Therapeutics for the degradation of mutant braf

A compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI:

• or a pharmaceutically acceptable salt thereof;
• wherein
• A1 is selected from —NR2— and —CHR2—;
• R1 is selected from hydrogen, alkyl and cycloalkyl;
• R2 is selected from hydrogen, alkyl, cycloalkyl and haloalkyl;
• or R1 and R2 together with the nitrogen atom to which they are attached form heterocycloalkyl optionally substituted with one or two R3;
• R2′ is selected from hydrogen, alkyl, cycloalkyl and haloalkyl;
• or R1 and R2′ together with the carbon atom to which they are attached form cycloalkyl optionally substituted with one or two R3;
• each R3 is independently selected from hydrogen, halogen, alkyl, cycloalkyl and alkoxy;
• R4 is selected from hydrogen, alkyl, cyano and halogen;
• R5 is selected from hydrogen, alkyl, cyano and halogen;
• A2 is selected from —O—, —NH— and —(C═O)—;
• A22 is selected from —O—, and —NH—;
• A24 is selected from a bond, —CH2—, —NH— and —O—;
• W1 is selected from —N— and —CH—;
• W2 is selected from —N—, and —CR26—;
• R6 is selected from hydrogen, halogen, hydroxy, amino, dialkyl]amino, alkoxy, alkyl and alkoxyalkyl;
• R26 is selected from hydrogen, halogen, hydroxy, amino, alkoxy and alkyl;
• A3 is selected from a bond, —CH2—, —CH2—CH2—, —CH2—CH2—CH2—, —CH(CH3)—CH2—CH2—, —CH2—CH(CH3)—CH2—, —CH2—CH2—CH(CH3)—, —CH2—CH2—CH2—CH2— and —CH2—CH2—CH2—CH2—CH2—;
• A23 is selected from a bond, —O— and —CH2—:
• A is selected from a bond, pyrimidinyl, pyridinyl, pyrazolyl and 3-azabicyclo[3.1.0]hexyl;
• A30 is selected from a bond, —CH2—, pyrimidinyl, pyridinyl, pyrazolyl and 3-azabicyclo[3.1.0]hexyl;
• B is selected from phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1,1-dioxo-1Iambda6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, 1,8-diazaspiro[4.5]decyl, and 8-azaspiro[4.5]decyl;
• wherein B is optionally substituted with one or two substituents independently selected from halogen, alkyl and alkoxy;
• B2 is selected from phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl and 8-azaspiro[4.5]decyl;
• wherein B2 is optionally substituted with one or two substituents independently selected from halogen, alkyl and alkoxy;
• B3 is selected from phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1,1-dioxo-1Iambda6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, 1,8-diazaspiro[4.5]decyl and 8-azaspiro[4.5]decyl;
• n is 0 or 1;
• A4 is selected from a bond, —CH2—, —(SO2)—CH2—, —CH(CH2OH)—, —NH— and —O—:
• A14 is selected from a bond, —CH2—, —CH2—CH2—, —CH(CH2OH)—, —NH—, —O—, cycloalkyl and alkyl]amino;
• C is selected from azepanyl, azetidinyl, cycloalkyl, piperazinyl and piperidinyl;
• wherein C is optionally substituted with one or two substituents independently selected from, hydroxy, alkyl and alkoxy;
• D is selected from
• R7 is selected from hydrogen, alkyl, cyano, halogen, and alkoxy;
• R8 is selected from hydrogen, alkyl, cyano, halogen, and alkoxy;
• R9 is selected from hydrogen, alkyl, cyano, halogen, and alkoxy;
• R17 is selected from hydrogen, alkyl, cyano, hydroxy, cycloalkyl, halogen and alkoxy;
• R18 is selected from hydrogen, alkyl, cyano, hydroxy, cycloalkyl, halogen and alkoxy;
• R19 is selected from hydrogen, alkyl, cyano, hydroxy, cycloalkyl, halogen and alkoxy;
• A5 is —CH— or —N—;
• A15 is selected from a bond, —O— and —NH—;
• A6 is —CH— or —N—;
• Linker is a bivalent chemical group selected from
• wherein:
• X1 and X2 are independently at each occurrence selected from bond, heterocycle, NR2, C(R2)2, O, C(O), and S;
• R20, R21, R22, R23, and R24 are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond alkyl, —C(O)—, —C(O)O—, —OC(O)—, —SO2—, —S(O)—, —C(S)—, —C(O)NR 2-, —NR 2C(O)—, —O—, —S—, —NR2—, —C(R40R40)—, —P(0)(OR36)O -, —P(O)(OR36)—, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, lactic acid, glycolic acid, and carbocycle;
• each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R;
• R36 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, and heterocycle;
• and
• R40 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, —NH(alkyl), —N(alkyl)2, —NHSO2(alkyl), —N(alkyl)SO2alkyl, —NHSO2(aryl, heteroaryl or heterocycle), —N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, —N(alkyl)SO2alkenyl, —NHSO2alkynyl, —N(alkyl)SO2alkynyl, haloalkyl, aryl, heteroaryl, heterocycle, and cycloalkyl.