Inhibitors of human immunodeficiency virus replication

Patent metadata

Field	Value
Publication number	US-10221129-B2
Application number	US-201615565690-A
Country	US
Kind code	B2
Filing date	Apr 22, 2016
Priority date	Apr 23, 2015
Publication date	Mar 5, 2019
Grant date	Mar 5, 2019

Abstract

Compounds of Formula I, including pharmaceutically acceptable salts thereof, and compositions and methods for treating human immunodeficiency virus (HIV) infection are set forth:

First claim

What is claimed is:

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein:
R 1a and R 1b are each independently selected from hydrogen, alkyl, aryl, arylalkyl, aryloxyaryl, cycloalkyl, heterocyclyl, heterocyclylalkyl, and -alkylCO(R x ); wherein said heterocyclyl is linked to the parent molecule through a carbon atom, and further wherein said R 1a and R 1b groups are substituted with 0-4 groups independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylthioxy, benzyloxy, alkynyl, aryl, arylalkyl, aryloxy, carboxylic acid, cyano, cycloalkyl, halo, haloalkyl, haloalkoxy, heterocyclyl, heterocylyl alkyl, hydroxy, hydroxyalkyl, thioxy, —CH 2 NH 2 , -alkyl-heteroaryl, —CO-alkyl, CO(R x ), —CON(R y ) 2 , —NHCON(R y ) 2 , —NHCO-alkyl, —NHCO 2 alkyl, —NHSO 2 -alkyl, —OCH 2 -aryl, —SO 2 -alkyl, —SO 2 —N(R y ) 2 , and —SO 2 -heterocyclyl; or
R 1a and R 1b together with the nitrogen atom to which they are attached form a heterocycle that is substituted with 0-4 groups independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylthioxy, benzyloxy, alkynyl, aryl, carboxylic acid, cyano, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, thioxy, —CH 2 NH 2 , -alkyl-heteroaryl, —CO-alkyl, —CO(R x ), —CON(R y ) 2 , —N(R y )CON(R y ) 2 , —N(R y )CO-alkyl, —N(R y )CO 2 alkyl, —N(R y )SO 2 -alkyl, —OCH 2 -aryl, —SO 2 -alkyl, —SO 2 —N(R y ) 2 , and —SO 2 -heterocyclyl;
R 2 is —H, C 1 -C 4 alkyl or C 3 -C 4 cycloalkyl;
R 3 is —H, C 1 -C 4 alkyl or C 3 -C 4 cycloalkyl;
R 4 is —H, alkyl, aryl, C 5 -C 10 bicycloalkyl, C 3 -C 7 cycloalkyl or heteroaryl with 0-4 groups independently selected from alkenoxy, alkenyl, alkoxy, alkoxycarbonyl, alkyl, benzyloxy, carboamide, cyano, halo, haloalkyl, haloalkyloxy, —NHCO(alkyl), —SO 2 (R x ), —OH, and —CH 2 OH;
R 5 and R 6 are independently H or alkyl, or R 5 and R 6 together with the atoms to which they are attached form a C 3 -C 4 cycloalkyl;
R 7 is —H, alkyl, aryl, heterocyclyl, or C 3 -C 7 cycloalkyl, wherein said aryl or heterocyclyl is substituted with 0-3 groups selected from —OH, —NHCOalkyl, —NHCON(alkyl) 2 , —NHCO 2 -alkyl, —CONH 2 , —CN, —SO 2 N(alkyl) 2 , alkoxy, alkyl, halo, haloalkoxy, and haloalkyl;
R 8 is —H, alkyl, cycloalkyl, haloalkyl, halocycloalkyl alkenyl, or aryloxyalkyl;
or R 7 and R 8 together with the nitrogen atom to which they are attached form a heterocycle that is substituted with 0-4 groups independently selected from —OH, —NHCOalkyl, —NHCON(alkyl) 2 , —NHCO 2 -alkyl, —CONH 2 , —CN, —SO 2 N(alkyl) 2 , alkoxy, alkyl, halo, haloalkoxy, and haloalkyl;
R x is dialkylamine or a nitrogen-containing heterocycle which is attached to the parent fragment through a nitrogen atom; and
each R y is independently hydrogen, alkyl, haloalkyl or aryl.

2. The compound or salt of claim 1 , wherein R 1a and R 1b are each independently selected from hydrogen, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and -alkylCO(R x ), wherein the heteroaryl is attached to the parent structure through a carbon atom.

3. The compound or salt of claim 2 , wherein R 1a and R 1b are each independently selected from hydrogen, alkyl, phenyl, biphenyl, naphthalene, dihydroindene, pyridine, pyrimidine, quinoline, isoquinoline, benzothiazole, benzimidazole, 1,3-dihydrobenzo[c]thiophene 2,2-dioxide, —CH 2 CO(R x ) and an alkyl moiety attached to any one of the following groups: phenyl, biphenyl, pyridiyl, quinoline, benzimidazole, imidazole, isothiazole, pyrrazole, thiazole, indazole, triazole, and triazolone.

4. The compound or salt of claim 2 , wherein R 1a and R 1b are each independently substituted by at least one member selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halide, phenyl, thiazole, pyrrazole, phenoxy, oxazole, pyrrole, benzyloxy, pyridiylalkyl, methylcarbamate, cyano, acetamide, morpholin-4-ylsulfonyl, pyrrolidin-1-ylsulfonyl, piperidin-1-yl sulfonyl, —NHSO 2 Me, —CONH 2 , —NHCONMe 2 , and —COCH 3 .

5. The compound or salt of claim 3 , wherein R 1a and R 1b are each independently substituted by at least one member selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halide, phenyl, thiazole, pyrrazole, phenoxy, oxazole, pyrrole, benzyloxy, pyridiylalkyl, methylcarbamate, cyano, acetamide, morpholin-4-ylsulfonyl, pyrrolidin-1-ylsulfonyl, piperidin-1-yl sulfonyl, —NHSO 2 Me, —CONH 2 , —NHCONMe 2 , and —COCH 3 .

6. The compound or salt of claim 1 , wherein R 1a and R 1b taken together form a heterocycle together with the nitrogen to which they are attached, and wherein said heterocycle has 1-3 rings with a total of 4-14 carbon atoms and at least one internal nitrogen atom, and optionally at least one atom selected from oxygen and sulfur.

7. The compound or salt of claim 6 , wherein the formed heterocycle will be selected from tetrahydroquinoline, azatetrahydroquinoline, diazatetrahydroquinoline, tetrahydroisoquinoline, indoline, azaindoline, diazaindoline, indole, azaindole, diazaindole, indazole, carbazole, azetidine, pyrrolidine, piperidine, piperizine, morpholine, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine, 2,3-dihydrobenzo[d]isothiazole 1,1-dioxide, 1H-pyrazolo[4,3-c]pyridine, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, and spiro[cyclopropane-1,3′-indoline].

8. The compound or salt of claim 6 , wherein the formed heterocycle is substituted with at least one member selected from phenyl, aminoalkyl, alkyl, alkoxy, haloalkyl, haloalkoxy, halide, hydroxyl, pyridine, sulfonylalkyl, —CO 2 NMe 2 , and cyano.

9. The compound or salt of claim 7 , wherein the formed heterocycle is substituted with at least one member selected from phenyl, aminoalkyl, alkyl, alkoxy, haloalkyl, haloalkoxy, halide, hydroxyl, pyridine, sulfonylalkyl, —CO 2 NMe 2 , and cyano.

10. The compound or salt of claim 2 , wherein at least one of said R 1a and R 1b is phenyl.

11. The compound or salt of claim 10 , wherein said phenyl is substituted with at least one member selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halide, phenyl, thiazole, pyrrazole, phenoxy, oxazole, pyrrole, benzyloxy, pyridiylalkyl, methylcarbamate, cyano, acetamide, morpholin-4-ylsulfonyl, pyrrolidin-1-ylsulfonyl, piperidin-1-ylsulfonyl, —NHSO 2 Me, —CONH 2 , —NHCONMe 2 , and —COCH 3 .

12. A composition comprising a compound or salt of claim 1 and a pharmaceutically acceptable carrier, excipient and/or diluent.

13. A method of treating HIV infection comprising administering a composition according to claim 12 to a patient in need thereof.

14. A compound of Formula II, or a pharmaceutically acceptable salt thereof:

wherein:
R 1a and R 1b are each independently selected from hydrogen, alkyl, aryl, arylalkyl, aryloxyaryl, cycloalkyl, heterocyclyl, heterocyclylalkyl, and -alkylCO(R x ); wherein said heterocyclyl is linked to the parent molecule through a carbon atom, and further wherein said R 1a and R 1b groups are substituted with 0-4 groups independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylthioxy, benzyloxy, alkynyl, aryl, arylalkyl, aryloxy, carboxylic acid, cyano, cycloalkyl, halo, haloalkyl, haloalkoxy, heterocyclyl, heterocylyl alkyl, hydroxy, hydroxyalkyl, thioxy, —CH 2 NH 2 , -alkyl-heteroaryl, —CO-alkyl, CO(R x ), —CON(R y ) 2 , —NHCON(R y ) 2 , —NHCO-alkyl, —NHCO 2 alkyl, —NHSO 2 -alkyl, —OCH 2 -aryl, —SO 2 -alkyl, —SO 2 —N(R y ) 2 , and —SO 2 -he

Assignees

• Viiv Healthcare Uk No 5 Ltd

Inventors

• Bender John A
• Gentles Robert G
• Pendri Annapurna
• Wang Alan Xiangdong
• Meanwell Nicholas A
• Beno Brett R
• Fridell Robert A
• Belema Makonen
• Nguyen Van N
• Yang Zhong
• Wang Gan
• Kumaravel Selvakumar
• Thangathirupathy Srinivasan
• Bora Rajesh Onkardas
• Holehatti Shilpa Maheshwarappa
• Mettu Mallikarjuna Rao
• Panda Manoranjan

Classifications

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D333/72

  Benzo[c]thiophenes; Hydrogenated benzo[c]thiophenes · CPC title