Modulators of HSD17B13 and methods of use thereof

A compound of according to formula (II):

• or a pharmaceutically acceptable salt thereof, wherein:
• k and k′ are independently from 0 to 4;
• X is a bond, —CH2—, —CH2—CH2—, —CH2—O—, —CH═CH—, —(C═O)—, —O—, —NR#—, —S—, —(S═O)—, or —(SO2)—;
• Y is N, —CR2, or —COR2;
• R1 is H, —(CH2)0-3—NH2, —(CH2)0-3NHR#, —(CH2)0-3—N(R#)2, C1-4alkyl, C1-4 haloalkyl, phenyl, benzyl, or —(CH2)0-3—X—(CH2)0-3-phenyl, wherein phenyl is optionally substituted with one or more R5 groups;
• R2 is H, halogen, —(CH2)0-3—NH2, —(CH2)0-3—NHR#, —(CH2)0-3—N(R#)2, C1-12 alkyl, C1-12 alkenyl, C6-12 aryl, C1-12 aralkyl, C1-12 arylalkyl, C1-4 haloalkyl, C3-7 cycloalkyl, or a 5-7-membered heterocycle with 1 to 4 heteroatoms independently selected from O, N and S or combinations thereof, any of which is optionally substituted by one or more of —OH, C1-4 alkyl, C1-4 alkoxy, ═O, phenyl, or benzyl;
• R3 is H, C1-4 alkyl, or C1-4 haloalkyl;
• and wherein:
• when Y is N, at least one of R1 and R3 is not H, and when Y is CR2, at least one of R1, R2, and R3 is not H;
• R5 is independently at each occurrence halogen, —CN, ═O, —OH, —NH2, —(CH2)1-3—OR#, —NH—(C═O)—R*, —NH—(C═O)O—R*, —NH—(SO2)—R8, —(CH2)1-3-NR#2, —NHR#, —N(R#)2, C1-4 alkoxy, phenoxy, C1-12 alkyl, C1-12 heteroalkyl comprising 1 to 3 hetero atoms selected from —O—, —S—, or —NH—, C1-12 alkynyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-12 aryl, a 3-7-membered heterocycle with 1 to 4 heteroatoms selected from O, N and S or combinations thereof, or wherein two adjacent R5 groups form a 5-7 membered ring that optionally contains 1 to 3 heteroatoms selected from O, N, and S;
• any of which is optionally substituted with R*;
• R* is halogen, —OH, C1-3 alkyl, C1-3 haloalkyl, phenyl, or benzyl, any of which is optionally substituted with a halogen;
• and
• R#is C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, phenyl, or benzyl, any of which is optionally substituted with a halogen.

A compound according to any one of formula (IIa), formula (IIb), formula (IIc), and formula (IId)

• or a pharmaceutically acceptable salt thereof, wherein:
• k and k′ are independently from 0 to 4;
• Y is N, —CR2, or —COR2;
• R1 is H, —(CH2)0-3—NH2, —(CH2)0-3—NHR#, —(CH2)0-3—N(R#)2, C1-4 alkyl, C1-4 haloalkyl, phenyl, benzyl, or —(CH2)0-3—X—(CH2)0-3-phenyl, wherein phenyl is optionally substituted with one or more R5 groupls;
• R2 is H, halogen, —(CH2)0-3—NH2, —(CH2)0-3—NHR#, —(CH2)0-3—N(R#)2, C1-12 alkyl, C1-12 alkenyl, C6-12 aryl, CH1-12 aralkyl, C1-12 arylalkyl, C1-4 haloalkyl, C3-7 cycloalkyl, or a 5-7-membered heterocycle with 1 to 4 heteroatoms independently selected fro O, N and S or combinations thereof, any of which is optionally substituted by one or more of —OH, C1-4 alkyl, C1-4 alkoxy, ═O, phenyl, or benzyl;
• R3 is H, C1-4 alkyl, or C1-4 haloalkyl;
• and wherein:
• when Y is N, at least one of R1 and R3 is not H, and when Y is CR2, at least one of R1, R2, and R3 is not H;
• R5 is independently at each occurrence halogen, —CN, ═O, —OH, —NH2, —(CH2)1-3—OR#, —NH(C═O)—R*, —NH—(C═O)O—R*, —NH—(SO2)—R*, —(CH2)1-3—NR#2, —NHR#, —N(R#)2, C1-4 alkoxy, phenoxy, C1-2 alkyl, C1-12 heteroalkyl comprising 1 to 3 hetero atoms selected from —O—, —S—, or —NH—, C1-12 alkenyl, C1-12 alkynyl, C1-4 haloalkyl, C1-4 halalkoxy, C6-12 aryl, a 3-7 membered heterocycle with 1 to 4 heteroatoms selected from O, N and S or combination thereof, or wherein two adjacent R5 groups form a 5-7 membered ring that optionally contains 1 to 3 heteroatoms selected from O, N, and S;
• any of which is optionally substituted with R*;
• R* is halogen, —OH, C1-3 alkyl, C1-3 haloalkyl, phenyl, or benzyl, any of which is optionally substituted with a halogen;
• and
• R#is C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, phenyl, or benzyl, any of which is optionally substitued with a halogen.

A compound according to formula (V′)

• or a pharmaceutically acceptable salt thereof, wherein:
• L is a bond, —(CH2)n—, —(CHB)n—, —CH2CHB—, or —CHBCH2—;
• wherein;
• B is benzyl or C1-12 alkyl optionally comprising 1-4 O atoms, either of which is optionally substituted by —OH or —OCH3;
• n is 1 or 2;
• and wherein:
• and Ar are as defined above.
• when Ar is phenyl, phenyl is optionally substituted by one or more R7 and not by R8;
• when L is —(CH2)n—, Ar is phenyl, then at least one R7 is a phenoxy that is optionally substituted with a halogen;
• and
• when L is —(CHB)n—, B is C1-4 alkyl, Ar is phenyl, then R7 is present and is not —Cl, —F, —CN, C1-4 alkyl, or C1-4 alkoxy;
• Ar is a phenyl, naphthyl, or a C4—C8 cycloalkyl, any of which is optionally substituted with one or more R8 or Het;
• Het is a 6-membered heterocycle comprising from 1 to 3 heteroatoms independently selected from N and O, wherein Het is optionally substituted with one or more of C1-3 alkyl, C1-3 alkenyl, halogen, —OH or ═O;
• R7 is independently at each occurrence halogen, —CN, ═O, —OH, —(CH2)1-3—OR#, —NH—(C═O)—R*, —NH—(SO2)—R*, —(CH2)1-3—NR#2, —NHR#, —N(R#)2, C1-4alkoxy, phenoxy, C1-12 alkyl, C1-12 alkenyl, C1-4 haloalkyl, or C6-12 aryl, any of which is optionally substituted with R*;
• R8 is independently at each occurrence halogen, —CN, ═O, —OH, —(CH2)0-3—SH, —(CH2)0-3—SR*, —(SO2)—R*, —NH2, —(CH2)1-3—OR#, —NH—(C═O)—R*, —NH—(SO2)—R*, —(CH2)1-3—NR#2, —NHR#, or —N(R#)2, C1-4 alkoxy, phenoxy, C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-12 aryl, a 4-7 membered heterocycle with 1 to 4 heteroatoms selected from O, N and S or combinations thereof, or wherein two adjacent R8 groups form a 5-7 membered ring that optionally contains 1 to 3 heteroatoms selected from O, N, and S;
• any of which is optionally substituted with R*;
• R* is halogen, —OH, C1-3 alkyl, C1-3 haloalkyl, phenyl, or benzyl, any of which is optionally substituted with a halogen;
• and
• R# is C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, phenyl, or benzyl, any of which is optionally substituted with a halogen.

A compound according to formula (VI):

• or a pharmaceutically acceptable salt thereof, wherein:
• k, k′ are independently from 0 to 4;
• X is a bond, —CH2, —CH2—CH2—, —CH2—O—, —CH═CH—, —(C═O)—, —O—, —NR#—, —S—, —(S═O)—, or —(SO2)—,
• Y is N, —CR2, or —COR2;
• R1 is H, —(CH2)0-3—NH2, —(CH2)0-3—NHR#, —(CH2)0-3—N(R#)2, C1-4 alkyl, C1-4 haloalkyl, phenyl, benzyl, or —(CH2)0-3—X—(CH2)0-3-phenyl, wherein phenyl is optionally substituted with one or more R5 groups;
• R2 is H, halogen, —(CH2)0-3—NH2, —(CH2)0-3—NHR#, —(CH2)0-3—N(R#)2, C1-12 alkyl, C1-12 alkenyl, C6-12 aryl, C1-12 aralkyl, C1-12 arylalkyl, C1-4 haloalkyl, C3-7 cycloalkyl, or a 5-7-membered heterocycle with 1 to 4 heteroatoms independently selected from O, N and S or combinations thereof, any of which is optionally substituted by one or more of —OH, C1-4 alkyl, C1-4 alkoxy, ═O, phenyl, or benzyl;
• R3 is H, C1-4 alkyl, or C1-4 haloalkyl;
• and wherein:
• when Y is N, at least one or R1 , and R3 is not H, and when Y is CR2, at least one of R1, R2, and R3 is not H;
• R5 is independently at each occurrence halogen, —CN, ═O, —OH, —NH2, —(CH2)1-3—OR#, —NH—(C═O)—R*, —NH—(C═O)O—R*, —NH—(SO2)—R*, —(CH2)1-3—NR#2, —NHR#, —N(R#)2, C1-4 alkoxy, phenoxy, C1-12 alkyl, C1-12 heteroalkyl comprising 1 to 3 hetero atoms selected from —O—, —S—, or —NH—, C1-12 alkenyl, C1-12 alkynyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-12 aryl, a 3-7-membered heterocycle with 1 to 4 heteroatoms selected from O, N and S or combinations thereof, or wherein two adjacent R5 groups form a 5-7 membered ring that optionally contains 1 to 3 heteroatoms selected from O, N, and S;
• any of which is optionally substituted with R*;
• R* is halogen, —OH, C1-3 alkyl, C1-3 haloalkyl, phenyl, or benzyl, any of which is optionally substituted with a halogen;
• and
• R# is C1-3 alkyl, C3-6 cycloalkyl, phenyl, or benzyl, any of which is optionally substituted with a halogen.

A compound according to formula (VII):

• or a pharmaceutically acceptable salt thereof, wherein:
• A is A′, A″, CR4(Ar)2, or Ar;
• wherein:
• A′ is
• A″ is
• Z is phenyl, Het, or a C4—C8 cycloalkyl;
• Ar is a phenyl, naphthyl, or a C4—C8 cycloalkyl, any of which is optionally substituted with one or more R8 Het;
• and
• Het is a 6-membered heterocycle comprising from 1 to 3 heteroatoms independently selected from N and O, wherein Het is optionally substituted with one or more of C1-3 alkyl, C1-3 alkenyl, halogen, —OH or ═O;
• wherein:
• when A is phenyl, phenyl is optionally substituted by one or more R7 and not by R8;
• and
• when B is C1-4 alkyl, A is phenyl and R4 is H, then R7 is present and is not —Cl, —F, —CN, C1-4 alkyl, or C1-4 alkoxy;
• R4 is H, C1-4 alkyl, or C1-4 haloalkyl;
• R6 is independently at each occurrence halogen, —OH, ═O, —CN, —(CH2)0-3—NH2, —(CH2)0-3—NHR#, —(CH2)0-3—N(R#)2, —(CH2)0-3—NHCOOR#, —(CH2)0-3—COOR#, C1-4 alkoxy, C1-12 alkyl, C1-12 alkenyl;
• C1-4 haloalkyl, C1-4 heteroalkyl with 1 or 2 methylene replaced with —O— or —S—, or C6-12 aryl, any of which is optionally substituted with R*;
• j and j′ are indenendently from 0 to 4;
• a and b are independently a single bond or a double bonde;
• W is ═CH—, ═C(R6)—, —CH2, —CH(R6)—, —(C═O)—, —CH2CH2—, —CH(R6)—CH2—, —O—, —O-13 CH2—, —O—CH(R6)—, —(NH)—, —N(R6)—, —CH2—NH—, —CH2—N(R6)—, or —S—,
• wherein:
• when W is —CH2—, or when W is —O—CH2—, then A′ is substituted with at least one R6 which is not —OH;
• R7 is independently at each occurrence halogen, —CN, ═O, —OH, —(CH2)1-3—OR#, —NH—(C═O)—R*, —NH—(SO2)—R*, —(CH2)1-3—NR#2, —NHR#, —N(R#)2, C1-4 alkoxy, phenoxy, C1-12 alkyl, C1-12 alkenyl, C1-4 haloalkyl, or C6-12 aryl, any of which is optionally substituted with R*;
• R8 is independently at each occurrence halogen, —CN, ═O, —OH, —(CH2)0-3—SH, —(CH2)0-3—SR*, —(SO2)—R*, —NH2, —(CH2)1-3—OR#, —NH—(C═O)—R*, —(CH2)1-3—NR#2, —NHR#, or —N(R#)2, C1-4 alkoxy, phenoxy, C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-12 aryl, a 4-7 membered heterocycle with 1 to 4 heteroatoms selected from O, N and S or combinations thereof, or wherein two adjacent R8 groups from a 5-7 membered ring that optionally contains 1 to 3 heteroatoms selected from O, N, and S;
• any of which is optionally substituted with R*;
• R* is halogen, —OH, C1-3 alkyl, C1-3 haloalkyl, phenyl, or benzyl any of which is optionally substitued with a halogen;
• R# is C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, phenyl, or benzyl, any of which is optionally substituted wiht a halogen;
• R5 is independently at each occurrence halogen, —CN, ═O, —OH, —NH2, —(CH2)1-3—OR#, —NH—(C═O)—R*, —NH-13 (C═O)O—R*, —NH—(SO2)—R*, —(CH2)1-3—NR#2, —NHR#, —N(R#)2, C1-4 alkoxy, phenoxy, C1-12 alkyl, C1-12 heteroalkyl comprising 1 to 3 hetero atoms selected from —O—, —S—, or —NH—, C1-12 alkenyl, C1-12 alkynyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-12 aryl, a 3-7-membered heterocycle with 1 to 4 heteroatoms selected from O, N and S or combinations thereof, or wherein two adjacent R5 groups form a 5-7 membered ring that optionally contains 1 to 3 heteroatoms selected from O, N, and S;
• any of which is optionally substituted with R*;
• k and k′ are independently from 0 to 4;
• X is a bond, —CH2—, —CH2—CH2—, —CH2—O—, —CH═CH—, —(C═O)—, —O—, —NR#—, —S—, —(S═O)—, or —(SO2)—;
• and
• B is benzyl or C1-12 alkyl optionally comprising 1-4 O atoms, either of which is optionally substituted by —OH or —OCH.

A compound according to formula (VIIa):

• or a pharmaceutically acceptable salt thereof, wherein:
• r is from 1 to 4;
• R7 is independently at each occurrence halogen, —CN, ═O, —OH, —(CH2)1-3—OR#, —NH—(C═O)—R*, —NH—(SO2)—R*, —(CH2)1-3—NR#2, —NHR#, —N(R#)2, C1-4 alkoxy, phenoxy, C1-12 alkyl, C1-12 alkenyl, C1-4 haloalkyl, or C6-12 aryl, any of which is optionally substituted with R*;
• R* is halogen, —OH, C1-3 alkyl, C1-3 haloalkyl, phenyl, or benzyl, any of which is optionally substituted with a halogen;
• R# is C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, phenyl, or benzyl, any of which is optionally substituted with a halogen;
• and
• B is benzyl or C1-12 alkyl optionally comprising 1-4 O atoms, either of which is optionally substituted by —OH or —OCH, wherein:
• when B is C1-4 alkyl, then R7 is not —Cl, —F, —CN, C1-4 alkyl, or C1-4 alkoxy.

A compound according to formula (VIII):

• or a pharmaceutically acceptable salt thereof, wherein:
• r and r′ are independently from 0 to 4;
• R8 is independently at each occurrence halogen, —CN, ═O, —OH, —(CH2)0-3—SH, —(CH2)0-3—SR*, —(SO2)—R*, —NH2, —(CH2)1-3—OR#, —NH—(C═O)—R*, —NH—(SO2)—R*, —(CH2)1-3—NR#2, —NHR#, or —N(R#)2, C1-4 alkoxy, phenoxy, C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-12 aryl, a 4-7-membered heterocycle with 1 to 4 heteroatoms selected from O, N and S or combinations thereof, or wherein two adjacent R8 groups form a 5-7 membered ring that optionally contains 1 to 3 heteroatoms selected from O, N, and S;
• any of which is optionally substituted with R*,
• R* is halogen, —OH, C1-3 alkyl, C1-3 haloalkyl, phenyl, or benzyl, any of which is optionally substituted with a halogen;
• and
• R# is C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, phenyl, or benzyl, any of which is optionally substituted with a halogen.