US2023105745A1PendingUtilityA1
Cycloalkyl and hetero-cycloalkyl inhibitors, preparation methods therefor, and use thereof
Assignee: SUZHOU ZELGEN BIOPHARMACEUTICALS CO LTDPriority: Oct 23, 2019Filed: Jun 2, 2022Published: Apr 6, 2023
Est. expiryOct 23, 2039(~13.2 yrs left)· nominal 20-yr term from priority
A61K 31/5377C07D 471/04C07D 519/00A61P 35/02A61K 31/519Y02P20/55A61P 35/00
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Claims
Abstract
Cycloalkyl and hetero-cycloalkyl inhibitors, preparation methods therefor, and the use thereof are described. Compounds of the present invention have a structure represented by formula (I). Further disclosed are preparation methods for said compounds, and the use of said compounds as KRAS G12C inhibitors. The compounds have an excellent ability to selectively inhibit KRAS G12C , improved pharmacodynamic and pharmacokinetic performance, and reduced toxic side effects.
Claims
exact text as granted — not AI-modified1 . A cycloalkyl and heterocycloalkyl compound of formula (I), or a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof:
wherein:
A and B are the same or different, independently selected from CH or N;
X is selected from 4-14 membered saturated or unsaturated cycloalkyl or heterocyclyl, C 6 -C 14 aryl or 5-14 membered heteroaryl, wherein said saturated or unsaturated cycloalkyl or heterocyclyl, aryl or heteroaryl may optionally be substituted by one or more R 8 ;
Y is selected from the group consisting of bond, O, S, NH, NR 5 , CR 5 R 6 , CONH, CONR 5 , SO 2 NH, SO 2 NR 5 , NHCO, NR 5 CO, NHSO 2 , NR 5 SO 2 ;
Z is selected from the group consisting of: bond, C 1 -C 18 alkylene, deuterated C 1 -C 18 alkylene, C 1 -C 18 haloalkylene, C 3 -C 2 O cycloalkylene, 4-20 membered heterocyclylene, C 1 -C 18 alkyleneoxy, deuterated C 1 -C 18 alkyleneoxy, C 1 -C 18 haloalkyleneoxy;
W is selected from the group consisting of: bond, O, NH, NR 5 , CONH, CONR 5 , SO 2 NH, SO 2 NR 5 , NHCO, NHSO 2 , NHCONH, NR 5 CONH, NHCONR 5 , NR 5 CONR 6 , NHSO 2 NH, NR 5 SO 2 NH, NHSO 2 NR 5 and NR 5 SO 2 NR 6 ;
R 1 is selected from the group consisting of: —C(O)C(R A ) C(R B ) p and —S(O) 2 C(R A ) C(R B ) p ;
R 2 is selected from the group consisting of —(CH 2 ) n R 7 , (CH 2 ) n O(CH 2 ) q R 7 , —(CH 2 ) n SR 7 , —(CH 2 ) n COR 7 , —(CH 2 ) n C(O)OR 7 , —(CH 2 ) n S(O) q R 7 , —(CH 2 ) n NR 5 R 7 , —(CH 2 ) n C(O)NR 5 R 7 , —(CH 2 ) n NR 5 C(O)R 7 , —(CH 2 ) n NR 5 C(O)NR 5 R 7 , —(CH 2 ) n S(O) q NR 5 R 7 , —(CH 2 ) n NR 5 S(O) q R 7 , and —(CH 2 ) n NR 5 S(O) q NR 5 R 7 , wherein H in CH 2 can be substituted;
R 3 is independently selected from the group consisting of hydrogen, deuterium, oxygen, C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
L is selected from the group consisting of: bond, —C(O)— and C 1 -C 3 alkylene;
R 4 is selected from the substituted or unsubstituted group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, C 1 -C 18 haloalkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, C 1 -C 18 haloalkoxy, amino, hydroxy, 4-20 membered heterocyclyl, C 6 -C 14 aryl and 5-14 membered heteroaryl;
R 5 and R 6 are the same or different, and each independently selected from substituted or unsubstituted group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, C 1 -C 18 haloalkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, C 1 -C 18 haloalkoxy, amino, hydroxyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl and 5-14 membered heteroaryl;
R 7 is selected from substituted or unsubstituted C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl or 4-20 membered heterocyclyl;
R 8 is independently selected from the substituted or unsubstituted group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, C 1 -C 18 haloalkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, C 1 -C 18 haloalkoxy, amino, hydroxyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
wherein, the “substituted” refers to be substituted with one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, C 1 -C 18 haloalkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, C 1 -C 18 haloalkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amino, amido, sulfonamido and ureido;
“ ” can be a double bond “═” or a triple bond “≡”;
R A is absent, or is independently selected from hydrogen, deuterium, fluorine, cyano or C 1 -C 3 alkyl;
R B is independently selected from hydrogen, deuterium, cyano or C 1 -C 3 alkyl;
wherein the “alkyl” can be substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, amino, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, NHR 9 and NR 9 R 10 ;
R 9 and R 10 are each independently C 1 -C 3 alkyl;
m is an integer of 0, 1, 2 or 3;
n is an integer of 0, 1, 2, 3, 4 or 5;
p is an integer of 1 or 2;
q is an integer of 0, 1, 2, 3, 4 or 5;
with the proviso that when both A and B are N, and X is 4-14 membered heterocyclyl, Y is selected from the group consisting of bond, O, S, NH and NR 5 , and R 5 is C 1 -C 18 alkyl, then Z is substituted or unsubstituted C 3 -C 20 cycloalkylene;
or,
when both A and B are N, and X is 4-14 membered heterocyclyl, Y is selected from the group consisting of bond, O, S, NH and NR 5 , W is bond, and R 5 is C 1 -C 18 alkyl, then R 7 is substituted or unsubstituted C 3 -C 20 cycloalkyl;
or,
when both A and B are N, and X is 4-14 membered heterocyclyl, Y is selected from the group consisting of bond, O, S, NH and NR 5 , W is selected from the group consisting of NH and NR 5 , and R 5 is C 1 -C 18 alkyl, then R 7 is substituted or unsubstituted C 3 -C 20 cycloalkyl or substituted or unsubstituted 4-20 membered heterocyclyl.
2 . The cycloalkyl and heterocycloalkyl compound of formula (I), and the stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of claim 1 , having a structure represented by formula (II-A) or (II-B):
wherein:
R 1 , R 2 , R 3 , R 4 , A, B, X, Y, Z, L, W and m are as defined in claim 1 .
3 . The cycloalkyl and heterocycloalkyl compound of formula (I), and the stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of claim 1 , having a structure represented by formula (III):
R 1 , R 2 , R 3 , R 4 , X, Y, Z, L, W and m are as defined in claim 1 .
4 . The cycloalkyl and heterocycloalkyl compound of formula (I), and the stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of claim 1 , having a structure represented by formula (IV):
wherein:
R 1 , R 2 , R 3 , R 4 , R 8 , Y, Z, L, W and m are as defined in claim 1 .
5 . The cycloalkyl and heterocycloalkyl compound of formula (I), and the stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of claim 1 , having a structure represented by formula (V):
wherein:
R 1 , R 2 , R 3 , R 4 , R 8 , Y, Z, W and m are as defined in claim 1 .
6 . The cycloalkyl and heterocycloalkyl compound of formula (I), and the stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of claim 1 , having a structure represented by formula (VI):
wherein:
R 1 , R 2 , R 3 , R 4 , R 8 , Z, W and m are as defined in claim 1 .
7 . The cycloalkyl and heterocycloalkyl compound of formula (I), and the stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of claim 1 , having a structure represented by formula (VII-A) or (VII-B):
wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , Z and m are as defined in claim 1 .
8 . The cycloalkyl and heterocycloalkyl compound of formula (I), and the stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of claim 1 , wherein:
Z is bond; W is bond; R 2 is —(CH 2 ) n R 7 , where H in CH 2 can be substituted; R 7 is selected from substituted or unsubstituted C 3 -C 20 cycloalkyl or 4-20 membered heterocyclyl; wherein the “substituted” refers to be substituted with one or more groups selected from the group consisting of C 1 -C 18 alkyl and deuterated C 1 -C 18 alkyl; and the alkyl can be substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, amino, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, NHR 9 and NR 9 R 10 ; R 9 and R 10 are each independently C 1 -C 3 alkyl; n is 1, 2, or 3; R 1 , R 3 , R 4 , R 8 and m are as defined in claim 1 .
9 . The cycloalkyl and heterocycloalkyl compound of formula (I), and the stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of claim 8 , wherein it have a structure represented by formula (VIII):
R 11 and R 12 are the same or different, and each independently selected from hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl;
ring A is a substituted or unsubstituted C 3 -C 20 cycloalkyl or 4-20 membered heterocyclyl;
L 1 is C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl;
Q is C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, NHR 9 or NR 9 R 10 ; R 9 and R 10 are each independently C 1 -C 3 alkyl.
10 . The cycloalkyl and heterocycloalkyl compound of formula (I), and the stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of claim 1 , wherein:
Z is C 1 -C 18 alkylene C 3 -C 20 cycloalkylene; W is bond; R 2 is —(CH 2 ) n NR 5 R 7 ; wherein H in CH 2 can be substituted; n is an integer of 0, 1, 2, 3, 4 or 5; R 5 is selected from the substituted or unsubstituted group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, C 1 -C 18 haloalkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, C 1 -C 18 haloalkoxy, amino, hydroxyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl; R 7 is selected from substituted or unsubstituted C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl or 4-20 membered heterocyclyl; wherein the “alkyl” can be substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, amino, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, NHR 9 and NR 9 R 1 ; R 9 and R 10 are each independently C 1 -C 3 alkyl; wherein, the “substituted” refers to be substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, C 1 -C 18 haloalkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, C 1 -C 18 haloalkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amino, amido, sulfonamido and ureido.
11 . The cycloalkyl and heterocycloalkyl compound of formula (I), and the stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of claim 1 , wherein the compound is selected from the group consisting of:
12 . A method for preparing the cycloalkyl and heterocycloalkyl compound of formula (I), or the stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of claim 1 , wherein the method comprises the steps:
(i) in the presence of base, reacting a compound of formula V-1 with one amino in diamino compound, and then reacting with amino protectant, thereby to obtain a compound of formula V-2;
(ii) in the presence of deprotectant, deprotecting the compound of formula V-2 is deprotected to obtain a compound of formula V-3;
(iii) subjecting the compound of formula V-3 coupling reaction, substitution or acylation reaction, to obtain a compound of formula V-4;
(iv) reacting the compound of formula V-4 with oxidant to obtain a compound of formula V-5;
(v), reacting the compound of formula V-5 in the presence of base to obtain a compound of formula V-6;
(vi) in the presence of acid, deprotecting the compound of formula V-6 to obtain a compound of formula V-7;
(vii) subjecting the compound of formula V-7 to substitution or acylation reaction to obtain a compound of formula (III);
wherein, Rs and Rs' are protective group of amino, and the protective group is selected from: Boc, Bn, Cbz or Fmoc;
R 1 , R 2 , R 3 , R 4 , L, X, Y, Z, W and m are as defined in claim 1 .
13 . A pharmaceutical composition comprises one or more of the compound of the formula (I), the stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of claim 1 ; and a pharmaceutically acceptable carrier.
14 . A method for treating or preventing a disease related to the activity or expression of KRAS G12C in a subject in need thereof, comprising administering to the subject an effective amount of the cycloalkyl or heterocycloalkyl compound of formula (I), the stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of claim 1 .
15 . A method for treating or preventing a disease related to the activity or expression of KRAS G12C in a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 13 .
16 . A non-diagnostic and non-therapeutic method for inhibiting KRAS G12C in a subject in need thereof, comprising administrating to the subject an effective amount of the compound of the formula (I), the stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of claim 1
17 . A non-diagnostic and non-therapeutic method for inhibiting KRAS G12C in a subject in need thereof, comprising administrating to the subject an effective amount of the pharmaceutical composition of claim 13 .Join the waitlist — get patent alerts
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