US 12,486,302 B2
Somatostatin receptor antagonist compounds and methods of using the same
Stephen Paul Arns, North Vancouver (CA); James Brian Jaquith, Cobourg (CA); Davy Jeremy Baudelet, Vancouver (CA); Eric Roy Simonson, Vancouver (CA); Richard Tom Liggins, Coquitlam (CA); Nag Sharwan Kumar, Surrey (CA); and Tom Han Hsiao Hsieh, Vancouver (CA)
Assigned to CDRD VENTURES INC., Vancouver (CA)
Filed by CDRD VENTURES INC., Vancouver (CA)
Filed on Dec. 29, 2021, as Appl. No. 17/564,893.
Application 17/564,893 is a continuation of application No. 16/076,826, granted, now 11,279,732, previously published as PCT/CA2017/050156, filed on Feb. 9, 2017.
Claims priority of provisional application 62/293,216, filed on Feb. 9, 2016.
Prior Publication US 2022/0112242 A1, Apr. 14, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07K 7/50 (2006.01); C07K 7/02 (2006.01); C07K 7/06 (2006.01); A61K 38/00 (2006.01)
CPC C07K 7/06 (2013.01) [C07K 7/02 (2013.01); A61K 38/00 (2013.01)] 53 Claims
 
1. A compound having the structure of Formula I:

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or a salt thereof, wherein:
RC is OH or NHR16, wherein R16 is H or C1-6 alkyl optionally substituted with one or more substituents;
RN is selected from the group consisting of:
(i) H;
(ii) C1-6 alkyl;
(iii) —C(O)R17, wherein R17 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;
(iv) —C(O)C1-6 alkylene-C(O)OR18, wherein R18 is H or C1-6 alkyl optionally substituted with one or more substituents;
(v) C(O)C1-6 alkylene-N(R20)C(O)R19, wherein R19 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents, and wherein R20 is H or C1-6 alkyl;
(vi) —C(O)C1-6 alkylene-NR21R22, wherein each of R21 and R22 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;
(vii) —C(O)C1-6 alkylene-C(O)NR23R24, wherein each of R23 and R24 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;
(viii) —C(O)C1-6 alkylene-S(O)2R25, wherein R25 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and
(ix) —S(O)2R26, wherein R26 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;
R1 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, —C1-6 alkylene(C6-10 aryl) and —C1-6 alkylene (5- to 10-membered heteroaryl), wherein the C1-6 alkyl, the C6-10 aryl, the C6-10 aryl of —C1-6 alkylene(C6-10 aryl), the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl of —C1-6 alkylene (5- to 10-membered heteroaryl) are optionally substituted with one or more substituents, and wherein the C1-6 alkylene of —C1-6 alkylene(C6-10 aryl) and —C1-6 alkylene (5- to 10-membered heteroaryl) is optionally substituted with one or more substituents;
R3 is selected from the group consisting of:
(i) C6-10 aryl which is optionally substituted with one or more substituents;
(ii) 5- to 10-membered heteroaryl which is optionally substituted with one or more substituents;
(iii) —C1-6 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents, and wherein the C1-6 alkylene is optionally substituted with one or more substituents;
(iv) —C1-6 alkylene (5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is optionally substituted with one or more substituents, and wherein the C1-6 alkylene is optionally substituted with one or more substituents;
(v) —C1-6 alkylene-NR27C(O)R28, wherein:
R27 is H or C1-6 alkyl;
R28 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and —NR29R30, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and
wherein each of R29 and R30 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;
(vi) —(C6-10 arylene)-C(O)NR31R32 or —C1-6 alkylene-(C6-10 arylene)-C(O)NR31R32, wherein each of R31 and R32 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;
(vii) —(C6-10 arylene)-NR33R34 or —C1-6 alkylene-(C6-10 arylene)-NR33R34, wherein:
each of R33 and R34 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, —C(O)R35, —C(O)NR36R37, and —SO2R38, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;
R35 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents;
each of R36 and R37 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and
R38 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;
(viii) —(C6-10 arylene)-SO2NR39R40 or —C1-6 alkylene-(C6-10 arylene)-SO2NR39R40, wherein each of R39 and R40 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;
(ix) —(C6-10 arylene)-(C1-6 alkylene)-NR41R42 or —C1-6 alkylene-(C6-10 arylene)-(C1-6 alkylene)-NR41R42, wherein:
each of R41 and R42 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, —C(O)R43, and —C(O)NR44R45, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;
R43 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and
each of R44 and R45 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;
(x) —(C6-10 arylene)-OR46 or —C1-6 alkylene-(C6-10 arylene)-OR46, wherein R46 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and
(xi) —C1-6 alkylene-(C6-10 arylene)-N(R47)—C(O)—CHR48—NR49R50, wherein R47 is H or CH3, R48 is H or C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyl, COOH, —NH2, C(O)NH2, and —N(H)C(O)NH2, and each of R49 and R50 is independently H, CH3 or acetyl;
R4 is selected from the group consisting of:
(i) —C1-6 alkylene-N(R53)C(O)NR51R52, wherein each of R51 and R52 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and wherein R53 is H or C1-6 alkyl;
(ii) —C1-6 alkylene-(C6-10 arylene)-N(R59)C(O)R58, wherein R58 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and wherein R59 is H or C1-6 alkyl;
(iii) —C1-6 alkylene-(C6-10 arylene)-N(R64)SO2R63, wherein R63 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and wherein R64 is H or C1-6 alkyl;
(iv) —C1-6 alkylene-(C6-10 arylene)-(C1-6 alkylene)-NR67R68, wherein:
each of R67 and R68 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, —C(O)R69, and —C(O)NR70R71;
R69 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and
each of R70 and R71 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl;
(v) —C1-6 alkylene-(C6-10 arylene)-NR72R73, wherein each of R72 and R73 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and
(vi) —C1-6 alkylene-(C6-10 arylene)-CN;
R5 is selected from the group consisting of:
(i) —NR79R80, wherein each of R79 and R80 is independently selected from the group consisting of H, C1-6 alkyl, —C(O)R81, and —C(═NR82)NR83R84, or R79 and R80, together with the N atom to which they are attached, form 5- to 10-membered heteroaryl or 5- to 10-membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the 5- to 10-membered heteroaryl and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents,
R81 is selected from the group consisting of H, —NH2, C1-16 alkyl, C1-6 haloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and
each of R82, R83, and R84 is independently selected from the group consisting of H, C1-16 alkyl, C1-6 haloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and
(ii) —N+R85R86R87, wherein each of R85, R86, and R87 is independently C1-6 alkyl;
n1 is 1, 2, 3, 4, 5, or 6;
R6 is C1-6 alkyl optionally substituted with one or more substituents;
R8 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, —C1-6 alkylene(C6-10 aryl) and —C1-6 alkylene (5- to 10-membered heteroaryl), wherein the C1-6 alkyl, the C6-10 aryl, the C6-10 aryl of —C1-6 alkylene(C6-10 aryl), the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl of —C1-6 alkylene (5- to 10-membered heteroaryl) are optionally substituted with one or more substituents, and wherein the C1-6 alkylene of —C1-6 alkylene(C6-10 aryl) and —C1-6 alkylene (5- to 10-membered heteroaryl) is optionally substituted with one or more substituents;
R9 is H or C1-6 alkyl;
R10 is H or C1-6 alkyl;
R11 is H or C1-6 alkyl;
R12 is H or C1-6 alkyl;
R13 is H or C1-6 alkyl;
R14 is H or C1-6 alkyl;
R15 is H or C1-6 alkyl; and
L is selected from the group consisting of:

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 wherein X is S or O; and

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chiral centre *1 is in the S configuration or the R configuration;
chiral centre *2 is in the S configuration or the R configuration;
chiral centre *3 is in the S configuration or the R configuration;
chiral centre *4 is in the S configuration or the R configuration;
chiral centre *5 is in the S configuration or the R configuration;
chiral centre *6 is in the S configuration or the R configuration;
chiral centre *7 is in the S configuration or the R configuration; and
chiral centre *8 is in the S configuration or the R configuration,
provided that:
i) when RC is NH2, RN is H or —C(O)CH2N3, R1 is

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R3 is

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 R5 is NH2, n1 is 4, R6 is —CH(OH)(CH3), R8 is

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 each of R9, R10, R11, R12, R13, R14 and R15 is H, and L is

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 then R4 is not

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 and
ii) when RC is NH2, RN is H, R1 is

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 R5 is NH2, n1 is 4, R6 is —CH(CH3)2, R8 is —CH(OH)(CH3), each of R9, R10, R11, R12, R13, R14 and R15 is H, and L is

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 then R4 is not

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