US 11,834,449 B2
TYK2 inhibitors and uses thereof
Jeremy Robert Greenwood, Brooklyn, NY (US); and Craig E. Masse, Cambridge, MA (US)
Assigned to Takeda Pharmaceutical Company Limited, Osaka (JP)
Filed by Nimbus Lakshmi, Inc., Cambridge, MA (US)
Filed on May 14, 2021, as Appl. No. 17/320,394.
Application 17/320,394 is a division of application No. 16/697,371, filed on Nov. 27, 2019, granted, now 11,053,241.
Claims priority of provisional application 62/773,620, filed on Nov. 30, 2018.
Prior Publication US 2022/0106306 A1, Apr. 7, 2022
Int. Cl. C07D 471/04 (2006.01); C07D 519/00 (2006.01)
CPC C07D 471/04 (2013.01) [C07D 519/00 (2013.01)] 20 Claims
 
1. A method of treating a TYK2-mediated disorder, disease, or condition in a patient comprising administering to said patient the compound of formula I′:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
X is N or CH;
L1 is a covalent bond or a C1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —C(R4)2—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)2—, —S(O)2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)2—;
R4 is independently RA or RB;
each instance of RA is independently halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, —S(O)(NR)R, —S(O)2NR2, —S(O)R, —S(O)NR2, —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)S(O)2NR2, —N(R)S(O)2R, or —P(O)R2; or two instances of RA are optionally taken together to form an oxo;
each instance of RB is independently C1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by q instances of RC;
each instance of RC is independently oxo, halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —S(O)NR2, —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)NR2, —N(R)S(O)2NR2, —N(R)S(O)2R, —N═S(O)R2, —S(NR)(O)R, —N(R)S(O)R, —N(R)CN, —P(O)(R)NR2, —P(O)(R)OR or —P(O)R2 or an optionally substituted group selected from C1-6 aliphatic; phenyl; naphthalenyl; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or for each instance of RB, optionally:
two RC groups on the same atom are taken together with the atom to form an optionally substituted 4-7 membered saturated, spirocyclic heterocyclic ring having 1-2 heteroatoms, independently selected from nitrogen, oxygen, and sulfur;
two RC groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated or partially unsaturated, fused ring having 0-2 heteroatoms, independently selected from nitrogen, oxygen, and sulfur; or
two RC groups are taken together with their intervening atoms to form an optionally substituted 5-6 membered fused aryl ring having 0-3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur;
each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic; phenyl; naphthalenyl; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or:
two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R1 is Cy1;
Cy1 is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy1 is substituted with p instances of R1A;
each instance of R1A, is independently RA or RB;
R2 is C1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by q instances of RC;
R3 is —C(O)NH2, —C(O)NHCH3, or —C(O)NHCD3;
each of p and q is independently 0, 1, 2, 3, or 4; and
r is 0 or 1;
wherein the TYK2-mediated disorder, disease, or condition is:
an autoimmune disorder selected from type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease;
an inflammatory disorder selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease;
a hematological cancer: or
Alzheimer's disease.