US2021220475A1PendingUtilityA1
Egfr proteolysis targeting chimeric molecules and associated methods of use
Est. expiryDec 23, 2036(~10.4 yrs left)· nominal 20-yr term from priority
A61K 31/519A61K 31/496A61K 31/506A61K 31/427A61K 31/551A61P 11/00A61P 17/06A61K 31/55A61K 47/55A61K 31/454A61K 31/517A61K 45/06A61P 17/00A61K 38/07A61P 29/00A61K 31/52C07D 403/14A61P 25/00A61P 35/00A61P 9/10A61K 47/545C07D 487/04A61P 43/00C07D 471/04A61P 1/04C07D 417/04
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Claims
Abstract
The present invention relates to bifunctional compounds, which find utility to degrade and (inhibit) TBK1. In particular, the present invention is directed to compounds, which contain on one end an E3 ubiquitin ligase binding moiety which binds to an E3 ubiquitin ligase and on the other end a moiety which binds TBK1 such that TBK1 is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of TBK1. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of TBK1.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having the chemical structure:
PTM-Linker-ULM, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof, wherein: (a) the ULM is a small molecule E3 ubiquitin ligase binding moiety that binds an E3 ubiquitin ligase selected from Von Hippel-Lindau (VLM) and cereblon (VLM); (b) the PTM is a receptor tyrosine kinase (RTK) protein targeting moiety having the generical structure:
wherein:
R k5 , R k6 and R k7 are independently selected from H, alkyl, alkyne, alkoxy, hydroxyl, cyano, halogen, haloalkyl, haloalkoxy, and NO 2 , wherein the alkyl or alkoxy is optionally substituted with 1 or 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, and cyano; and
X is N, CH, halogen, C(C 1-6 alkyl), C(C 1-6 haloalkyl), C(C 1-6 alkoxy), C(C 1-6 haloalkyl), C(NO 2 ), C(NH 2 ), C(OH), or C(CN);
the PTM is coupled via the L to the ULM; and
(c) the Linker is a bond or a chemical linking moiety covalently coupling the ULM and the PTM.
2 . The compound according to claim 1 , wherein:
R k5 , R k6 and R k7 are independently selected from H, alkyl, alkyne, alkoxy, hydroxyl, cyano, and halogen, wherein the alkyl or alkoxy is optionally substituted with 1 to 2 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and cyano; and X is N or CH.
3 . The compound according to claim 1 , wherein the Linker is coupled to R k5 , R k6 , or R k7 .
4 . The compound according to claim 1 , wherein the PTM is selected from a PTM of compound 80, 82-84, 90, 91-96, 254-267, 275, 283, 289, 290, 293-300, 307, or 309-311 of FIG. 2 .
5 . The compound according to claim 1 , wherein the ULM is a VLM represented by:
wherein:
X 1 and X 2 are each independently selected from the group of a bond, O, NR Y3 , CR Y3 R Y4 , C═O, C═S, SO, and SO 2 ;
R Y3 and R Y4 are each independently selected from the group of H, linear or branched C 1-6 alkyl, optionally substituted by 1 or more halogen, C 1-6 alkoxyl optionally substituted by 0-3 R P groups;
R P is 0, 1, 2, or 3 groups, each independently selected from the group consisting of H, halogen, —OH, C 1-3 alkyl, C═O;
W 3 is selected from the group of an optionally substituted -T-N(R 1a R 1b )X 3 , optionally substituted -T-N(R 1a R 1b ), optionally substituted -T-Aryl, an optionally substituted -T-Heteroaryl, an optionally substituted -T-Heterocycle, an optionally substituted —NR 1 -T-Aryl, an optionally substituted —NR 1 -T-Heteroaryl or an optionally substituted —NR 1 -T-Heterocycle;
X 3 is C═O, R 1 , R 1a , or R 1b ;
each of R 1 , R 1a , and R 1b is independently selected from the group consisting of H, linear or branched C 1 -C 6 alkyl group optionally substituted by 1 or more halogen or —OH groups, R Y3 C═O, R Y3 C═S, R Y3 SO, R Y3 SO 2 , N(R Y3 R Y4 )C═O, N(R Y3 R Y4 )C═S, N(R Y3 R Y4 )SO, and N(R Y3 R Y4 )SO 2 ;
T is selected from the group of an optionally substituted alkyl, —(CH 2 ) n — group, wherein each one of the methylene groups is optionally substituted with one or two substituents selected from the group of halogen, methyl, a linear or branched C 1 -C 6 alkyl group optionally substituted by 1 or more halogen or —OH groups or an amino acid side chain optionally substituted; and
n is 0 to 6;
W 4 is
R 14a and R 14b are each independently selected from the group of H, haloalkyl, or optionally substituted alkyl;
W 5 is selected from the group of a phenyl or a 5-10 membered heteroaryl,
R 15 is selected from the group of H, halogen, CN, OH, NO 2 , NR 14a R 14b , OR 14a , CONR 14a R 14b , NR 14a COR 14b , SO 2 NR 14a R 14b , NR 14a SO 2 R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted cycloalkyl; or optionally substituted cycloheteroalkyl; and
the indicates the site of attachment of the PTM or the chemical linking moiety coupling the PTM to the ULM.
6 . The compound according to any of claim 1 , wherein the ULM is a VLM represented by:
wherein:
W 3 is selected from the group of an optionally substituted aryl, optionally substituted heteroaryl, or
R 9 and R 10 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R 9 , R 10 , and the carbon atom to which they are attached form an optionally substituted cycloalkyl;
R 11 is selected from the group of an optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,
R 12 is selected from the group of H or optionally substituted alkyl;
R 13 is selected from the group of H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl;
R 14a , R 14b , are each independently selected from the group of H, haloalkyl, or optionally substituted alkyl;
W 5 is selected from the group of a phenyl or a 5-10 membered heteroaryl,
R 15 is selected from the group of H, halogen, CN, OH, NO 2 , NR 14a R 14b , OR 14a , CONR 14a R 14b , NR 14a COR 14b , SO 2 NR 14a R 14b , NR 14a SO 2 R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted cycloalkyl; or optionally substituted cycloheteroalkyl;
R 16 is independently selected from the group of halogen, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy;
o is 0, 1, 2, 3, or 4;
R 18 is independently selected from the group of H, halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker; and
p is 0, 1, 2, 3, or 4; and
the indicates the site of attachment of the PTM or the chemical linking moiety coupling the PTM to the ULM.
7 . The compound of any of the claim 1 , wherein the ULM is a VLM selected from the group of:
wherein:
R 1 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl;
R 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;
R 15 is selected from the group consisting of H, halogen, CN, OH, NO 2 , optionally substituted heteroaryl, optionally substituted thiazole, optionally substituted imidazole, optionally substituted oxazole, optionally substituted pyrazole, optionally substituted pyrrole, optionally substituted furan, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl, or cycloheteroalkyl;
X is C or C═O;
R 3 is an optionally substituted 5 or 6 membered heteroaryl; and
the indicates the site of attachment of the PTM or the chemical linking moiety coupling the PTM to the ULM.
8 . The compound according of claim 1 , wherein the ULM is a VLM represented by:
wherein:
R 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;
R 9 is H;
R 10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
R 11 is
optionally substituted heteroaryl,
p is 0, 1, 2, 3, or 4; and
each R 18 is independently halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy;
R12 is H or C═O;
R13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl,
R 15 is selected from the group consisting of H, halogen, Cl, CN, OH, NO 2 , optionally substituted heteroaryl, optionally substituted aryl;
and
the indicates the site of attachment of the PTM or the chemical linking moiety coupling the PTM to the ULM.
9 . The compound of claim 1 , wherein the ULM is a CLM selected from thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives thereof.
10 . The compound of claim 1 , wherein the ULM is a CLM represented by:
wherein:
W is selected from the group consisting of CH 2 , CHR, C═O, SO 2 , NH, and N-alkyl;
each X is independently selected from the group consisting of absent, O, and S;
Y is selected from the group consisting of CH 2 , —C═CR′, NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S;
Z is selected from the group consisting of absent, O, and S;
G and G′ are independently selected from the group consisting of H, optionally substituted alkyl, OH, R′OCOOR, R′OCONRR″, CH 2 -heterocyclyl optionally substituted with R′, and benzyl optionally substituted with R′;
Q 1 , Q 2 , Q 3 , and Q 4 represent a carbon C substituted with a group independently selected from H, R, N or N-oxide;
A is independently selected from the group H, alkyl, cycloalkyl, Cl and F;
n is an integer from 1 to 10;
R comprises —CONR′R″, —OR′, —NR′R″, —SR′, —SO 2 R′, —SO 2 NR′R″, —CR′R″—, —CR′NR′R″—, (—CR′O) n R″, -aryl, -hetaryl, -alkyl, -cycloalkyl, -heterocyclyl, —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″, —OP(O)R′R″, —Cl, —F, —Br, —I, —CF 3 , —CN, —NR′SO 2 NR′R″, —NR′CONR′R″, —CONR′COR″, —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″, —NR′C(═N—CN)R″, —NR′C(═C—NO 2 )NR′R″, —SO 2 NR′COR″, —NO 2 , —CO 2 R′, —C(C═N—OR′)R″, —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF 5 and —OCF 3 , wherein one R is covalently joined to the linker group (L) or to the PTM;
R′ and R″ are independently selected from the group consisting of a H, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and heterocyclyl, each of which is optionally substituted; and
represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific.
11 . The compound of claim 1 , wherein the ULM is a CLM represented by:
wherein:
W is independently selected from the group CH 2 , C═O, NH, and N-alkyl;
A is independently selected from a H, methyl, and optionally substituted alkyl;
n is an integer from 1 to 4; and
represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific.
12 . The compound of claim 1 , wherein the chemical linking moiety comprises a chemical structural unit represented by the formula:
-(A L ) q -, wherein:
(A L ) q is a group which is connected to the ULM and the PTM;
q is an integer greater than or equal to 1;
each A L is independently selected from the group consisting of CR L1 R L2 , O, S, SO, SO 2 , NR L3 , SO 2 NR L3 , SONR L3 , CONR L3 , NR L3 CONR L4 , NR L3 SO 2 NR L4 , CO, CR L1 ═CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 C(═NCN)NR L4 , NR L3 C(═NCN), NR L3 C(═CNO 2 )NR L4 , C 3-11 cycloalkyl optionally substituted with 0-6 R L1 and/or R L2 groups, C 3-11 heteocyclyl optionally substituted with 1-6 R L1 and/or R L2 groups, aryl optionally substituted with 1-6 R L1 and/or R L2 groups, and heteroaryl optionally substituted with 1-6 R L1 and/or R L2 groups, where R L1 or R L2 , each independently are optionally linked to other groups to form cycloalkyl and/or heterocyclyl moiety, optionally substituted with 1-4 R L5 groups; and
R L1 , R L2 , R L3 , R L4 and R L5 are, each independently, H, halogen, C 1-8 alkyl, OC 1-8 alkyl, SC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OC 3-8 cycloalkyl, SC 3-8 cycloalkyl, NHC 3-8 cycloalkyl, N(C 3-8 cycloalkyl) 2 , N(C 3-8 cycloalkyl)(C 1-8 alkyl), OH, NH 2 , SH, SO 2 C 1-8 alkyl, P(O)(OC 1-8 alkyl)(C 1-8 alkyl), P(O)(OC 1-8 alkyl) 2 , CC—C 1-8 alkyl, CCH, CH═CH(C 1-8 alkyl), C(C 1-8 alkyl)═CH(C 1-8 alkyl), C(C 1-8 alkyl)═C(C 1-8 alkyl) 2 , Si(OH) 3 , Si(C 1-8 alkyl) 3 , Si(OH)(C 1-8 alkyl) 2 , COC 1-8 alkyl, CO 2 H, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NHC 1-8 alkyl, SO 2 N(C 1-8 alkyl) 2 , SONHC 1-8 alkyl, SON(C 1-8 alkyl) 2 , CONHC 1-8 alkyl, CON(C 1-8 alkyl) 2 , N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl) 2 , NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl) 2 , NHCONH 2 , N(C 1-8 alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 alkyl) SO 2 N(C 1-8 alkyl) 2 , NH SO 2 NH(C 1-8 alkyl), NH SO 2 N(C 1-8 alkyl) 2 , or NH SO 2 NH 2 .
13 . The compound of claim 1 , wherein the chemical linking moiety is selected from the group consisting of:
N(R)—(CH2) m -O(CH2) n -O(CH2) o —O(CH2) p —O(CH2) q —O(CH2) r -OCH2-, —O—(CH2) m -O(CH2) n -O(CH2) o —(CH2) p —O(CH2) q —O(CH2) r -OCH2-, —O—(CH2) m -O(CH2) n -O(CH2) o —O(CH2) p —O(CH2) q —O(CH2) r -O—; —N(R)—(CH2) m -O(CH2) n -O(CH2) o —O(CH2) p —O(CH2) q —O(CH2) r -O—; —(CH2) m -O(CH2) n -O(CH2) o —O(CH2) p —O(CH2) q —O(CH2) r -O—; —(CH2) m -O(CH2) n -O(CH2) o —O(CH2) p —O(CH2) q —O(CH2) r -OCH2-;
wherein m, n, o, p, q, and r, are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, with the proviso that when m, n, o, p, q, and r is zero, there is no N—O or O—O bond, R is selected from the group H, methyl and ethyl, and X is selected from the group H and F.
14 . The compound of claim 1 , wherein the chemical linking moiety is selected from the group consisting of:
wherein each m and n is independently selected from 0, 1, 2, 3, 4, 5, or 6.
15 . The compound of claim 1 , wherein the chemical linking moiety is selected from the group consisting of:
wherein each m, n, o, p, q, and r is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
16 . The compound of claim 1 , wherein the chemical linking moiety is selected from the group consisting of:
17 . The compound of claim 1 , wherein the chemical linking moiety has a chemical structure selected from:
wherein:
W L1 and W L2 are each independently a 4-8 membered ring with 0-4 heteroatoms, optionally substituted with H, halogen, OH, CN, CF 3 , optionally substituted linear or branched C 1 -C 6 alkyl, optionally substituted linear or branched C 1 -C 6 alkoxy, or groups taken together with the atom they are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms;
Y L1 is each independently a bond, optionally substituted linear or branched C 1 -C 6 alkyl and optionally one or more C atoms are replaced with O; or optionally substituted linear or branched C 1 -C 6 alkoxy;
n is 0-10; and
the
indicates the attachment point to the PTM or the ULM.
18 . The compound of claim 1 , wherein the chemical linking moiety has a chemical structure selected from:
wherein:
W L1 and W L2 are each independently aryl, heteroaryl, cyclic, heterocyclic, C 1-6 alkyl, bicyclic, biaryl, biheteroaryl, or biheterocyclic, each independently optionally substituted with H, halogen, OH, CN, NH 2 , NR Y1 R Y2 , CF 3 , hydroxyl, nitro, C≡CH, C 2-6 alkenyl, C 2-6 alkynyl, optionally substituted linear or branched C 1 -C 6 alkyl, optionally substituted linear or branched C 1 -C 6 alkoxy, OC 1-3 alkyl optionally substituted by 1 or more —F, or groups taken together with the atom they are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms;
Y L1 is each independently a bond, NR YL1 , O, S, NR YL2 , CR YL1 R YL2 , C═O, C═S, SO, SO 2 , optionally substituted linear or branched C 1 -C 6 alkyl and optionally one or more C atoms are replaced with O; optionally substituted linear or branched C 1 -C 6 alkoxy;
Q L is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, optionally substituted with 0-6 R Q , each R Q is independently H, linear or branched C 1-6 alkyl optionally substituted by 1 or more halogen or C 1-6 alkoxyl, or 2 R Q groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms;
R YL1 , R YL2 are each independently H, OH, linear or branched C 1-6 alkyl optionally substituted by 1 or more halogen or C 1-6 alkoxyl, or R YL1 , R YL2 together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms;
n is 0-10; and
the
indicates the attachment point to the PTM or the ULM.
19 . The compound of claim 1 , wherein the chemical linking moiety is a polyethylenoxy group optionally substituted with aryl or phenyl comprising from 1 to 10 ethylene glycol units.
20 . A compound selected from the group consisting of examples 80, 82-84, 90, 91-96, 254-267, 275, 283, 289, 290, 293-300, 307, or 309-311 of FIG. 2 .
21 . A composition comprising an effective amount of a compound of claim 1 , and a pharmaceutically acceptable carrier or excipient.
22 . The composition of claim 21 , wherein the composition further comprises at least one of an additional bioactive agent or an additional compound of claim 2 .
23 . The composition of claim 22 , wherein the additional bioactive agent is an anti-cancer or anti-inflammatory agent.
24 . A composition comprising a pharmaceutically acceptable carrier and an effective amount of at least one compound from examples 80, 82-84, 90, 91-96, 254-267, 275, 283, 289, 290, 293-300, 307, or 309-311 of FIG. 2 .
25 . A method of treating a receptor tyrosine kinase (RTK)-related disease or disorder in a subject comprising administering to a subject in need thereof an effective amount of a compound of claim 1 or a composition comprising the same, wherein the compound or composition is effective for ameliorating at least one symptom of the RTK-related disease or disorder related to EGFR overexpression or hyperactivity, wherein the RTK-related disease or disorder is at least one of squamous-cell carcinoma of the lung, colon cancer, anal cancer, glioblastoma, epithelial tumor of the head and neck, psoriasis, eczema, atherosclerosis, or a combination thereof.
26 . The method of claim 25 , wherein the RTK-related disease or disorder is squamos-cell carcinoma of the lung.
27 . The method of claim 25 , wherein the RTK-related disease or disorder is colon cancer.
28 . The method of claim 25 , wherein the RTK-related disease or disorder is epithelial tumor of the head and neck.Join the waitlist — get patent alerts
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