Compounds, compositions and methods

A method of preparing a compound of Formula I, or a salt, isotopically enriched analog, stereoisomer, or mixture of stereoisomers thereof:

• comprising contacting a compound of Formula A:
• with a compound of formula HNR1R2, under conditions suitable to provide a compound of Formula I;
• wherein
• R100 is hydrogen or alkyl;
• p is 0, 1, 2, 3, 4, 5 or 6;
• L is heteroaryl optionally substituted with one to six R13, or a linker of Formula:
• where bond a is attached to the tetrahydropyran and bond b is attached to R3;
• X is O, NR7, or a bond;
• z is 0 or 1;
• R1 is C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one to five R11;
• R2 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which, other than hydrogen, is optionally substituted with one to five R11;
• or R1 and R2, together with the nitrogen atom to which they are attached, join to form a heterocyclyl or heteroaryl, each of which is optionally substituted with one to five R11;
• R3 is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one to six R11;
• R4 and R5 are independently hydrogen, C1-12 alkyl, C2-12 alkenyl or C2-12 alkynyl, each of which, other than hydrogen, is independently optionally substituted with one to five R11;
• or R4 and R5, together with the atoms to which they are attached, join to form a C3-10 cycloalkyl or heterocyclyl, each of which is optionally substituted with one to five R11;
• R6 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, or heterocyclyl, each of which, other than hydrogen, is optionally substituted with one to three R11;
• or R4 and R6, together with the atoms to which they are attached, join to form a C3-10 cycloalkyl or heterocyclyl, each of which is optionally substituted with one to five R11;
• R7 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, or heterocyclyl, each of which, other than hydrogen, is optionally substituted with one to three R11;
• or R4 and R7, together with the atoms to which they are attached, join to form a C3-10 cycloalkyl or heterocyclyl, each of which is optionally substituted with one to five R11;
• each R8 is independently halo, cyano, —NR16R17, C1-6 alkyl, C1-6 alkoxy, or C1-6 haloalkyl, or two R8 attached to the same atom, together form a C(O) or spiro C3-6 cycloalkyl, or two R8 attached to different atoms, together with the atoms to which they are attached, form a fused C3-6 cycloalkyl or a C1-3 alkylene bridge, wherein each C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 cycloalkyl or C1-3 alkylene bridge of R8 is optionally substituted with one to six R10;
• each R10 is independently halo, hydroxy, C1-6 alkyl, or C1-6 haloalkyl;
• each R11 is independently halo, cyano, nitro, oxo, —OR16, —SR16, —SF5, —NR16R17, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R16, —C(O)OR16, —OC(O)OR16, —OC(O)R16, —C(O)NR16R17, —OC(O)NR16R17, —NR16C(O)NR16R17, —S(O)1-2R16, —S(O)1-2NR16R17, —NR16S(O)1-2R17, —NR16S(O)1-2NR16R17, —NR16C(O)R17, or —NR16C(O)OR17, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R11 is independently optionally substituted with one to five R12;
• each R12 is independently halo, cyano, nitro, oxo, —OR30, —SR30, —SF5, —NR30R31, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R30, —C(O)OR30, —OC(O)OR30, —OC(O)R30, —C(O)NR30R31, —OC(O)NR30R31, —NR30C(O)NR3OR31, —S(O)1-2R30, —S(O)1-2NR30R31, —NR30S(O)1-2R31, —NR30S(O)1-2NR30R31, —NR30C(O)R31, or —NR30C(O)OR31, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R12 is independently optionally substituted with one to five halo or C1-12 alkyl independently optionally substituted by one to five oxo, halo, hydroxyl, or amino;
• each R13 is independently halo, cyano, nitro, oxo, —OR30, —SR30, —SF5, —NR30R31, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R30, —C(O)OR30, —OC(O)OR30, —OC(O)R30, —C(O)NR30R31, —OC(O)NR30R31, —NR30C(O)NR30R31, —S(O)1-2R30, —S(O)1-2NR30R31, —NR30S(O)1-2R31, —NR30S(O)1-2NR30R31, —NR30C(O)R31, or —NR30C(O)OR31, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R13 is independently optionally substituted with one to five halo or C1-12 alkyl independently optionally substituted by one to five oxo, halo, hydroxyl, or amino;
• R16 and R17 are independently hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R20, —C(O)OR20, —C(O)NR20R21, —S(O)1-2R20 or —S(O)1-2NR20R21, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R16 and R17 are independently optionally substituted with one to five R12;
• or two R16, or R16 and R17, are taken together with the atoms to which they are attached to form a heterocyclyl independently optionally substituted by one to five halo, oxo, or C1-12 alkyl independently optionally substituted by one to five oxo, halo, hydroxyl, or amino;
• each R20 and R21 is independently hydrogen or C1-12 alkyl independently optionally substituted with one to five oxo, halo, hydroxyl, or amino;
• or R20 and R21 are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five halo or C1-12 alkyl independently optionally substituted by one to five oxo, halo, hydroxyl, or amino;
• and
• each R30 and R31 is independently hydrogen or C1-12 alkyl independently optionally substituted with one to five oxo, halo, hydroxyl, or amino;
• or R30 and R31 are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five halo or C1-12 alkyl independently optionally substituted by one to six five, halo, hydroxyl, or amino.