US 12,448,396 B2
Methods of using heterocyclic compounds as Delta-5 Desaturase inhibitors
Jennifer R. Allen, Newbury Park, CA (US); Michela Beltrani, Verona (IT); Matthew P. Bourbeau, Woodland Hills, CA (US); Teodora P. Damyanova, Verona (IT); Iain Lingard, Verona (IT); Ana E. Minatti, Los Angeles, CA (US); and Paolo Vincetti, Verona (IT)
Assigned to AMGEN INC., Thousand Oaks, CA (US)
Filed by AMGEN INC., Thousand Oaks, CA (US)
Filed on Nov. 18, 2022, as Appl. No. 18/056,863.
Application 18/056,863 is a division of application No. 17/103,389, filed on Nov. 24, 2020, granted, now 11,512,097.
Claims priority of provisional application 62/939,821, filed on Nov. 25, 2019.
Prior Publication US 2023/0159560 A1, May 25, 2023
Int. Cl. C07D 513/04 (2006.01); A61P 3/04 (2006.01); C07D 487/04 (2006.01); C07D 498/04 (2006.01)
CPC C07D 513/04 (2013.01) [A61P 3/04 (2018.01); C07D 487/04 (2013.01); C07D 498/04 (2013.01)] 59 Claims
 
1. A method of reducing the body weight or the body-mass-index of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I

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or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer,
wherein

OG Complex Work Unit Chemistry
each instance of R is independently selected from H, halogen, —OH, —CN, —CO(C1-4alkyl), —S(O)n(C1-4alkyl), —COOH, —COO(C1-4alkyl), —CONH2, —CONH(C1-4alkyl), —CO(diC1-4alkylamino), —NH2, C1-4alkylamino, diC1-4alkylamino, —NH(COC1-4alkyl), —N(C1-4alkyl)C(═O)F, C1-4alkyl, —(CH2)m(C3-5cycloalkyl), —CH2(C3-5heterocycloalkyl), C1-4deuteroalkyl, C3-5cycloalkyl, C3-4heterocycloalkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4deuteroalkoxy, 5-membered heteroaryl, and 6-membered heteroaryl;
wherein the C1-4alkyl group is optionally substituted with 1 to 4 F atoms or is optionally substituted with a substituent selected from —OH, —CN, C1-4alkoxy, —NH2, C1-4alkylamino, diC1-4alkylamino, and —S(O)n(C1-4alkyl);
wherein the C1-4alkoxy group is optionally substituted with 1 to 4 independently selected halogens or optionally substituted with a substituent selected from —OH, —CN, C1-4alkoxy, —NH2, C1-4alkylamino, diC1-4alkylamino, and —S(O)n(C1-4alkyl);
wherein the —CH2(C3-5cycloalkyl), C3-4heterocycloalkyl, 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, —CN, C1-4alkoxy, C1-4alkyl, —NH2, C1-4alkylamino, diC1-4alkylamino, and —S(O)n(C1-4alkyl); and
wherein R of a first CR group and R of a second CR group, if present, may, together with the atoms to which they are attached, form a C3-5carbocycle;
each R″, if present, is independently selected from H, —OH, —CO(C1-4alkyl), —S(O)n(C1-4alkyl), —COO(C1-4alkyl), —CONH2, —CONH(C1-4alkyl), —CO(diC1-4alkylamino), C1-4alkyl, —(CH2)m(C3-5cycloalkyl), —CH2(C3-5heterocycloalkyl), C1-4deuteroalkyl, C3-5cycloalkyl, C3-4heterocycloalkyl, C2-4alkenyl, C2-4alkynyl, 5-membered heteroaryl, and 6-membered heteroaryl;
wherein the C1-4alkyl group is optionally substituted with 1 to 4 F atoms or is optionally substituted with a substituent selected from —OH, —CN, C1-4alkoxy, —NH2, C1-4alkylamino, diC1-4alkylamino, and —S(O)n(C1-4alkyl); and
wherein the —(CH2)m(C3-5cycloalkyl), C3-4heterocycloalkyl, 5-membered heteroaryl, or 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, —CN, C1-4alkoxy, C1-4alkyl, —NH2, C1-4alkylamino, diC1-4alkylamino, and —S(O)n(C1-4alkyl);
R1 is O, S, or NH;
R2 is

OG Complex Work Unit Chemistry
 wherein
Ring A is a 5-membered heteroaryl containing one heteroatom selected from N, S, and O and optionally one or two further N atoms with the remaining ring atoms of the 5-membered heteroaryl being carbon, wherein
i) Ring A is attached via a C atom to the bicyclic core and R3 is attached via an N atom; or
ii) Ring A is attached via an N atom to the bicyclic core and R3 is attached via a C atom; or
iii) Ring A is attached via a C atom to the bicyclic core and R3 is attached via a C atom;
and wherein the

OG Complex Work Unit Chemistry
 portion of R2 is further optionally substituted with one or two independently selected substituents R3′;
R3 is C1-6alkyl, C3-5cycloalkyl, C2-6alkoxy, C1-6alkylamino, diC1-6alkylamino, —S(O)n(C1-6alkyl), —CH2(C3-5cycloalkyl), —OCH2(C3-5cycloalkyl), —NHCH2(C3-5cycloalkyl), —S(O)nCH2(C3-5cycloalkyl), —CH2(C3-5heterocycloalkyl), or phenyl; wherein the C1-6alkyl, C3-5cycloalkyl, C2-6alkoxy, C1-6alkylamino, diC1-6alkylamino, —S(O)n(C1-6alkyl), —CH2(C3-5cycloalkyl), —OCH2(C3-5cycloalkyl), —NHCH2(C3-5cycloalkyl), and —S(O)nCH2(C3-5cycloalkyl) groups are optionally substituted with 1-9 halogen atoms and are optionally substituted with —CN and wherein the phenyl is optionally substituted with 1-3 substituents selected from halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy;
R3′, if present, is independently halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, or C1-4haloalkoxy;
R4 is C1-3alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, C3-5cycloalkyl, or C3-5cyclohaloalkyl;
n is 0, 1, or 2; and
m is 1 or 2.