Tyk2 inhibitors and compositions and methods thereof

A compound having the structural formula (II):

• or a pharmaceutically acceptable form or an isotope derivative thereof,
• wherein
• Y1 is CH, CF or N;
• Y2 is CH or N;
• Y3 is NR, O, CH2, CF2 or O—NH;
• Y4 is CH or N;
• R41 is a H, F, C1-C3 alkyl and CD3, provided that R41 is not F when Y3 is NR, O or O—NH;
• R42 is
• R42′, wherein R42′ is a C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, each substituted with 0-2 of halogen, CN, OR, NRR′, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;
• an aryl or heteroaryl group, each substituted with 0-2 R42a;
• or
• each of RA and RB is independently selected from H, D, halo, OR, and C1-3 alkyl;
• RC is H, D, F, Cl, OR, C1-5 alkyl, C3-5 cycloalkyl or heterocyclic group, substituted with 0-2 R42a.
• each of R and R′ is independently H or a C1-C6 alkyl, C1-C6 acyl, or R and R′, together with the nitrogen atom to which they are bound, form a 4- to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO2;
• R42a at each occurrence is independently D, halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR′, (CH2)nNRR′ or a 4- to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;
• R42b is a C1-6 alkyl or C3-6 cycloalkyl, C5-7 spirocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R42c;
• and
• R42c at each occurrence is independently halo, CN, OR, NRR′, OCF3, CF3, C1-6 alkyl substituted with 0-3 R42a, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 R42a, C2-6 alkynyl substituted with 0-3 R42a;
• and
• R47 is a C1-3 alkoxy group optionally substituted with 1-3 D or halo.

A compound having the structural formula (III):

• or a pharmaceutically acceptable form or an isotope derivative thereof,
• wherein
• Y1 is CH, CF or N;
• Y2 is CH or N;
• Y3 is NR, O, CH2, CF2 or O—NH;
• Y4 is CH or N;
• R41 is a H, F, C1-C3 alkyl and CD3, provided that R41 is not F when Y3 is NR, O or O—NH;
• R42 is
• R42′, wherein R42′ is a C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, each substituted with 0-2 of halogen, CN, OR, NRR′, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;
• an aryl or heteroaryl group, each substituted with 0-2 R42a;
• or
• each of RA and RB is independently selected from H, D, halo, OR, and C1-3 alkyl, provided that when both RA and RB is H, RC is not CH3 or F;
• RC is H, D, F, Cl, OR, C1-5 alkyl, C3-5 cycloalkyl or heterocyclic group, substituted with 0-2 R42a.
• each of R and R′ is independently H or a C1-C6 alkyl, C1-C6 acyl, or R and R′, together with the nitrogen atom to which they are bound, form a 4- to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO2;
• R42a at each occurrence is independently D, halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR′, (CH2)nNRR′ or a 4- to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;
• R42b is a C1-6 alkyl or C3-6 cycloalkyl, C5-7 spirocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R42c;
• and
• R42c at each occurrence is independently halo, CN, OR, NRR′, OCF3, CF3, C1-6 alkyl substituted with 0-3 R42a, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 R42a, C2-6 alkynyl substituted with 0-3 R42a;
• and
• R47 is a C1-3 alkoxy group optionally substituted with 1-3 D or halo.

A compound having the structural formula (IV):

• or a pharmaceutically acceptable form or an isotope derivative thereof,
• wherein
• Y1 is CH, CF or N;
• Y2 is CH or N;
• Y3 is NR, O, CH2, CF2 or O—NH;
• Y4 is CH or N;
• R41 is a H, F, C1-C3 alkyl and CD3, provided that R41 is not F when Y3 is NR, O or O—NH;
• R42 is
• R42′, wherein R42′ is a C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, each substituted with 0-2 of halogen, CN, OR, NRR′, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;
• an aryl or heteroaryl group, each substituted with 0-2 R42a;
• or
• each of RA and RB is independently selected from H, D, halo, OR, and C1-3 alkyl, provided that when both RA and RB is H, RC is not H or F;
• RC is H, D, F, Cl, OR, C1-5 alkyl, C3-5 cycloalkyl or heterocyclic group, substituted with 0-2 R42a.
• each of R and R′ is independently H or a C1-C6 alkyl, C1-C6 acyl, or R and R′, together with the nitrogen atom to which they are bound, form a 4- to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO2;
• R42a at each occurrence is independently D, halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR′, (CH2)nNRR′ or a 4- to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;
• R42b is a C1-6 alkyl or C3-6 cycloalkyl, C5-7 spirocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R42c;
• and
• R42c at each occurrence is independently halo, CN, OR, NRR′, OCF3, CF3, C1-6 alkyl substituted with 0-3 R42a, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 R42a, C2-6 alkynyl substituted with 0-3 R42a;
• and
• R47 is a C1-3 alkoxy group optionally substituted with 1-3 D or halo.

A compound having the structural formula (V):

• or a pharmaceutically acceptable form or an isotope derivative thereof,
• wherein
• Y1 is CH, CF or N;
• Y2 is CH or N;
• Y3 is NR, O, CH2, CF2 or O—NH;
• Y4 is CH or N;
• R41 is a H, F, C1-C3 alkyl and CD3, provided that R41 is not F when Y3 is NR, O or O—NH;
• R42 is
• R42′, wherein R42′ is a C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, each substituted with 0-2 of halogen, CN, OR, NRR′, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;
• an aryl or heteroaryl group, each substituted with 0-2 R42a;
• each of R and R′ is independently H or a C1-C6 alkyl, C1-C6 acyl, or R and R′, together with the nitrogen atom to which they are bound, form a 4- to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO2;
• R42a at each occurrence is independently D, halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR′, (CH2)nNRR′ or a 4- to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;
• R42b is a C1-6 alkyl or C3-6 cycloalkyl, C5-7 spirocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R42a;
• R42c at each occurrence is independently halo, CN, OR, NRR′, OCF3, CF3, C1-6 alkyl substituted with 0-3 R42a, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 R42a, C2-6 alkynyl substituted with 0-3 R42a;
• R46 is H, CD3, a C1-C6 alkyl or C3-C6 cycloalkyl, with 0-4 of halogen, CN and OR;
• R47 is a C1-3 alkoxy group optionally substituted with 1-3 D or halo;
• and
• R48 is H, halo or a C1-C3 alkyl.

The compound of claim 45, having the structure:

• wherein
• each of RA and RB is independently selected from H, D, halo, OR, and C1-3 alkyl;
• RC is H, D, F, Cl, OR, C1-5 alkyl, C3-5 cycloalkyl or heterocyclic group, substituted with 0-2 R42a;
• 51. The compound of any one of claims 45-50, wherein Y4 is CH.

A method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structural formula of (I):

• or a pharmaceutically acceptable form or an isotope derivative thereof,
• wherein
• Y1 is CH, CF or N;
• Y2 is CH or N;
• Y3 is NR, O, CH2, CF2 or O—NH;
• Y4 is CH or N;
• R41 is a H, F, C1-C3 alkyl and CD3, provided that R41 is not F when Y3 is NR, O or O—NH;
• R42 is
• R42′, wherein R42′ is a C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, each substituted with 0-2 of halogen, CN, OR, NRR′, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;
• an aryl or heteroaryl group, each substituted with 0-2 R42a;
• or
• each of RA and RB is independently selected from H, D, halo, OR, and C1-3 alkyl;
• RC is H, D, F, Cl, OR, C1-5 alkyl, C3-5 cycloalkyl or heterocyclic group, substituted with 0-2 R42a;
• each of R and R′ is independently H or a C1-C6 alkyl, C1-C6 acyl, or R and R′, together with the nitrogen atom to which they are bound, form a 4- to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO2;
• R42a at each occurrence is independently D, halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR′, (CH2)nNRR′ or a 4- to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;
• R42b is a C1-6 alkyl or C3-6 cycloalkyl, C5-7 spirocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R42c;
• R42c at each occurrence is independently halo, CN, OR, NRR′, OCF3, CF3, C1-6 alkyl substituted with 0-3 R42a, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 R42a, C2-6 alkynyl substituted with 0-3 R42a;
• and
• R47 is a C1-3 alkoxy group optionally substituted with 1-3 D or halo,
• wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or a related disease or disorder thereof, in a mammal, including a human.

A method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structural formula of (II):

• or a pharmaceutically acceptable form or an isotope derivative thereof,
• wherein
• Y1 is CH, CF or N;
• Y2 is CH or N;
• Y3 is NR, O, CH2, CF2 or O—NH;
• Y4 is CH or N;
• R41 is a H, F, C1-C3 alkyl and CD3, provided that R41 is not F when Y3 is NR, O or O—NH;
• R42 is
• R42′, wherein R42′ is a C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, each substituted with 0-2 of halogen, CN, OR, NRR′, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;
• an aryl or heteroaryl group, each substituted with 0-2 R42a;
• or
• each of RA and RB is independently selected from H, D, halo, OR, and C1-3 alkyl;
• RC is H, D, F, Cl, OR, C1-5 alkyl, C3-5 cycloalkyl or heterocyclic group, substituted with 0-2 R42a.
• each of R and R′ is independently H or a C1-C6 alkyl, C1-C6 acyl, or R and R′, together with the nitrogen atom to which they are bound, form a 4- to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO2;
• R42a at each occurrence is independently D, halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR′, (CH2)nNRR′ or a 4- to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;
• R42b is a C1-6 alkyl or C3-6 cycloalkyl, C5-7 spirocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R42a;
• and
• R42c at each occurrence is independently halo, CN, OR, NRR′, OCF3, CF3, C1-6 alkyl substituted with 0-3 R42a, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 R42a, C2-6 alkynyl substituted with 0-3 R42a;
• and
• R47 is a C1-3 alkoxy group optionally substituted with 1-3 D or halo,
• wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or a related disease or disorder thereof, in a mammal, including a human.

A method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structural formula of (III):

• or a pharmaceutically acceptable form or an isotope derivative thereof,
• wherein
• Y1 is CH, CF or N;
• Y2 is CH or N;
• Y3 is NR, O, CH2, CF2 or O—NH;
• Y4 is CH or N;
• R41 is a H, F, C1-C3 alkyl and CD3, provided that R41 is not F when Y3 is NR, O or O—NH;
• R42 is
• R42′, wherein R42′ is a C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, each substituted with 0-2 of halogen, CN, OR, NRR′, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;
• an aryl or heteroaryl group, each substituted with 0-2 R42a;
• or
• each of RA and RB is independently selected from H, D, halo, OR, and C1-3 alkyl, provided that when both RA and RB is H, RC is not CH3 or F;
• RC is H, D, F, Cl, OR, C1-5 alkyl, C3-5 cycloalkyl or heterocyclic group, substituted with 0-2 R42a.
• each of R and R′ is independently H or a C1-C6 alkyl, C1-C6 acyl, or R and R′, together with the nitrogen atom to which they are bound, form a 4- to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO2;
• R42a at each occurrence is independently D, halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR′, (CH2)nNRR′ or a 4- to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;
• R42b is a C1-6 alkyl or C3-6 cycloalkyl, C5-7 spirocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R42c;
• and
• R42c at each occurrence is independently halo, CN, OR, NRR′, OCF3, CF3, C1-6 alkyl substituted with 0-3 R42a, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 R42a, C2-6 alkynyl substituted with 0-3 R42a;
• and
• R47 is a C1-3 alkoxy group optionally substituted with 1-3 D or halo,
• wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or a related disease or disorder thereof, in a mammal, including a human.

A method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structural formula of (IV):

• or a pharmaceutically acceptable form or an isotope derivative thereof,
• wherein
• Y1 is CH, CF or N;
• Y2 is CH or N;
• Y3 is NR, O, CH2, CF2 or O—NH;
• Y4 is CH or N;
• R41 is a H, F, C1-C3 alkyl and CD3, provided that R41 is not F when Y3 is NR, O or O—NH;
• R42 is
• R42′, wherein R42′ is a C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, each substituted with 0-2 of halogen, CN, OR, NRR′, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;
• an aryl or heteroaryl group, each substituted with 0-2 R42a;
• or
• each of RA and RB is independently selected from H, D, halo, OR, and C1-3 alkyl, provided that when both RA and RB is H, RC is not H or F;
• RC is H, D, F, Cl, OR, C1-5 alkyl, C3-5 cycloalkyl or heterocyclic group, substituted with 0-2 R42a.
• each of R and R′ is independently H or a C1-C6 alkyl, C1-C6 acyl, or R and R′, together with the nitrogen atom to which they are bound, form a 4- to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO2;
• R42a at each occurrence is independently D, halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR′, (CH2)nNRR′ or a 4- to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;
• R42b is a C1-6 alkyl or C3-6 cycloalkyl, C5-7 spirocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R42a;
• and
• R42c at each occurrence is independently halo, CN, OR, NRR′, OCF3, CF3, C1-6 alkyl substituted with 0-3 R42a, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 R42a, C2-6 alkynyl substituted with 0-3 R42a;
• and
• R47 is a C1-3 alkoxy group optionally substituted with 1-3 D or halo,
• wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or a related disease or disorder thereof, in a mammal, including a human.

A method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structural formula of (V):

• or a pharmaceutically acceptable form or an isotope derivative thereof,
• wherein
• Y1 is CH, CF or N;
• Y2 is CH or N;
• Y3 is NR, O, CH2, CF2 or O—NH;
• Y4 is CH or N;
• R41 is a H, F, C1-C3 alkyl and CD3, provided that R41 is not F when Y3 is NR, O or O—NH;
• R42 is
• R42′, wherein R42′ is a C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, each substituted with 0-2 of halogen, CN, OR, NRR′, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;
• an aryl or heteroaryl group, each substituted with 0-2 R42a;
• each of R and R′ is independently H or a C1-C6 alkyl, C1-C6 acyl, or R and R′, together with the nitrogen atom to which they are bound, form a 4- to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO2;
• R42a at each occurrence is independently D, halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR′, (CH2)nNRR′ or a 4- to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;
• R42b is a C1-6 alkyl or C3-6 cycloalkyl, C5-7 spirocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R42c;
• R42c at each occurrence is independently halo, CN, OR, NRR′, OCF3, CF3, C1-6 alkyl substituted with 0-3 R42a, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 R42a, C2-6 alkynyl substituted with 0-3 R42a;
• R46 is H, CD3, a C1-C6 alkyl or C3-C6 cycloalkyl, with 0-4 of halogen, CN and OR;
• R47 is a C1-3 alkoxy group optionally substituted with 1-3 D or halo;
• and
• R48 is H, halo or a C1-C3 alkyl,
• wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or a related disease or disorder thereof, in a mammal, including a human.