US 12,122,785 B2
Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors
Anjali Pandey, Fremont, CA (US); Gregory Dietsch, Snohomish, WA (US); Bhaskar Chaudhuri, San Jose, CA (US); Seetharaman Manojveer, Bangalore (IN); Mahesh Thakkar, Bangalore (IN); Athisayamani Jeyaraj Duraiswamy, Bangalore (IN); and Sukesh Kalva, Bangalore (IN)
Assigned to SUDO BIOSCIENCES LIMITED, Altrincham (GB)
Filed by Sudo Biosciences Limited, Altrincham (GB)
Filed on Jan. 27, 2023, as Appl. No. 18/160,479.
Application 18/160,479 is a continuation of application No. 17/737,872, filed on May 5, 2022, granted, now 11,613,548.
Application 17/737,872 is a continuation of application No. PCT/IB2022/000086, filed on Feb. 16, 2022.
Claims priority of provisional application 63/291,222, filed on Dec. 17, 2021.
Claims priority of provisional application 63/234,934, filed on Aug. 19, 2021.
Claims priority of provisional application 63/193,511, filed on May 26, 2021.
Claims priority of provisional application 63/151,287, filed on Feb. 19, 2021.
Prior Publication US 2023/0242546 A1, Aug. 3, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/4162 (2006.01); C07D 231/54 (2006.01); C07D 471/04 (2006.01); C07D 471/14 (2006.01); C07D 487/04 (2006.01); C07D 491/052 (2006.01)
CPC C07D 491/052 (2013.01) [C07D 471/04 (2013.01); C07D 471/14 (2013.01); C07D 487/04 (2013.01)] 20 Claims
 
1. A compound of Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, tautomer, or solvate thereof,
wherein:

OG Complex Work Unit Chemistry
Z is —NR10—, —O—, —S—, —S(═O)—, or —S(═O)2—;
X1 is CR11 or N;
X2 is CR11 or N;
X3 is CR11 or N;
B1 is N or CR12a;
B2 is N or CR12b;
W is —NR3— or —O—;
R1 is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl;
R2 is a Ring B that is an unsubstituted or substituted heterocyclyl or unsubstituted or substituted carbocyclyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R13;
or R2 is —C(═O)R14, —C(═O)NR14R15, or —C(═O)OR14;
R3 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocyclyl;
R4 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocyclyl;
or R3 and R4 are taken together with the nitrogen atom to which they are attached to form an unsubstituted or substituted heterocyclyl, wherein the substituted heterocyclyl is substituted with one or two groups independently selected from the group consisting of halogen, —CN, —NH2, —NH(CH3), —N(CH3)2, —OH, —C(═O)OH, —C(═O)O(C1-C4alkyl), —C(═O)NH2, —C(═O)NH(C1-C4alkyl), —C(═O)N(C1-C4alkyl)2, —S(═O)2NH2, —S(═O)2NH(C1-C4alkyl), —S(═O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, —S(C1-C4alkyl), —S(═O)(C1-C4alkyl), and —S(═O)2(C1-C4alkyl);
R5 is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocyclyl;
each R6 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, a monocyclic heterocyclyl, —CN, —OH, —OR17, —C(═O)R16, —C(═O)OR16, —C(═O)N(R16)2, —N(R16)2, —NR16C(═O)R17, —SR16, —S(═O)R17, —S(═O)2R17, or —S(═O)2N(R16)2;
each R7 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, a monocyclic heterocyclyl, —CN, —OH, —OR17, —C(═O)R16, —C(═O)OR16, —C(═O)N(R16)2, —N(R16)2, —NR16C(═O)R17, —SR16, —S(═O)R17, —S(═O)2R17, or —S(═O)2N(R16)2;
or one R6 and one R7 attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a —C(═O)— or C3-C4 cycloalkyl;
each R8 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, —CN, —OH, —OR17, —C(═O)R16, —C(═O)OR16, —C(═O)N(R16)2, —N(R16)2, —NR16C(═O)R7, —SR16, —S(═O)R17, —S(═O)2R17, or —S(═O)2N(R16)2;
R10 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocyclyl;
each R11 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, —CN, —OH, —OR17, —C(═O)R16, —C(═O)OR16, —C(═O)N(R16)2, —N(R16)2, —NR16C(═O)R17, —SR16, —S(═O)R17, —S(═O)2R17, or —S(═O)2N(R16)2;
R12a is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, —CN, —OH, —OR17, —C(═O)R16, —C(═O)OR16, —C(═O)N(R16)2, —N(R16)2, —NR16C(═O)R17, —SR16, —S(═O)R17, —S(═O)2R17, or —S(═O)2N(R16)2;
R12b is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, —CN, —OH, —OR17, —C(═O)R16, —C(═O)OR16, —C(═O)N(R16)2, —N(R16)2, —NR16C(═O)R17, —SR16, —S(═O)R17, —S(═O)2R17, or —S(═O)2N(R16)2;
each R13 is independently halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, —CN, —OH, —OR17, —C(═O)R16, —C(═O)OR16, —C(═O)N(R16)2, —N(R16)2, —NR16C(═O)R17, —SR16, —S(═O)R17, —S(═O)2R17, or —S(═O)2N(R16)2;
R14 is hydrogen, unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl;
R15 is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl;
or R14 and R15 are taken together with the nitrogen atom to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl, wherein the substituted heterocyclyl is substituted with one or two groups independently selected from the group consisting of halogen, —CN, —NH2, —NH(CH3), —N(CH3)2, —OH, —C(═O)OH, —C(═O)O(C1-C4alkyl), —C(═O)NH2, —C(═O)NH(C1-C4alkyl), —C(═O)N(C1-C4alkyl)2, —S(═O)2NH2, —S(═O)2NH(C1-C4alkyl), —S(═O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, —S(C1-C4alkyl), —S(═O)(C1-C4alkyl), and —S(═O)2(C1-C4alkyl);
or R1 and R15 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl, wherein the substituted heterocyclyl is substituted with one or two groups independently selected from the group consisting of halogen, —CN, —NH2, —NH(CH3), —N(CH3)2, —OH, —C(═O)OH, —C(═O)O(C1-C4alkyl), —C(═O)NH2, —C(═O)NH(C1-C4alkyl), —C(═O)N(C1-C4alkyl)2, —S(═O)2NH2, —S(═O)2NH(C1-C4alkyl), —S(═O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, —S(C1-C4alkyl), —S(═O)(C1-C4alkyl), and —S(═O)2(C1-C4alkyl);
each R16 is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl;
or two R16 are taken together with the nitrogen atom to which they are attached to form an unsubstituted or substituted heterocyclyl, wherein the substituted heterocyclyl is substituted with one or two groups independently selected from the group consisting of halogen, —CN, —NH2, —NH(CH3), —N(CH3)2, —OH, —C(═O)OH, —C(═O)O(C1-C4alkyl), —C(═O)NH2, —C(═O)NH(C1-C4alkyl), —C(═O)N(C1-C4alkyl)2, —S(═O)2NH2, —S(═O)2NH(C1-C4alkyl), —S(═O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, —S(C1-C4alkyl), —S(═O)(C1-C4alkyl), and —S(═O)2(C1-C4alkyl); and
each R17 is independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl;
wherein when any R8, R11, R12a, R12b, R13, R14, R16, or R17 is substituted:
each substituted C1-C6 alkyl, substituted C1-C6 deuteroalkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, or substituted C1-C6 heteroalkyl is independently substituted with one or two groups independently selected from the group consisting of halogen, —CN, —NH2, —NH(CH3), —N(CH3)2, —OH, —C(═O)OH, —C(═O)O(C1-C4alkyl), —C(═O)NH2, —C(═O)NH(C1-C4alkyl), —C(═O)N(C1-C4alkyl)2, —S(═O)2NH2, —S(═O)2NH(C1-C4alkyl), —S(═O)2N(C1-C4alkyl)2, C3-C6cycloalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, —S(C1-C4alkyl), —S(═O)(C1-C4alkyl), and —S(═O)2(C1-C4alkyl);
each substituted C1-C6 fluoroalkyl is independently substituted with one or two groups independently selected from the group consisting of —CN, —NH2, —NH(CH3), —N(CH3)2, —OH, —C(═O)OH, —C(═O)O(C1-C4alkyl), —C(═O)NH2, —C(═O)NH(C1-C4alkyl), —C(═O)N(C1-C4alkyl)2, —S(═O)2NH2, —S(═O)2NH(C1-C4alkyl), —S(═O)2N(C1-C4alkyl)2, C3-C6cycloalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, —S(C1-C4alkyl), —S(═O)(C1-C4alkyl), and —S(═O)2(C1-C4alkyl);
each substituted carbocyclyl, substituted cycloalkyl, substituted phenyl, substituted heterocyclyl, substituted heterocycloalkyl, and substituted heterocyclyl is independently substituted with one or two groups independently selected from the group consisting of halogen, —CN, —NH2, —NH(CH3), —N(CH3)2, —OH, —C(═O)OH, —C(═O)O(C1-C4alkyl, —C(═O)NH2, —C(═O)NH(C1-C4alkyl), —C(═O)N(C1-C4alkyl)2, —S(═O)2NH2, —S(═O)2NH(C1-C4alkyl), —S(═O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, —S(C1-C4alkyl), —S(═O)(C1-C4alkyl), and —S(═O)2(C1-C4alkyl);
n is 1, 2, or 3; and
q is 1, 2, 3, or 4;
with the provisos that:
(i) if R8 is attached to a nitrogen atom, then R8 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, —C(═O)R16, —C(═O)OR16, —C(═O)N(R16)2, —S(═O)R17, —S(═O)2R17, or —S(═O)2N(R16)2;
(ii) the compound of Formula (I) is not selected from the group consisting of: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-N-methylpyridazine-3-carboxamide, 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methylnicotinamide, 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((2,6-dimethylpyrimidin-4-yl)amino)-N-methylnicotinamide, and 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxalin-6-yl)amino)-N-methylpyridazine-3-carboxamide.