US 11,078,208 B1 · HIV inhibitor 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.

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.

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HIV inhibitor compounds

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HIV inhibitor compounds

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Abstract

Claims23