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1. (WO2018140513) 1-(3-(6-(3-HYDROXYNAPHTHALEN-1-YL)BENZOFURAN-2-YL)AZETIDIN-1YL)PROP-2-EN-1-ONE DERIVATIVES AND SIMILAR COMPOUNDS AS KRAS G12C MODULATORS FOR TREATING CANCER
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Pub. No.: WO/2018/140513 International Application No.: PCT/US2018/015071
Publication Date: 02.08.2018 International Filing Date: 24.01.2018
IPC:
C07D 405/04 (2006.01) ,C07D 405/14 (2006.01) ,C07D 403/04 (2006.01) ,C07D 403/14 (2006.01) ,C07D 401/04 (2006.01) ,C07D 401/14 (2006.01) ,C07D 413/04 (2006.01) ,C07D 413/14 (2006.01) ,C07D 471/04 (2006.01) ,C07D 209/42 (2006.01) ,A61K 31/343 (2006.01) ,A61K 31/397 (2006.01) ,A61K 31/4184 (2006.01) ,A61K 31/416 (2006.01) ,A61K 31/403 (2006.01)
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
D
HETEROCYCLIC COMPOUNDS
405
Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
02
containing two hetero rings
04
directly linked by a ring-member-to-ring- member bond
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
D
HETEROCYCLIC COMPOUNDS
405
Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
14
containing three or more hetero rings
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
D
HETEROCYCLIC COMPOUNDS
403
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/167
02
containing two hetero rings
04
directly linked by a ring-member-to-ring- member bond
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
D
HETEROCYCLIC COMPOUNDS
403
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/167
14
containing three or more hetero rings
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
D
HETEROCYCLIC COMPOUNDS
401
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
02
containing two hetero rings
04
directly linked by a ring-member-to-ring- member bond
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
D
HETEROCYCLIC COMPOUNDS
401
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
14
containing three or more hetero rings
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
D
HETEROCYCLIC COMPOUNDS
413
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
02
containing two hetero rings
04
directly linked by a ring-member-to-ring- member bond
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
D
HETEROCYCLIC COMPOUNDS
413
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
14
containing three or more hetero rings
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
D
HETEROCYCLIC COMPOUNDS
471
Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/-C07D463/251
02
in which the condensed system contains two hetero rings
04
Ortho-condensed systems
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
D
HETEROCYCLIC COMPOUNDS
209
Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
02
condensed with one carbocyclic ring
04
Indoles; Hydrogenated indoles
30
with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
42
Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
33
Heterocyclic compounds
335
having oxygen as the only ring hetero atom, e.g. fungichromin
34
having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
343
condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
33
Heterocyclic compounds
395
having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
397
having four-membered rings, e.g. azetidine
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
33
Heterocyclic compounds
395
having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
41
having five-membered rings with two or more ring hetero atoms, at least one of which is nitrogen, e.g. tetrazole
4164
1,3-Diazoles
4184
condensed with carbocyclic rings, e.g. benzimidazoles
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
33
Heterocyclic compounds
395
having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
41
having five-membered rings with two or more ring hetero atoms, at least one of which is nitrogen, e.g. tetrazole
415
1,2-Diazoles
416
condensed with carbocyclic ring systems, e.g. indazole
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
33
Heterocyclic compounds
395
having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
40
having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
403
condensed with carbocyclic rings, e.g. carbazole
Applicants:
ARAXES PHARMA LLC [US/US]; 3033 Science Park Road, Suite 220 San Diego, California 92121, US
Inventors:
LI, Liansheng; US
FENG, Jun; US
LIU, Yuan; US
REN, Pingda; US
LIU, Yi; US
Agent:
HARWOOD, Eric, A.; US
OBEIDAT, Baha, A.; US
KUMABE, Blake, K.; US
SOLTANI, Bobby, B.; US
SARGEANT, Brooke; US
QUIST, Brooke, W.; US
ROTH, Carol, J.; US
EIDT, Chandra, E.; US
O'BRIEN, Daniel; US
CARLSON, David, V.; US
STARK, Duncan; US
TARLETON, E., Russell; US
SUN, Eileen, S.; US
ABRAMONTE, Frank; US
HAN, Hai; US
TALBERT, Hayley, J.; US
CARTER, James, J.; US
WHITE, James, A. D.; US
BARRETT, Jared, M.; US
PEPE, Jeffrey, C.; US
DANLEY, Jeffrey, E.; US
SAKOI, Jeffrey, M.; US
BAUNACH, Jeremiah, J.; US
KARLEN, John, R.; US
MORGAN, John, A.; US
WAKELEY, John, J.; US
COE, Justin, E.; US
HENCKEL, Karen, M.; US
HEFTER, Karl, A.; US
HERMANNS, Karl, R.; US
MORGAN, Kevan, L.; US
COSTANZA, Kevin, S.; US
LINFORD, Lorraine; US
COOPER, Michael, P.; US
RUSYN, Paul; US
LIN, Qing; US
HALLER, Rachel, A.; US
IANNUCCI, Robert; US
KOVELMAN, Robert, L.; US
WEBB, Samuel, E.; US
LEEK, Shoko, I.; US
ROSENMAN, Stephen, J.; US
ABEDI, Syed; US
SATAGAJ, Thomas, J.; US
BOLLER, Timothy, L.; US
LIGON, Toby, J.; US
FERRON, William, O., Jr.; US
Priority Data:
62/450,91426.01.2017US
Title (EN) 1-(3-(6-(3-HYDROXYNAPHTHALEN-1-YL)BENZOFURAN-2-YL)AZETIDIN-1YL)PROP-2-EN-1-ONE DERIVATIVES AND SIMILAR COMPOUNDS AS KRAS G12C MODULATORS FOR TREATING CANCER
(FR) DÉRIVÉS DE 1-(3-(6-(3-HYDROXYNAPHTALEN-1-YL)BENZOFURAN-2-YL)AZÉTIDIN-1YL)PROP-2-EN-1-ONE ET COMPOSÉS SIMILAIRES UTILISÉS EN TANT QUE MODULATEURS DE KRAS G12C POUR LE TRAITEMENT DU CANCER
Abstract:
(EN) Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, wherein A is a five-membered heteroaryl comprising 1 or 2 non-adjacent heteroatoms, inclusive of X and Y; W, X, Y, Z, L, L1, E, R1, R2b R2c and the dotted circle are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and compounds for use in methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided. Preferred compounds are e.g. l-(3-(6-(3-hydroxynaphthalen-l- yl)benzofuran-2-yl)azetidin-lyl)prop-2-en-l-one derivatives and related compounds such as e.g. the corresponding derivatives with e.g. a benzoimidazole, indole, benzooxazole, imidazopyridine or imidazole core structure, substituted on ring A by e.g. azetidine, pyrrolidine, azepane or bicyclopentane-amine (L1) each substituted by e.g. propenone (E), and the core structure substituted on the six-membered ring with e.g. 3-hydroxynaphthalene or indazole or hydroxy-, alkoxy- and/or fluoro-substituted phenyl (R1).
(FR) La présente invention concerne des composés ayant une activité en tant qu'inhibiteurs de la protéine KRAS portant la mutation G12C. Les composés de l'invention ont la structure suivante (I) : ou un sel pharmaceutiquement acceptable, une forme isotopique ou un stéréoisomère de ceux-ci. Dans la structure (I), A représente un hétéroaryle à cinq chaînons comprenant 1 ou 2 hétéroatomes non adjacents, inclus de X et Y ; W, X, Y, Z, L, L1, E, R1, R2b R2c et le cercle en pointillé sont tels que définis dans la description. L’invention concerne également des procédés associés à la préparation et à l'utilisation desdits composés, des compositions pharmaceutiques comprenant ces composés et des procédés de modulation de l'activité de la protéine KRAS portant la mutation G12C pour le traitement de troubles tels que le cancer. Les composés préférés, selon l'invention sont par exemple, les dérivés de l-(3-(6-(3-hydroxynaphtalen-l- yl)benzofuran-2-yl)azétidin-lyl)prop-2-en-l-one et les composés apparentés tels que, par exemple, les dérivés correspondants, par exemple une structure à noyau benzoimidazole, indole, benzooxazole, imidazopyridine ou imidazole, substituée sur le cycle A par l'azétidine, la pyrrolidine, l'azépane ou le bicyclopentane-amine (L1) par exemple, chacun étant substitué par un propénone (E) par exemple, et la structure à noyau substituée sur le cycle à six chaînons avec, par exemple, le 3-hydroxynaphtalène ou l'indazole ou l'hydroxy, l'alcoxy et/ou le phényle (R1) substitué par le fluor.
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Designated States: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW
African Regional Intellectual Property Organization (ARIPO) (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW)
Eurasian Patent Office (AM, AZ, BY, KG, KZ, RU, TJ, TM)
European Patent Office (EPO) (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR)
African Intellectual Property Organization (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG)
Publication Language: English (EN)
Filing Language: English (EN)