r=83.884, θ (theta)=36.166, and φ (phi)=49.227 and a spherical radius of about 1.2 Å;
functional group F(V)7 donates a hydrogen bond to a side chain nitrogen of receptor Gln411 of SEQ ID NO: 1 and has coordinates of r=82.006, θ (theta)=35.523, and φ (phi)=49.076 and a spherical radius of about 1.5 Å;
functional group F(V)8 accepts a hydrogen bond to a side chain imidazole of receptor His409 of SEQ ID NO: 1 and has coordinates of r=85.100, θ (theta)=38.590, and φ (phi)=43.143 and a spherical radius of about 1.2 Å;
functional group F(V)9 forms a favorable π-π interaction with a phenyl ring of receptor Phe412 of SEQ ID NO: 1 and has coordinates of r=84.418, θ (theta)=37.489, and φ (phi)=46.968 and a spherical radius of about 1.2 Å;
functional group F(V)10 forms a favorable π-π interaction with a phenyl ring of receptor Phe412 of SEQ ID NO: 1 and has coordinates of r=82.486, θ (theta)=38.027, and φ (phi)=47.246 and a spherical radius of about 1.5 Å; and
functional group F(V)11 forms a favorable hydrophobic interaction with a side chain of receptors Val417 and Ile448 of SEQ ID NO: 1 and has coordinates of r=84.438, θ (theta)=40.753, and φ (phi)=48.557 and a spherical radius of about 1.2 Å;
functional group F11 forms a favorable hydrophobic interaction with a side chain of receptors Val417 and Ile448 of SEQ ID NO: 1 and has coordinates of r=84.438, θ (theta)=40.753, and φ (phi)=48.557 and a spherical radius of about 1.2 Å; and
the compound substantially maintains a non-extended tether inactive configuration of EGFR or substantially prevents stabilization of an extended tether active configuration of EGFR.
13 . A method of treating a proliferative disease, disorder, or condition, comprising:
administering to a subject in need thereof a composition comprising a therapeutically effective amount of
(i) a compound of any one of claims 1 , 4 , 7 , or 10 , or a stereoisomer or pharmaceutically acceptable salt thereof;
(ii) a compound selected from the group consisting of:
or
a stereoisomer or pharmaceutically acceptable salt thereof; or (iii) a compound selected from the group consisting of:
or a stereoisomer or pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable carrier or excipient.
14 . The method of claim 13 , wherein the proliferative disease, disorder, or condition is
(i) selected from the group consisting of: cancer; a blood vessel proliferative disorder; a fibrotic disorder; a mesangial cell proliferative disorder; psoriasis; actinic keratoses; seborrheic keratoses; warts; keloid scars; eczema; and hyperproliferative diseases caused by a viral infection; (ii) is a disease, disorder, or condition associated with EGFR; or (iii) is a disease, disorder, or condition associated with EGFR selected from the group consisting of: cancer; a blood vessel proliferative disorder; a fibrotic disorder; a mesangial cell proliferative disorder; psoriasis; actinic keratoses; seborrheic keratoses; warts; keloid scars; eczema; and hyperproliferative diseases caused by a viral infection.
15 . A method for identifying an epidermal growth factor receptor (EGFR) inhibitor, comprising:
providing a pharmacophore comprising a scheme selected from the group consisting of: Scheme II, Scheme III, Scheme IV, or Scheme V as input to a 3-dimensional database; comparing a three dimensional structure of a candidate compound to the three dimensional structure of the pharmacophore; selecting a candidate compound with a three dimensional structure that substantially aligns with:
five or more functional groups of Scheme II (ADS-1734-like);
seven or more functional groups of Scheme III (AD4-1886-like);
eight or more of functional groups of Scheme IV (AD4-10381-like); or
nine or more of functional groups of Scheme V (AD4-11091-like); wherein
similarity between the three-dimensional structure of the candidate compound and the three-dimensional structure of the pharmacophore is indicative of an ability of the candidate compound to inhibit EGFR by substantially maintaining a tethered inactive configuration of EGFR or substantially preventing stabilization of the untethered active configuration of EGFR;
Scheme II (ADS-1734-like) comprises functional groups F(II)1, F(II)2, F(II)3, F(II)4, F(II)5, F(II)6, F(II)7, F(II)8, and F(II)9; wherein
functional group F(II)1 donates an H-bond or forms a salt bridge to a carboxylate side chain of receptor Asp553 of SEQ ID NO: 1 and has coordinates of r=56.363, θ (theta)=94.368, and φ (phi)=−17.752 and a spherical radius of about 1.2 Å;
functional group F(II)2 is a donor and has coordinates of r=53.290, θ (theta)=101.494, and φ (phi)=−23.244 and a spherical radius of about 1.0 Å;
functional group F(II)3 forms a hydrophobic contact with a side chain of receptor Val568, imidazolidine side chain of receptor Pro552 and with a side chain of Met253 of SEQ ID NO: 1 and has coordinates of r=53.726, θ (theta)=97.830, and φ (phi)=−18.377 and a spherical radius of about 1.7 Å;
functional group F(II)4 forms a hydrophobic contact with side chain of receptor Val575, Met253, and with an imidazolidine ring of receptor Pro552 of SEQ ID NO: 1 and has coordinates of r=53.647, θ (theta)=103.844, and φ (phi)=−20.990 and a spherical radius of about 1.4 Å;
functional group F(II)5 donates an H-bond to a side chain hydroxyl of Thr570 of SEQ ID NO: 1 and has coordinates of r=51.093, θ (theta)=104.261, and φ (phi)=−25.552 and a spherical radius of about 1.2 Å;
functional group F(II)6 is a donor having directionality of F4 with respect to a backbone carbonyl of receptor Thr570 of SEQ ID NO: 1 and has coordinates of r=52.340, θ (theta)=103.980, and φ (phi)=−27.461 and a spherical radius of about 1.5 Å;
functional group F(II)7 accepts an H-bond from a receptor backbone NH of Ala573 of SEQ ID NO: 1 and has coordinates of r=51.383, θ (theta)=106.455, and φ (phi)=−24.319 and a spherical radius of about 1.2 Å;
functional group F(II)8 is an acceptor having directionality of F7 with respect to the backbone NH of receptor Ala573 of SEQ ID NO: 1 and has coordinates of r=52.861, θ (theta)=107.691, and φ (phi)=−25.448 and a spherical radius of about 1.5 Å; and
functional group F(II)9 donates an H-bond to a backbone carbonyl of Asp563 and forms a salt bridge to a side chain carboxylate of receptor Asp563 of SEQ ID NO: 1 and has coordinates of r=57.688, θ (theta)=99.198, and φ (phi)=−21.588 and a spherical radius of about 1.2 Å;
Scheme III (AD4-1886-like) comprises functional groups F(III)1, F(III)2, F(III)3, F(III)4, F(III)5, F(III)6, F(III)7, F(III)8, and F(III)9; wherein
functional group F(III)1 donates a hydrogen bond to a side chain carbonyl of receptor Gln408 and accepts a hydrogen bond from the side chain NH 2 of receptor Gln384 of SEQ ID NO: 1 and has coordinates of r=81.552, θ (theta)=41.243, and φ (phi)=45.369 and a spherical radius of about 1.2 Å;
functional group F(III)2 accepts a hydrogen bond from a side chain OH of receptor Ser440 of SEQ ID NO: 1 and has coordinates of r=87.287, θ (theta)=40.739, and φ (phi)=51.781 and a spherical radius of about 1.2 Å;
functional group F(III)3 accepts a hydrogen bond from a side chain OH of receptor Ser440 of SEQ ID NO: 1 and has coordinates of r=86.320, θ (theta)=41.915, and φ (phi)=52.323 and a spherical radius of about 1.5 Å;
functional group F(III)4 forms a favorable coulombic interaction with an imidazole side chain of receptor His409 of SEQ ID NO: 1 and has coordinates of r=85.870, θ (theta)=38.463, and φ (phi)=41.650 and a spherical radius of about 1.2 Å;
functional group F(III)5 forms a favorable coulombic interaction with an imidazole side chain of receptor His409 of SEQ ID NO: 1 and has coordinates of r=82.241, θ (theta)=37.431, and φ (phi)=44.151 and a spherical radius of about 1.5 Å;
functional group F(III)6 accepts a hydrogen bond from, or forms a salt bridge to, NH 3+ of receptor Lys465 of SEQ ID NO: 1 and has coordinates of r=88.009, θ (theta)=37.822, and φ (phi)=54.903 and a spherical radius of about 1.2 Å;
functional group F(III)7 accepts a hydrogen bond from, or forms a salt bridge to, NH 3+ of receptor Lys465 of SEQ ID NO: 1 and has coordinates of r=86.513, θ (theta)=36.889, and φ (phi)=54.484 and a spherical radius of about 1.5 Å;
functional group F(III)8 donates a hydrogen bond to a side chain carbonyl of receptor Gln408 of SEQ ID NO: 1 and has coordinates of r=81.552, θ (theta)=41.243, and φ (phi)=45.369 and a spherical radius of about 1.2 Å; and
functional group F(III)9 donates a hydrogen bond to a side chain carbonyl of receptor Gln408 of SEQ ID NO: 1 and has coordinates of r=79.652, θ (theta)=40.928, and φ (phi)=44.528 and a spherical radius of about 1.6 Å;
Scheme IV (AD4-10381-like) comprises functional group F(IV)1, F(IV)2, F(IV)3, F(IV)4, F(IV)5, F(IV)6, F(IV)7, F(IV)8, and F(IV)9; wherein
functional group F(IV)1 accepts a hydrogen bond from receptor side chain OH of Thr239 of SEQ ID NO: 1 and has coordinates of r=49.686, θ (theta)=113.993, and φ (phi)=−17.014 and a spherical radius of about 1.2 Å;
functional group F(IV)2 accepts a hydrogen bond from receptor side chain OH of Thr239 of SEQ ID NO: 1 and has coordinates of r=48.071, θ (theta)=115.388, and φ (phi)=−16.211 and a spherical radius of about 1.6 Å;
functional group F(IV)3 forms a hydrophobic contact with a side chain of receptor Met576 and imidazolidine ring of Pro242 of SEQ ID NO: 1 and has coordinates of r=50.781, θ (theta)=113.121, and φ (phi)=−17.520 and a spherical radius of about 1.2 Å;
functional group F(IV)4 forms a hydrophobic contact with a side chain of receptor Met576 and imidazolidine ring of Pro242 of SEQ ID NO: 1 and has coordinates of r=52.021, θ (theta)=114.264, and φ (phi)=−15.878 and a spherical radius of about 1.5 Å;
functional group F(IV)5 forms a hydrophobic contact with a side chain of receptor Met576 and imidazolidine ring of Pro242 of SEQ ID NO: 1 and has coordinates of r=50.322, θ (theta)=111.253, and φ (phi)=−15.426 and a spherical radius of about 1.2 Å;
functional group F(IV)6 forms a hydrophobic contact with a side chain of receptor Met576 and imidazolidine ring of Pro242 of SEQ ID NO: 1 and has coordinates of r=51.575, θ (theta)=112.433, and φ (phi)=−13.827 and a spherical radius of about 1.5 Å;
functional group F(IV)7 forms a hydrophobic contact with a side chain of receptor Leu243 and a side chain of Thr239 of SEQ ID NO: 1 and has coordinates of r=47.767, θ (theta)=112.521, and φ (phi)=−10.196 and a spherical radius of about 1.2 Å;
functional group F(IV)8 donates a hydrogen bond to a backbone carbonyl of His280 of SEQ ID NO: 1 and has coordinates of r=45.184, θ (theta)=112.328, and φ (phi)=−8.875 and a spherical radius of about 1.2 Å;
functional group F(IV)9 forms a hydrophobic contact with a side chain of receptor Met244 and Leu243 of SEQ ID NO: 1 and has coordinates of r=49.512, θ (theta)=108.007, and φ (phi)=−8.504 and a spherical radius of about 1.2 Å; and
functional group F(IV)10 forms a hydrophobic contact with a side chain of receptor Met244 of SEQ ID NO: 1 and has coordinates of r=50.431, θ (theta)=104.985, and φ (phi)=−7.420 and a spherical radius of about 1.8 Å; and
Scheme V (AD4-11091-like) comprises functional group functional groups F(V)1, F(V)2, F(V)3, F(V)4, F(V)5, F(V)6, F(V)7, F(V)8, F(V)9, F(V)10, and F(V)11; wherein
functional group F(V)1 accepts a hydrogen bond from a side chain amino of receptor Lys465 of SEQ ID NO: 1 and has coordinates of r=85.329, θ (theta)=34.962, and φ (phi)=53.394 and a spherical radius of about 1.2 Å;
functional group F(V)2 accepts a hydrogen bond from a side chain amino of receptor Lys465 of SEQ ID NO: 1 and has coordinates of r=87.180, θ (theta)=35.618, and φ (phi)=53.267 and a spherical radius of about 1.5 Å;
functional group F(V)3 accepts a hydrogen bond from a side chain amino of receptor Lys465 of SEQ ID NO: 1 and has coordinates of r=86.349, θ (theta)=34.560, and φ (phi)=55.424 and a spherical radius of about 1.5 Å;
functional group F(V)4 donates a hydrogen bond to a side chain carbonyl of receptor Gln411 of SEQ ID NO: 1 and has coordinates of r=83.958, θ (theta)=35.296, and φ (phi)=51.296 and a spherical radius of about 1.2 Å;
functional group F(V)5 donates a hydrogen bond to a side chain carbonyl of receptor Gln411 of SEQ ID NO: 1 and has coordinates of r=82.060, θ (theta)=34.984, and φ (phi)=50.365 and a spherical radius of about 1.5 Å;
functional group F(V)6 donates a hydrogen bond to a side chain nitrogen of receptor Gln411 of SEQ ID NO: 1 and has coordinates of r=83.884, θ (theta)=36.166, and φ (phi)=49.227 and a spherical radius of about 1.2 Å;
functional group F(V)7 donates a hydrogen bond to a side chain nitrogen of receptor Gln411 of SEQ ID NO: 1 and has coordinates of r=82.006, θ (theta)=35.523, and φ (phi)=49.076 and a spherical radius of about 1.5 Å;
functional group F(V)8 accepts a hydrogen bond to a side chain imidazole of receptor His409 of SEQ ID NO: 1 and has coordinates of r=85.100, θ (theta)=38.590, and φ (phi)=43.143 and a spherical radius of about 1.2 Å;
functional group F(V)9 forms a favorable π-π interaction with a phenyl ring of receptor Phe412 of SEQ ID NO: 1 and has coordinates of r=84.418, θ (theta)=37.489, and φ (phi)=46.968 and a spherical radius of about 1.2 Å;
functional group F(V)10 forms a favorable π-π interaction with a phenyl ring of receptor Phe412 of SEQ ID NO: 1 and has coordinates of r=82.486, θ (theta)=38.027, and φ (phi)=47.246 and a spherical radius of about 1.5 Å; and
functional group F(V)11 forms a favorable hydrophobic interaction with a side chain of receptors Val417 and Ile448 of SEQ ID NO: 1 and has coordinates of r=84.438, θ (theta)=40.753, and φ (phi)=48.557 and a spherical radius of about 1.2 Å.
16 . The method of claim 15 , further comprising one or more of the following features:
determining identity and spatial orientation of at least a portion of atoms of EGFR associated with stabilizing a tethered configuration of domain II and domain IV of EGFR in an inactive conformation; and constructing a pharmacophore, wherein the pharmacophore comprises a pluralitiy of pharmacophoric features that approximates the identity and the spatial orientation of the at least a portion of atoms of EGFR associated with stabilizing a tethered configuration of domain II and domain IV of EGFR in an inactive conformation such that the pharmacophore structural features are complementary to the inactive EGFR configuration. determining identity and spatial orientation of at least a portion of atoms of EGFR associated with stabilizing a tethered configuration of domain II and domain IV of EGFR in an inactive conformation by analysis of X-ray crystallographic data derived from a crystalline form of EGFR in an inactive, tethered conformation; wherein at least one pharmacophoric feature approximates identity and spatial orientations of at least a portion of atoms of domain II of EGFR in a tethered inactive conformation; wherein at least one pharmacophoric feature approximates identity and spatial orientations of at least a portion of atoms of a cleft region between domain II and domain IV of EGFR in a tethered inactive conformation; or determining a docking affinity of the candidate molecule for the at least a portion of atoms of EGFR associated with stabilizing a tethered configuration of domain II and domain IV of EGFR in an inactive conformation, wherein docking affinity is quantified by energy gained upon interaction of the candidate molecule with the target biomolecule, energy required to attain the docked conformation relative to the lowest energy conformation, or a combination thereof.Cited by (0)
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