Ras inhibitors

A compound having the structure of Formula Ic:

• or a Pharmaceutically acceptable salt thereof, wherein A is —N(H or CH3)C(O)—(CH2)— where the amino nitrogen is bound to the carbon atom of —CH(R10)—, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene;
• B is —CH(R9)— where the carbon is bound to the carbonyl carbon of —NHC(O)—, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5 to 6-membered heteroarylene;
• L is absent or a linker;
• W is a cross-linking group comprising a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, an aziridine, a trifluoromethyl ketone, a boronic acid, a boronic ester, an N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an epoxide, an oxazolium, or a glycal;
• R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl;
• R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl;
• R3 is absent, or
• R2 and R3 combine with the atom to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or optionally substituted 3 to 14-membered heterocycloalkyl;
• R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl;
• R6 is hydrogen or methyl;
• R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or
• R6 and R7 combine with the carbon atoms to which they are attached to form an optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
• R8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
• R7 and R8 combine with the carbon atom to which they are attached to form C═CR7′R8′;
• C=N(OH), C=N(O—C1-C3 alkyl), C═O, C=S, C═NH, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl;
• R7′ is hydrogen, halogen, or optionally substituted C1-C3 alkyl;
• R8′ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
• R7′ and R8′ combine with the carbon atom to which they are attached to form optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
• R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl;
• and
• R10 is hydrogen.

A conjugate, or salt thereof, comprising the structure of Formula IV:

• M-L-P Formula IV
• wherein L is a linker;
• P is a monovalent organic moiety;
• and
• M has the structure of Formula V:
• wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds;
• A is —N(H or CH3)C(O)—(CH2)— where the amino nitrogen is bound to the carbon atom of —CH(R10)—, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene;
• B is —CH(R9)— or >C═CR9R9′ where the carbon is bound to the carbonyl carbon of —N(R11)C(O)—, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5 to 6-membered heteroarylene;
• G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, —C(O)O—CH(R6)— where C is bound to —C(R7R8)—, —C(O)NH—CH(R6)— where C is bound to —C(R7R8)—, optionally substituted C1-C4 heteroalkylene, or 3 to 8-membered heteroarylene;
• X1 is optionally substituted C1-C2 alkylene, NR, O, or S(O)n;
• X2 is O or NH;
• X3 is N or CH;
• n is 0, 1, or 2;
• R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R′, C(O)OR′, C(O)N(R′)2, S(O)R′, S(O)2R′, or S(O)2N(R′)2;
• each R′ is, independently, H or optionally substituted C1-C4 alkyl;
• Y1 is C, CH, or N;
• Y2, Y3, Y4, and Y7 are, independently, C or N;
• Y5 is CH, CH2, or N;
• Y6 is C(O), CH, CH2, or N;
• R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl, or
• R1 and R2 combine with the atoms to which they are attached to form an optionally substituted 3 to 14-membered heterocycloalkyl;
• R2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl;
• R3 is absent, or
• R2 and R3 combine with the atom to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or optionally substituted 3 to 14-membered heterocycloalkyl;
• R4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens;
• R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl;
• R6 is hydrogen or methyl;
• R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or
• R6 and R7 combine with the carbon atoms to which they are attached to form an optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
• R8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
• R7 and R8 combine with the carbon atom to which they are attached to form C═CR7′R8′;
• C=N(OH), C=N(O—C1-C3 alkyl), C═O, C=S, C═NH, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl;
• R7a and R8a are, independently, hydrogen, halo, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl;
• R7′ is hydrogen, halogen, or optionally substituted C1-C3 alkyl;
• R8′ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
• R7′ and R8′ combine with the carbon atom to which they are attached to form optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
• R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl, or
• R9 and L combine with the atoms to which they are attached to form an optionally substituted 3 to 14-membered heterocycloalkyl;
• R9′ is hydrogen or optionally substituted C1-C6 alkyl;
• R10a is hydrogen or halo;
• R11 is hydrogen or C1-C3 alkyl;
• and
• R34 is hydrogen or C1-C3 alkyl.