US 11,878,965 B2
Inhibitors of peptidylarginine deiminases
Daniel H. Byun, Foster City, CA (US); Zhenhong R. Cai, Palo Alto, CA (US); Eda Y. Canales, San Mateo, CA (US); Laurent P. Debien, San Francisco, CA (US); Timothy R. Hansen, San Francisco, CA (US); Richard Huang, San Mateo, CA (US); Petr Jansa, Foster City, CA (US); Rick A. Lee, Livermore, CA (US); Jennifer A. Loyer-Drew, Seattle, WA (US); Ryan McFadden, Foster City, CA (US); Michael L. Mitchell, Castro Valley, CA (US); Hyung-Jung Pyun, Fremont, CA (US); Roland D. Saito, San Mateo, CA (US); Michael S. Sangi, San Mateo, CA (US); Adam J. Schrier, Redwood City, CA (US); Marina E. Shatskikh, Irvine, CA (US); James G. Taylor, Burlingame, CA (US); Joshua J. Van Veldhuizen, Seattle, WA (US); and Lianhong Xu, Palo Alto, CA (US)
Assigned to Gilead Sciences, Inc., Foster City, CA (US)
Filed by Gilead Sciences, Inc., Foster City, CA (US)
Filed on Dec. 21, 2021, as Appl. No. 17/557,860.
Claims priority of provisional application 63/129,416, filed on Dec. 22, 2020.
Prior Publication US 2023/0090053 A1, Mar. 23, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 401/04 (2006.01); A61K 31/437 (2006.01); A61K 31/454 (2006.01); A61K 31/501 (2006.01); A61K 31/506 (2006.01); A61K 31/5355 (2006.01); A61K 31/5383 (2006.01); A61K 45/06 (2006.01); C07D 401/14 (2006.01); C07D 519/00 (2006.01)
CPC C07D 401/04 (2013.01) [A61K 31/437 (2013.01); A61K 31/454 (2013.01); A61K 31/501 (2013.01); A61K 31/506 (2013.01); A61K 31/5355 (2013.01); A61K 31/5383 (2013.01); A61K 45/06 (2013.01); C07D 401/14 (2013.01); C07D 519/00 (2013.01)] 20 Claims
 
1. A compound of Formula I:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
X5 is N or C-R5;
X7 is N or C-R7;
R1 is hydrogen, halo, —CN, —OR12, —N(R12)2, —SR12, —C1-8 alkyl optionally substituted with 1 to 3 Z1,
C3-6 cycloalkyl optionally substituted with 1 to 3 Z1, or 4-6 membered heterocyclyl optionally substituted with 1 to 3 Z1;
R2 is hydrogen, halo, —CN, —OR12, —N(R12)2, —SR12, —C1-8 alkyl optionally substituted with 1 to 3 Z1,
C3-6 cycloalkyl optionally substituted with 1 to 3 Z1, or 4-6 membered heterocyclyl optionally substituted with 1 to 3 Z1;
R3 is hydrogen, C1-8 alkyl optionally substituted with 1 to 3 Z1, C3-10 alkenyl optionally substituted with 1 to 3 Z1, C3-10 alkynyl optionally substituted with 1 to 3 Z1, C3-10 cycloalkyl optionally substituted with 1 to 3 Z1, or 4-10 membered heterocyclyl optionally substituted with 1 to 3 Z1; or
R2 and R3 are taken together with the atoms to which they are attached to form an optionally substituted 6 to 8 membered heterocyclyl ring;
R4 is hydrogen, C1-8 alkyl optionally substituted with 1 to 3 Z1, C3-10 alkenyl optionally substituted with 1 to 3 Z1, C3-10 alkynyl optionally substituted with 1 to 3 Z1, C3-10 cycloalkyl optionally substituted with 1 to 3 Z′, or 4-10 membered heterocyclyl optionally substituted with 1 to 3 Z1;
R5 is hydrogen, halo, —CN, or —OR12;
R6 is

OG Complex Work Unit Chemistry
 where q is 0, 1 or 2, and
n is 0, 1, 2, 3, 4, 5, or 6;
R7 is hydrogen, halo, —CN, or —OR12;
R9 is C1-8 alkyl optionally substituted with 1 to 3 Z1, C2-8 alkenyl optionally substituted with 1 to 3 Z1, C2-8 alkynyl optionally substituted with 1 to 3 Z1, C3-10 cycloalkyl optionally substituted with 1 to 3 Z1, 4-10 membered heterocyclyl optionally substituted with 1 to 3 Z1, C6-10 aryl optionally substituted with 1 to 3 Z1, or 5-10 membered heteroaryl optionally substituted with 1 to 3 Z1;
R10 is hydrogen, C1-8 alkyl optionally substituted with 1 to 3 Z10, or C3-6 cycloalkyl optionally substituted with 1 to 3 Z10;
R11 is hydrogen, C1-8 alkyl optionally substituted with 1 to 4 Z10, C3-8 cycloalkyl optionally substituted with 1 to 4 Z10, or 4-12-membered heterocyclyl optionally substituted with 1 to 4 Z10; or
R10 and R11 are taken together with the nitrogen to which they are attached to form a 4-12-membered heterocyclyl optionally substituted with 1 to 4 Z10;
each R12 is independently hydrogen, C1-8 alkyl optionally substituted with 1 to 3 Z1b, C3-8 alkenyl optionally substituted with 1 to 3 Z1b, C3-8 alkynyl optionally substituted with 1 to 3 Z1b, C3-10 cycloalkyl optionally substituted with 1 to 3 Z1b, 4-10 membered heterocyclyl optionally substituted with 1 to 3 Z1b, C6-10 aryl optionally substituted with 1 to 3 Z1b, or 5-10 membered heteroaryl optionally substituted with 1 to 3 Z1b;
R13 is C1-8 alkyl optionally substituted with 1 to 3 Z1b, C3-8 alkenyl optionally substituted with 1 to 3 Z1b, C3-8 alkynyl optionally substituted with 1 to 3 Z1b, C3-10 cycloalkyl optionally substituted with 1 to 3 Z1b, 4-10 membered heterocyclyl optionally substituted with 1 to 3 Z1b, C6-10 aryl optionally substituted with 1 to 3 Z1b, or 5-10 membered heteroaryl optionally substituted with 1 to 3 Z1b;
R15 is C6-10 aryl optionally substituted with 1 to 3 Z1 or 5-10 membered heteroaryl optionally substituted with 1 to 3 Z1;
each R17 is independently hydrogen, halo, —NO2, —N3, —CN, C1-8 alkyl optionally substituted by 1 to 3 Z1a, C2-8 alkenyl optionally substituted by 1 to 3 Z1a, C2-8 alkynyl optionally substituted by 1 to 3 Z1a, C3-8 cycloalkyl optionally substituted by 1 to 3 Z1a, 6-10 membered aryl optionally substituted by 1 to 3 Z1a, 4-10 membered heterocyclyl optionally substituted by 1 to 3 Z1a, 5-10 membered heteroaryl optionally substituted with 1 to 3 Z1a, —OR20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —N(R20)2, —N(R20)3+, —N(R20)C(O)R20, —N(R20)C(O)OR20, —N(R20)C(O)N(R20)2, —N(R20)S(O)2(R20), —NR20S(O)2N(R20)2, —NR20S(O)2O(R20), —NS(O)(R20)2, —OC(O)R20, —OC(O)OR20, —OC(O)N(R20)2, —Si(R20)3, —SR20, —S(O)R20, —SF5, —S(O)(NR20)R20, —S(NR20)(NR20)R20, —S(O)(NR20)N(R20)2, —S(O)(NCN)R20, —S(O)2R20, —S(O)2N(R20)2, —C(O)N(R20)S(O)2R20, or —S(O)2N(R20)C(O)R20; or two R17 on the same or different carbon atoms are taken together to form a 3-8-membered ring optionally substituted with 1 to 4 Z1;
each R18 independently hydrogen, halo, —NO2, —N3, —CN, C1-8 alkyl optionally substituted by 1 to 3 Z1a, C2-8 alkenyl optionally substituted by 1 to 3 Z1a, C2-8 alkynyl optionally substituted by 1 to 3 Z1a, C3-8 cycloalkyl optionally substituted by 1 to 3 Z1a, 6-10 membered aryl optionally substituted by 1 to 3 Z1a, 4-10 membered heterocyclyl optionally substituted by 1 to 3 Z1a, 5-10 membered heteroaryl optionally substituted with 1 to 3 Z1a, —OR20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —N(R20)2, —N(R20)3+, —N(R20)C(O)R20, —N(R20)C(O)OR20, —N(R20)C(O)N(R20)2, —N(R20)S(O)2(R20), —NR20S(O)2N(R20)2, —NR20S(O)2O(R20), —NS(O)(R20)2, —OC(O)R20, —OC(O)OR20, —OC(O)N(R20)2, —Si(R20)3, —SR20, —S(O)R20, —SF5, —S(O)(NR20)R20, —S(NR20)(NR20)R20, —S(O)(NR20)N(R20)2, —S(O)(NCN)R20, —S(O)2R20, —S(O)2N(R20)2, —C(O)N(R20)S(O)2R20, or —S(O)2N(R20)C(O)R20;
each Z1 is independently halo, —NO2, —N3, —CN, C1-8 alkyl optionally substituted by 1 to 3 Z1a, C2-8 alkenyl optionally substituted by 1 to 3 Z1a, C2-8 alkynyl optionally substituted by 1 to 3 Z1a, C3-8 cycloalkyl optionally substituted by 1 to 3 Z1a, 6-10 membered aryl optionally substituted by 1 to 3 Z1a, 4-10 membered heterocyclyl optionally substituted by 1 to 3 Z1a, 5-10 membered heteroaryl optionally substituted with 1 to 3 Z1a, —OR20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —N(R20)2, —N(R20)3+, —N(R20)C(O)R20, —N(R20)C(O)OR20, —N(R20)C(O)N(R20)2, —N(R20)S(O)2(R20), —NR20S(O)2N(R20)2, —NR20S(O)2O(R20), —NS(O)(R20)2, —OC(O)R20, —OC(O)OR20, —OC(O)N(R20)2, —Si(R20)3, —S(O)R20, —SF5, —S(O)(NR20)R20, —S(NR20)(NR20)R20, —S(O)(NR20)N(R20)2, —S(O)(NCN)R20, —S(O)2R20, —S(O)2N(R20)2, —C(O)N(R20)S(O)2R20, or —S(O)2N(R20)C(O)R20;
each Z1a is independently oxo, halo, —NO2, —N3, —CN, C1-8 alkyl optionally substituted by 1 to 3 Z1b, C2-8 alkenyl optionally substituted by 1 to 3 Z1b, C2-8 alkynyl optionally substituted by 1 to 3 Z1b, C3-8 cycloalkyl optionally substituted by 1 to 3 Z1b, 6-10 membered aryl optionally substituted by 1 to 3 Z1b, 4-10 membered heterocyclyl optionally substituted by 1 to 3 Z1b, 5-10 membered heteroaryl optionally substituted with 1 to 3 Z1b, —OR21, —C(O)R21, —C(O)OR21, —C(O)N(R21)2, —N(R21)2, —N(R21)3+, —N(R21)C(O)R21, —N(R21)C(O)OR21, —N(R21)C(O)N(R21)2, —N(R21)S(O)2(R21), —NR21S(O)2N(R21)2, —NR21S(O)2O(R21), —NS(O)(R21)2, —OC(O)R21, —OC(O)OR21, —OC(O)N(R21)2, —Si(R21)3, —SR21, —S(O)R21, —SF5, —S(O)(NR21)R21, —S(NR21)(NR21)R21, —S(O)(NR21)N(R21)2, —S(O)(NCN)R21, —S(O)2R21, —S(O)2N(R21)2, —C(O)N(R21)S(O)2R21, or —S(O)2N(R21)C(O)R21;
each Z10 is independently selected from oxo, halo, —CN, C1-8 alkyl optionally substituted by 1 to 3 Z1b, C3-8 cycloalkyl optionally substituted by 1 to 3 Z1b, aryl optionally substituted by 1 to 3 Z1b, 4-10 membered heterocyclyl optionally substituted by 1 to 3 Z1b, 5-10 membered heteroaryl optionally substituted with 1 to 3 Z1b, —OR22, —C(O)R22, —C(O)OR22, —C(O)N(R22)2, —N(R22)2, —N(R22)3+, —N(R22)C(O)R22, —N(R22)C(O)OR22, —N(R22)C(O)N(R22)2, —N(R22)S(O)2R22, —OC(O)R22, —OC(O)OR22, —OC(O)—N(R22)2, and —S—R22; and
each R20, R21 and R22 is independently hydrogen, C1-8 alkyl optionally substituted with 1 to 3 Z1b, C2-8 alkenyl optionally substituted with 1 to 3 Z1b, C2-8 alkynyl optionally substituted with 1 to 3 Z1b, C3-10 cycloalkyl optionally substituted with 1 to 3 Z1b, 4-10 membered heterocyclyl optionally substituted with 1 to 3 Z1b, C6-10 aryl optionally substituted with 1 to 3 Z1b, or 5-10 membered heteroaryl optionally substituted with 1 to 3 Z1b;
each Z1b is independently oxo, hydroxy, halo, —NO2, —N3, —CN, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl heteroaryl, 4-10 membered heterocyclyl, —O(C1-9 alkyl), —O(C2-6 alkenyl), —O(C2-6 alkynyl), —O(C3-15 cycloalkyl), —O(C1-8 haloalkyl), —O(aryl), —O(heteroaryl), —O(heterocyclyl), —OC(O) (C1-9 alkyl), —OC(O)(C2-6 alkenyl), —OC(O)(C2-6 alkenyl), —OC(O)(C2-6 alkynyl), —OC(O)(C3-15 cycloalkyl), —OC(O)(C1-8 haloalkyl), —OC(O)(aryl), —OC(O)(heteroaryl), —OC(O)(heterocyclyl), —NH2, —NH(C1-9 alkyl), —NH(C2-6 alkenyl), —NH(C2-6 alkynyl), —NH(C3-15 cycloalkyl), —NH(C1-8 haloalkyl), —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C1-9 alkyl)2, —N(C3-15 cycloalkyl)2, —N(C2-6 alkenyl)2, —N(C2-6 alkynyl)2, —N(C3-15 cycloalkyl)2, —N(C1-8 haloalkyl)2, —N(aryl)2, —N(heteroaryl)2, —N(heterocyclyl)2, —N(C1-9 alkyl)(C3-15 cycloalkyl), —N(C1-9 alkyl)(C2-6 alkenyl), —N(C1-9 alkyl)(C2-6 alkynyl), —N(C1-9 alkyl)(C3-15 cycloalkyl), —N(C1-9 alkyl)(C1-8 haloalkyl), —N(C1-9 alkyl)(aryl), —N(C1-9 alkyl)(heteroaryl), —N(C1-9 alkyl)(heterocyclyl), —C(O)(C1-9 alkyl), —C(O)(C2-6 alkenyl), —C(O)(C2-6 alkynyl), —C(O)(C3-15 cycloalkyl), —C(O)(C1-8 haloalkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl), —C(O)O(C1-9 alkyl), —C(O)O(C2-6 alkenyl), —C(O)O(C2-6 alkynyl), —C(O)O(C3-15 cycloalkyl), —C(O)O(C1-8 haloalkyl), —C(O)O(aryl), —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH2, —C(O)NH(C1-9 alkyl), —C(O)NH(C2-6 alkenyl), —C(O)NH(C2-6 alkynyl), —C(O)NH(C3-15 cycloalkyl), —C(O)NH(C1-8 haloalkyl), —C(O)NH(aryl), —C(O)NH(heteroaryl), —C(O)NH(heterocyclyl), —C(O)N(C1-9 alkyl)2, —C(O)N(C3-15 cycloalkyl)2, —C(O)N(C2-6 alkenyl)2, —C(O)N(C2-6 alkynyl)2, —C(O)N(C1-8 haloalkyl)2, —C(O)N(aryl)2, —C(O)N(heteroaryl)2, —C(O)N(heterocyclyl)2, —NHC(O)(C1-9 alkyl), —NHC(O)(C2-6 alkenyl), —NHC(O)(C2-6 alkynyl), —NHC(O)(C3-15 cycloalkyl), —NHC(O)(C1-8 haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C1-9 alkyl), —NHC(O)O(C2-6 alkenyl), —NHC(O)O(C2-6 alkynyl), —NHC(O)O(C3-15 cycloalkyl), —NHC(O)O(C1-8 haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl), —NHC(O)NH(C1-9 alkyl), —NHC(O)NH(C2.6 alkenyl), —NHC(O)NH(C2-6 alkynyl), —NHC(O)NH(C3-15 cycloalkyl), —NHC(O)NH(C1-8 haloalkyl), —NHC(O)NH(aryl), —NHC(O)NH(heteroaryl), —NHC(O)NH(heterocyclyl), —SH, —S(C1-9 alkyl), —S(C2-6 alkenyl), —S(C2-6 alkynyl), —S(C3-15 cycloalkyl), —S(C1-8 haloalkyl), —S(aryl), —S(heteroaryl), —S(heterocyclyl), —NHS(O)(C1-9 alkyl), —N(C1-9 alkyl)(S(O)(C1-9 alkyl), —S(O)N(C1-9 alkyl)2, —S(O)(C1-9 alkyl), —S(O)(NH)(C1-9 alkyl), —S(O)(C2-6 alkenyl), —S(O)(C2-6 alkynyl), —S(O)(C3-15 cycloalkyl), —S(O)(C1-8 haloalkyl), —S(O)(aryl), —S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)2(C1-9 alkyl), —S(O)2(C2-6 alkenyl), —S(O)2(C2-6 alkynyl), —S(O)2(C3-15 cycloalkyl), —S(O)2(C1-8 haloalkyl), —S(O)2(aryl), —S(O)2(heteroaryl), —S(O)2(heterocyclyl), —S(O)2NH(C1-9 alkyl), or —S(O)2N(C1-9 alkyl)2;
wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of Z1b is optionally substituted with one or more halo, C1-9 alkyl, C1-8 haloalkyl, —OH, —NH2, —NH(C1-9 alkyl), —NH(C3-15 cycloalkyl), —NH(C1-8 haloalkyl), —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C1-9 alkyl)2, —N(C3-15 cycloalkyl)2, —NHC(O)(C3-15 cycloalkyl), —NHC(O)(C1-8 haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C1-9 alkyl), —NHC(O)O(C2-6 alkynyl), —NHC(O)O(C3-15 cycloalkyl), —NHC(O)O(C1-8 haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl), —NHC(O)NH(C1-9 alkyl), —S(O)(NH)(C1-9 alkyl), —S(O)2(C1-9 alkyl), —S(O)2(C3-15 cycloalkyl), —S(O)2(C1-8 haloalkyl), —S(O)2(aryl), —S(O)2(heteroaryl), —S(O)2(heterocyclyl), —S(O)2NH(C1-9 alkyl), —S(O)2N(C1-9 alkyl)2, —O(C3-15 cycloalkyl), —O(C1-8 haloalkyl), —O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C1-9 alkyl).