	US 12,121,511 B2
	GLP-1R modulating compounds
Stephen E. Ammann, Redwood City, CA (US); Gediminas J. Brizgys, San Carlos, CA (US); James S. Cassidy, Foster City, CA (US); Elbert Chin, San Mateo, CA (US); Chienhung Chou, Dublin, CA (US); Jeromy J. Cottell, Redwood City, CA (US); Chao-I Hung, Foster City, CA (US); Kavoos Kolahdouzan, San Francisco, CA (US); Daniel G. Shore, Redwood City, CA (US); Suzanne M. Szewczyk, San Mateo, CA (US); James G. Taylor, Burlingame, CA (US); Rhiannon Thomas-Tran, San Jose, CA (US); Nathan E. Wright, Foster City, CA (US); and Zheng-Yu Yang, Palo Alto, CA (US)
Assigned to Gilead Sciences, Inc., Foster City, CA (US)
Filed by Gilead Sciences, Inc., Foster City, CA (US)
Filed on Jan. 27, 2021, as Appl. No. 17/159,485.
Claims priority of provisional application 62/967,289, filed on Jan. 29, 2020.
Prior Publication US 2022/0288030 A1, Sep. 15, 2022
Int. Cl. A61K 31/4184 (2006.01); A61K 31/4192 (2006.01); A61K 31/4196 (2006.01); A61K 31/422 (2006.01); A61K 31/424 (2006.01); A61K 31/437 (2006.01); A61K 31/4439 (2006.01); A61K 31/444 (2006.01); A61K 45/06 (2006.01); C07D 405/10 (2006.01); C07D 405/14 (2006.01); C07D 409/14 (2006.01); C07D 413/10 (2006.01); C07D 471/04 (2006.01); C07D 493/04 (2006.01); C07D 493/10 (2006.01); C07D 498/04 (2006.01)

CPC A61K 31/4184 (2013.01) [A61K 31/4192 (2013.01); A61K 31/4196 (2013.01); A61K 31/422 (2013.01); A61K 31/424 (2013.01); A61K 31/437 (2013.01); A61K 31/4439 (2013.01); A61K 31/444 (2013.01); A61K 45/06 (2013.01); C07D 405/10 (2013.01); C07D 405/14 (2013.01); C07D 409/14 (2013.01); C07D 413/10 (2013.01); C07D 471/04 (2013.01); C07D 493/04 (2013.01); C07D 493/10 (2013.01); C07D 498/04 (2013.01)]

39 Claims

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

R¹is C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, heterocyclyl, C_6-10aryl, heteroaryl, —C(O)N(R^1b)(R^1c), —C(O)R^1b, or —C(O)OR^1c,

wherein the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is each optionally substituted with one to four Z¹;

ring A is an aromatic ring in which U¹, U², U³, are each independently —C(H)═, —C(Z^1a)═, or —N═;

ring B is C_6-10aryl or heteroaryl, which is each optionally substituted with one to four R⁴;

R²is H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, heterocyclyl, C_6-10aryl, heteroaryl, —S—R^2a, —S(O)R^2a, —S(O)(NH)R^2a, —S(O)₂R^2a, —S(O)₂N(R^2a)(R^2b), or —S(O)(NR^2a)R^2b,

wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with one to four Z¹;

X¹, X², and X³are each independently —N═, —C(H)═, or —C(R⁸)═;

Y¹and Y²are each —C(R^y1)(R^y2)—, —N(R^y1)—, —O—, —S—, —S(O)₂—, or —C(O)—;

W is —C(R⁵)—, or —N—,

wherein when W is —N, one of Y¹and Y²is —C(R^y1) (R^y2)— or —C(O)— and the other of Y¹and Y²is —C(R^y1) (R^y2)—, —C(O)—, or —S(O)₂—;

R³is H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, C_3-10cycloalkyl, heterocyclyl, C_6-10aryl, heteroaryl, —CN, —NO₂, —OR^3a, —C(O)R^3a, —C(O)OR^3a, —C(O)N(R^3a) (R^3b), —N(R^3a)C(O)R^3b, —N(R^3a)C(O)OR^3b, —N(R^3a)C(O)N(R^3b)₂, —C(O)NHS(O)₂R^3a, —C(O)NR^3aS(O)₂R^3b, —C(O)NR^3aS(O)₂NR^3bR^3c, —S(O)₂OR^3a, —S(O)₂N(R^3a)(R^3b), —N(R^3a)S(O)₂R^3b, —S(O)₂NHC(O)R^3a, —S(O)(═NR^3a)R^3b, —S(═NR^3a)(═NR^3b)R^3c, —P(O)(OR^3a)(R^3b), —P(O)(OR^3a)(OR^3b), or —B(OR^3a)(OR^3b), wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with one to four R^3d;

each R^3a, R^3b, and R^3cis independently H, C_1-6alkyl, C_1-6haloalkyl, C_2-8alkoxyalkyl, —C_1-4alkyl-N(R^9a)(R^9b), —C_1-4alkyl-C(O)N(R^9a) (R^9b), —C_1-4alkyl-O—C(O)—C_1-4alkyl, —C_1-4alkyl-O—C(O)—O—C_1-4alkyl, —C_1-4alkyl-O—C(O)—C_1-4alkyl-N(R^9a) (R^9b), —C_1-4alkyl-C_3-8cycloalkyl, —C_1-4alkyl-heterocyclyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, heterocyclyl, C_6-10aryl, heteroaryl, —P(O)(OR^9c)₂, —OP(O)(OR^9c)₂, —CH₂P(O)(OR^9c)₂, —OCH₂P(O)(OR^9c)₂, —C(O)OCH₂P(O)(OR^9c)₂, —P(O)(R^9c)(OR^9d), —OP(O)(R^9c)(OR^9d), —CH₂P(O)(R^9c)(OR^9d), —OCH₂P(O)(R^9c)(OR^9d), —C(O)OCH₂P(O)(R^9c)(OR^9d), —P(O)(N(R^9c)₂)₂, —OP(O)(N(R^9c)₂)₂, —CH₂P(O)(N(R^9c)₂)₂, —OCH₂P(O)(N(R^9c)₂)₂, —C(O)OCH₂P(O)(N(R^9c)₂)₂, —P(O)(N(R^9c)₂)(OR^9d), —OP(O)(N(R^9c)₂)(OR^9d), —CH₂P(O)(N(R^9c)₂)(OR^9d), —OCH₂P(O)(N(R^9c)₂)(OR^9d), —C(O)OCH₂P(O)(N(R^9c)₂)(OR^9d), —P(O)(R^9c)(N(R^9d)₂), —OP(O)(R^9c)(N(R^9d)₂), —CH₂P(O)(R^9c)(N(R^9d)₂), —OCH₂P(O)(R^9c)(N(R^9d)₂), or —C(O)OCH₂P(O)(R^9c)(N(R^9d)₂);

wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with one to four Z^1b,

each R⁴is independently C_1-9alkyl, C_1-8haloalkyl, C_1-6haloalkoxy, C_2-6alkoxyalkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, C_3-15cycloalkyl, heterocyclyl, C_6-10aryl, heteroaryl, oxo, —NO₂, —CN, —N₃, —O—R^4a, —C(O)R^4a, —C(O)O—R^4a, —C(O)N(R^4a) (R^4b), —N(R^4a) (R^4b), —N(R^4a)₂(R^4b)⁺, —N(R^4a)—C(O)R^4b, —N(R^4a)C(O)O(R^4b), —N(R^4a)C(O)N(R^4b)(R^4c), —N(R^4a)S(O)₂(R^4b), —N(R^4a)S(O)₂—N(R^4b)(R^4c), —N(R^4a)S(O)₂O(R^4b), —OC(O)R^4a, —OC(O)OR^4a, —OC(O)—N(R^4a) (R^4b), —S—R^4a, —S(O)R^4a, —S(O)(NH)R^4a, —S(O)₂R^4a, —S(O)₂N(R^4a)(R^4b), —S(O)(NR^4a)R^4b, or —Si(R^4a)₃;

wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with one to four Z^1b;

or two R⁴groups attached to adjacent ring atoms are combined with the atoms to which they are attached to form a C_5-10cycloalkyl or heterocyclyl, which is each optionally substituted with one to four Z^1b;

R⁵is H, cyclopropyl, or C_1-3alkyl, wherein the C_1-3alkyl is optionally substituted with one, two or three groups selected from halogen, —OH, —OCH₃, —CN, oxo, and —N(R^x1)(R^x2);

or R⁵and R^y1are combined with the atoms to which they are attached to form a C_3-10cycloalkyl or heterocyclyl optionally substituted with oxo;

R^x1and R^x2are each independently H, C_1-6alkyl, C_3-10cycloalkyl, heterocyclyl, —S(O)₂R^6a1, or —S(O)₂N(R^6a1)(NR^6a2), wherein the C_1-6alkyl, cycloalkyl or heterocyclyl is each optionally substituted with F, —CN, oxo, or C_3-6cycloalkyl;

or R^x1and R^x2are combined with the atom to which they are attached to form a heterocyclyl, which is optionally substituted with one to four R^6b1;

V is —C(O)—, —O—, —N(R^6a)—, or —C(R^6b) (R^6c)—;

R^6ais H, C_1-6alkyl, C_3-10cycloalkyl, heterocyclyl, —S(O)₂R^6a1, or —S(O)₂N(R^6a1)(NR^6a2), wherein the cycloalkyl or heterocyclyl is each optionally substituted with C_1-6alkyl, F, or —CN;

each R^6band R^6cis independently H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkoxyalkyl, halogen, C_3-10cycloalkyl, heterocyclyl, —C_1-6alkyl-N(R^9a) (R^9b), —CN, —OR^6c1, or —N(R^6c2) (R^6c3), wherein the alkyl, cycloalkyl, or heterocyclyl is each optionally substituted with one to four R^6b1;

or R^6band R^6care combined with the atom to which they are attached to form C_3-10cycloalkyl or heterocyclyl, which is each optionally substituted with one to four R^6b1;

or R^6aor R^6cis combined with one R⁴group and the atoms to which they are attached to form a C_5-10cycloalkyl or heterocyclyl, which is each optionally substituted with one to four R¹⁰;

each R^y1and R^y2is independently H, halo, C_1-6alkyl, C_1-6haloalkyl, wherein the alkyl and haloalkyl are each optionally substituted with oxo;

each R^3d, R^6b1, and R¹⁰is independently C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_2-6alkoxyalkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, C_3-10cycloalkyl, heterocyclyl, C_6-10aryl, heteroaryl, oxo, —OH, —CN, —NO₂, or —C(O)N(R^2a)(R^2b), wherein the heterocyclyl or heteroaryl is optionally substituted with C_1-6alkyl, C_1-6haloalkyl, or C_1-6haloalkoxy; and

each R^6a1, R^6a2, R^6c1, R^6c2, and R^6c3is independently H, C_1-6alkyl or C_3-10cycloalkyl;

each R^9aand R^9bis independently H, C_1-6alkyl, or C_1-6haloalkyl;

each Z¹is independently C_1-9alkyl, C_1-8haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_2-6alkoxyalkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, C_3-15cycloalkyl, heterocyclyl, C_6-10aryl, heteroaryl, oxo, —NO₂, —N₃, —CN, —O—R^12a, —C(O)—R^12a, —C(O)O—R^12a, —C(O)—N(R^12a)(R^12b), —N(R^12a)(R^12b), —N(R^12a)₂(R^12b)⁺, —N(R^12a)C(O)—R^12b, —N(R^12a)C(O)O—R^12b, —N(R^12a)C(O)N(R^12b)(R^12c), —N(R^12a)S(O)₂(R^12b), —NR^12aS(O)₂N(R^12b)(R^12c), —NR^12aS(O)₂O(R^12b), —OC(O)R^12a, —OC(O)OR^12a, —OC(O)—N(R^12a)(R^12b), —S—R^12a, —S(O)R^12a, —S(O)(NH)R^12a, —S(O)₂R^12a, —S(O)₂N(R^12a)(R^12b), —S(O)(NR^12a)R^12b, or —Si(R^12a)₃;

wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with one to four Z^1a;

each Z^1ais independently C_1-9alkyl, C_1-8haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_2-6alkoxyalkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, C_3-15cycloalkyl, heterocyclyl, C_6-10aryl, heteroaryl, oxo, —NO₂, —CN, —N₃, —O—R^12a, —C(O)R^12a, —C(O)O—R^12a, —C(O)N(R^12a)(R^12b), —N(R^12a)(R^12b), —N(R^12a)₂(R^12b)⁺, —N(R^12a)—C(O)R^12b, —N(R^12a)C(O)O(R^12b), —N(R^12a)C(O)N(R^12b)(R^12c), —N(R^12a)S(O)₂(R^12b), —N(R^12a)S(O)₂—N(R^12b)(R^12c), —N(R^12a)S(O)₂O(R^12b), —OC(O)R^12a, —OC(O)OR^12a, —OC(O)—N(R^12a)(R^12b), —S—R^12a, —S(O)R^12a, —S(O)(NH)R^12a, —S(O)₂R^12a, —S(O)₂N(R^12a)(R^12b), —S(O)(NR^12a)R^12b, or —Si (R^12a)₃;

wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with one to four Z^1b;

each R⁸or Z^1bis independently C_1-9alkyl, C_1-8haloalkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, C_3-15cycloalkyl, heterocyclyl, C_6-10aryl, heteroaryl, oxo, —OH, —CN, —NO₂, —NH₂, —N₃, —SH, —O(C_1-9alkyl), —O(C_1-8haloalkyl), —O(C_2-6alkenyl), —O(C_2-6alkynyl), —O(C_3-15cycloalkyl), —O(heterocyclyl), —O(C_6-10aryl), —O(heteroaryl), —NH(C_1-9alkyl), —NH(C_1-8haloalkyl), —NH(C_2-6alkenyl), —NH(C_2-6alkynyl), —NH(C_3-15cycloalkyl), —NH(heterocyclyl), —NH(C_6-10aryl), —NH(heteroaryl), —N(C_1-9alkyl)₂, —N(C_1-8haloalkyl)₂, —N(C_2-6alkenyl)₂, —N(C_2-6alkynyl)₂, —N(C_3-15cycloalkyl)₂, —N(heterocyclyl)₂, —N(C_6-10aryl)₂, —N(heteroaryl)₂, —N(C_1-9alkyl)(C_1-8haloalkyl), —N(C_1-9alkyl)(C_2-6alkenyl), —N(C_1-9alkyl)(C_2-6alkynyl), —N(C_1-9alkyl)(C_3-15cycloalkyl), —N(C_1-9alkyl)(heterocyclyl), —N(C_1-9alkyl)(C_6-10aryl), —N(C_1-9alkyl)(heteroaryl), —C(O)(C_1-9alkyl), —C(O)(C_1-8haloalkyl), —C(O)(C_2-6alkenyl), —C(O)(C_2-6alkynyl), —C(O)(C_3-15cycloalkyl), —C(O)(heterocyclyl), —C(O)(C_6-10aryl), —C(O)(heteroaryl), —C(O)O(C_1-9alkyl), —C(O)O(C_1-8haloalkyl), —C(O)O(C_2-6alkenyl), —C(O)O(C_2-6alkynyl), —C(O)O(C_3-15cycloalkyl), —C(O)O(heterocyclyl), —C(O)O(C_6-10aryl), —C(O)O(heteroaryl), —C(O)NH₂, —C(O)NH(C_1-9alkyl), —C(O)NH(C_1-8haloalkyl), —C(O)NH(C_2-6alkenyl), —C(O)NH(C_2-6alkynyl), —C(O)NH(C_3-15cycloalkyl), —C(O)NH(heterocyclyl), —C(O)NH(C_6-10aryl), —C(O)NH(heteroaryl), —C(O)N(C_1-9alkyl)₂, —C(O)N(C_1-8haloalkyl)₂, —C(O)N(C_2-6alkenyl)₂, —C(O)N(C_2-6alkynyl)₂, —C(O)N(C_3-15cycloalkyl)₂, —C(O)N(heterocyclyl)₂, —C(O)N(C_6-10aryl)₂, —C(O)N(heteroaryl)₂, —NHC(O)(C_1-9alkyl), —NHC(O)(C_1-8haloalkyl), —NHC(O)(C_2-6alkenyl), —NHC(O)(C_2-6alkynyl), —NHC(O)(C_3-15cycloalkyl), —NHC(O)(heterocyclyl), —NHC(O)(C_6-10aryl), —NHC(O)(heteroaryl), —NHC(O)O(C_1-9alkyl), —NHC(O)O(C_1-8haloalkyl), —NHC(O)O(C_2-6alkenyl), —NHC(O)O(C_2-6alkynyl), —NHC(O)O(C_3-15cycloalkyl), —NHC(O)O(heterocyclyl), —NHC(O)O(C_6-10aryl), —NHC(O)O(heteroaryl), —NHC(O)NH(C_1-9alkyl), —NHC(O)NH(C_1-8haloalkyl), —NHC(O)NH(C_2-6alkenyl), —NHC(O)NH(C_2-6alkynyl), —NHC(O)NH(C_3-15cycloalkyl), —NHC(O)NH(heterocyclyl), —NHC(O)NH(C_6-10aryl), —NHC(O)NH(heteroaryl), —NHS(O)(C_1-9alkyl), —N(C_1-9alkyl)S(O)(C_1-9alkyl), —S(C_1-9alkyl), —S(C_1-8haloalkyl), —S(C_2-6alkenyl), —S(C_2-6alkynyl), —S(C_3-15cycloalkyl), —S(heterocyclyl), —S(C_6-10aryl), —S(heteroaryl), —S(O)N(C_1-9alkyl)₂, —S(O)(C_1-9alkyl), —S(O)(C_1-8haloalkyl), —S(O)(C_2-6alkenyl), —S(O)(C_2-6alkynyl), —S(O)(C_3-15cycloalkyl), —S(O)(heterocyclyl), —S(O)(C_6-10aryl), —S(O)(heteroaryl), —S(O)₂(C_1-9alkyl), —S(O)₂(C_1-8haloalkyl), —S(O)₂(C_2-6alkenyl), —S(O)₂(C_2-6alkynyl), —S(O)₂(C_3-15cycloalkyl), —S(O)₂(heterocyclyl), —S(O)₂(C_6-10aryl), —S(O)₂(heteroaryl), —S(O)(NH) (C_1-9alkyl), —S(O)₂NH(C_1-9alkyl), or —S(O)₂N(C_1-9alkyl)₂;

wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl in each instance is optionally substituted with one to three C_1-9alkyl, C_1-8haloalkyl, halogen, —OH, —NH₂, —O(C_1-9alkyl), —O(C_1-8haloalkyl), —O(C_3-15cycloalkyl), —O(heterocyclyl), —O(aryl), —O(heteroaryl), —NH(C_1-9alkyl), —NH(C_1-8haloalkyl), —NH(C_3-15cycloalkyl), —NH(heterocyclyl), —NH(aryl), —NH(heteroaryl), —N(C_1-9alkyl)₂, —N(C_3-15cycloalkyl)₂, —NHC(O)(C_1-8haloalkyl), —NHC(O)(C_3-15cycloalkyl), —NHC(O)(heterocyclyl), —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)O(C_1-9alkyl), —NHC(O)O(C_1-8haloalkyl), —NHC(O)O(C_2-6alkynyl), —NHC(O)O(C_3-15cycloalkyl), —NHC(O)O(heterocyclyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl), —NHC(O)NH(C_1-9alkyl), S(O)₂(C_1-9alkyl), —S(O)₂(C_1-8haloalkyl), —S(O)₂(C_3-15cycloalkyl), —S(O)₂(heterocyclyl), —S(O)₂(aryl), —S(O)₂(heteroaryl), —S(O)(NH) (C_1-9alkyl), —S(O)₂NH(C_1-9alkyl), or —S(O)₂N (C_1-9alkyl)₂; and

each R^1b, R^1c, R^2a, R^2b, R^4a, R^4b, R^4c, R^9c, R^9d, R^12a, R^12b, and R^12cis independently H, C_1-9alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-15cycloalkyl, heterocyclyl, C_6-10aryl, or heteroaryl wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with one to four Z^1b;

wherein each heteroaryl has 5 to 12 ring members and has one to four heteroatoms each independently N, O, or S; and

wherein each heterocyclyl has 3 to 12 ring members and has one to four heteroatoms each independently N, O, or S.