Non-nucleoside reverse transcriptase inhibitors

Patent metadata

Field	Value
Publication number	US-9718819-B2
Application number	US-201615012445-A
Country	US
Kind code	B2
Filing date	Feb 1, 2016
Priority date	Oct 8, 2012
Publication date	Aug 1, 2017
Grant date	Aug 1, 2017

Abstract

Compounds of Formula I:

are HIV reverse transcriptase inhibitors, wherein R 1 , R 2 , R E , L, M and Z are defined herein. The compounds of Formula I and their pharmaceutically acceptable salts are useful in the inhibition of HIV reverse transcriptase, the prophylaxis and treatment of infection by HIV and in the prophylaxis, delay in the onset or progression, and treatment of AIDS. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.

First claim

What is claimed is:

1. A compound of Formula Ib:

or a pharmaceutically acceptable salt thereof, wherein:
K 1 and K 2 are each independently F, Br, C1, OCHF 2 , CF 3 or CN;
R 2 is selected from the group consisting of:
(1) H,
(2) C 1-6 alkyl,
(3) C 1-6 haloalkyl,
(4) C 1-6 alkyl substituted with from 1 to 3 substituents each of which is independently OH, O—C 1-6 alkyl, O—C 1-6 haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , S(O) 2 R A , S(O) 2 N(R A )R B , N(R A )C(O)R B , N(R A )CO 2 R B , N(R A )S(O) 2 R B , N(R A )S(O) 2 N(R A )R B , OC(O)N(R A )R B , N(R A )C(O)N(R A )R B , or N(R A )C(O)C(O)N(R A )R B ,
(5) O—C 1-6 alkyl in which the alkyl is optionally substituted with 1 to 3 substituents independently selected from OH, O—C 1-6 alkyl, O—C 1-6 haloalkyl, CN, N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , S(O) 2 R A , or S(O) 2 N(R A )R B ,
(6) O—C 1-6 haloalkyl,
(7) halogen,
(8) CN,
(9) NO 2 ,
(10) N(R A )R B ,
(11) C(O)N(R A )R B ,
(12) C(O)R A ,
(13) C(O)—C 1-6 haloalkyl,
(14) C(O)OR A ,
(15) OC(O)R A ,
(16) OC(O)N(R A )R B ,
(17) SR A ,
(18) S(O)R A ,
(19) S(O) 2 R A ,
(20) S(O) 2 N(R A )R B ,
(21) N(R A )S(O) 2 R B ,
(22) N(R A )S(O) 2 N(R A )R B ,
(23) N(R A )C(O)R B ,
(24) N(R A )C(O)N(R A )R B ,
(25) N(R A )C(O)—C(O)N(R A )R B ,
(26) N(R A )CO 2 R B ,
(27) N(R C )R D ,
(28) C(O)N(R C )R D ,
(29) OC(O)N(R C )R D ,
(30) S(O) 2 N(R C )R D ,
(31) N(R A )S(O) 2 N(R C )R D ,
(32) N(R A )C(O)N(R C )R D ,
(33) N(R A )C(O)—C(O)N(R C )R D ,
(34) CycA,
(35) —O-CycA,
(36) ArylA, or
(37) HetA;

R 4 and R 5 are each independently selected from:
(1) H,
(2) C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, each optionally substituted with one or more substituents up to the maximum number allowed by valence selected from OH, O—C 1-6 alkyl, O—C 1-6 haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , S(O) 2 R A , S(O) 2 N(R A )R B , N(R A )C(O)R B , N(R A )CO 2 R B , N(R A )S(O) 2 R B , N(R A )S(O) 2 N(R A )R B , OC(O)N(R A )R B , N(R A )C(O)N(R A )R B , N(R A )C(O)C(O)N(R A )R B , CycB, ArylB and HetB,
(3) C 1-6 haloalkyl optionally additionally substituted with one or more substituents up to the maximum number allowed by valence selected from OH, O—C 1-6 alkyl, O—C 1-6 haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , S(O) 2 R A , S(O) 2 N(R A )R B , N(R A )C(O)R B , N(R A )CO 2 R B , N(R A )S(O) 2 R B , N(R A )S(O) 2 N(R A )R B , OC(O)N(R A )R B , N(R A )C(O)N(R A )R B , N(R A )C(O)C(O)N(R A )R B , CycB, ArylB and HetB
(4) O—C 1-6 alkyl in which the alkyl portion is optionally substituted with one or more substituents up to the maximum number allowed by valence selected from OH, O—C 1-6 alkyl, O—C 1-6 haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , S(O) 2 R A , S(O) 2 N(R A )R B , N(R A )C(O)R B , N(R A )CO 2 R B , N(R A )S(O) 2 R B , N(R A )S(O) 2 N(R A )R B , OC(O)N(R A )R B , N(R A )C(O)N(R A )R B , N(R A )C(O)C(O)N(R A )R B , CycB, ArylB and HetB,
(5) O—C 1-6 haloalkyl, optionally additionally substituted with one or more substituents up to the maximum number allowed by valence selected from OH, O—C 1-6 alkyl, O—C 1-6 haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , S(O) 2 R A , S(O) 2 N(R A )R B , N(R A )C(O)R B , N(R A )CO 2 R B , N(R A )S(O) 2 R B , N(R A )S(O) 2 N(R A )R B , OC(O)N(R A )R B , N(R A )C(O)N(R A )R B , N(R A )C(O)C(O)N(R A )R B , CycB, ArylB and HetB,
(6) halogen,
(7) CN,
(8) NO 2 ,
(9) N(R A )R B ,
(10) C(O)N(R A )R B ,
(11) C(O)R A ,
(12) C(O)—C 1-6 haloalkyl,
(13) C(O)OR A ,
(14) OC(O)R A ,
(15) OC(O)N(R A )R B ,
(16) SR A ,
(17) S(O)R A ,
(18) S(O) 2 R A ,
(19) S(O) 2 N(R A )R B ,
(20) N(R A )S(O) 2 R B ,
(21) N(R A )S(O) 2 N(R A )R B ,
(22) N(R A )C(O)R B ,
(23) N(R A )C(O)N(R A )R B ,
(24) N(R A )C(O)—C(O)N(R A )R B ,
(25) N(R A )CO 2 R B ,
(26) N(R C )R D ,
(27) C(O)N(R C )R D ,
(28) OC(O)N(R C )R D ,
(29) S(O) 2 N(R C )R D ,
(30) N(R A )S(O) 2 N(R C )R D ,
(31) N(R A )C(O)N(R C )R D ,
(32) N(R A )C(O)—C(O)N(R C )R D ,
(33) OH,
(34) CycB,
(35) ArylB,
(36) HetB,
(37) -J-CycB,
(38) -J-ArylB, and
(39) -J-HetB,

or R 4 and R 5 on adjacent atoms may be joined together with the atoms to which they are attached to form a fused CycC, ArylC or HetC;
CycA, CycB and CycC are independently a carbocyclyl which is a C 3-8 cycloalkyl, a C 5-8 cycloalkenyl, or a C 7-12 bicyclic, saturated or unsaturated, non-aromatic ring system wherein one ring is fused to or bridged with the other ring; wherein the carbocyclyl is optionally substituted with a total of from 1 to 6 substituents, wherein:
(i) from zero to 6 substituents are each independently:
(1) halogen,
(2) CN,
(3) C 1-6 alkyl,
(4) OH,
(5) O—C 1-6 alkyl,
(6) C 1-6 haloalkyl,
(7) O—C 1-6 haloalkyl,
(8) C 1-6 alkenyl, or
(9) C 1-6 alkenyl substituted with CN, and

(ii) from zero to 2 substituents are each independently:
(1) CycQ,
(2) AryQ,
(3) HetQ,
(4) HetR,
(5) J-CycQ,
(6) J-AryQ,
(7) J-HetQ,
(8) J-HetR,
(9) C 1-6 alkyl substituted with CycQ, AryQ, HetQ, HetR, J-CycQ, J-AryQ, J-HetQ, or J-HetR,
(10) C 2-6 alkenyl substituted with CycQ, AryQ, HetQ, HetR, J-CycQ, J-AryQ, J-HetQ, or J-HetR, or
(11) C 2-6 alkynyl substituted with CycQ, AryQ, HetQ, HetR, J-CycQ, J-AryQ, J-HetQ, or J-HetR;

ArylA, ArylB and ArylC are independently aryl which is optionally substituted with a total of from 1 to 8 substituents, wherein:
(i) from zero to 8 substituents are each independently:
(1) C 1-6 alkyl,
(2) C 1-6 haloalkyl, which is optionally substituted with 1 to 3 additional substituents each of which is independently selected from OH, O—C 1-6 alkyl, O—C 1-6 haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , S(O) 2 R A , S(O) 2 N(R A )R B , N(R A )C(O)R B , N(R A )CO 2 R B , N(R A )S(O) 2 R B , N(R A )S(O) 2 N(R A )R B , OC(O)N(R A )R B , N(R A )C(O)N(R A )R B , or N(R A )C(O)C(O)N(R A )R B ,
(3) C 1-6 alkyl substituted with from 1 to 3 substituents each of which is independently selected from OH, O—C 1-6 alkyl, O—C 1-6 haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , S(O) 2 R A , S(O) 2 N(R A )R B , N(R A )C(O)R B , N(R A )CO 2 R B , N(R A )S(O) 2 R B , N(R A )S(O) 2 N(R A )R B , OC(O)N(R A )R B , N(R A )C(O)N(R A )R B , or N(R A )C(O)C(O)N(R A )R B ,
(4) C 2-6 alkenyl,
(5) C 2-6 alkenyl substituted with from 1 to 3 substituents each of which is independently OH, O—C 1-6 alkyl, O—C 1-6 haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , S(O) 2 R A , S(O) 2 N(R A )R B , N(R A )C(O)R B , N(R A )CO 2 R B , N(R A )S(O) 2 R B , N(R A )S(O) 2 N(R A )R B , OC(O)N(R A )R B , N(R A )C(O)N(R A )R B , or N(R A )C(O)C(O)N(R A )R B ,
(6) C 2-6 alkynyl,
(7) C 2-6 alkynyl substituted with from 1 to 3 substituents each of which is independently OH, O—C 1-6 alkyl, O—C 1-6 haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , S(O) 2 R A , S(O) 2 N(R A )R B , N(R A )C(O)R B , N(R A )CO 2 R B , N(R A )S(O) 2 R B , N(R A )S(O) 2 N(R A )R B , OC(O)N(R A )R B , N(R A )C(O)N(R A )R B , or N(R A )C(O)C(O)N(R A )R B ,
(8) O—C 1-6 alkyl,
(9) O—C 1-6 haloalkyl,
(10) OH,
(11) halogen,
(12) CN,
(13) NO 2 ,
(14) N(R A )R B ,
(15) C(O)N(R A )R B ,
(16) C(O)R A ,
(17) C(O)—C 1-6 haloalkyl,
(18) C(O)OR A ,
(19) OC(O)N(R A )R B ,
(20) SR A ,
(21) S(O)R A ,
(22) S(O) 2 R A ,
(23) S(O) 2 N(R A )R B ,
(24) N(R A )S(O) 2 R B ,
(25) N(R A )

Assignees

• Merck Sharp & Dohme

Inventors

• Arrington Kenneth L
• Burgey Christopher
• Gilfillan Robert
• Han Yongxin
• Patel Mehul
• Li Chun Sing
• Luo Yunfu
• Lei Zhiyu

Classifications

• A61P31/18

  for HIV · CPC title

• C07D239/54

  as doubly bound oxygen atoms or as unsubstituted hydroxy radicals · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D239/52

  Two oxygen atoms · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title