US2011269244A1PendingUtilityA1
Ligand-directed covalent modification of protein
Est. expiryDec 30, 2029(~3.5 yrs left)· nominal 20-yr term from priority
Inventors:Russell C. PetterCharles F. JewellKwangho LeeAravind Prasad MedikondaDeqiang NiuLixin QiaoJuswinder SinghZhendong Zhu
C07D 405/14C12Y 207/11001G16B 15/00C07D 487/04C07D 409/12C07D 495/04C12Y 304/21098C12N 9/93C07D 491/08C07D 417/06C07D 401/04C12Q 1/485C07D 519/00C12Q 1/37C07D 403/14C12Y 603/02C07D 403/12G01N 33/68C12N 9/506C12Q 1/25C12N 9/96C07D 417/14A61P 31/14C07D 207/16A61P 43/00C07D 493/04C07D 405/12C12N 9/12C07D 401/14C07D 239/49C07D 513/04G16C 20/50G16B 15/30
47
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The present invention relates to enzyme inhibitors. More specifically, the present invention relates to ligand-directed covalent modification of proteins; method of designing same; pharmaceutical formulation of same; and method of use.
Claims
exact text as granted — not AI-modified1 . A method for designing a ligand that covalently binds a target protein, the method comprising:
A) providing a structural model of a reversible ligand docked within, or in proximity to, a ligand-binding site in a target protein; B) identifying a lysine residue of the target protein in, or in proximity to, the ligand-binding site that is less than about 15 Å from the reversible ligand when the reversible ligand is docked in, or in proximity to, the ligand-binding site; C) producing at least a structural model of at least one ligand-warhead compound docked within, or in proximity to, the ligand-binding site wherein the ligand-warhead compound comprises the reversible ligand in step B) or a portion thereof, a warhead comprising a reactive chemical moiety, and optionally a Tether; and D) identifying a ligand-warhead compound whose structural model allows the lysine residue in step B) to readily assume a conformation that brings the side chain primary amine group of the lysine residue within bond-forming proximity of the warhead electrophile.
2 . The method of claim 1 , further comprising:
E) forming, for the ligand-warhead compound identified in step D), a ligand-protein covalent adduct by forming a covalent bond between the side chain primary amine group of the lysine residue identified in step B) and the warhead electrophile in ligand-warhead compound identified in step D) while substantially maintaining the non-covalent interactions between the pharmacophore of the ligand and the ligand-binding site.
3 . The method of claim 2 , further comprising:
F) evaluating the conformation of the resulting ligand-protein covalent adduct formed in step E) by analyzing the global energy of the resulting conformation, or by analyzing the energy of the conformation of the Tether.
4 . The method of claim 3 , wherein steps A)-F) are iterated with changes to the Tether and the global energy of the resulting conformation is less than the previous iteration.
5 . The method of claim 2 , further comprising:
F) determining whether the ligand-binding site is occluded when the covalent bond is formed between the side chain primary amine group of the lysine residue in, or in proximity to, the ligand-binding site and the warhead electrophile.
6 . The method of claim 2 , wherein the covalent bond formed in step E) is formed using a computational method in which the warhead and the side chain of the lysine residue are flexible and the remainder of the structures of the ligand-warhead compound and the ligand-binding site are fixed.
7 . The method of claim 1 , wherein in step B) each of the lysine residues in, or in proximity to, the ligand-binding site of the target protein, which is less than about 15 Å from the reversible ligand when the reversible ligand is docked in, or in proximity to, the ligand-binding site, is identified.
8 . The method of claim 1 , wherein step C) comprises providing a plurality of models of the ligand-warhead compound, wherein the warhead is bonded to a different substitutable position of the ligand or a portion of the ligand in each model of the ligand-warhead compound, optionally with the Tether in between the warhead and the substitutable position.
9 . The method of claim 1 , wherein the target protein is an identified member of an identified protein family and the lysine residue is not conserved across the identified members of the protein family.
10 . The method of claim 1 , wherein the target protein is an identified member of an identified protein family and the lysine residue is conserved among more than one identified member of the identified protein family.
11 . The method of claim 10 , wherein the lysine residue is conserved across the identified members of the protein family.
12 . The method of claim 1 , wherein the target protein has catalytic activity.
13 . The method of claim 1 , wherein the protein family is selected from the group consisting of BCL-2, Calpains, Caspases, Cathepsins, HCV, HDAC, HSP70, HSP90, IAP, Kinase, MDM2, MMP, NHR, PI3K, Phosphatase, PARP, and HIV Protease.
14 . The method of claim 13 , wherein the target protein is selected from the group consisting of XIAP, cIAP1 and cIAP2, PI3Kβ/γ, PDPK1, and HCV-NS3.
15 . The method of claim 1 , wherein the ligand-binding site is a ligand-binding site for a substrate or cofactor.
16 . The method of claim 1 , wherein the lysine residue is not a catalytic residue.
17 . The method of claim 1 , wherein the ligand-warhead compound has a structure of Formula I:
wherein
Scaffold is
a) a radical resulting from the removal of a hydrogen of a ligand capable of binding to, or in proximity to, the ligand-binding site; or
b) a portion of a pharmacophore of a ligand resulting from truncation of the pharmacophore, such that the Scaffold is capable of binding to, or in proximity to, the ligand-binding site;
Warhead is an organic moiety optionally containing one or more heteroatoms selected from O, N, and S; the organic moiety having a molecular weight of about 14 daltons to about 200 daltons; Warhead being capable of reaction with a side chain primary amine group of a lysine residue; and Warhead being attached to Scaffold through Tether; and
Tether is null, a bond, or a bivalent C 1 -C 15 saturated, unsaturated, straight, branched, cyclic, bicyclic, tricyclic alkyl, alkenyl, alkynyl; bridged bicyclic, heterocycle, heteroaryl, or aryl moiety; wherein optionally one or more methylene units of the hydrocarbon chain are independently replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —C(═S)—, or C(═NR 1 )—; optionally one or more hydrogens are independently replaced by heteroatoms; and optionally one or more methine groups of the C 1 -C 15 alkyl, when present, are independently replaced by
x is 0, 1, or 2;
y is 1, 2, or 3; and
R 1 is hydrogen or C 1 -C 8 alkyl;
with the proviso that the compound of Formula I is not wortmannin:
or known analogues of wortmannin that covalently modify lysine through substantially the same mechanism as wortmannin:
or any mechanism-based irreversible inhibitors.
18 . The method of claim 17 , wherein the ligand-warhead compound has a structure of Formula I′:
19 . The method of claim 18 , wherein Warhead is a radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, I-s, and I-t:
wherein
each X 1 and X 8 is independently —O—, —S—, or —NR 6 —;
each X 2 is independently —R 6 , —OR 6 , or —NR 6 R 7 ;
each X 9 is independently
each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl;
wherein optionally when proper any two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group; and optionally X 2 and any one of R 2 , R 3 , and R 4 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group;
A and B are each independently an optionally substituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl; and
n is an integer from 2-4; each n 1 and n 2 is independently an integer from 0-2; n 3 is an integer from 1-2; n 4 is an integer from 1-3; and each one of n 9 , n 10 , n 11 , and n 12 is an integer from 0-1; and n 13 is an integer from 0-2, wherein when any one of the foregoing n integers is more than 1, the adjacent carbons represented by the integer can form a single or double bond.
20 . The method of claim 19 , wherein as least one of R 2 and R 3 of the compounds of Formulas I-b and I-c is hydrogen.
21 . The method of claim 19 , wherein the compound of Formula I-a, I-d, I-e, I-j, I-k, or I-l is a compound of Formula II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, II-i, II-j, II-k, II-l, II-m, II-n, II-o, II-p, II-q, II-r, II-s, II-t, II-u, II-v, II-w, II-x, II-y, II-z, II-aa, II-bb, II-cc, II-dd, II-ee, II-ff, II-gg, II-hh, II-jj, II-kk, II-ll, II-mm, II-nn, II-oo, or II-pp;
wherein
each m is independently an integer from 0-4;
each m 5 is independently an integer from 0-3;
each m 4 is independently an integer from 0-5;
each n 2 is independently an integer from 0-2;
each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 is independently hydrogen or C 1 -C 6 alkyl; R z is hydrogen, C 1 -C 6 alkyl, halogen, CF 3 , or nitro; wherein
one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl; and
optionally when proper any two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group.
22 . The method of claim 19 , wherein the compound of Formula I-d, or I-h is a compound of Formula III-a, III-b, III-h, or III-i;
wherein
n 3 is an integer from 0-2;
each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl;
each B 1 , B 2 , B 4 , and B 5 is independently CR 7 or N and each B 3 is NR 7 , O, or S;
each R z1 , R z2 , R z3 , R z4 , and R z5 is hydrogen, C 1 -C 6 alkyl, halogen, CF 3 , or nitro;
one or more methylene groups of the C 1 -C 6 alkyl can be optionally replaced by —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl; and
optionally when proper any two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group.
23 . The method of claim 19 , wherein the compound of Formula I-h is a compound of Formula IV-a, IV-b, IV-c, IV-d, IV-e, IV-f, IV-g, IV-h, or IV-i:
wherein any of the substitutable hydrogens on the nitrogen heterocycle of the compound can be substituted with alkyl, alkoxy, amido, acyl, acyloxy, oxoacyl, halogen.
24 . The method of claim 19 , wherein the radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-d, I-k, or I-m is a radical of Formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, or V-j;
wherein
m 1 and m 2 are each independently an integer from 0 to 2;
each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is independently hydrogen or C 1 -C 6 alkyl;
one or more methylene groups of the C 1 -C 6 alkyl can be optionally replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—;
one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl; and
optionally when proper any two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group.
25 . The method of claim 19 , wherein the compounds of Formulae I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, I-s, and I-t are selected from the group consisting of:
wherein any substitutable hydrogen may be substituted with the substituents as those defined by R 2 -R 8 in formulas I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, I-s, and I-t.
26 . The method of claim 19 , wherein the radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-d, I-k, or I-m is a radical of Formula VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, VI-j, VI-k, VI-l, VI-m, VI-n, VI-o, VI-p, or VI-q:
wherein R zz is hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, —CH 2 OCH 3 , and —CH 2 CH 2 OCH 3 .
27 . The method of claim 19 , wherein Scaffold is selected from the group consisting of Formulas VII, VIII, IX-a, IX-b, XI, XII, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXXVI, and XXXVII.
28 . The method of claim 18 , wherein Scaffold is a radical resulting from the removal of one or more hydrogens of a compound of Formula VII:
wherein
V and W are each independently —(CR 14 R 15 ) q X 3 (CR 16 R 17 ) r —;
q and r are each independently 0, 1, 2, 3, or 4;
X 3 is —CR 18 R 19 —, or —NR 20 —; and
R x , R y , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 are each independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —SO—, —C(═S)—, optionally substituted aryl or heteroaryl groups; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
and R 1 is hydrogen or C 1 -C 8 alkyl.
29 . The method of claim 28 , wherein the compound of Formula VII is a compound of Formula VII-a:
wherein
V and W are each independently —(CR 14 R 15 ) q X 3 (CR 16 R 17 ) r —;
q and r are each independently 0, 1, 2, 3, or 4;
X 3 is —CR 18 R 19 —, or —NR 20 —;
p is 0, 1, 2, 3, or 4;
R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 are each independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, —C(═S)—, optionally substituted aryl or heteroaryl groups; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl; and;
R 23 is hydrogen, C 1 -C 6 alkyl, halogen, amino, or nitro; wherein one or more methylene groups of C 1 -C 6 alkyl can be optionally replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
and
optionally R 21 and R 23 taken together can form a 4- to 8-membered carbocyclic or heterocyclic ring.
30 . The method of claim 19 , wherein the compound of Formula I′ is a compound of Formula VII-b:
wherein
V and W are each independently —(CR 14 R 15 ) q X 3 (CR 16 R 17 ) r —;
q and r are each independently 0, 1, 2, 3, or 4;
X 3 is —CR 18 R 19 —, or —NR 20 —;
p is 0, 1, 2, 3, or 4;
R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 are each independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, —C(═S)—, optionally substituted aryl or heteroaryl groups; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl; and;
R 23 is hydrogen, C 1 -C 6 alkyl, halogen, amino, or nitro; wherein one or more methylene groups of C 1 -C 6 alkyl can be optionally replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
and
optionally R 21 and R 23 taken together can form a 4- to 8-membered carbocyclic or heterocyclic ring;
T is Tether; and
R wh is Warhead.
31 . The method of claim 30 , wherein the compound of Formula VII-b is a compound of Formula VII-h;
32 . The method of claim 31 , wherein the compound of Formula VII-h is a compound of Formula VII-j, VII-k, VII-l, VII-m, VII-n, or VII-o:
33 . The method of claim 31 , wherein the compound is selected from the group consisting of:
34 . The method of claim 19 , wherein Scaffold is a radical resulting from the removal of a hydrogen of a compound of Formula VIII:
wherein
X 4 is —CR 33 — or —N—;
s and p are each independently 0, 1, 2, 3, or 4;
R 12 , R 13 , R 21 , R 22 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , and R 33 are each independently hydrogen or C 1 -C 6 alkyl;
R 23 is hydrogen, C 1 -C 6 alkyl, halogen, amino, or nitro; wherein one or more methylene groups of C 1 -C 6 alkyl can be optionally replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl; and
optionally R 21 and R 23 taken together can form a 4- to 8-membered carbocyclic or heterocyclic ring.
35 . The method of claim 18 , wherein the compound of Formula I′ is a compound of Formula VIII-a or VIII-b:
wherein
X 4 is —CR 33 — or —N—;
s and p are each independently 0, 1, 2, 3, or 4;
R 12 , R 13 , R 21 , R 22 , R 24 , R 25 , R 26 , R 27 , R 28 , and R 33 are each independently hydrogen or C 1 -C 6 alkyl;
R 23 is hydrogen, C 1 -C 6 alkyl, halogen, amino, or nitro; wherein one or more methylene groups of C 1 -C 6 alkyl can be optionally replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl; and
optionally R 21 and R 23 taken together can form a 4- to 8-membered carbocyclic or heterocyclic ring; and
Warhead is a radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, I-s, and I-t:
wherein
each X 1 and X 8 is independently —O—, —S—, or —NR 6 —;
each X 2 is independently —R 6 , —OR 6 , or —NR 6 R 7 ;
each X 9 is independently
each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl;
wherein optionally when proper any two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group; and optionally X 2 and any one of R 2 , R 3 , and R 4 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group;
A and B are each independently an optionally substituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl; and
n is an integer from 2-4; each n 1 and n 2 is independently an integer from 0-2; n 3 is an integer from 1-2; n 4 is an integer from 1-3; and each one of n 9 , n 10 , n 11 , and n 12 is an integer from 0-1; and n 13 is an integer from 0-2, wherein when any one of the foregoing n integers is more than 1, the adjacent carbons represented by the integer can form a single or double bond.
36 . The method of claim 35 , wherein the compound of Formula VIII-a or VIII-b is selected from the group consisting of:
37 . The method of claim 19 , wherein Scaffold is a radical resulting from the removal of a hydrogen of a compound of Formula IX-a or IX-b,
wherein
X 5 is —O—, —CR 42 R 43 — or —NR 42 —;
R 12 , R 13 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , and R 43 are each independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of C 1 -C 6 alkyl can be optionally replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl;
D, E, F, G, and H are each independently optionally substituted aryl or heteroaryl; wherein F and G are fused together to form a bicyclic optionally substituted aryl or heteroaryl.
38 . The method of claim 18 , wherein the compound of Formula I′ is a compound of Formula IX-c or IX-d:
wherein
R 12 , R 13 , R 31 , are each independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of C 1 -C 6 alkyl can be optionally replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl;
F, G, and H are each independently optionally substituted aryl or heteroaryl; wherein F and G are fused together to form a bicyclic optionally substituted aryl or heteroaryl;
T is Tether;
R wh is Warhead which is a radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, I-s, and I-t:
wherein
each X 1 and X 8 is independently —O—, —S—, or —NR 6 —;
each X 2 is independently —R 6 , —OR 6 , or —NR 6 R 7 ;
each X 9 is independently
each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl;
wherein optionally when proper any two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group; and optionally X 2 and any one of R 2 , R 3 , and R 4 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group;
A and B are each independently an optionally substituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl; and
n is an integer from 2-4; each n 1 and n 2 is independently an integer from 0-2; n 3 is an integer from 1-2; n 4 is an integer from 1-3; and each one of n 9 , n 10 , n 11 , and n 12 is an integer from 0-1; and n 13 is an integer from 0-2, wherein when any one of the foregoing n integers is more than 1, the adjacent carbons represented by the integer can form a single or double bond.
39 . The method of claim 18 , wherein the compound of Formula I′ is a compound of Formula XI:
wherein
p is an integer from 0 to 4, u is an integer from 1 to 4;
B 6 and B 7 are each independently CR 7 or N;
R 69 is hydrogen, C 1 -C 6 alkyl, halogen, amino, nitro, or —NH(CO)NR 78 R 79 ;
R 70 is hydrogen, C 1 -C 6 alkyl, halogen, amino, nitro;
R 7 , R 71 , R 72 , R 73 , R 74 , R 75 , R 76 , R 77 , R 78 , and R 79 are each independently hydrogen or C 1 -C 6 alkyl; R 1 is hydrogen or C 1 -C 8 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
optionally R 78 , and R 79 taken together form a 4- to 8-membered carbocyclic or heterocyclic ring;
T is Tether; and
R wh is Warhead which is a radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, I-s, and I-t:
wherein
each X 1 and X 8 is independently —O—, —S—, or —NR 6 —;
each X 2 is independently —R 6 , —OR 6 , or —NR 6 R 7 ;
each X 9 is independently
each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl;
wherein optionally when proper any two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group; and optionally X 2 and any one of R 2 , R 3 , and R 4 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group;
A and B are each independently an optionally substituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl; and
n is an integer from 2-4; each n 1 and n 2 is independently an integer from 0-2; n 3 is an integer from 1-2; n 4 is an integer from 1-3; and each one of n 9 , n 10 , n 11 , and n 12 is an integer from 0-1; and n 13 is an integer from 0-2, wherein when any one of the foregoing n integers is more than 1, the adjacent carbons represented by the integer can form a single or double bond.
40 . The method of claim 39 , wherein the compound of Formula XI is a compound of Formula XI-a, XI-b, or XI-c:
41 . The method of claim 40 , wherein the compound of Formula XI-a, XI-b or XI-c is a compound of Formula XI-d, XI-e, XI-f, XI-g, XI-h, XI-i, or XI-j:
42 . The method of claim 41 , wherein the compound of Formula XI-d, XI-e, XI-f, XI-g, XI-h, XI-i, or XI-j is a compound of Formula XI-k, XI-l, XI-m, XI-n, XI-o, XI-p, or XI-q;
wherein
R 88 , and R 89 are each independently hydrogen or C 1 -C 6 alkyl; R 1 is hydrogen or C 1 -C 8 alkyl;
one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—;
one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
and
n 5 is an integer from 0 to 3.
43 . The method of claim 42 , wherein the compound of Formula XI-d, XI-e, XI-f, XI-g, XI-h, XI-i, or XI-j is a compound of Formula XI-r, XI-s, XI-t, XI-u, XI-v, XI-w, or XI-x;
44 . The method of claim 41 , wherein the compound of Formula XI-d, XI-e, XI-f, XI-g, XI-h, XI-i, or XI-j is a compound of Formula XI-y, XI-z, XI-aa, or XI-bb;
45 . The method of claim 41 , wherein the compound of Formula XI-d, XI-e, XI-f, XI-g, XI-h, XI-i, or XI-j is a compound of Formula XI-cc, XI-dd, XI-ee, or XI-ff:
46 . The method of claim 39 , wherein the compound of Formula XI is selected from the group consisting of:
47 . The method of claim 18 , wherein the compound of Formula I′ is a compound of Formula XII:
wherein
R 1 and R 2 are each independently hydrogen or C 1 -C 8 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
T is Tether;
R wh is Warhead which is a radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, I-s, and I-t:
wherein
each X 1 and X 8 is independently —O—, —S—, or —NR 6 —;
each X 2 is independently —R 6 , —OR 6 , or —NR 6 R 7 ;
each X 9 is independently
each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl;
wherein optionally when proper any two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group; and optionally X 2 and any one of R 2 , R 3 , and R 4 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group;
A and B are each independently an optionally substituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl; and
n is an integer from 2-4; each n 1 and n 2 is independently an integer from 0-2; n 3 is an integer from 1-2; n 4 is an integer from 1-3; and each one of n 9 , n 10 , n 11 , and n 12 is an integer from 0-1; and n 13 is an integer from 0-2, wherein when any one of the foregoing n integers is more than 1, the adjacent carbons represented by the integer can form a single or double bond.
48 . The method of claim 18 , wherein the compound of Formula I′ is a compound of Formula XXXVI:
wherein
R v is H, optionally substituted C 1 -C 3 branched or straight chain alkyl, or optionally substituted C 1 -C 3 branched or straight chain acyl;
T is Tether; and
R wh is Warhead which is a radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, I-s, and I-t:
wherein
each X 1 and X 8 is independently —O—, —S—, or —NR 6 —;
each X 2 is independently —R 6 , —OR 6 , or —NR 6 R 7 ;
each X 9 is independently
each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl;
wherein optionally when proper any two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group; and optionally X 2 and any one of R 2 , R 3 , and R 4 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group;
A and B are each independently an optionally substituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl; and
n is an integer from 2-4; each n 1 and n 2 is independently an integer from 0-2; n 3 is an integer from 1-2; n 4 is an integer from 1-3; and each one of n 9 , n 10 , n 11 , and n 12 is an integer from 0-1; and n 13 is an integer from 0-2, wherein when any one of the foregoing n integers is more than 1, the adjacent carbons represented by the integer can form a single or double bond.
49 . The method of claim 18 , wherein the compound of Formula I′ is selected from the group consisting of:
50 . The method of claim 19 , wherein Scaffold is a radical resulting from the removal of a hydrogen of a compound of Formula XVI-a, XVI-b, or XVI-c:
wherein
R 90 , R 91 , R 92 , R 93 , R 94 , R 95 , R 96 , R 97 , R 98 , R 99 , R 100 , R 102 , R 104 , R 105 , R 106 , R 107 , R 108 , R 109 , R 110 , R 111 , R 112 , R 113 , and R 114 are each independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of C 1 -C 6 alkyl can be optionally replaced by —NR 1 —, —O—, —C(O)—, —SO—, —SO 2 —, or —C(═S)—;
R 103 is hydrogen, C 1 -C 6 alkyl, or C 2 -C 8 alkenyl;
one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl;
each R 101 and R 101 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, halogen, amino, nitro, optionally substituted aryl or heteroaryl; and
n 6 and n 7 are each independently integer from 0 to 4; and
n 8 is an integer from 0 to 2.
51 . The method of claim 18 , wherein the compound of Formula I′ is a compound of Formula XVI-d, XVI-e, or XVI-f:
wherein
R 90 and R 114 are each independently hydrogen or C 1 -C 6 alkyl;
R 103 is hydrogen, C 1 -C 6 alkyl, or C 2 -C 8 alkenyl;
R 101 is hydrogen, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, halogen, amino, nitro, optionally substituted aryl or heteroaryl; and
n 6 is an integer from 0 to 4;
n 8 is an integer from 0 to 2;
wherein one or more methylene groups of C 1 -C 6 alkyl can be optionally replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; and
R wh is Warhead which is a radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, I-s, and I-t:
wherein
each X 1 and X 8 is independently —O—, —S—, or —NR 6 —;
each X 2 is independently —R 6 , —OR 6 , or —NR 6 R 7 ;
each X 9 is independently
each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl;
wherein optionally when proper any two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group; and optionally X 2 and any one of R 2 , R 3 , and R 4 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group;
A and B are each independently an optionally substituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl; and
n is an integer from 2-4; each n 1 and n 2 is independently an integer from 0-2; n 3 is an integer from 1-2; n 4 is an integer from 1-3; and each one of n 9 , n 10 , n 11 , and n 12 is an integer from 0-1; and n 13 is an integer from 0-2, wherein when any one of the foregoing n integers is more than 1, the adjacent carbons represented by the integer can form a single or double bond; and
T is Tether.
52 . The method of claim 51 , wherein the compound of Formula XVI-d, XVI-e, or XVI-f is a compound of Formula XVI-g, XVI-h, or XVI-i:
53 . The method of claim 18 , wherein the compound of Formula XVI-d, XVI-e, or XVI-f is selected from the group consisting of:
54 . The method of claim 18 wherein the compound of Formula I′ is a compound of Formula XXII-a, Formula XXII-b, or Formula XXII-c:
wherein
n, m, p, and q for Formula XXII-a and Formula XXII-b are each independently 0, 1, 2, 3; provided that n and q are not 0 at the same time, and m and q are not 0 at the same time;
T is tether;
R wh is Warhead and is a radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, I-s, and I-t:
wherein
each X 1 and X 8 is independently —O—, —S—, or —NR 6 —;
each X 2 is independently —R 6 , —OR 6 , or —NR 6 R 7 ;
each X 9 is independently
each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl;
wherein optionally when proper any two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group; and optionally X 2 and any one of R 2 , R 3 , and R 4 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group;
A and B are each independently an optionally substituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl; and
n is an integer from 2-4; each n 1 and n 2 is independently an integer from 0-2; n 3 is an integer from 1-2; n 4 is an integer from 1-3; and each one of n 9 , n 10 , n 11 , and n 12 is an integer from 0-1; and n 13 is an integer from 0-2, wherein when any one of the foregoing n integers is more than 1, the adjacent carbons represented by the integer can form a single or double bond;
A 2 is an optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated heterocyclic ring having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-10 membered saturated or partially unsaturated bridged bicyclic heterocyclic ring having at least one nitrogen, at least one oxygen, and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;
B′ is an optionally substituted group selected from phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or -T-Rwh; and
C 2 is hydrogen or an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
55 . The method of claim 54 , wherein the compound of Formula XXII-a, XXII-b, XXII-c is selected from the group consisting of:
56 . The method of claim 18 , wherein the compound of Formula I′ is a compound of Formula XXIII:
wherein:
R wh is Warhead which is a radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, I-s, and I-t:
wherein
each X 1 and X 8 is independently —O—, —S—, or —NR 6 —;
each X 2 is independently —R 6 , —OR 6 , or —NR 6 R 7 ;
each X 9 is independently
each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl;
wherein optionally when proper any two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group; and optionally X 2 and any one of R 2 , R 3 , and R 4 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group;
A and B are each independently an optionally substituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl; and
n is an integer from 2-4; each n 1 and n 2 is independently an integer from 0-2; n 3 is an integer from 1-2; n 4 is an integer from 1-3; and each one of n 9 , n 10 , n 11 , and n 12 is an integer from 0-1; and n 13 is an integer from 0-2, wherein when any one of the foregoing n integers is more than 1, the adjacent carbons represented by the integer can form a single or double bond;
R 201 is hydrogen or C 1-6 alkyl;
R 202 is hydrogen or an optionally substituted group selected from C 1-6 alkyl, C 1-6 alkoxy, or (C 1-6 alkylene)-R 203 ; or
R 201 and R 202 are taken together with the intervening carbon to form an optionally substituted ring selected from a 3- to 7-membered carbocyclic ring or a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 203 is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, a 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
Ring A 6 is absent or an optionally substituted group selected from a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
57 . The method of claim 56 , where the compound of Formula XXIII is selected from the group consisting of:
58 . The method of claim 18 , wherein the compound of Formula I′ is a compound of Formula XXIV-a or Formula XXIV-b:
wherein
R wh is Warhead which is a radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, I-s, and I-t:
wherein
each X 1 and X 8 is independently —O—, —S—, or —NR 6 —;
each X 2 is independently —R 6 , —OR 6 , or —NR 6 R 7 ;
each X 9 is independently
each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl;
wherein optionally when proper any two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group; and optionally X 2 and any one of R 2 , R 3 , and R 4 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group;
A and B are each independently an optionally substituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl; and
n is an integer from 2-4; each n 1 and n 2 is independently an integer from 0-2; n 3 is an integer from 1-2; n 4 is an integer from 1-3; and each one of n 9 , n 10 , n 11 , and n 12 is an integer from 0-1; and n 13 is an integer from 0-2, wherein when any one of the foregoing n integers is more than 1, the adjacent carbons represented by the integer can form a single or double bond;
R 204 is an hydrogen or an optionally substituted group selected from C 1-6 aliphatic, —(CH 2 ) m -(3- to 7-membered saturated or partially unsaturated carbocyclic ring), —(CH 2 ) m -(7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic ring), —(CH 2 ) m -(4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur), —(CH 2 ) m -(7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur), —(CH 2 ) m -phenyl, —(CH 2 ) m -(8- to 10-membered bicyclic aryl ring), —(CH 2 ) m -(5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur), or —(CH 2 ) m -(8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur);
each R 205 and R 206 is independently —R″, halogen, —NO 2 , —CN, —OR″, —SR″, —N(R″) 2 , —C(O)R″, —CO 2 R″, —C(O)C(O)R″, —C(O)CH 2 C(O)R″, —S(O)R″, —S(O) 2 R″, —C(O)N(R″) 2 , —SO 2 N(R″) 2 , —OC(O)R″, —N(R″)C(O)R″, —N(R″)N(R″) 2 , —N(R″)C(═NR″)N(R″) 2 , —C(═NR″)N(R″) 2 , —C═NOR″, —N(R″)C(O)N(R″) 2 , —N(R″)SO 2 N(R″) 2 , —N(R″)SO 2 R″, or —OC(O)N(R″) 2 ;
each R″ is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
two R″ groups on the same nitrogen are taken together with the nitrogen to which they are attached to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
m is an integer from 0 to 6, inclusive;
each n for Formula XXIV-a or Formula XXIV-b is independently 0, 1, or 2; and
Ring A 5 is an optionally substituted 6-membered heterocyclic or heteroaryl ring having 1-2 nitrogens.
59 . The method of claim 58 , wherein the compound of Formula XXIV-a or Formula XXIV-b is selected from the group consisting of
60 . The method of claim 18 , wherein the compound of Formula I′ is a compound of Formula XXV:
wherein
R wh is Warhead which is a radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, I-s, and I-t:
wherein
each X 1 and X 8 is independently —O—, —S—, or —NR 6 —;
each X 2 is independently —R 6 , —OR 6 , or —NR 6 R 7 ;
each X 9 is independently
each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl;
wherein optionally when proper any two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group; and optionally X 2 and any one of R 2 , R 3 , and R 4 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group;
A and B are each independently an optionally substituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl; and
n is an integer from 2-4; each n 1 and n 2 is independently an integer from 0-2; n 3 is an integer from 1-2; n 4 is an integer from 1-3; and each one of n 9 , n 10 , n 11 , and n 12 is an integer from 0-1; and n 13 is an integer from 0-2, wherein when any one of the foregoing n integers is more than 1, the adjacent carbons represented by the integer can form a single or double bond;
each R 205 and R 206 is independently —R″, halogen, —NO 2 , —CN, —OR″, —SR″, —N(R″) 2 , —C(O)R″, —CO 2 R″, —C(O)C(O)R″, —C(O)CH 2 C(O)R″, —S(O)R″, —S(O) 2 R″, —C(O)N(R″) 2 , —SO 2 N(R″) 2 , —OC(O)R″, —N(R″)C(O)R″, —N(R″)N(R″) 2 , —N(R″)C(═NR″)N(R″) 2 , —C(═NR″)N(R″) 2 , —C═NOR″, —N(R″)C(O)N(R″) 2 , —N(R″)SO 2 N(R″) 2 , —N(R″)SO 2 R″, or —OC(O)N(R″) 2 ;
each R″ is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
optionally, two R″ groups on the same nitrogen are taken together with the nitrogen to which they are attached to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
m is an integer from 0 to 6, inclusive;
each n for Formula XXV is independently 0, 1, or 2; and
Ring A 5 is an optionally substituted 6-membered heterocyclic or heteroaryl ring having 1-2 nitrogens.
61 . The method of claim 60 , wherein the compound of Formula XXV is selected from the group consisting of:
62 . The method of claim 18 , wherein the compound of Formula I′ is a compound of Formula XXVII:
wherein:
T is Tether;
R wh is Warhead which is a radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, I-s, and I-t:
wherein
each X 1 and X 8 is independently —O—, —S—, or —NR 6 —;
each X 2 is independently —R 6 , —OR 6 , or —NR 6 R 7 ;
each X 9 is independently
each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl;
wherein optionally when proper any two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group; and optionally X 2 and any one of R 2 , R 3 , and R 4 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group;
A and B are each independently an optionally substituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl; and
n is an integer from 2-4; each n 1 and n 2 is independently an integer from 0-2; n 3 is an integer from 1-2; n 4 is an integer from 1-3; and each one of n 9 , n 10 , n 11 , and n 12 is an integer from 0-1; and n 13 is an integer from 0-2, wherein when any one of the foregoing n integers is more than 1, the adjacent carbons represented by the integer can form a single or double bond.
63 . The method of claim 62 , wherein the compound of Formula XXVII is selected from the group consisting of:
64 . The method of claim 18 , wherein the compound of Formula I′ is a compound of Formula XXXVII:
wherein
T is Tether;
R wh is Warhead which is a radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, I-s, and I-t:
wherein
each X 1 and X 8 is independently —O—, —S—, or —NR 6 —;
each X 2 is independently —R 6 , —OR 6 , or —NR 6 R 7 ;
each X 9 is independently
each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C(═S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
R 1 is hydrogen or C 1 -C 8 alkyl;
wherein optionally when proper any two of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group; and optionally X 2 and any one of R 2 , R 3 , and R 4 when taken together form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group;
A and B are each independently an optionally substituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl; and
n in Warhead is an integer from 2-4; each n 1 and n 2 is independently an integer from 0-2; n 3 is an integer from 1-2; n 4 is an integer from 1-3; and each one of n 9 , n 10 , n 11 , and n 12 is an integer from 0-1; and n 13 is an integer from 0-2, wherein when any one of the foregoing n integers is more than 1, the adjacent carbons represented by the integer can form a single or double bond; and
each n in Formula XXXVII is 0, 1, or 2.
65 . The method of claim 64 , wherein the compound of Formula XXXVII is selected from the group consisting of:
66 - 184 . (canceled)Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.