US 12,240,862 B2
Inhibitors of peptidylarginine deiminases
Daniel H. Byun, Foster City, CA (US); Eda Y. Canales, San Mateo, CA (US); Laurent P. Debien, San Francisco, CA (US); Petr Jansa, Foster City, CA (US); Rick A. Lee, Livermore, CA (US); Jennifer A. Loyer-Drew, Seattle, WA (US); Stephane Perreault, Brier, WA (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); Jennifer A. Treiberg, Redmond, WA (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. 17/558,130.
Claims priority of provisional application 63/129,421, filed on Dec. 22, 2020.
Prior Publication US 2022/0227787 A1, Jul. 21, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. A61P 35/02 (2006.01); C07D 519/00 (2006.01)
CPC C07D 519/00 (2013.01) 12 Claims
 
1. A compound of Formula I:

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or a pharmaceutically acceptable salt thereof, wherein:
X5 is N;
X7 is CH or CF;
R1 is hydrogen, or halo;
R2 is hydrogen, halo, —CN, —OR12, —N(R12)2, —SR12, —S(O)R20, C1-8 alkyl optionally substituted with 1 to 5 Z1, C3-6 cycloalkyl optionally substituted with 1 to 5 Z1, or 4-6 membered heterocyclyl optionally substituted with 1 to 5 Z1;
R3 is hydrogen, —N(R12)2, C1-8 alkyl optionally substituted with 1 to 5 Z1, C2-8 alkenyl optionally substituted with 1 to 5 Z1, C2-8 alkynyl optionally substituted with 1 to 5 Z1, C3-10 cycloalkyl optionally substituted with 1 to 5 Z1, or 4-10 membered heterocyclyl optionally substituted with 1 to 5 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 5 Z1, C6-10 aryl optionally substituted with 1 to 5 Z1, or 5-10 membered heteroaryl optionally substituted with 1 to 5 Z1;
R6 is —N(R14)S(O)2R9, —N(R14)C(O)OR9, —OC(O)R9, —OC(O)OR9, -L-R13, —OR15, C2-8 alkenyl optionally substituted with 1 to 5 Z1, C2-8 alkynyl optionally substituted with 1 to 5 Z1, C3-10 cycloalkyl substituted with 1 to 5 Z1, C6-10 aryl substituted with 1 to 5 Z1, 4-10 membered heterocyclyl substituted with 1 to 5 Z1,

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where q is 0, 1 or 2; and n is 0,1,2, 3, 4, 5, or 6;
R8 is hydrogen;
each R9 is independently C1-8 alkyl optionally substituted with 1 to 5 Z1, C2-8 alkenyl optionally substituted with 1 to 5 Z1, C2-8 alkynyl optionally substituted with 1 to 5 Z1, C3-10 cycloalkyl optionally substituted with 1 to 5 Z1, 4-10 membered heterocyclyl optionally substituted with 1 to 5 Z1, C6-10 aryl optionally substituted with 1 to 5 Z1, or 5-10 membered heteroaryl optionally substituted with 1 to 5 Z1;
the moiety

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each R12 is independently hydrogen, C1-8 alkyl optionally substituted with 1 to 5 Z1b, C3-8 alkenyl optionally substituted with 1 to 5 Z1b, C3-8 alkynyl optionally substituted with 1 to 5 Z1b, C3-10 cycloalkyl optionally substituted with 1 to 5 Z1b, 4-10 membered heterocyclyl optionally substituted with 1 to 5 Z1b, C6-10 aryl optionally substituted with 1 to 5 Z1b, or 5-10 membered heteroaryl optionally substituted with 1 to 5 Z1b;
L is C1-8 alkylene, C1-8 haloalkylene, or 5-10 membered heteroarylene; and each C1-8 alkylene, C1-8 haloalkylene, or 5-10 membered heteroarylene of L is optionally substituted with 1 to 5 Z1;
R13 is —OR15, —N(R15)(R14), —C(O)N(R14)2, —OC(O)N(R14)2, —N(R14)C(O)R9, —N(R14)C(O)OR9, —N(R14)C(O)N(R14)2, —N(R14)S(O)2R9, —NR14S(O)2N(R14)2, —NR14S(O)2OR9, —NS(O)(R9)2, —Si(R14)2R9, —SR9, —S(O)R9, —S(O)2R9, —SF5, —S(O)(NR14)R9, —S(NR14)(NR14)R9, —S(O)(NR14)N(R14)2, —S(O)(NCN)R9, —S(O)2N(R14)2, —C(O)N(R14)S(O)2R9, —S(O)2N(R14)C(O)R9, or C3-10 cycloalkyl substituted with 1 to 5 Z1;
each R14 is independently hydrogen, C1-8 alkyl optionally substituted with 1 to 5 Z1, C2-8 alkenyl optionally substituted with 1 to 5 Z1, C2-8 alkynyl optionally substituted with 1 to 5 Z1, C3-10 cycloalkyl optionally substituted with 1 to 5 Z1, 4-10 membered heterocyclyl optionally substituted with 1 to 5 Z1, C6-10 aryl optionally substituted with 1 to 5 Z1, or 5-10 membered heteroaryl optionally substituted with 1 to 5 Z1;
R15 is cycloalkyl optionally substituted with 1 to 5 Z1, 4-10 membered heterocyclyl optionally substituted with 1 to 5 Z1, C6-10 aryl optionally substituted with 1 to 5 Z1, 5-10 membered heteroaryl optionally substituted with 1 to 5 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 4Z1;
each Z1 is independently halo, —NO2, —N3, —CN, C1-8 alkyl optionally substituted by 1 to 5 Zia C2-8 alkenyl optionally substituted by 1 to 5 Z1a, C2-8 alkynyl optionally substituted by 1 to 5 Zia C3-10 cycloalkyl optionally substituted by 1 to 5 Z1a, 6-10 membered C6-10 aryl optionally substituted by 1 to 5 Z1a, 4-10 membered heterocyclyl optionally substituted by 1 to 5 Z1a, 5-10 membered heteroaryl optionally substituted with 1 to 5 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 Z1a is independently oxo, halo, —NO2, —N3, —CN, C1-8 alkyl optionally substituted by 1 to 5 Zlb, C2-8 alkenyl optionally substituted by 1 to 5 Z1b, C2-8 alkynyl optionally substituted by 1 to 5 Z1b, C3-10 cycloalkyl optionally substituted by 1 to 5 Z1b, 6-10 membered aryl optionally substituted by 1 to 5 Z1b, 4-10 membered heterocyclyl optionally substituted by 1 to 5 Z1b, 5-10 membered heteroaryl optionally substituted with 1 to 5 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 R20, R21 and R22 is independently hydrogen, C1-8 alkyl optionally substituted with 1 to 5 Z1b, C2-8 alkenyl optionally substituted with 1 to 5 Z1b, C2-8 alkynyl optionally substituted with 1 to 5 Z1b, C3-10 cycloalkyl optionally substituted with 1 to 5 Z1b, 4-10 membered heterocyclyl optionally substituted with 1 to 5 Z1b, C6-10 aryl optionally substituted with 1 to 5 Z1b, or 5-10 membered heteroaryl optionally substituted with 1 to 5 Z1b; and
each Z1b is independently oxo, hydroxy, halo, —NO2, —N3, —CN, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-8 haloalkyl, C60.1o aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, —O(C1-9 alkyl), —O(C2-6 alkenyl), —O(C2-6 alkynyl), —O(C3-10 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)(C3-10 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(C3-10 cycloalkyl), —NH(C1-8 haloalkyl), —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C1-9 alkyl)2, —N(C3-10 cycloalkyl)2, —N(C2-6 alkenyl)2, —N(C2-6 alkynyl)2, —N(C3-10 cycloalkyl)2, —N(C1-8 haloalkyl)2, —N(aryl)2, —N(heteroaryl)2, —N(heterocyclyl)2, —N(C1-9 alkyl)(C3-10 cycloalkyl), —N(C1-9 alkyl)(C2-6 alkenyl), —N(C1-9 alkyl)(C2-6 alkynyl), —N(C1-9 alkyl)(C3-10 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)(C3-10 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(C3-10 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(C3-10 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(C3-10 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)(C3-10 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(C3-10 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(C3-10 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(C3-10 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)(C3-10 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(C3-10 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(C3-10 cycloalkyl), —NH(C1-8 haloalkyl), —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C1-9 alkyl)2, —N(C3-10 cycloalkyl)2, —NHC(O)(C3-10 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(C3-10 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(C3-10 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(C3-10 cycloalkyl), —O(C1-8 haloalkyl), —O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C1-9 alkyl).