Tricyclic compounds as inhibitors of KRAS

A compound having Formula (1):

• or a pharmaceutically acceptable salt thereof, wherein:
• XY is selected from —NR5—C(═O)—, —N═N—, and —N═CR6—;
• R1 is selected from H, D, C1-2 alkyl, and C1-2 haloalkyl;
• wherein said C1-2 alkyl is optionally substituted with 1 or 2 substituents independently selected from R11;
• Cy1 is selected from C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 6-10 membered heteroaryl;
• wherein the 4-10 membered heterocycloalkyl and 6-10 membered heteroaryl each has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S;
• wherein a ring-forming carbon atom of 6-10 membered heteroaryl and 4-10 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group;
• and wherein the C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 6-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
• R4 is selected from H, C1-3 alkyl, C1-3 haloalkyl, 5-10 membered heteroaryl, ORa3, and NRc3Rj3;
• wherein said C1-3 alkyl and 5-10 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R30;
• or
• R4 is selected from
• R5 is selected from H, C1-2 alkyl, and C1-2 haloalkyl;
• R7 is selected from H, C1-3 alkyl, C1-3 haloalkyl, phenyl, 5-6 membered heteroaryl, F, Cl, D, CN, ORa7, and NRc7Rd7;
• wherein said phenyl and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R70;
• Cy2 is selected from
• when Cy2 is Cy2-a and XY is —N═CR6—, then, R6 is selected from H, D, C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl;
• wherein said C1-3 alkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R60;
• when Cy2 is Cy2-a, then R2 is selected from H, C1-2 alkyl, C1-2 haloalkyl, F, Cl, and —CH2CH2CN;
• when Cy2 is Cy2-b and XY is —N═CR6—, then R6 is selected from C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl;
• wherein said C1-3 alkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R60;
• when Cy2 is Cy2-b, then R2 is selected from H, C1-2 alkyl, C1-2 haloalkyl, F, —CH2CH2CN,
• each R10 is independently selected from C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, halo, D, CN, ORa10, C(O)NRc10Rd10, NRc10C(O)ORa10, NRc10C(O)NRc10Rd10, and NRc10Rd10;
• wherein said C1-3 alkyl and C3-6 cycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from Rg;
• each R11 is independently selected from C1-2 alkyl, C1-2 haloalkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, ORa11, and NRc11Rd11;
• wherein said C12 alkyl, C3-6 cycloalkyl, and 4-6 membered heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from Rg;
• each R21 is independently selected from C1-3 alkyl, C1-3 haloalkyl, halo, D, CN, ORa21 and NRc21Rd21;
• each R30 is independently selected from C1-3 alkyl, C1-3 haloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, ORa30, C(O)NRc30Rd30, NRc30C(O)ORa30, NRc30C(O)NRc30Rd30, and NRc30Rd30;
• wherein said C1-3 alkyl and 4-10 membered heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R31 each R31 is independently selected from C1-3 alkyl, C1-3 haloalkyl, halo, D, and CN;
• each R60 is independently selected from C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, ORa60, C(O)Rb60, C(O)NRc60Rd60, and NRc60Rd60;
• wherein said C1-3 alkyl, C3-6cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R61;
• each R61 is independently selected from C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, ORa61, C(O)Rb61, and NRc61Rd61;
• each R70 is independently selected from C1-3 alkyl, C1-3 haloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, ORa70, and NRc70Rd70;
• each Ra3 and Rc3 is independently selected from H, C1-3 alkyl, C1-3 haloalkyl, 5-6 membered heteroaryl, and phenyl;
• wherein said C1-3 alkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted with 1 or 2 substituents independently selected from R30;
• each Rj3 is independently selected from C1-3 alkyl and C1-3 haloalkyl;
• each Ra7, Rc7 and Rd7 is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
• wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from R70;
• each Ra10, Rc10 and Rd10 is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
• each Ra11, Rc11 and Rd11, is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
• Rb20 is selected from NH2, C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl;
• wherein said C1-3 alkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R21;
• each Ra21, Rc21 and Rd21, is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
• each Ra30, Rc30 and Rd30 is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
• each Ra60, Rb60, Rc60 and Rd60 is independently selected from H, C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl;
• wherein said C1-3 alkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R61;
• or any Rc60 and Rd60 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, 7-, 8-, or 9-membered heterocycloalkyl group optionally substituted with 1 or 2 substituents independently selected from R61;
• each Ra61, Rb61 Rc61 and Rd61 is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
• each Ra70, Rc70 and Rd70 is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
• and
• each Rg is independently selected from D, OH, CN, halo, C1-2 alkyl, amino, and C1-2 haloalkyl;
• provided that the compound of Formula I is other than
• 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-
• yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N,N-
• dimethylpropanamide,
• 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-2-ethyl-6-
• fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-8-yl)propanenitrile,
• 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-
• hydroxynaphthalen-1-yl)-2-((3-oxomorpholino)methyl)-1H-imidazo[4,5-c]quinolin-8-
• yl)propanenitrile,
• 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-(3-(dimethylamino)azetidin-1-
• yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N-methyl-N-(pyridin-
• 2-ylmethyl)propanamide, and
• 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-7-(3-
• hydroxynaphthalen-1-yl)-2-(2-(piperazin-1-yl)thiazol-4-yl)-1H-imidazo[4,5-c]quinolin-8-
• yl)propanenitrile.