US 2013/0296382 A1Published application

Non-nucleoside reverse transcriptase inhibitors

AssigneeMerck Canada Inc.

InventorsJason Burch, Bernard Cote, Natalie Nguyen, Chun Sing Li, Miguel St-Onge, Danny Gauvreau

Life of this patent

Estimating the term…

Abstract

Heteroaromatic compounds of Formula I: are HIV reverse transcriptase inhibitors, wherein R1, R2, R3, R4 and R5 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.

Claims27

Dependent claims

A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R1 is C1-10 alkyl, CycA, or AryA;
CycA is C3-8 cycloalkyl, wherein the cycloalkyl is optionally substituted with from 1 to 4 substituents, each of which is independently halogen, C1-6 alkyl, OH, O—C1-6 alkyl, C1-6 haloalkyl, or O—C1-6 haloalkyl;
AryA is aryl which is optionally substituted with a total of from 1 to 6 substituents, wherein:
(i) from zero to 6 substituents are each independently:
(1) C1-6 alkyl,
(2) C1-6 haloalkyl,
(3) C1-6 alkyl substituted with from 1 to 3 substituents each of which is independently OH, O—C1-6 alkyl, O—C1-6 haloalkyl, CN, NO2, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, S(O)2RA, S(O)2N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)S(O)2RB, N(RA)S(O)2N(RA)RB, OC(O)N(RA)RB, N(RA)C(O)N(RA)RB, or N(RA)C(O)C(O)N(RA)RB,
(4) C2-6 alkenyl,
(5) C2-6 alkenyl substituted with from 1 to 3 substituents each of which is independently OH, O—C1-6 alkyl, O—C1-6 haloalkyl, CN, NO2, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, S(O)2RA, S(O)2N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)S(O)2RB, N(RA)S(O)2N(RA)RB, OC(O)N(RA)RB, N(RA)C(O)N(RA)RB, or N(RA)C(O)C(O)N(RA)RB,
(6) C2-6 alkynyl,
(7) C2-6 alkynyl substituted with from 1 to 3 substituents each of which is independently OH, O—C1-6 alkyl, O—C1-6 haloalkyl, CN, NO2, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, S(O)2RA, S(O)2N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)S(O)2RB, N(RA)S(O)2N(RA)RB, OC(O)N(RA)RB, N(RA)C(O)N(RA)RB, or N(RA)C(O)C(O)N(RA)RB,
(8) O—C1-6 alkyl,
(9) O—C1-6 haloalkyl,
(10) OH,
(11) halogen,
(12) CN,
(13) NO2,
(14) N(RA)RB,
(15) C(O)N(RA)RB,
(16) C(O)RA,
(17) C(O)—C1-6 haloalkyl,
(18) C(O)ORA,
(19) OC(O)N(RA)RB,
(20) SRA,
(21) S(O)RA,
(22) S(O)2RA,
(23) S(O)2N(RA)RB,
(24) N(RA)S(O)2RB,
(25) N(RA)S(O)2N(RA)RB,
(26) N(RA)C(O)RB,
(27) N(RA)C(O)N(RA)RB,
(28) N(RA)C(O)—C(O)N(RA)RB, or
(29) N(RA)CO2RB, 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) C1-6 alkyl substituted with CycQ, AryQ, HetQ, HetR, J-CycQ, J-AryQ, J-HetQ, or J-HetR,
(10) C2-6 alkenyl substituted with CycQ, AryQ, HetQ, HetR, J-CycQ, J-AryQ, J-HetQ, or J-HetR, or
(11) C2-6 alkynyl substituted with CycQ, AryQ, HetQ, HetR, J-CycQ, J-AryQ, J-HetQ, or J-HetR;
each CycQ is independently C3-8 cycloalkyl or C5-8 cycloalkenyl, wherein the cycloalkyl or cycloalkenyl is optionally substituted with from 1 to 4 substituents, each of which is independently halogen, C1-6 alkyl, OH, O—C1-6 alkyl, C1-6 haloalkyl, or O—C1-6 haloalkyl;
each AryQ is independently phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with from 1 to 5 substituents each of which is independently halogen, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, OH, O—C1-6 alkyl, O—C1-6 haloalkyl, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, SO2RA, SO2N(RA)RB, or SO2N(RA)C(O)RB;
each HetQ is independently a heteroaryl which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, C1-6 alkyl, C1-6 haloalkyl, OH, O—C1-6 alkyl, O—C1-6 haloalkyl, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SO2RA, N(RA)C(O)N(RA)RB, or N(RA)CO2RB;
each HetR is independently a 4- to 7-membered, saturated or unsaturated, non-aromatic heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(O)2, and wherein the saturated or unsaturated heterocyclic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, CN, C1-6 alkyl, OH, oxo, O—C1-6 alkyl, C1-6 haloalkyl, O—C1-6 haloalkyl, C(O)N(RA)RB, C(O)RA, CO2RA, or SO2RA;
each J is independently:
(i) O,
(ii) S,
(iii) S(O),
(iv) S(O)2,
(v) O—C1-6 alkylene,
(vi) S—C1-6 alkylene,
(vii) S(O)—C1-6 alkylene,
(viii) S(O)2—C—6 alkylene,
(ix) N(RA), or
(x) N(RA)—C1-6 alkylene;
R2 and R3 are each independently:
(1) H,
(2) C1-6 alkyl,
(3) C1-6 haloalkyl,
(4) C1-6 alkyl substituted with from 1 to 3 substituents each of which is independently OH, O—C1-6 alkyl, O—C1-6 haloalkyl, CN, NO2, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, S(O)2RA, S(O)2N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)S(O)2RB, N(RA)S(O)2N(RA)RB, OC(O)N(RA)RB, N(RA)C(O)N(RA)RB, or N(RA)C(O)C(O)N(RA)RB,
(5) O—C1-6 alkyl in which the alkyl is optionally substituted with OH, O—C1-6 alkyl, O—C1-6 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, S(O)2RA, or S(O)2N(RA)RB,
(6) O—C1-6 haloalkyl,
(7) halogen,
(8) CN,
(9) NO2,
(10) N(RA)RB,
(11) C(O)N(RA)RB,
(12) C(O)RA,
(13) C(O)—C1-6 haloalkyl,
(14) C(O)ORA,
(15) OC(O)RA,
(16) OC(O)N(RA)RB,
(17) SRA,
(18) S(O)RA,
(19) S(O)2RA,
(20) S(O)2N(RA)RB,
(21) N(RA)S(O)2RB,
(22) N(RA)S(O)2N(RA)RB,
(23) N(RA)C(O)RB,
(24) N(RA)C(O)N(RA)RB,
(25) N(RA)C(O)—C(O)N(RA)RB,
(26) N(RA)CO2RB,
(27) N(RC)RD,
(28) C(O)N(RC)RD,
(29) OC(O)N(RC)RD,
(30) S(O)2N(RC)RD,
(31) N(RA)S(O)2N(RC)RD,
(32) N(RA)C(O)N(RC)RD,
(33) N(RA)C(O)—C(O)N(RC)RD,
(34) C3-8 cycloalkyl,
(35) O—C3-8 cycloalkyl,
(36) AryX, or
(37) HetX;
wherein AryX independently has the same definition as AryQ, and HetX independently has the same definition as HetQ;
R4 is H, C1-6 alkyl, AryZ, HetZ, halogen, CN, or C1-6 fluoroalkyl;
AryZ independently has the same definition as AryQ;
HetZ independently has the same definition as HetQ;
R5 is H or C1-6 alkyl;
each aryl is independently (i) phenyl, (ii) a 9- or 10-membered bicyclic, fused carbocylic ring system in which at least one ring is aromatic, or (iii) an 11- to 14-membered tricyclic, fused carbocyclic ring system in which at least one ring is aromatic;
each heteroaryl is independently (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, or (ii) a 9- or 10-membered heterobicyclic, fused ring system containing from 1 to 6 heteroatoms independently selected from N, O and S, wherein either one or both of the rings contain one or more of the heteroatoms, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a ring which is not aromatic is optionally S(O) or S(O)2;
each RA is independently H or C1-6 alkyl;
each RB is independently H or C1-6 alkyl;
and
each pair of RC and RD together with the nitrogen to which they are both attached form a 4- to 7-membered saturated or unsaturated, non-aromatic ring which optionally contains a heteroatom in addition to the N to which RC and RD are attached, wherein the additional heteroatom is selected from N, O, and S;
wherein the ring is optionally substituted with 1 or 2 substituents each of which is independently C1-6 alkyl, C(O)RA, C(O)ORA, C(O)N(RA)RB, or S(O)2RA;
and wherein the optional S in the ring is optionally in the form of S(O) or S(O)2,
excluding 3-Chloro-5-({1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl}oxy)benzonitrile and pharmaceutically acceptable salts thereof.

110 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/934,633Filed 3 Jul 2013
Priority: 30 Mar 2010
Published: 7 Nov 2013
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
A61K 31/4439
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 31/00
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Family

Application61/318,824Us provisional application · filed 30 Mar 2010
Application61/321,573Us provisional application · filed 7 Apr 2010
Application13/073,631Continuation · filed 28 Mar 2011
Application13/934,633Continuation
US 2011/0245296 A1Published application
US 8,486,975 B2Related patent
US 2013/0296382 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R1 is C1-10 alkyl, CycA, or AryA;
CycA is C3-8 cycloalkyl, wherein the cycloalkyl is optionally substituted with from 1 to 4 substituents, each of which is independently halogen, C1-6 alkyl, OH, O—C1-6 alkyl, C1-6 haloalkyl, or O—C1-6 haloalkyl;
AryA is aryl which is optionally substituted with a total of from 1 to 6 substituents, wherein:
(i) from zero to 6 substituents are each independently:
(1) C1-6 alkyl,
(2) C1-6 haloalkyl,
(3) C1-6 alkyl substituted with from 1 to 3 substituents each of which is independently OH, O—C1-6 alkyl, O—C1-6 haloalkyl, CN, NO2, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, S(O)2RA, S(O)2N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)S(O)2RB, N(RA)S(O)2N(RA)RB, OC(O)N(RA)RB, N(RA)C(O)N(RA)RB, or N(RA)C(O)C(O)N(RA)RB,
(4) C2-6 alkenyl,
(5) C2-6 alkenyl substituted with from 1 to 3 substituents each of which is independently OH, O—C1-6 alkyl, O—C1-6 haloalkyl, CN, NO2, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, S(O)2RA, S(O)2N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)S(O)2RB, N(RA)S(O)2N(RA)RB, OC(O)N(RA)RB, N(RA)C(O)N(RA)RB, or N(RA)C(O)C(O)N(RA)RB,
(6) C2-6 alkynyl,
(7) C2-6 alkynyl substituted with from 1 to 3 substituents each of which is independently OH, O—C1-6 alkyl, O—C1-6 haloalkyl, CN, NO2, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, S(O)2RA, S(O)2N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)S(O)2RB, N(RA)S(O)2N(RA)RB, OC(O)N(RA)RB, N(RA)C(O)N(RA)RB, or N(RA)C(O)C(O)N(RA)RB,
(8) O—C1-6 alkyl,
(9) O—C1-6 haloalkyl,
(10) OH,
(11) halogen,
(12) CN,
(13) NO2,
(14) N(RA)RB,
(15) C(O)N(RA)RB,
(16) C(O)RA,
(17) C(O)—C1-6 haloalkyl,
(18) C(O)ORA,
(19) OC(O)N(RA)RB,
(20) SRA,
(21) S(O)RA,
(22) S(O)2RA,
(23) S(O)2N(RA)RB,
(24) N(RA)S(O)2RB,
(25) N(RA)S(O)2N(RA)RB,
(26) N(RA)C(O)RB,
(27) N(RA)C(O)N(RA)RB,
(28) N(RA)C(O)—C(O)N(RA)RB, or
(29) N(RA)CO2RB, 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) C1-6 alkyl substituted with CycQ, AryQ, HetQ, HetR, J-CycQ, J-AryQ, J-HetQ, or J-HetR,
(10) C2-6 alkenyl substituted with CycQ, AryQ, HetQ, HetR, J-CycQ, J-AryQ, J-HetQ, or J-HetR, or
(11) C2-6 alkynyl substituted with CycQ, AryQ, HetQ, HetR, J-CycQ, J-AryQ, J-HetQ, or J-HetR;
each CycQ is independently C3-8 cycloalkyl or C5-8 cycloalkenyl, wherein the cycloalkyl or cycloalkenyl is optionally substituted with from 1 to 4 substituents, each of which is independently halogen, C1-6 alkyl, OH, O—C1-6 alkyl, C1-6 haloalkyl, or O—C1-6 haloalkyl;
each AryQ is independently phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with from 1 to 5 substituents each of which is independently halogen, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, OH, O—C1-6 alkyl, O—C1-6 haloalkyl, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, SO2RA, SO2N(RA)RB, or SO2N(RA)C(O)RB;
each HetQ is independently a heteroaryl which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, C1-6 alkyl, C1-6 haloalkyl, OH, O—C1-6 alkyl, O—C1-6 haloalkyl, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SO2RA, N(RA)C(O)N(RA)RB, or N(RA)CO2RB;
each HetR is independently a 4- to 7-membered, saturated or unsaturated, non-aromatic heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(O)2, and wherein the saturated or unsaturated heterocyclic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, CN, C1-6 alkyl, OH, oxo, O—C1-6 alkyl, C1-6 haloalkyl, O—C1-6 haloalkyl, C(O)N(RA)RB, C(O)RA, CO2RA, or SO2RA;
each J is independently:
(i) O,
(ii) S,
(iii) S(O),
(iv) S(O)2,
(v) O—C1-6 alkylene,
(vi) S—C1-6 alkylene,
(vii) S(O)—C1-6 alkylene,
(viii) S(O)2—C—6 alkylene,
(ix) N(RA), or
(x) N(RA)—C1-6 alkylene;
R2 and R3 are each independently:
(1) H,
(2) C1-6 alkyl,
(3) C1-6 haloalkyl,
(4) C1-6 alkyl substituted with from 1 to 3 substituents each of which is independently OH, O—C1-6 alkyl, O—C1-6 haloalkyl, CN, NO2, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, S(O)2RA, S(O)2N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)S(O)2RB, N(RA)S(O)2N(RA)RB, OC(O)N(RA)RB, N(RA)C(O)N(RA)RB, or N(RA)C(O)C(O)N(RA)RB,
(5) O—C1-6 alkyl in which the alkyl is optionally substituted with OH, O—C1-6 alkyl, O—C1-6 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, S(O)2RA, or S(O)2N(RA)RB,
(6) O—C1-6 haloalkyl,
(7) halogen,
(8) CN,
(9) NO2,
(10) N(RA)RB,
(11) C(O)N(RA)RB,
(12) C(O)RA,
(13) C(O)—C1-6 haloalkyl,
(14) C(O)ORA,
(15) OC(O)RA,
(16) OC(O)N(RA)RB,
(17) SRA,
(18) S(O)RA,
(19) S(O)2RA,
(20) S(O)2N(RA)RB,
(21) N(RA)S(O)2RB,
(22) N(RA)S(O)2N(RA)RB,
(23) N(RA)C(O)RB,
(24) N(RA)C(O)N(RA)RB,
(25) N(RA)C(O)—C(O)N(RA)RB,
(26) N(RA)CO2RB,
(27) N(RC)RD,
(28) C(O)N(RC)RD,
(29) OC(O)N(RC)RD,
(30) S(O)2N(RC)RD,
(31) N(RA)S(O)2N(RC)RD,
(32) N(RA)C(O)N(RC)RD,
(33) N(RA)C(O)—C(O)N(RC)RD,
(34) C3-8 cycloalkyl,
(35) O—C3-8 cycloalkyl,
(36) AryX, or
(37) HetX;
wherein AryX independently has the same definition as AryQ, and HetX independently has the same definition as HetQ;
R4 is H, C1-6 alkyl, AryZ, HetZ, halogen, CN, or C1-6 fluoroalkyl;
AryZ independently has the same definition as AryQ;
HetZ independently has the same definition as HetQ;
R5 is H or C1-6 alkyl;
each aryl is independently (i) phenyl, (ii) a 9- or 10-membered bicyclic, fused carbocylic ring system in which at least one ring is aromatic, or (iii) an 11- to 14-membered tricyclic, fused carbocyclic ring system in which at least one ring is aromatic;
each heteroaryl is independently (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, or (ii) a 9- or 10-membered heterobicyclic, fused ring system containing from 1 to 6 heteroatoms independently selected from N, O and S, wherein either one or both of the rings contain one or more of the heteroatoms, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a ring which is not aromatic is optionally S(O) or S(O)2;
each RA is independently H or C1-6 alkyl;
each RB is independently H or C1-6 alkyl;
and
each pair of RC and RD together with the nitrogen to which they are both attached form a 4- to 7-membered saturated or unsaturated, non-aromatic ring which optionally contains a heteroatom in addition to the N to which RC and RD are attached, wherein the additional heteroatom is selected from N, O, and S;
wherein the ring is optionally substituted with 1 or 2 substituents each of which is independently C1-6 alkyl, C(O)RA, C(O)ORA, C(O)N(RA)RB, or S(O)2RA;
and wherein the optional S in the ring is optionally in the form of S(O) or S(O)2,
excluding 3-Chloro-5-({1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl}oxy)benzonitrile and pharmaceutically acceptable salts thereof.

110 more elements

Facts

Application

13/934,633Filed 3 Jul 2013

Priority

30 Mar 2010

Published

7 Nov 2013

Term ends

Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
A61K 31/4439
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 31/00
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Family

Application61/318,824Us provisional application · filed 30 Mar 2010

Application61/321,573Us provisional application · filed 7 Apr 2010

Application13/073,631Continuation · filed 28 Mar 2011

Application13/934,633Continuation

US 2011/0245296 A1Published application

US 8,486,975 B2Related patent

US 2013/0296382 A1This patent

From the US filing history. Foreign family members aren’t listed.