Gilead’s Patent Portfolio as a Map of Future Blockbusters

Gilead's Patent Portfolio as a Map of Future Blockbusters

An anovIP™ Industry White Paper on Anchor Patents, Platform Science & Long-Horizon Value Creation

Prepared by: anovIP™

Audience: CXOs • Investors • R&D Leaders • In-house IP Counsel • Strategy Teams

Executive Summary

This anovIP™ industry white paper analyzes how Gilead Sciences is systematically using anchor patents to architect its future blockbuster pipeline. Rather than protecting individual drug candidates, Gilead has focused on mechanism-level and platform-level patents that enable multiple products, indications, and lifecycle extensions across HIV, liver disease, antivirals, and immuno-oncology.

anovIP™ core insight:

Gilead's patents do not merely defend innovation—they pre-define future therapeutic markets.

anovIP™ Definition: Anchor Patents

An Anchor Patent, as defined by anovIP™, is IP that:
a) Controls a core biological or chemical control point
b) Enables multiple downstream assets
c) Supports combination therapy and lifecycle engineering
d) Is inherently difficult to design around

Such patents are the earliest predictors of future blockbuster drugs, often years before clinical or commercial validation.

Anchor Patent Cluster I

HIV Capsid Inhibitors

A New Therapeutic Modality for Treatment and Prevention

Key Anchor Patents

US 20200038389 – Capsid Inhibitors for the Treatment of HIV

Publication Number: US20200038389A1

Publication Date: February 6, 2020

Applicant: Gilead Sciences, Inc.

Abstract: or a pharmaceutically acceptable salt thereof, which are useful in the treatment of an HIV infection in heavily treatment-experienced patients with multidrug resistant HIV infection.

First Indepedendent Claim: 1. A method of treating human immunodeficiency virus (HIV) infection in a heavily treatment-experienced patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (Ia) or Formula (Ib):

or a pharmaceutically acceptable salt thereof.

US 20200030327 – Anti-HIV Compounds

Publication Number: US20200030327A1

Publication Date: January 30, 2020

Applicant: Gilead Sciences, Inc.

Abstract: The invention provides compounds having Formula (I): or a pharmaceutically acceptable salt thereof, as well as pharmaceutical compositions comprising the same, processes for their preparation, and methods of treating and preventing HIV infection by their administration.

First Indepedendent Claim: 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R1 is a 5 to 10-membered heterocycle having 1 to 5 heteroatoms selected from N, O, and S, or a 5 to 10-membered heteroaryl having 1 to 5 heteroatoms selected from N, O, and S, wherein the 5 to 10-membered heterocycle or 5 to 10-membered heteroaryl is optionally substituted with 1 to 5 Ra groups;

R2 and R3 are each independently C1-4 alkyl, C3-6 cycloalkyl, O—R2A, C1-2 alkyl-O—R2A, N—(R3A)2, or C1-2 alkyl-N—(R3A)2,

wherein each R2A is independently C1-4 alkyl, C3-6 cycloalkyl, or a 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S,

wherein each R3A is independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, or COO(Re), wherein each Re is independently hydrogen or C1-4 alkyl, and wherein each C3-6 cycloalkyl or 4 to 10-membered heterocyclyl is optionally substituted by 1 to 3 Rf groups, wherein each Rf is independently C1-2 alkyl or halogen;

R4 is hydrogen, halo, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkoxy, or C1-4 haloalkoxy;

R7 is hydrogen, halo, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkoxy, or C1-4 haloalkoxy;

R5, R6, R8, and R9 are each independently hydrogen, halo, C1-2 alkyl, C1-2 haloalkyl, or C3-6 cycloalkyl;

and wherein two or more of R4, R5 and R6 or two or more of R7, R8, and R9 optionally join together to form one or more C3-6 cycloalkyl groups that are optionally substituted with 1 to 4 groups selected from halogen, C1-2 alkyl, and C1-2 haloalkyl;

each R10 is independently halogen, cyano, C1-4 alkoxy, C1-6 alkyl, or C3-6 cycloalkyl;

n is 0 to 4;

each Ra is independently halogen, C1-4 alkyl, C1-4 alkyl with 1 to 2 groups selected from hydroxyl and C1-4 alkoxy, C1-4 haloalkyl, C1-4 alkoxy, C3-6 cycloalkyl, 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S which is optionally substituted with Ra1, or O—R3B,

wherein R3B is C3-6 cycloalkyl optionally substituted with Ra1 or a 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S optionally substituted with Ra1,

wherein each Ra1 is independently C1-4 alkyl, C3-6 cycloalkyl, C1-4 haloalkyl, or 4 to 8-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S;

A is ethynyl or a bond;

X1 is a 6 to 10-membered aryl or a 5 to 10-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein each 6 to 10-membered aryl or 5 to 10-membered heteroaryl is optionally substituted with 1 to 4 Rb groups;

X2 is hydrogen or a 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, wherein the 4 to 10-membered heterocyclyl is optionally substituted with one R11 and optionally substituted with 1 to 5 Rb groups;

R11 is —C?O(Rc), CH2(Rd), S(O)1-2(C1-4 alkyl), S(O)1-2—(C3-6 cycloalkyl), a 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, or a 5 to 9-membered heteroaryl having 1 to 5 heteroatoms selected from N, O, and S, wherein each 4 to 10-membered heterocyclyl or 5 to 9-membered heteroaryl is optionally substituted with 1 to 5 Rb groups;

each Rb is independently halogen, oxo, C1-4 alkyl, C1-4 alkyl with 1 to 2 groups selected from hydroxyl and C1-4 alkoxy, C1-4 haloalkyl, C1-4 alkoxy, or COO(Re);

Rc is C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, N(Re)2, C3-6 cycloalkyl, or a 4 to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the C3-6 cycloalkyl and the 4 to 6-membered heterocyclyl are optionally substituted by 1 to 5 Rb groups;

Rd is COO(Re), N(Re)2, C3-6 cycloalkyl, or a 4 to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the C3-6 cycloalkyl and the 4 to 6-membered heterocyclyl is optionally substituted by 1 to 5 Rb groups;

each R12 is C1-2 alkyl, halo, —OC1-2 alkyl, or cyano;

each p is 0 to 4;

R13 is —C(?O)Rg1, —C(?O)ORg2, or —P(?O)(ORh)2;

Rg1 is H, C1-6 alkyl, C3-6 cycloalkyl, or 5- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S;

wherein the C1-6 alkyl of Rg1 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halogen, C1-4 alkoxy, —N(Ri)2, —C1-4 alkyl-N(R1)2, —N(Ri)3 +, and 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the 4- to 6-membered heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halogen, C1-4 alkyl, C1-4 alkoxy, —N(Ri)2, and —C1-4 alkyl-N(Ri)2;

wherein the 5- to 6-membered heteroaryl and C3-6 cycloalkyl of Rg1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halogen, C1-6 alkyl, C1-4 alkoxy, —N(Ri)2, and —C1-4 alkyl-N(R1)2;

Rg2 is C1-6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halogen, C1-6 alkyl, C1-4 alkoxy, —N(Ri)2, —C1-4 alkyl-N(Ri)2, and —O—P(?O)(ORh)2; and

Rh and Ri are each independently selected from H and C1-3 alkyl.

US 20210188815 – Capsid Inhibitors for the Prevention of HIV

Publication Number: US20210188815A1

Publication Date: June 24, 2021

Applicant: Gilead Sciences, Inc.

Abstract: The present disclosure provides methods of preventing HIV in a subject, comprising administering to the subject a therapeutically effective amount of a compounds of Formula (Ia) or (Ib): or a pharmaceutically acceptable salt thereof, optionally in combination with one or more additional therapeutic agents. Methods of reducing the risk of acquiring HIV (e.g., HIV-1 and/or HIV-2) are also provided.

First Indepedendent Claim: 1. A method of preventing an HIV infection in a subject, comprising administering to the subject a compound of Formula (Ia)

or Formula (Ib): or a pharmaceutically acceptable salt thereof.

US 20230038823 – Capsid Inhibitors for the Treatment of HIV

Publication Number: US20230038823A1

Publication Date: February 9, 2023

Applicant: Gilead Sciences, Inc.

Abstract: The present disclosure relates generally to certain compounds, pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions. The compounds and compositions disclosed herein may be used for the treatment or prevention of a Retroviridae viral infection, including an infection caused by the HIV virus.

First Indepedendent Claim: 1. A compound of Formula I,

or a pharmaceutically acceptable salt thereof,

wherein

R2 and R3 are each independently H or C1-3 alkyl;

each R5 is halogen which may be the same or different;

R1 is H, —CN, halogen, C1-8 alkyl, C3-7 monocyclic cycloalkyl, —C(O)NR6R6, —NR6R6, —NR7C(O)R8, or —C(O)R8, wherein the C1-8 alkyl and C3-7 monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from —OH, halogen, —CN, and C1-4 alkoxy;

Ring B, together with the two carbons to which it is attached, forms a C3-7 monocyclic cycloalkyl, 5-9 membered fused or bridged bicyclic cycloalkyl, 3-4 membered monocyclic heterocyclyl, 5-7 membered monocyclic heterocyclyl, or 5-9 membered fused or bridged bicyclic heterocyclyl,

wherein the C3-7 monocyclic cycloalkyl, 5-9 membered fused or bridged bicyclic cycloalkyl, 3-7 membered monocyclic heterocyclyl, and 5-9 membered fused or bridged bicyclic heterocyclyl are each optionally substituted with 1-5 R16 groups,

wherein the 3-4 membered monocyclic heterocyclyl has 1-2 ring heteroatoms independently selected from N, O, and S, and

wherein the 5-7 membered monocyclic heterocyclyl and 5-9 membered fused or bridged bicyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S;

each R16 is independently oxo, —OH, halogen, —CN, C1-8 alkyl, C1-4 alkoxy, C3-7 monocyclic cycloalkyl, —C(O)NR6R6, —NR6R6, —NR6C(O)R8, or —C(O)R8, wherein the C1-8 alkyl and C3-7 monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from —OH, halogen, —CN, and C1-4 alkoxy;

R4 is a phenyl, 5-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, 9-12 membered fused or bridged tricyclic heterocyclyl, or 9-12 membered fused tricyclic heteroaryl,

wherein the phenyl, 5-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, 9-12 membered fused or bridged tricyclic heterocyclyl, and 9-12 membered fused tricyclic heteroaryl are each optionally substituted with 1-3 R4a groups, and

wherein the 5-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, 9-12 membered fused or bridged tricyclic heterocyclyl, and 9-12 membered fused tricyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S;

each R4a is independently oxo, —OH, halogen, —CN, C1-8 alkyl, C1-8 alkoxy, —NR6R6, —NR7S(O)2R9, —NR7S(O)2NR6R6, —NR7C(O)R8, —NRC(O)R10NR6R6, —NR7C(O)NR6R6, or —C(O)NR6R6, wherein the C1-8 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, —CN, and C1-4 alkoxy, or two R4a of the 1-3 R4a groups are attached to the same carbon and the two R4a, together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl;

each R6 is independently H, C1-8 alkyl, C3-7 monocyclic cycloalkyl, or 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein the C1-8 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, —CN, and C1-4 alkoxy, and

wherein the C3-7 monocyclic cycloalkyl and 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S are each optionally substituted with 1-3 groups independently selected from —OH, halogen, —CN, C1-4 alkyl, and C1-4 alkoxy; or

both R6, together with the nitrogen to which they are attached, form a 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S;

each R7 is independently H or C1-8 alkyl which may be the same or different, wherein the C1-8 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, —CN, and C1-4 alkoxy;

each R8 is independently —OH, C1-8 alkyl, C1-8 alkoxy, C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 4-6 membered monocyclic heteroaryl,

wherein the C1-8 alkyl and C1-8 alkoxy are each optionally substituted with 1-3 groups independently selected from —OH, halogen, —CN, and C1-4 alkoxy,

wherein the C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 4-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from —OH, halogen, —CN, C1-4 alkyl, and C1-4 alkoxy, and

wherein the 4-6 membered monocyclic heterocyclyl and 4-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S;

each R9 is independently C1-8 alkyl, C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl,

wherein the C1-8 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, —CN, and C1-4 alkoxy,

wherein the C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from —OH, halogen, —CN, C1-4 alkyl, and C1-4 alkoxy, and

wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S;

each R10 is C1-4 alkylene, which may be the same or different;

Ring A, together with the two carbons to which it is attached, forms a 5-6 membered monocyclic heterocyclyl or 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each substituted with one Z group and each have 1-3 ring heteroatoms independently selected from N, O, and S;

Z is

i) oxo,

ii) —OH,

iii) —CN,

iv) C1-5 alkyl, wherein the C1-8 alkyl is substituted with one group selected from —OH and C1-4 alkoxy, and wherein the C1-8 alkyl is optionally further substituted with 1-2 groups independently selected from —OH, halogen, and —CN,

v) C6-8 alkyl, wherein the C6-8 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, —CN, and C1-4 alkoxy,

vi) —Z1-Z2—Z3—Z4,

wherein Z1 is C2-6 alkynylene optionally substituted with 1-3 groups independently selected from —OH, halogen, —CN, and C1-4 alkoxy,

wherein Z2 and Z3 are each independently C3-7 monocyclic cycloalkylene, C6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, or 7-10 membered spirocyclic heterocyclylene, wherein the C3-7 monocyclic cycloalkylene, C6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, and 7-10 membered spirocyclic heterocyclylene are each optionally substituted with 1-3 groups independently selected from —OH, halogen, —CN, C1-4 alkyl, C1-4 alkoxy, and —C(O)R8, and wherein the 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, and 7-10 membered spirocyclic heterocyclylene each have 1-3 ring heteroatoms independently selected from N, O, and S, and

wherein Z4 is a C3-7 monocyclic cycloalkyl, C6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the C3-7 monocyclic cycloalkyl, C6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from —OH, halogen, —CN, C1-4 alkyl, C1-4 alkoxy, and —C(O)R8, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S,

vii) C3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from —OH, halogen, —CN, C1-4 alkyl, and C1-4 alkoxy,

viii) —S(C1-8 alkyl), wherein the C1-8 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, —CN, and C1-4 alkoxy,

ix) —NR11R12, wherein one of R11 and R12 is H or C1-8 alkyl and the other of R11 and R12 is C1-8 alkyl, C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein each C1-8 alkyl is substituted with 1-3 R17 groups, wherein the C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from oxo, —OH, halogen, —CN, C1-4 alkyl, and C1-4 alkoxy, and

wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S,

x) C6-10 monocyclic or fused bicyclic aryl optionally substituted with 1-3 groups independently selected from —OH, halogen, —CN, C1-4 alkyl, C1-4 alkoxy, —C(O)NR6R6, —C(O)R8, —NR6R6, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl,

wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from —OH, halogen, —CN, C1-4 alkyl, C1-4 alkoxy, —C(O)NR6R6, —C(O)R8, and —NR6R6, and

wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S,

xi) 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R13 groups,

xii) 8-10 membered fused or bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R13 groups,

xiii) 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R13 groups,

xiv) 8-10 membered fused bicyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R13 groups, or

xv) 7-10 membered spirocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R13 groups;

each R17 is independently —OH, halogen, —CN, C1-4 alkoxy, —NR6R6, C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl,

wherein the C1-4 alkoxy, C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from oxo, —OH, halogen, —CN, C1-4 alkyl, and C1-4 alkoxy, and

wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S;

each R13 is independently oxo, —OH, halogen, —CN, C1-4 alkyl, C1-4 alkoxy, —NR6R6, —C(O)R10NR6R6, —C(O)NR6R6, —C(O)R8, C6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl,

wherein the C6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 R14 groups, and

wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S;

each R14 is independently halogen, C1-4 alkyl, —C(O)R8, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl,

wherein the C1-4 alkyl is optionally substituted with 1-3 groups independently selected from —OH, halogen, CN, and C1-4 alkoxy, and

wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with —OR10Si(R15)3;

wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S;

each R15 is independently C1-3 alkyl, which may be the same or different; and

n is 0, 1, 2, or 3.

anovIP™ Assessment

These patents anchor a novel HIV modality that intervenes at multiple lifecycle stages—viral assembly, disassembly, and nuclear transport. The claims span chemical scaffolds, pharmaceutical compositions, and methods of treatment and prevention, allowing Gilead to dominate both therapy and PrEP markets.

Blockbuster Vector

anovIP™ Verdict:

This cluster is a multi-decade HIV franchise anchor, not a single-drug play.

Anchor Patent Cluster II

NASH & Metabolic Liver Disease

Owning Combination-Driven Chronic Care

Key Anchor Patents

US 20190248807 – COT Modulators and Methods of Use Thereof

Publication Number: US20190248807A1

Publication Date: August 15, 2019

Applicant: Gilead Sciences, Inc.

Abstract: The present disclosure relates generally to modulators of Cot (cancer Osaka thyroid) and methods of use and manufacture thereof.

First Indepedendent Claim: 1. A compound of formula (A):

US 20190308962 – FXR (NR1H4) Modulating Compounds

Publication Number: US20190308962A1

Publication Date: October 10, 2019

Applicant: Gilead Sciences, Inc.

Abstract: The present disclosure relates generally to compounds (I) which bind to the NR1H4 receptor (FXR) and act as agonists of FXR. The disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of said nuclear receptor by said compounds and to a process for the synthesis of said compounds.

First Indepedendent Claim: 1. A compound according to Formula (I):

wherein:

Q is phenylene or pyridylene, each of which is optionally substituted with one or two substituents independently selected from halogen, methyl, C1-4-alkoxy, halo-C1-4-alkoxy, —CH2F, —CHF2, and —CF3;

Y is N or CH;

A is pyridylene or phenylene, each of which is optionally substituted with one or two groups independently selected from halogen, C1-4-alkoxy, halo-C1-4-alkoxy, C1-4-alkyl, and halo-C1-4-alkyl;

Z is isoxazole substituted with R1 or pyrazole substituted with R1;

R1 is C1-4-alkyl or C3-6-cycloalkyl, wherein

said C1-4-alkyl is optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxyl, C1-3-alkoxy, and fluoro-C1-3-alkoxy, and

said C3-6-cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxyl, C1-3-alkyl, fluoro-C1-3-alkyl, C1-3-alkoxy, and fluoro-C1-3-alkoxy;

R2 and R3 are independently selected from hydrogen, halogen, methoxy, —CF3, —CHF2, —CH2F, —OCH2F, —OCHF2, —OCF3, and methyl;

R4 is —CO2R5 or —C(O)NR5R6;

R5 is hydrogen, C1-6-alkyl, or halo-C1-6-alkyl; and

R6 is hydrogen or C1-6-alkyl, wherein said C1-6-alkyl is optionally substituted with 1 to 6 substituents independently selected from halogen, —SO3H, and —CO2H;

or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.

US 20220047678 – Combination Therapy for Treatment of Liver Disease

Publication Number: US20220047678A1

Publication Date: February 17, 2022

Applicant: Gilead Sciences, Inc.

Abstract: The present disclosure relates to a method of treating non-alcoholic steatohepatitis (NASH) comprising administering to a subject with NASH a combination therapy comprising semaglutide, firsocostat, and/or cilofexor.

First Indepedendent Claim: 1. A method of treating non-alcoholic steatohepatitis (NASH), comprising administering to a subject with NASH in need of such treatment:

a) semaglutide at a dose of 0.1-3 mg once weekly; and

b) firsocostat at a dose of 15-25 mg once daily.

US 20240066016 – Methods of Treating NASH

Publication Number: US20240066016A1

Publication Date: February 29, 2024

Applicant: Gilead Sciences, Inc.

Abstract: The present disclosure relates generally to methods of using modulators of COT (cancer Osaka thyroid) for treating, stabilizing, or lessening the severity or progression of liver disease, in particular, Nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).

First Indepedendent Claim: 1. A method for treating, stabilizing, or lessening the severity or progression of non-alcoholic steatohepatitis (NASH) in a subject, the method comprising administering to a subject in need thereof, an effective amount of a compound which inhibits COT (cancer Osaka thyroid).

US 20240307502 – Combination Therapy for Treatment of Liver Disease

Publication Number: US20240307502A1

Publication Date: September 19, 2024

Applicant: Gilead Sciences, Inc.

Abstract: The present disclosure relates to a method of treating non-alcoholic steatohepatitis (NASH) comprising administering to a subject with NASH a combination therapy comprising semaglutide, firsocostat, and/or cilofexor.

First Indepedendent Claim: 1. A method of treating non-alcoholic steatohepatitis (NASH), comprising administering to a subject with cirrhosis (F4) due to NASH and in need of such treatment:

a) semaglutide at a dose of 0.1-3 mg once weekly; and

b) firsocostat at a dose of 15-25 mg once daily.

anovIP™ Assessment

Unlike competitors pursuing monotherapies, Gilead has patented the logic of combination therapy itself—including GLP-1 modulation, FXR agonism, ACC inhibition, and COT pathway control. These filings explicitly acknowledge NASH as a systems disease, positioning Gilead to own treatment architecture, not just ingredients.

Blockbuster Vector

anovIP™ Verdict:

This cluster represents one of the strongest long-term metabolic disease IP moats in pharma.

Anchor Patent Cluster III

Broad-Spectrum Antiviral Small Molecules

Reusable Chemical Platforms for Viral Control

Key Anchor Patents

US 20230365511 – Antiviral Pyrazolopyridinone Compounds

Publication Number: US20230365511A1

Publication Date: November 16, 2023

Applicant: Gilead Sciences, Inc.

Abstract: The invention provides compounds of Formula (I) as described herein, along with pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods to use these compounds, salts and compositions for treating viral infections, particularly infections caused by herpesviruses.

First Indepedendent Claim: 1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof,

wherein:

X is

a 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members, a 5-6 membered heterocycloalkyl containing 1 to 4 ring members independently selected from N, NH, NR

17, O or S or a 5-6 membered heterocyclyl containing 1 to 4 ring members independently selected from N, NH, NR17, O or S;

Y is a bond,

O- or

wherein the * of Y indicates the point of attachment to X and the ** of Y indicates the point of attachment to R

B;

q is 1;

LMC is *—((CR11R12)nO)m(CR11R12)p—**, *—

C(?O)NR15((CR11R12)nO)m(CR11R12)p—**, *—

(CR11R12)nNR15((CR11R12)nO)m(CR11R12)p—**, *—(CR11R12)n—**, *—

((CR11R12)nNR15)m(CR11R12)p—**, *—(CR11R12)C(?O)NR15(CR11R12)n—**, *

—C(?O)NR15(CR11R12)n—**, *—O(CR11R12)n—**, or *—NR15(CR11R12)n—**,

wherein the * of LMC indicates the point of attachment to Z and the ** of LMC indicates the point of attachment to A;

A is a bond and Z is

wherein the * of Z indicates the point of attachment to L MC and the ** of Z indicates the point of attachment to L;

m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

each n is independently selected from 1, 2, 3, 4, 5, 7, 8, 9 and 10;

p is 1, 2, 3, 4, 5 or 6;

RB is H, C1-C6alkyl, phenyl, pyridinyl, thiophenyl, pyrimidinyl, or a 5-8 membered cycloalkyl, wherein RB is optionally substituted with 1 to 3 R5 groups;

R1 is selected from H, C1-C3alkyl and C1-C3alkyl substituted with 1 to 3 —OH groups;

R2 is selected from H, C1-C3alkyl and C1-C3alkyl substituted with 1 to 3 —OH groups;

or R1 and R2 taken together with the carbon to which they are attached can form a 3-6 membered cycloalkyl ring;

t is 0, 1 or 2;

each R3, when present, is a substituent on the ring to which -L-Z is directly attached, wherein each R3 is independently selected from halo, CN, C1-C3alkoxy, C1-C3alkyl, C(?O)OR10, and C(?O)NR13R14;

each R5 is independently selected from halo, —CN, hydroxy, -NR13R14, C3-C6cycloalkyl, C1-C3alkoxy, C1-C3haloalkyl, and C1-C3alkyl optionally substituted with 1 to 3 R6 groups, wherein when RB is substituted with two R5 and each R5 is a C1-C3alkyl optionally substituted with 1 to 3 R6 groups, when directly attached to the same carbon atom, may be taken together with the carbon to which both are directly attached to form a 3-5 membered cycloalkyl ring optionally substituted with 1 to 3 R6 groups;

each R6 is independently selected from halo, hydroxy, CN, C1-C3alkoxy, C1-C3alkyl, and C3- C5cycloalkyl,

or two R6 groups, taken together with a carbon atom to which both are directly attached may form a 3-5 membered cycloalkyl ring or a 4-6 membered heterocyclic ring containing O, N or S as a ring member and optionally substituted with 1 to 2 groups independently selected from oxo and C1-C3alkyl;

L is a C1-C4 straight chain or branched alkylene linker

R10 is selected from C1-C5alkyl, C1-C3haloalkyl, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members, 4-6 membered heterocycloalkyl containing one or two ring members independently selected from N, NH, NR17, O or S and 4-6 membered heterocyclyl containing 1 to 2 ring members independently selected from N, NH, NR17, O or S, wherein each R10 is optionally substituted with 1 to 5 groups independently selected from C1-C4alkyl, deuterium, C1-C4haloalkoxy, —L3OH, —L3CN, —L3OC(?O)R14, —L3OR13, C1-C2haloalkyl, oxo, -L3halo, -L3C1-C3alkoxy, —L3OC(?O)NR13R14, —L3SO2R13, —L3SO2NR13R14, —L3SO2NR13C(?O)R13, —L3C(?O)NR13SO2R13, —L3S(?O)R13, —L3S(?O)(?NR14)R13, —L3NR13SO2NR13R14, —L3NR13SO2R13, —L3NR13R14, —L3NR14C(?O)R13, —L3NR14C(?O)OR13, —L3C(?O)NR13R14, —L3C(?O)OR13, -L3-(4-7-membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR17, O or S), -L3-(4-7-membered heterocyclyl containing 1 to 2 ring members independently selected from N, NH, NR17, O or S), -L3-C3- C5cycloalkyl, and -L3-(5-6 membered heteroaryl ring having 1 to 4 heteroatoms comprising 1-4 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms as ring members), where the C1-C4alkyl, 4-7-membered heterocycloalkyl, 4-7-membered heterocyclyl, C3-C5cycloalkyl and 5-6 membered heteroaryl ring are each optionally further substituted with 1 to 3 groups independently selected from halo, C1-C3alkyl, C1-C3haloalkyl, -L4OR13, —L4CN, and -L4NR13R14;

R11 and R12 are each independently selected from H and C1-C4alkyl;

each R13 is independently selected from H, C1-C4alkyl, a 4-7-membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR17, O or S, a 4-7-membered heterocyclyl containing 1 to 2 ring members independently selected from N, NH, NR17, O or S, and a C3-C6cycloalkyl, wherein the C1-C4alkyl, heterocyclyl and C3- C6cycloalkyl are optionally substituted with 1 to 3 groups independently selected from C1-C4alkyl, halo, —OH, -NR15R16, —C(?O)OR15, C1-C2alkoxy and C1-C4alkyl substituted with 1 to 2 hydroxy groups;

R14 is selected from H, C1-C4alkyl and C3-C6cycloalkyl, wherein the C1-C4alkyl and C3- C6cycloalkyl are optionally substituted with 1 to 3 groups independently selected from C1-C4alkyl, halo, —OH, -NR15R16, C1-C2alkoxy and C1-C4alkyl substituted with 1 to 2 hydroxy groups; or

R13 and R14, taken together with a nitrogen atom to which both are directly attached, can form a 4-6 membered ring optionally containing an additional N, O or S as a ring member and optionally substituted with one to three groups selected from C1-C2alkyl, C1- C2alkoxy, oxo, and hydroxy;

R15 and R16 are each independently selected from H and C1-C4alkyl;

each R17 is independently selected from H, C1-C4alkyl and C3-C8cycloalkyl,

or R17 is C1-C4alkyl which, together with a nitrogen atom to which it is directly attached and a nitrogen atom from the pyrazole ring, can form a 5-8 membered ring fused to the pyrazole ring;

each L3 and L4 is independently a bond or a straight chain or branched C1-C3alkylene; and

represents a single or double bond.

US 20250353820 – Antiviral Pyrazolopyridinone Compounds

Publication Number: US20250353820A1

Publication Date: November 20, 2025

Applicant: Gilead Sciences, Inc.

Abstract: The invention provides compounds of Formula (I) as described herein, along with pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods to use these compounds, salts and compositions for treating viral infections, particularly infections caused by herpesviruses.

First Indepedendent Claim: 1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof,

wherein:

X is

a 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members, or a saturated or partially saturated 5-6 membered heterocyclyl containing 1 to 4 ring members independently selected from N, NH, NR17, O or S;

Y is a bond,

—O— or

wherein the * of Y indicates the point of attachment to X and the ** of Y indicates the point of attachment to RB;

q is 0;

LMC is absent, and Z is W, and A is R4;

RB is phenyl, pyridinyl, thiophenyl, pyrimidinyl, or a 5-8 membered cycloalkyl, wherein RB is optionally substituted with 1 to 3 R5 groups;

R1 is selected from H, C1-C3alkyl and C1-C3alkyl substituted with 1 to 3-OH groups;

R2 is selected from H, C1-C3alkyl and C1-C3alkyl substituted with 1 to 3-OH groups;

or R1 and R2 taken together with the carbon to which they are attached can form a 3-6 membered cycloalkyl ring;

t is 0, 1 or 2;

each R3, when present, is a substituent on the ring to which-L-W is directly attached, wherein each R3 is independently selected from halo, CN, C1-C3alkoxy, C1-C3alkyl, C(?O)OR10, and C(?O)NR13R14;

R4 is selected from the group consisting of (CH2)2—O(CH2)2—OH and (CH2)2—O—(CH2)2—NH2;

each R5 is independently selected from halo, —CN, hydroxy, —NR13R14, C3-C6cycloalkyl, C1-C3alkoxy, C1-C3haloalkyl, and C1-C3alkyl optionally substituted with 1 to 3 R6 groups, wherein when RB is substituted with two R5 and each R5 is a C1-C3alkyl optionally substituted with 1 to 3 R6 groups, when directly attached to the same carbon atom, may be taken together with the carbon to which both are directly attached to form a 3-5 membered cycloalkyl ring optionally substituted with 1 to 3 R6 groups;

each R6 is independently selected at each occurrence from halo, hydroxy, CN, C1-C3alkoxy, C1-C3alkyl, and C3-C5cycloalkyl,

or two R6 groups, taken together with a carbon atom to which both are directly attached may form a 3-5 membered cycloalkyl ring or a 4-6 membered heterocyclic ring containing O, N or S as a ring member and optionally substituted with 1 to 2 groups independently selected from oxo and C1-C3alkyl;

L is a C1-C4 straight chain or branched alkylene linker, or L can be a C1-C4 straight chain or branched alkylene linker or a bond when W is an optionally substituted ring;

W is H, —OH, —OR10, —C(?O)NR13R14, —C(?O)OR13, —NR13R14, —NR13C(?O)OR10, —NR13C(?O)R10, —SO2R10, —SO2NR13R14, —NR13SO2R10, —P (?O) (OR13)2, —S(?O)R10, —S(?O) (?NR13)R10, —CR11R12C(?O)NR13R14, —CR11R12C(?O)OR13, —CR11R12NR13R14, —CR11R12NR13C(?O)OR10, —CR11R12NR13C(?O)R10, —CR11R12SO2R10, —CR11R12SO2NR13R14, —CR11R12NR13SO2R10, —CR11R12P (?O) (OR13)2, —CR11R12S(?O)R10, —CR11R12S(?O) (?NR13)R10, a 3-6 membered cycloalkyl, phenyl, a saturated or partially saturated 5-6-membered heterocyclyl containing one or two ring members independently selected from N, NH, NR17, O or S, or a 5-membered heteroaryl having 1 to 4 heteroatoms selected from N, O and S as ring members that is optionally fused to phenyl,

wherein the 3-6 membered cycloalkyl, phenyl, saturated or partially saturated 5-6-membered heterocyclyl and 5-membered heteroaryl of W are each optionally substituted with 1 to 3 groups independently selected from C1-C3alkyl, oxo, halo, C1-C3haloalkyl, —OH, —OR10, —OC(?O)NR13R14, —SO2R10, —SO2NR14R10, —SO2NR13R14, —SO2N?CR13NR13R14, —SO2NR13C(?O)R10, —C(?O)NR13SO2R10, —S(?O)R10, —S(?O) (?NR13)R10, —NR13502NR13R14, —NR13SO2R10, —NR13R14, —NR13C(?O)R13, —NR13C(?O)OR10, —C(?O)NR13R14, and —C(?O)OR13;

R10 is selected from C1-C5alkyl, C1-C3haloalkyl, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members, and saturated or partially saturated 4-6 membered heterocyclyl containing 1 to 2 ring members independently selected from N, NH, NR17, O or S,

wherein each R10 is optionally substituted with 1 to 5 groups independently selected from C1-C4alkyl, deuterium, C1-C4haloalkoxy, —OH, —CN, —OC(?O)R14, -L3OR13, C1-C2haloalkyl, oxo, -halo, —C1-C3alkoxy, —OC(?O)NR13R14, —SO 2R13, —SO2NR13R14, —SO2NR13C(?O)R13,—C(?O)NR13SO2R13, —S(?O)R13, —S(?O) (?NR14)R13, —NR13SO2NR13R14, —NR13SO2R13, —NR13R14, —NR14C(?O)R13, —NR14C(?O)OR13, —C(?O)NR13R14, —C(?O)OR13, (saturated or partially saturated 4-7-membered heterocyclyl containing 1 to 2 ring members independently selected from N, NH, NR17, O or S), —C3-C5cycloalkyl, and (5-6 membered heteroaryl ring having 1 to 4 heteroatoms comprising 1-4 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms as ring members), where the C1-C4alkyl, saturated or partially saturated 4-7-membered heterocyclyl, C3-C5cycloalkyl and 5-6 membered heteroaryl ring are each optionally further substituted with 1 to 3 groups independently selected from halo, C1-C3alkyl, C1-Chaloalkyl, —OR13, —CN, and —NR13R14;

R11 and R12 are each independently selected from H and C1-C4alkyl;

each R13 is independently selected from H, C1-C4alkyl, a saturated or partially saturated 4-7-membered heterocyclyl containing 1 to 2 ring members independently selected from N, NH, NR17, O or S, and a C3-C6cycloalkyl, wherein the C1-C4alkyl, the saturated or partially saturated 4-7 membered heterocyclyl, and the C3-C6cycloalkyl are optionally substituted with 1 to 3 groups independently selected from C1-C4alkyl, halo, —OH, —NR15R16, —C(?O)OR15, C1-C2alkoxy and C1-C4alkyl substituted with 1 to 2 hydroxy groups;

R14 is selected from H, C1-C4alkyl and C3-C6cycloalkyl, wherein the C1-C4alkyl and C3-C6cycloalkyl are optionally substituted with 1 to 3 groups independently selected from C1-C4alkyl, halo, —OH, —NR15R16, C1-C2alkoxy and C1-C4alkyl substituted with 1 to 2 hydroxy groups;

or R13 and R14, taken together with a nitrogen atom to which both are directly attached, can form a 4-6 membered ring optionally containing an additional N, O or S as a ring member and optionally substituted with one to three groups selected from C1-C2alkyl, C1-C2alkoxy, oxo, and hydroxy;

R15 and R16 are each independently selected from H and C1-C4alkyl;

each R17 is independently selected from H, C1-C4alkyl and C3-C8cycloalkyl,

or R17 is C1-C4alkyl which, together with a nitrogen atom to which it is directly attached and a nitrogen atom from the pyrazole ring, can form a 5-8 membered ring fused to the pyrazole ring;

L3 is a bond or a straight chain or branched C1-C3alkylene; and

'' represents a single or double bond.

anovIP™ Assessment

These patents protect a repeatable antiviral chemical scaffold applicable across viral families, particularly herpesviruses. By securing composition-of-matter and method-of-use claims, Gilead gains optionality—the ability to rapidly pivot these compounds toward new or emerging viral threats.

Blockbuster Vector

anovIP™ Verdict:

This is platform IP, capable of spawning multiple mid-to-large revenue products over time.

Anchor Patent Cluster IV

Immuno-Oncology & Immune Modulation

Precision Control Beyond Antibodies

Key Anchor Patents

US 20210053946 – PD-1 / PD-L1 Inhibitors

Publication Number: US20210053946A1

Publication Date: February 25, 2021

Applicant: Gilead Sciences, Inc.

Abstract: Compounds of Formula (I), methods of using said compounds singly or in combination with additional agents and compositions of said compounds for the treatment of cancer are disclosed.

First Indepedendent Claim: 1. A compound of Formula (I):

wherein:

each n is independently 0, 1, 2, 3 or 4;

each Z1 is independently halo, —ORa, —NO2, —CN, —NRaRb, —N3, —S(O)2Ra, —C2-6 alkyl, —C2-6 haloalkyl, —C2-6 alkenyl, —C2-6 alkynyl, —O—C2-6 alkyl, —O—C2-6haloalkyl, —C3-8 cycloalkyl or —C2-6 alkylC3-8 cycloalkyl; wherein each alkyl, alkenyl, alkynyl, and cycloalkyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, —NO2, —N3, —ORa, halo, and cyano;

Q is aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl and heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of halo, oxo, —ORa, —SRa, N3, NO2, —CN, —NR1R2, —S(O)2Ra, —S(O)2NRaRb, —NRaS(O)2Ra, —NRaC(O)Ra, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —NRaC(O)ORa, —NRaC(O)NR1R2, —O—C(O)NRaRb, —NRaS(O)2NRaRb, —C(O)NRaS(O)2NRaRb, —C1-6 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, —O—C1-6 alkyl, —C3-8 cycloalkyl, —C1-6 alkylC3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl and RN;

wherein the alkyl, alkenyl, alkynyl, C3-8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, —NO2, N3, —ORa, halo, cyano, —NRaRb, —C(O)Ra, —C(O)ORa, —O—C1-6 alkylCN, —C(O)NRaRb, NRaC(O)Ra, —NRaC(O)ORa, —S(O)2Ra, —NRaS(O)2Rb, —S(O)2NRaRb, —NRaS(O)2NRaRb, —C(O)NRaS(O)2NRaRb and —C3-8 cycloalkyl; and wherein the heteroaryl or heterocyclyl group may be oxidized on a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to form a sulfoxide or sulfone; m is 0, 1 or 2;

each Z3 is independently halo, oxo, —ORa, SRa, N3, NO2, —CN, —NR1R2, —S(O)2Ra, —S(O)2NRaRb, —NRaS(O)2Ra, —NRaC(O)Ra, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —NRaC(O)ORa, —NRaC(O)NR1R2, —O—C(O)NRaRb, —NRaS(O)2NRaRb, —C(O)NRaS(O)2NRaRb, —C2-6 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, —O—C2-6 alkyl, —C3-5 cycloalkyl, —C2-6 alkylC3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl and RN;

wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, —NO2, N3, —ORa, halo, cyano, —NRaRb, —C(O)Ra, —C(O)ORa, —O—C2-6 alkylCN, —C(O)NRaRb, NRaC(O)Ra, —NRaC(O)ORa, —S(O)2Ra, —NRaS(O)2Rb, —S(O)2NRaRb, —NRaS(O)2NRaRb, —C(O)NRaS(O)2NRaRb and —C3-8 cycloalkyl;

each RN is independently —C2-6 alkylNR1R2, —O—C2-6 alkylNR1R2, —C2-6 alkylOC2-6 alkylNR1R2, —NRa—C2-6 alkylNR1R2, —C2-6 alkylC(O)NR1R2, —O—C2-6 alkylC(O)NR1R2, —O—C2-6 alkylC(O)OR1, —S—C2-6 alkylNR1R2, —C2-6 alkylORa, or

wherein

L1 is independently a bond, O, NRa, S, S(O), or S(O)2;

V is independently selected from the group consisting of a bond, C1-6 alkyl, C2-6 alkenyl, and C2-6alkynyl;

wherein the alkyl, alkenyl or alkynyl group is optionally independently substituted with —ORa, halo, cyano, NRaRb and —C3-8 cycloalkyl;

L2 is independently a bond, O, NRa, S, S(O), or S(O)2;

ring A is independently cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, —NO2, N3, —ORa, halo, cyano, —C2-6 alkyl, —C2-6 haloalkyl, —C2-6 alkenyl, —C2-6 alkynyl, —O—C2-6 haloalkyl, NRaRb, —C(O)Ra, —C(O)ORa, —O—C2-6 alkylCN, —C(O)NRaRb, —NRaC(O)Ra, —NRaC(O)ORa, —NRaC(O)ORa, —C(O)N(Ra)ORb, —S(O)2Ra, —S(O)2NRaRb, —NRaS(O)2Rb, —NRaS(O)2NRaRb, —C(O)NRaS(O)2NRaRb, C3-8 cycloalkyl and C2-6 alkylC3-8 cycloalkyl;

wherein the alkyl, alkenyl or alkynyl group is optionally independently substituted with —ORa, halo, cyano, NRaRb and —C3-5 cycloalkyl;

RE and RW are each independently —NR1R2, —C1-6 alkylNR1R2, —O—C1-6 alkylNR1R2, —C2-6 alkylOC1-6 alkylNR1R2, —NRa—C1-6 alkylNR1R2, —C1-6 alkylN+R1R2R3, —S—C1-6 alkylNR1R2, —C(O)NR1R2, —S(O)2Ra, —(CH2)uS(O)2NR1R2, —(CH2)uNRaS(O)2NRaRb, —S(O)2NRaC1-6 alkylNR1R2, —NRaS(O)2C1-6 alkylNR1R2, —(CH2)uC(O)NRaS(O)2NRaRb, —(CH2)uN+R1R2O?, —(CH2)uP+RbRcRd, —(CH2)uP+RcRdO?, —(CH2)uP+O[NRaRb][NRcRd], —(CH2)uNRcP(O)(ORc)2, —(CH2)uCH2OP(O)(ORc)(ORd), —(CH2)uOP(O)(ORc)(ORd), —(CH2)uOP(O)NRaRb)(ORa), or

wherein:

V2 is independently a bond, O, NRa, S, S(O), S(O)2, C(O)NRa, NRaC(O), S(O)2NR1, or NRaS(O)2;

L3 is independently a bond, O, NRa, S, S(O), S(O)2, C(O)NRa, NRaC(O), S(O)2NR1, or NRaS(O)2;

ring B is cycloalkyl, aryl, heteroaryl or heterocyclyl;

T is independently H, —ORa, (CH2)qNR1R2, (CH2)qNRaC(O)Re or (CH2)qC(O)Re;

p is independently 0, 1, 2, 3, 4, or 5;

q is independently 0, 1, 2, 3, 4, or 5;

u is 0, 1, 2, 3 or 4;

z is 0, 1, 2 or 3; and

wherein the alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group of RE and RW is optionally substituted with 1 to 3 substituents independently selected from the group consisting of NRaRb, halo, cyano, oxo, —ORa, —C2-6 alkyl, —C2-6haloalkyl, —C2-6 cyanoalkyl, —C2-6 alkylNRaRb, —C2-6 alkylOH, —C3-8 cycloalkyl and —C1-3 alkylC3-8 cycloalkyl;

provided that at least one of V2, L3, ring B and T contains a nitrogen atom;

each R1 is independently selected from the group consisting of H, —C1-6 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, —C3-6cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, —C1-6 alkylheterocyclyl, —C1-6 alkylC(O)ORa, —C2-6 alkenylC(O)ORa, —S(O)2Ra, —S(O)2ORa, —S(O)2NRaRb, —C(O)NRaS(O)2Ra, and C1-6 alkylC3-8 cycloalkyl;

wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of —ORa, —CN, —NO2, halo, C1-6 alkyl, —C1-6 alkylORa, —C1-6 cyanoalkyl, —C1-6 haloalkyl, C3-8 cycloalkyl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C(O)Ra, —C1-6 alkylC(O)Ra, —C(O)ORa, —C1-6 alkylC(O)ORa, —NRaRb, —OC(O)NRaRb, —NRaC(O)ORb, —NRaC(O)Rb, —C1-6 alkylNRaRh, —C(O)NRaRb, —C1-6 alkylC(O)NRaRb, —S(O)2Ra, —S(O)2ORa, —C1-6 alkylS(O)2Ra, —S(O)2NRaRb, —C1-6 alkylS(O)2NRaRb, —C(O)NRaS(O)2Rb, —NRaC(O)NRb, —C1-6 alkylC(O)NRaS(O)2Rb, —NRaC(O)Rb, and —C1-6 alkylNRaC(O)Rb;

each R2 is independently selected from the group consisting of H, —C1-6 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, —C3-6cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, —C1-6 alkylheterocyclyl, —C2-6 alkyl-ORa, —C1-6 alkylC(O)ORa, and —C2-6 alkenylC(O)ORa;

wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of —ORa, —CN, halo, C1-6 alkyl, —C1-6 alkylORa, —C1-6 cyanoalkyl, —C1-6haloalkyl, —C3-5 cycloalkyl, —C1-3 alkylC3-8 cycloalkyl, —C(O)Ra, —C1-6 alkylC(O)Ra, —C(O)ORa, —C1-6 alkylC(O)ORa, —NRaRb, —C1-6 alkylNRaRb, —C(O)NRaRb, C1-6 alkylC(O)NRaRb, —S(O)2Ra, —C1-6 alkylS(O)2Ra, —S(O)2NRaRb, —C1-6 alkylS(O)2NRaRb, —C(O)NRaS(O)2Rb and —NRaC(O)Rb;

or R1 and R2 combine to form a heterocyclyl group optionally containing 1, 2, or 3 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 to 3 groups independently selected from the group consisting of oxo, —C2-6 alkyl, —C3-8 cycloalkyl, —C2-6 alkenyl, —C2-6 alkynyl, aryl, heteroaryl, heterocyclyl, —ORa, —CN, halo, —C(O)ORa, —C2-6 cyanoalkyl, —C2-6 alkylORa, —C2-6haloalkyl, —C1-3 alkylC3-8 cycloalkyl, —C(O)Ra, C2-6 alkylC(O)Ra, —C2-6 alkylC(O)ORa,

—NRaRb, —C2-6 alkylNRaRb, —C(O)NRaRb, —NRaC(O)ORb, —NRaC(O)NRaRb, —NRaS(O)2NRaRb, —NRaS(O)2Rb, —C2-6 alkylC(O)NRaRb, —S(O)2Ra, —C2-6 alkylS(O)2Ra, —S(O)2NRaRb, and C2-6 alkylS(O)2NRaRb;

each R3 is independently H, —C2-6 alkyl, —C2-6 alkenyl, —C3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C2-6 alkylaryl, —C2-6 alkylheteroaryl, —C2-6 alkylheterocyclyl, —C2-6 alkyl-ORa, —C2-6 alkylC(O)ORa, or —C2-6 alkenylC(O)ORa;

each Ra is independently selected from the group consisting of H, —C1-6 alkyl, —C1-6 haloalkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl;

each Rb is independently selected from the group consisting of H, —C1-6 alkyl, —C1-6 haloalkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl;

or Ra and Rb may combine together to form a ring consisting of 3-8 ring atoms that are C, N, O, or S; wherein the ring is optionally substituted with 1 to 4 groups independently selected from the group consisting of —ORf, —CN, halo, —C1-6 alkylORf, —C1-6 cyanoalkyl, —C1-6 haloalkyl, —C3-5 cycloalkyl, —C1-3 alkylC3-8 cycloalkyl, —C(O)Rf, —C1-6 alkylC(O)Rf, —C(O)ORf, —C1-6 alkylC(O)ORf, —NRfRg, —C1-6 alkylNRfRg, —C(O)NRfRg, C1-6 alkylC(O)NRfRg, —S(O)2Rf, —C1-6 alkylS(O)2Rf, —S(O)2NRfRg, —C1-6 alkylS(O)2NRfRg, —C(O)NRfS(O)2Rg and —NRfC(O)Rg;

each Rc is independently selected from the group consisting of H, OH, —C1-6 alkyl, —C3-5 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl;

each Rd is independently selected from the group consisting of H, —C2-6 alkyl, —C3-C8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C2-6 alkylaryl, —C2-6 alkylheteroaryl, and —C2-6 alkylheterocyclyl;

each Re is independently selected from the group consisting of H, —C2-6 alkyl, —O—C2-6 alkyl, —C3-5 cycloalkyl, aryl, heteroaryl, heterocyclyl, —O—C3-5 cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C2-6 alkylaryl, —C2-6 alkylheteroaryl, —NRfRg, —C2-6 alkylNRfRg, —C(O)NRfRg, —C2-6 alkylC(O)NRfRg, —NHS(O)2Rf, —C2-6 alkylS(O)2Rf, and —C2-6 alkylS(O)2NRfRg;

each Rf is independently selected from the group consisting of H, —C2-6 alkyl, —C3-5 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C2-6 alkylaryl, —C2-6 alkylheteroaryl, and —C2-6 alkylheterocyclyl;

each Rg is independently selected from the group consisting of H, —C2-6 alkyl, —C3-5 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C2-6 alkylaryl, —C2-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl; or a pharmaceutically acceptable salt thereof.

US 20210323922 – PD-1 / PD-L1 Inhibitors

Publication Number: US20210323922A1

Publication Date: October 21, 2021

Applicant: Gilead Sciences, Inc.

Abstract: Compounds according to formula (I), methods of using said compounds singly or in combination with additional agents and compositions of said compounds for the treatment of cancer are disclosed.

First Indepedendent Claim: 7. A compound of formula (VIII):

Figure US20210323922A1-20211021-C01016

wherein:

each of X4 and X5 are independently N, CH or CZ3;

each Z1 is independently is halo, —ORa, —NO2, —CN, —NRaRb, —N3, —SO2Ra, —C1-6 alkyl, —C1-6 haloalkyl, —C2-6alkenyl, —C2-6 alkynyl, —O—C1-6 alkyl, —O—C1-6haloalkyl, —C3-8 cycloalkyl, or —C1-6 alkyl-C3-8 cycloalkyl; and

wherein each alkyl, alkenyl, alkynyl, and cycloalkyl is optionally substituted with 1 to 4 groups independently selected from oxo, —NO2, —N3, —ORa, halo, and cyano;

each w is independently 0, 1 or 2;

each Z3 is independently halo, —ORa, —N3, —NO2, —CN, —NR1R2, —SO2Ra, —SO2NRaRb, —NRaSO2Ra, —NRaC(O)Ra, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —NRaC(O)ORa, —NRaC(O)NR1R2, —OC(O)NRaRb, —NRaSO2NRaRb, —C(O)NRaSO2NRaRb, —C1-6 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, —O—C1-6 alkyl, —C3-8 cycloalkyl, —C1-6 alkylC3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, and RN; and

wherein the alkyl, alkenyl, alkynyl, C3-8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from oxo, —NO2, —N3, —ORa, halo, cyano, —NRaRb, —C(O)Ra, —C(O)ORa, —O—C1-6cyanoalkyl, —C(O)NRaRb, NRaC(O)Ra, —NRaC(O)ORa, —SO2Ra, —NRaSO2Rb, —SO2NRaRb, —NRaSO2NRaRb, —C(O)NRaSO2NRaRb and —C3-8 cycloalkyl;

RN is independently-C1-6 alkylNR1R2, —O—C1-6 alkylNR1R2, —C1-6 alkylOC1-6 alkylNR1R2, —NRaC1-6 alkylNR1R2, —C1-6 alkylC(O)NR1R2, —O—C1-6 alkylC(O)NR1R2, —O—C1-6 alkylC(O)OR1, —SC1-6 alkylNR1R2, —C1-6 alkylORa, or

Figure US20210323922A1-20211021-C01017

wherein: L1 is independently a bond, O, NRa, S, SO, or SO2;

V is independently selected from a bond, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl;

wherein each alkyl, alkenyl, or alkynyl is optionally independently substituted with ORa, halo, cyano, —NRaRb or —C3-8 cycloalkyl;

L2 is independently a bond, O, NRa, S, SO, or SO2;

ring A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;

wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from oxo, —NO2, —N3, —ORa, halo, cyano, —C1-6 alkyl, —C1-6 haloalkyl, —C2-6alkenyl, —C2-6 alkynyl, —O—C1-6haloalkyl, NRaRb, —C(O)Ra, —C(O)ORa, —O—C1-6 alkyCN, —C(O)NRaRb, —NRaC(O)Ra, —NRaC(O)ORa, —NRaC(O)ORa, —C(O)N(Ra)ORb, —SO2Ra, —SO2NRaRb, —NRaSO2Rb, —NRaSO2NRaRb, —C(O)NRaSO2NRaRb, C3-8cycloalkyl, and C1-6alkylC3-s cycloalkyl; and

wherein the alkyl, alkenyl, or alkynyl group is optionally independently substituted with —ORa, halo, cyano, —NRaRb or —C3-8 cycloalkyl;

each t is independently 0, 1 or 2;

RE and RW are each independently —NR1R2, —C1-6 alkylNR1R2, —O—C1-6 alkylNR1R2, —C1-6 alkylOC1-6alkylNR1R2, —NRa—C1-6 alkylNR1R2, —C1-6 alkylN+R1R2R3, —S—C1-6 alkyNR1R2, —C(O)NR1R2, —SO2Ra, —(CH2)uSO2NR1R2, —(CH2)uNRa—SO2NRaRb, —SO2NRa—C1-6 alkyNR1R2, —NRaSO2—C1-6 alkylNR1R2, —(CH2)uC(O)NRaSO2NRaRb, —(CH2)uN+R1R2O—, —(CH2)uP+RbRcRd, —(CH2)uP+RcRdO?, —(CH2)uP+O[NRaRb][NRcRd], —(CH2)uNRcP(O)(ORc)2, —(CH2)uCH2OP(O)(ORc)(ORd), —(CH2)uOP(O)(ORc)(ORd), —(CH2)uOP(O)NRaRb)(ORa), or

Figure US20210323922A1-20211021-C01018

wherein:

V2 is independently a bond, O, NRa, S, SO, SO2, C(O)NRa, NRaC(O), SO2NR1, or NRaSO2;

L3 is independently a bond, O, NRa, S, SO, SO2, C(O)NRa, NRaC(O), SO2NR1, or NRaSO2;

ring B is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;

T is independently H, ORa, (CH2)qNR1R2, (CH2)qNRaC(O)Re, or (CH2)qC(O)Re;

p is independently 0, 1, 2, 3, 4, or 5;

q is independently 0, 1, 2, 3, 4, or 5;

u is 0, 1, 2, 3, or 4;

z is 0, 1, 2, or 3; and

wherein the alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of RE or RW is optionally substituted with 1 to 3 substituents independently selected from the group consisting of NRaRb, halo, cyano, oxo, ORa, —C1-6 alkyl, —C1-6 haloalkyl, —C1-6 cyanoalkyl, —C1-6 alkylNRaRb, —C1-6 alkylOH, —C3-8 cycloalkyl, and —C1-3 alkyC3-8cycloalkyl;

provided that at least one of V2, L3, ring B and T contains a nitrogen atom;

each R1 is independently selected from H, —C1-8 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, —C3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, —C1-6 alkylheterocyclyl, —C1-6 alkylC(O)ORa, —C2-6 alkenylC(O)ORa, —SO2Ra, —SO2NRaRb, —C(O)NRaSO2Ra, and C1-6 alkylC3-8cycloalkyl;

wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from —ORa, —CN, halo, C1-6alkyl, —C1-6 alkylORa, —C1-6 cyanoalkyl, —C1-6 haloalkyl, C3-8 cycloalkyl, —C1-3 alkylC3-8cycloalkyl, —C(O)Ra, —C1-6 alkylC(O)Ra, —C(O)ORa, —C1-6 alkylC(O)ORa, —NRaR, —OC(O)NRaRb, NRaC(O)ORb, —C1-6 alkylNRaRb, —C(O)NRaRb, —C1-6 alkylC(O)NRaRb, —SO2Ra, —C1-6 alkylSO2Ra, —SO2NRaRb, —C1-6 alkylSO2NRaRb, —C(O)NRaSO2Rb, —C1-6 alkylC(O)NRaSO2Rb, —NRaC(O)Rb, and —C1-6alkylNRaC(O)Rb;

each R2 is independently selected from H, —C1-6 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, —C3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, —C1-6 alkylheterocyclyl, —C2-6 alkyl-ORa, —C1-6 alkylC(O)ORa, and —C2-6 alkenylC(O)ORa;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from —ORa, —CN, halo, C1-6alkyl, —C1-6 alkylORa, —C1-6 cyanoalkyl, —C1-6 haloalkyl, —C3-8 cycloalkyl, —C1-3 alkylC3-8cycloalkyl, —C(O)Ra, —C1-6 alkylC(O)Ra, —C(O)ORa, —C1-6 alkylC(O)ORa, —NRaRb, —C1-6 alkylNRaRb, —C(O)NRaRb, C1-6 alkylC(O)NRaRb, —SO2Ra, —C1-6 alkylSO2Ra, —SO2NRaRb, —C1-6 alkylSO2NRaRb, —C(O)NRaSO2R1 and —NRaC(O)Rb;

or R1 and R2 combine to form a heterocyclyl group optionally containing 1, 2, or 3 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 to 3 groups independently selected from oxo, —C1-6 alkyl, —C3-8 cycloalkyl, —C2-6 alkenyl, —C2-6 alkynyl, —ORa, —C(O)ORa, —C1-6 cyanoalkyl, —C1-6 alkylORa, —C1-6 haloalkyl, —C1-3 alkylC3-8cycloalkyl, —C(O)Ra, C1-6 alkylC(O)Ra, —C1-6 alkylC(O)ORa, —NRaRb, —C1-6alkylNRaRb, —C(O)NRaRb, —C1-6 alkylC(O)NRaRb, —SO2Ra, —C1-6 alkylSO2Ra, —SO2NRaRb, and C1-6 alkylSO2NRaRb;

each R3 is independently H, —C1-6 alkyl, —C2-6 alkenyl, —C3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, —C1-6 alkylheterocyclyl, —C2-6 alkyl-ORa, —C1-6 alkylC(O)ORa, or —C2-6 alkenylC(O)ORa;

each Ra is independently selected from H, —C1-6 alkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6alkylheterocyclyl;

each Rb is independently selected from H, —C1-6 alkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl;

or Ra and Rb may combine together to form a ring consisting of 3-8 ring atoms that are C, N, O, or S; wherein the ring is optionally substituted with 1 to 4 groups independently selected from —ORf, —CN, halo, —C1-6 alkylORf, —C1-6 cyanoalkyl, —C1-6 haloalkyl, —C3-8 cycloalkyl, —C1-3 alkylC3-8cycloalkyl, —C(O)Rf, —C1-6 alkylC(O)Rf, —C(O)ORf, —C1-6 alkylC(O)ORf, —NRfRg, —C1-6 alkylNRfRg, —C(O)NRfRg, —C1-6 alkylC(O)NRfRg, —SO2Rf, —C1-6 alkylSO2Rf, —SO2NRfRg, —C1-6 alkylSO2NRfRg, —C(O)NRfSO2Rg and —NRfC(O)Rg;

each Rc is independently selected from H, OH, —C1-6 alkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl;

Rd is independently selected from H, —C1-6 alkyl, —C3-C8cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl;

each Re is independently selected from H, —C1-6 alkyl, —O—C1-6alkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —O—C3-8 cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —C1-3 alkylC3-8cycloalkyl, —C1-6 alkylaryl, —C1-6alkylheteroaryl, —NRfRg, —C1-6 alkylNRfRg, —C(O)NRfRg, —C1-6 alkylC(O)NRfRg, —NHSO2Rf, —C1-6 alkylSO2Rf, and —C1-6 alkylSO2NRfRg;

each Rf is independently selected from H, —C1-6 alkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl; and

each Rg is independently selected from H, —C1-6 alkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl;

or a pharmaceutically acceptable salt thereof.

US 20230242508 – IKAROS Zinc Finger Family Degraders and Uses Thereof

Publication Number: US20230242508A1

Publication Date: August 3, 2023

Applicant: Gilead Sciences, Inc.

Abstract: The present disclosure relates generally to compounds that bind to and act as degraders of an IKAROS Family Zink Finger (IKZF) protein, such as IKZF2 (Helios) and/or IKZF4 (Eos). The disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding and degradation of an IKZF protein, such as IKZF2 and/or IKZF4, including cancer.

First Indepedendent Claim: 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

R4 is H, F, or Cl;

R5 is H, F, or Cl;

R7 is H;

R1 is H, C1-6 alkyl, C1-6haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, —C(O)N(R1b)(R1c), —C(O)R1b, or —C(O)OR1c,

wherein the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R1 is each optionally substituted with one to four Z1, which may be the same or different;

R2 is H, C1-6 alkyl, C1-6haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, —C(O)N(R2b)(R2c), —C(O)R2b, or —C(O)OR2c, —S(O)2R2b,

wherein the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R2 is each optionally substituted with one to four Z2, which may be the same or different; or

or R1 and R2 together with the nitrogen to which they are attached form a heterocyclyl, which is optionally substituted with one to four Z4, which may be the same or different; wherein the heterocyclyl formed by R1 and R2 is 3 to 20 membered heterocyclyl having 0-3 additional heteroatoms each independently N, O or S;

R3 is H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, —C(O)N(R3b)(R3c), —C(O)R3b, or —C(O)OR3c, —S(O)2R3b,

wherein the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R3 is each optionally substituted with one to four Z3, which may be the same or different;

each R6 is independently C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, halogen, —OH, ?O, or —NH2; or two R6 together with the atoms or the atom to which they are attached form a C3-10 cycloalkyl or a heterocyclyl, wherein the cycloalkyl or the heterocyclyl is each optionally substituted with one to four R6a, which may be the same or different; each R6a is independently C1-9 alkyl or halogen;

each Z1, Z2, Z3, or Z4 is independently C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, —NO2, —N3, —CN, —O—R12a, —C(O)—R12a, —C(O)O—R12a, —C(O)—N(R12a)(R12b), —N(R12a)(R12b), —N(R12a)2(R12b)+, —N(R12a)C(O)—R12b, —N(R12a)C(O)O—R12b, —N(R12a)C(O)N(R12b)(R12c), —N(R12a)S(O)2(R12b), —NR12aS(O)2N(R12b)(R12c), —NR12aS(O)2O(R12b), —OC(O)R12a, —OC(O)OR12a, —OC(O)—N(R12a)(R12b), —S—R12a, —S(O)R12a, —S(O)(NH)R12a, —S(O)2R12a, —S(O)2N(R12a)(R12b), —S(O)(NR12a)R12b, or —Si(R12a)3;

wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each Z1, Z2, Z3, or Z4 is each optionally substituted with one to four Z1a, which may be the same or different;

each Z1a is independently C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, —NO2, —CN, —N3, —O—R12a, —C(O)R12a, —C(O)O—R12a, —C(O)N(R12a)(R12b), —N(R12a)(R12b), —N(R12a)2(R12b)+, —N(R12a)—C(O)R12b, —N(R12a)C(O)O(R12b), —N(R12a)C(O)N(R12b)(R12c), —N(R12a)S(O)2(R12b), —N(R12a)S(O)2—N(R12b)(R12c), —N(R12a)S(O)2O(R12b), —OC(O)R12a, —OC(O)OR12a, —OC(O)—N(R12a)(R12b), —S—R12a, —S(O)R12a, —S(O)(NH)R12a, —S(O)2R12a, —S(O)2N(R12a)(R12b), —S(O)(NR12a)R12b, or —Si(R12a)3;

wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1a is each optionally substituted with one to four Z1b, which may be the same or different;

each Z1b is independently C1-9 alkyl, C1-8 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, —OH, —CN, —NO2, —NH2, —N3, —SH, —O(C1-9 alkyl), —O(C1-8 haloalkyl), —O(C2-6 alkenyl), —O(C2-6 alkynyl), —O(C3-15 cycloalkyl), —O(heterocyclyl), —O(C6-10 aryl), —O(heteroaryl), —NH(C1-9 alkyl), —NH(C1-8 haloalkyl), —NH(C2-6 alkenyl), —NH(C2-6 alkynyl), —NH(C3-15 cycloalkyl), —NH(heterocyclyl), —NH(C6-10 aryl), —NH(heteroaryl), —N(C1-9 alkyl)2, —N(C1-8 haloalkyl)2, —N(C2-6 alkenyl)2, —N(C2-6 alkynyl)2, —N(C3-15 cycloalkyl)2, —N(heterocyclyl)2, —N(C6-10 aryl)2, —N(heteroaryl)2, —N(C1-9 alkyl)(C1-8 haloalkyl), —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)(heterocyclyl), —N(C1-9 alkyl)(C6-10 aryl), —N(C1-9 alkyl)(heteroaryl), —C(O)(C1-9 alkyl), —C(O)(C1-8 haloalkyl), —C(O)(C2-6 alkenyl), —C(O)(C2-6 alkynyl), —C(O)(C3-15 cycloalkyl), —C(O)(heterocyclyl), —C(O)(C6-10 aryl), —C(O)(heteroaryl), —C(O)O(C1-9 alkyl), —C(O)O(C1-8 haloalkyl), —C(O)O(C2-6 alkenyl), —C(O)O(C2-6 alkynyl), —C(O)O(C3-15 cycloalkyl), —C(O)O(heterocyclyl), —C(O)O(C6-10 aryl), —C(O)O(heteroaryl), —C(O)NH2, —C(O)NH(C1-9 alkyl), —C(O)NH(C1-8 haloalkyl), —C(O)NH(C2-6 alkenyl), —C(O)NH(C2-6 alkynyl), —C(O)NH(C3-15 cycloalkyl), —C(O)NH(heterocyclyl), —C(O)NH(C6-10 aryl), —C(O)NH(heteroaryl), —C(O)N(C1-9 alkyl)2, —C(O)N(C1-8 haloalkyl)2, —C(O)N(C2-6 alkenyl)2, —C(O)N(C2-6 alkynyl)2, —C(O)N(C3-15 cycloalkyl)2, —C(O)N(heterocyclyl)2, —C(O)N(C6-10 aryl)2, —C(O)N(heteroaryl)2, —NHC(O)(C1-9 alkyl), —NHC(O)(C1-8 haloalkyl), —NHC(O)(C2-6 alkenyl), —NHC(O)(C2-6 alkynyl), —NHC(O)(C3-15 cycloalkyl), —NHC(O)(heterocyclyl), —NHC(O)(C6-10 aryl), —NHC(O)(heteroaryl), —NHC(O)O(C1-9 alkyl), —NHC(O)O(C1-8 haloalkyl), —NHC(O)O(C2-6 alkenyl), —NHC(O)O(C2-6 alkynyl), —NHC(O)O(C3-15 cycloalkyl), —NHC(O)O(heterocyclyl), —NHC(O)O(C6-10 aryl), —NHC(O)O(heteroaryl), —NHC(O)NH(C1-9 alkyl), —NHC(O)NH(C1-8 haloalkyl), —NHC(O)NH(C2-6 alkenyl), —NHC(O)NH(C2-6 alkynyl), —NHC(O)NH(C3-15 cycloalkyl), —NHC(O)NH(heterocyclyl), —NHC(O)NH(C6-10 aryl), —NHC(O)NH(heteroaryl), —NHS(O)(C1-9 alkyl), —N(C1-9 alkyl)(S(O)(C1-9 alkyl), —S(C1-9 alkyl), —S(C1-8 haloalkyl), —S(C2-6 alkenyl), —S(C2-6 alkynyl), —S(C3-15 cycloalkyl), —S(heterocyclyl), —S(C6-10 aryl), —S(heteroaryl), —S(O)N(C1-9 alkyl)2, —S(O)(C1-9 alkyl), —S(O)(C1-8 haloalkyl), —S(O)(C2-6 alkenyl), —S(O)(C2-6 alkynyl), —S(O)(C3-15 cycloalkyl), —S(O)(heterocyclyl), —S(O)(C6-10 aryl), —S(O)(heteroaryl), —S(O)2(C1-9 alkyl), —S(O)2(C1-8 haloalkyl), —S(O)2(C2-6 alkenyl), —S(O)2(C2-6 alkynyl), —S(O)2(C3-15 cycloalkyl), —S(O)2(heterocyclyl), —S(O)2(C6-10 aryl), —S(O)2(heteroaryl), —S(O)(NH)(C1-9 alkyl), —S(O)2NH(C1-9 alkyl), or —S(O)2N(C1-9 alkyl)2;

wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1b is optionally substituted with one to three C1-9 alkyl, C1-8 haloalkyl, halogen, —OH, —NH2, —O(C1-9 alkyl), —O(C1-8 haloalkyl), —O(C3-15 cycloalkyl), —O(heterocyclyl), —O(aryl), —O(heteroaryl), —NH(C1-9 alkyl), —NH(C1-8 haloalkyl), —NH(C3-15 cycloalkyl), —NH(heterocyclyl), —NH(aryl), —NH(heteroaryl), —N(C1-9 alkyl)2, —N(C3-15 cycloalkyl)2, —NHC(O)(C1-8 haloalkyl), —NHC(O)(C3-15 cycloalkyl), —NHC(O)(heterocyclyl), —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)O(C1-9 alkyl), —NHC(O)O(C1-8 haloalkyl), —NHC(O)O(C2-6 alkynyl), —NHC(O)O(C3-15 cycloalkyl), —NHC(O)O(heterocyclyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl), —NHC(O)NH(C1-9 alkyl), S(O)2(C1-9 alkyl), —S(O)2(C1-8 haloalkyl), —S(O)2(C3-15 cycloalkyl), —S(O)2(heterocyclyl), —S(O)2(aryl), —S(O)2(heteroaryl), —S(O)(NH)(C1-9 alkyl), —S(O)2NH(C1-9 alkyl), or —S(O)2N(C1-9 alkyl)2;

each R1b, R1c, R2b, R2c, R3b, R3c, R12a, R12b, and R12c is independently H, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each R1b, R1c, R2b, R2c, R3b, R3c, R12a, R12b, and R12c is each optionally substituted with one to four Z1b, which may be the same or different;

each n and m is independently 1, 2, or 3, wherein n+m?4; and

q is 0, 1, or 2;

wherein each heteroaryl is 5 to 12 membered heteroaryl having one to four heteroatoms each independently N, O, or S;

wherein each heterocyclyl is 3 to 20 membered heterocyclyl having one to four heteroatoms each independently N, O or S.

anovIP™ Assessment

These filings signal a post-antibody immuno-oncology strategy. By focusing on small-molecule checkpoint modulation and targeted protein degradation (IKZF2/IKZF4), Gilead avoids crowded biologics space while unlocking combination and intracellular targeting opportunities.

Blockbuster Vector

anovIP™ Verdict:

A high-differentiation immune-control platform with strong lifecycle potential.

Lifecycle Engineering: How Anchors Become Blockbusters

Across all clusters, anovIP™ observes disciplined lifecycle execution:
a) Continuation and divisional filings
b) Solid-state, salt, and formulation protection
c) Indication expansion and combination layering

This converts each anchor patent family into a 10–15 year revenue engine.

anovIP™ Conclusion: Patents as Strategic Cartography

Gilead's patent portfolio is best understood as a map of future blockbusters:
a) Each anchor patent defines a biological control point
b) Each cluster enables multiple commercial assets
c) The portfolio as a whole forms a defensive, extensible innovation moat

Final anovIP™ Insight:

Gilead is not waiting for blockbusters to emerge—it is engineering them at the patent stage.

About anovIP™

anovIP™ is a global IP strategy and analytics firm helping life-sciences innovators, investors, and legal teams translate patents into strategic, monetizable business assets.