# US 11,078,208 B1 · HIV inhibitor compounds

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- Number: US 11,078,208 B1
- Document ID: US11078208B1
- Status: Granted
- Kind: B1
- Application number: 16/805,933
- Filed: 2020-03-02
- Granted: 2021-08-03
- Earliest claimed: 2017-02-06
- Assignees: Gilead Sciences, Inc.
- Applicants: Gilead Sciences, Inc.
- Inventors: Elizabeth M. Bacon; Elbert Chin; Jeromy J. Cottell; Ashley Anne Katana; Darryl Kato; John O. Link; Nathan Shapiro; Teresa Alejandra Trejo Martin; Zheng-Yu Yang
- Web page: https://patentgrep.com/patent/US11078208B1

## CPC

- C07D 487/08: Bridged systems
- A61K 31/52: Purines, e.g. adenine
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 31/553: having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
- A61K 31/685: one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
- A61K 31/688: both hydroxy compounds having nitrogen atoms, e.g. sphingomyelins
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/18: for HIV
- C07C 243/28: to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
- C07C 275/16: being further substituted by carboxyl groups
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 471/08: Bridged systems
- C07D 487/10: Spiro-condensed systems
- C07D 491/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof as described herein. The invention also provides pharmaceutical compositions comprising a compound of Formula I, processes for preparing compounds of Formula I, therapeutic methods for treating the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS symptoms in a mammal using compounds of Formula I.

## Claims

### Claim 1

A pharmaceutical composition comprising 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 C1-4alkyl, C3-6cycloalkyl, O—R2A, C1-2alkyl-O—R2A, N—(R3A)2, or C1-2alkyl-N—(R3A)2,
wherein each R2A is independently C1-4alkyl, C3-6cycloalkyl, or a 4 to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, wherein each R3A is independently hydrogen, C1-4alkyl, C3-6cycloalkyl, or COO(Re),
and wherein each C3-6cycloalkyl or 4 to 10-membered heterocyclyl is optionally substituted by 1 to 3 Rf groups, wherein each Rf is independently C1-2alkyl or halogen;
R4 is hydrogen, halo, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C1-4alkoxy, or C1-4haloalkoxy;
R7 is hydrogen, halo, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C1-4alkoxy, or C1-4haloalkoxy;
R5, R6, R8, and R9 are each independently hydrogen, halo, C1-2alkyl, C1-2haloalkyl, or C3-6cycloalkyl;
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 C3-6cycloalkyl groups that are optionally substituted with 1 to 4 groups selected from halogen, C1-2alkyl, and C1-2haloalkyl;
each R10 is independently halogen, cyano, C1-4alkoxy, C1-6alkyl, or C3-6cycloalkyl;
n is 0 to 4;
each Ra is independently halogen, C1-4alkyl, C1-4alkyl substituted with 1 to 2 groups selected from hydroxyl and C1-4 alkoxy, C1-4 haloalkyl, C1-4alkoxy, 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 C3-6cycloalkyl 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 C1-4alkyl, C3-6 cycloalkyl, C1-4haloalkyl, or 4 to 8-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S;
A is ethynyl;
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(C1-4alkyl), S(O)1-2C3-6cycloalkyl, 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, C1-4alkyl, C1-4alkyl substituted with 1 to 2 groups selected from hydroxyl and C1-4 alkoxy, C1-4 haloalkyl, C1-4 alkoxy, or COO(Re);
Rc is C1-4alkyl, C1-4 haloalkyl, C1-4alkoxy, N(Re)2, C3-6cycloalkyl, 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 C1-2alkyl, halo, —OC1-2alkyl, or cyano;
each p is 0 to 4;
and each Re is independently hydrogen or C1-4alkyl;
and one or more additional therapeutic agents selected from the group consisting of combination drugs for HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversing agents, compounds that target the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and “antibody-like” therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or any combinations thereof.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein the composition comprises one, two, three, or four additional therapeutic agents.

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein the additional therapeutic agents are selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and pharmacokinetic enhancers, or any combinations thereof.

### Claim 4 (depends on 1)

The pharmaceutical composition of claim 1, wherein the HIV nucleoside or nucleotide inhibitors of reverse transcriptase are selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate.

### Claim 5 (depends on 1)

The pharmaceutical composition of claim 1, wherein the integrase inhibitors are selected from the group consisting of bictegravir, cabotegravir and dolutegravir.

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1, wherein the HIV nucleoside or nucleotide inhibitors of reverse transcriptase are selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate.

### Claim 7 (depends on 1)

The pharmaceutical composition of claim 1, wherein R2 and R3 are each methoxy.

### Claim 8 (depends on 1)

The pharmaceutical composition of claim 1, wherein R4 is CF3.

### Claim 9 (depends on 1)

The pharmaceutical composition of claim 1, wherein R7 is CF3.

### Claim 10 (depends on 1)

The pharmaceutical composition of claim 1, wherein R5 and R6 are methyl.

### Claim 11 (depends on 1)

The pharmaceutical composition of claim 1, wherein R8 and R9 are methyl.

### Claim 12 (depends on 1)

The pharmaceutical composition of claim 1, wherein n is 2.

### Claim 13 (depends on 1)

The pharmaceutical composition of claim 1, wherein each R10 is fluoro.

### Claim 14 (depends on 1)

The pharmaceutical composition of claim 1, wherein R1 is:

### Claim 15 (depends on 1)

The pharmaceutical composition of claim 1, wherein Ra is:

### Claim 16 (depends on 1)

The pharmaceutical composition of claim 1, wherein X1 is:

### Claim 17 (depends on 1)

The pharmaceutical composition of claim 1, wherein X2 is:

### Claim 18 (depends on 17)

The pharmaceutical composition of claim 17, wherein R11 is oxetan-3-yl, tetrahydrofuran-3-yl, or tetrahydropyran-4-yl.

### Claim 19 (depends on 1)

The pharmaceutical composition of claim 1, wherein p is 0.

### Claim 20

A pharmaceutical composition comprising a compound selected from:
EXAMPLE 1
EXAMPLE 2
EXAMPLE 3
EXAMPLE 4
EXAMPLE 5
EXAMPLE 6
EXAMPLE 7
EXAMPLE 8
EXAMPLE 9
EXAMPLE 10
EXAMPLE 11
EXAMPLE 12
EXAMPLE 13
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EXAMPLE 16
EXAMPLE 17
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EXAMPLE 21
EXAMPLE 22
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EXAMPLE 235
EXAMPLE 236
EXAMPLE 237
EXAMPLE 238
EXAMPLE 239
EXAMPLE 240
EXAMPLE 241
EXAMPLE 242
EXAMPLE 243
EXAMPLE 244, AND
EXAMPLE 245
or a pharmaceutically acceptable salt thereof,
and one or more additional therapeutic agents selected from the group consisting of combination drugs for HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversing agents, compounds that target the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and “antibody-like” therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or any combinations thereof.

### Claim 21 (depends on 1)

The pharmaceutical composition of claim 1, wherein the compound of Formula (I) is selected from:
and
or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 1)

A method of treating a human immunodeficiency virus (HIV) infection comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 1 to a subject in need thereof.

### Claim 23

A pharmaceutical composition comprising a compound selected from:
EXAMPLE 49
EXAMPLE 83
EXAMPLE 222, AND
EXAMPLE 223
or a pharmaceutically acceptable salt thereof,
and one or more additional therapeutic agents selected from the group consisting of combination drugs for HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversing agents, compounds that target the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and “antibody-like” therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or any combinations thereof.