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WO 2018/217651 Al 29 November 2018 (29.11.2018) W !P O PCT

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WO 2018/217651 Al 29 November 2018 (29.11.2018) W !P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/217651 Al 29 November 2018 (29.11.2018) W !P O PCT (51) International Patent Classification: KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, C07D 471/04 (2006.01) A61P 35/00 (2006.01) MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, A61K 31/519 (2006.01) C07D 475/00 (2006.01) 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, (21) International Application Number: TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. PCT/US2018/033714 (84) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of regional protection available): ARIPO (BW, GH, 2 1 May 2018 (21 .05.2018) GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (25) Filing Language: English UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (26) Publication Language: English EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (30) Priority Data: MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 62/509,629 22 May 2017 (22.05.2017) US TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (71) Applicant: AMGEN INC. [US/US]; One Amgen Center Drive, Thousand Oaks, California 91320-1799 (US). Published: (72) Inventors: LANMAN, Brian Alan; One Amgen Cen — with international search report (Art. 21(3)) ter Drive, Thousand Oaks, California 91320-1799 (US). CHEN, Jian; One Amgen Center Drive, Thousand Oaks, California 91320-1799 (US). REED, Anthony B.; One Amgen Center Drive, Thousand Oaks, California 91320-1799 (US). CEE, Victor J.; One Amgen Cen ter Drive, Thousand Oaks, California 91320-1799 (US). LIU, Longbin; One Amgen Center Drive, Thousand Oaks, California 91320-1799 (US). KOPECKY, David John; One Amgen Center Drive, Thousand Oaks, California 91320-1799 (US). LOPEZ, Patricia; One Amgen Cen ter Drive, Thousand Oaks, California 91320-1799 (US). WURZ, Ryan Paul; One Amgen Center Drive, Thousand Oaks, California 91320-1799 (US). NGUYEN, Thomas T.; One Amgen Center Drive, Thousand Oaks, Califor nia 91320-1799 (US). BOOKER, Shon; One Amgen Cen ter Drive, Thousand Oaks, California 91320-1799 (US). NISHIMURA, Nobuko; One Amgen Center Drive, Thou sand Oaks, California 91320-1799 (US). SHIN, Young- sook; One Amgen Center Drive, Thousand Oaks, Califor nia 91320-1799 (US). TAMAYO, Nuria A.; One Amgen Center Drive, Thousand Oaks, California 91320- 1799 (US). ALLEN, John Gordon; One Amgen Center Drive, Thou sand Oaks, California 91320- 1799 (US). ALLEN, Jennifer Rebecca; One Amgen Center Drive, Thousand Oaks, Cali fornia 91320-1799 (US). (74) Agent: REIDY, Joseph F.; AMGEN INC., One Am gen Center Drive, M S 35-1-B, Thousand Oaks, California 91320-1799 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): 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, o (54) Title: KRAS G12C INHIBITORS AND METHODS OF USING THE SAME (57) Abstract: Provided herein are KRAS G12C inhibitors, composition of the same, and methods of using the same. These inhibitors o are useful for treating a number of disorders, including pancreatic, colorectal, and lung cancers. KRAS G12C INHIBITORS AND METHODS OF USING THE SAME FIELD OF INVENTION [0001] Provided herein are KRAS G12C inhibitors, composition of the same, and methods of using the same. These inhibitors are useful for treating a number of disorders, including pancreatic, colorectal, and lung cancers. BACKGROUND [0002] KRAS gene mutations are common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gall bladder cancer, thyroid cancer, and bile duct cancer. KRAS mutations are also observed in about 25% of patients with NSCLC, and some studies have indicated that KRAS mutations are a negative prognostic factor in paptients with NSCLC. Recently, V-Ki- ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations have been found to confer resistance to epidermal growth factor receptor (EGFR) targeted therapies in colorectal cancer; accordingly, the mutational status of KRAS can provide important information prior to the prescription of TKI therapy. Taken together, there is a need for new medical treatments for patients with pancreatic cancer, lung adenocarcinoma, or colorectal cancer, especially those who have been diagnosed to have such cancers characterized by a KRAS mutation, and including those who have progressed after chemotherapy. SUMMARY [0003] Provided herein are com ound having a structure of formula (I) wherein E 1 and E2 are each independently N or CR 1; R 1 is independently H , hydroxy, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, NH-Ci-6alkyl, N(Ci-6alkyl)2, cyano, or halo; R2 is halo, Ci-ealkyl, Ci-ehaloalkyl, OR', N(R')2, C2-3alkenyl, C2-3alkynyl, Co-3 alkylene-C3 i4cycloalkyl, Co-3alkylene-C2-i4heterocycloalkyl, aryl, heteroaryl, Co-3 alkylenearyl, or Co-3 alkyleneheteroaryl, and each R' is independently H, Ci-6 alkyl, Ci- 6haloalkyl, C3-i4cycloalkyl, C2-i4heterocycloalkyl, C2-3alkenyl, C2-3alkynyl, aryl, or heteroaryl, or two R' substituents, together with the nitrogen atom to which they are attached, form a 3-7- membered ring; 3 R is halo, Ci C2- 3 alkenyl, C2- 3alkynyl, aryl, or heteroaryl; is ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused, or spiro 6- 11 membered ring; L is a bond, Ci-6alkylene, -O-Co-salkylene, -S-Co-salkylene, or -NH-C0- 5 alkylene, and for C2-6alkylene, -0 -C2-5alkylene, -S-C2-5alkylene, and NH-C2 -5 alkylene, one carbon atom of the alkylene group can optionally be replaced with O, S, or NH; 4 R ' is H, Ci-ealkyl, C2-6alkynyl, Ci-6alkylene -0 -Ci -4alkyl, Ci-ealkylene -OH, Ci-e haloalkyl, cycloalklyl, heterocycloalkyl, Co-3alkylene-C3-4cycloalkyl, Co-3alkylene -C2-i4 heterocycloalkyl, aryl, heteroaryl, Co-3alky lene-C6-i4ary selected from 5 6 R and R are each independently H, halo, Ci-6alkyl, C2-6alkynyl, Ci-6 alkylene -O-Ci- 4alkyl, Ci ealkylene-OH, Ci ehaloalkyl, Ci ealkyleneamine, Co-6 alkylene-amide, Co- 3alkylene-C (0)OH, Co-3alkylene-C (0 )OCi -4alkyl, C 1-6 alky lene-O-aryl, Co- alkylene- C(0 )Ci -4alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Co-3alkylene-C3- i4cycloalkyl, Co-3alkylene -C2-i4heterocycloalkyl, Co-3alkylene-C6-i4aryl, Co-3alkylene -C2- i4heteroaryl, or cyano, or R5 and R6, together with the atoms to which they are attached, form a 4-6 membered ring; and R7 is H or Ci-ealkyl, or R7 and R5, together with the atoms to which they are attached, form a 4-6 membered ring, or a pharmaceutically acceptable salt thereof. [0004] In another embodiment, provided herein are compounds having a structure of formula (I) wherein E1 and E2 are each independently N or CR 1; R 1 is independently H, hydroxy, Ci ealkyl, Ci ehaloalkyl, Ci-6alkoxy, NH-Ci -6alkyl, N(Ci -4alkyl)2, cyano, or halo; 2 R is halo, Ci-ealkyl, Ci-ehaloalkyl, OR', N(R') 2, C2- alkenyl, C2- alkynyl, Co- 3alkylene-C3-i4cycloalkyl, Co-3alkylene -C2-i4heterocycloalkyl, aryl, heteroaryl, Co- 3alkylene-C6-i4aryl, or Co-3alkylene -C2-i4heteroaryl, and each R' is independently H, Ci- 6alkyl, Ci-6haloalkyl, C 3-i4cycloalkyl, C2-3alkenyl, C2-3alkynyl, aryl, or heteroaryl, or two R' substituents, together with the nitrogen atom to which they are attached, form a 3-7- membered ring; 3 R is halo, Ci ^alkyl, Ci-2haloalkyl, Ci ^alkoxy, C 3-i4cycloalkyl, C2-3alkenyl, C2- 3alkynyl, aryl, or heteroaryl; ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused, or spiro 6- 11 membered ring; L is a bond, Ci-6alkylene, -O-Co-salkylene, -S-Co-salkylene, or -NH-C0- 5 alkylene, and for C2-6alkylene, -0 -C2-5alkylene, -S-C2-5alkylene, and NH-C2-5 alkylene, one carbon atom of the alkylene group can optionally be replaced with O, S, or NH; R5 and R6 are each independently H, halo, Ci-salkyl, C2-salkynyl, Ci-6 alkylene -O-Ci- 4alkyl, Ci ealkylene-OH, Ci ehaloalkyl, Ci-6alkyleneamine, Co- 6 alkylene-amide, Co- alkylene-C (0 )OH, Co-3alkylene-C (0 )OCi -4alkyl, Ci-e alkylene -O-aryl, Co-3alkylene- C(0 )Ci -4alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Co-3alkylene-C3- i4cycloalkyl, Co-3alkylene-C2-i4heterocycloalkyl, Co-3alkylene-C6-i4aryl, Co-3alkylene-C2- i4heteroaryl, or cyano, or R5 and R6, together with the atoms to which they are attached, form a 4-6 membered ring; and R7 is H or Ci ealkyl, or R7 and R5, together with the atoms to which they are attached, form a 4-6 membered ring, or a pharmaceutically acceptable salt thereof. [0005] Further provided are compounds of formula (II), or a pharmaceutically acceptable salt thereof: wherein E1 and E2 are each independently N or CR1; J is N, NR10, or CR10 ; M is N, NR13, or CR 13 ; is a single or double bond as necessary to give every atom its normal valence; R1 is independently H, hydroxy, Ci 6alkyl, Ci 4haloalkyl, Ci-4alkoxy, NH-Ci-4alkyl, N(Ci-4alkyl)2, cyano, or halo; R2 is halo, Ci ealkyl, Ci 6haloalky l, OR', N(R')2, C2 3alkenyl, C2 3alky nyl, Co 3alkylene-C3-i4cycloalkyl, Co 3alky lene-C2 i4heterocycloalkyl, aryl, heteroaryl, Co 3alky lene- C 6-i4aryl, or Co 3alkylene-C2 i4heteroaryl, and each R' is independently H, Ci-6alkyl, Ci- 6haloalkyl, C 3-i4cycloalkyl, C2-i4heterocycloalkyl, C2-3alkenyl, C2-3alkynyl, aryl,
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