ZA200203131B

ZA200203131B - Condensed naphthyridines as HIV reverse transcriptase inhibitors.

Info

Publication number: ZA200203131B
Application number: ZA200203131A
Authority: ZA
Inventors: Barry L Johnson; Mona Patel; Rodgers James D Wang Haisheng; Christine M Tarby; Rajagopal Bakthavatchalam
Original assignee: Bristol Myers Squibb Pharma Co
Priority date: 1999-10-19
Filing date: 2000-10-19
Publication date: 2003-04-22

Description

TITLE

TRICYCLIC COMPOUNDS USEFUL AS HIV REVERSE TRANSCRIPTASE

INHIBITORS

FIELD OF THE INVENTION

This invention relates generally to tricyclic compounds and also tricyclic compounds which are useful as inhibitors of HIV reverse transcriptase, pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as assay standards or reagents, and intermediates and processes for making such tricyclic compounds.

BACKGROUND OF THE INVENTION

Two distinct retroviruses, human immunodeficiency virus (HIV) type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by

AIDS. Affected individuals exhibit severe .. lmmunosuppression which predisposes them to debilitating and ultimately fatal opportunistic infections.

The disease AIDS is the consequence of HIV-1 or

HIV-2 virus following its complex viral life cycle. The virion life cycle involves the virion attaching itself to the host human T-4 lymphocyte immune cell through the binding of a glycoprotein on the surface of the virion’s protective coat with the CD4 glycoprotein on the lymphocyte cell. Once attached, the virion sheds its glycoprotein cecat, penetrates into the membrane of the host cell, and uncoats its RNA. The virion enzyme, reverse transcriptase, directs the process of transcribing the RNA into single-stranded DNA. The viral RNA is degraded and a second DNA strand is created. The now double-stranded DNA is integrated into the human cell’s genes and those genes are used for virus reproduction.

RNA polymerase transcribes the integrated viral DNA into viral mRNA. The viral RNA is translated into the precursor gag-pol fusion polyprotein. The polyprotein is then cleaved by the HIV protease enzyme to yield the nature viral proteins. Thus, HIV protease is responsible for regulating a cascade of cleavage events that lead to the virus particle’s maturing into a virus that is capable of full infectivity.

The typical human immune system response, killing , the invading virion, is taxed because the virus infects and kills the immune system's T cells. In addition, viral reverse transcriptase, the enzyme used in making a new virion particle, is not very specific, and causes transcription mistakes that result in continually changed glycoproteins on the surface of the viral protective coat. This lack of specificity decreases the immune system's effectiveness because antibodies specifically produced against one glycoprotein may be useless against another, hence reducing the number of antibodies available to fight the virus. The virus continues to reproduce while the immune response system continues to weaken. In most cases, without therapeutic intervention, HIV causes the host's immune system to be debilitated, allowing opportunistic infections to set in. Without the administration of antiviral agents, immunomodulators, or both, death may result.

There are at least three critical points in the HIV life cycle which have been identified as possible targets for antiviral drugs: (1) the initial attachment of the virion to the T-4 lymphocyte or macrophage site,

(2) the transcription of viral RNA to viral DNA (reverse transcriptase, RT), and (3) the processing of gag-pol protein by HIV protease.

Inhibition of the virus at the second critical point, the viral RNA to viral DNA transcription process, has provided a number of the current therapies used in treating AIDS. This transcription must occur for the virion to reproduce because the virion’s genes are encoded in RNA and the host cell transcribes only DNA.

By introducing drugs that block the reverse transcriptase from completing the formation of viral

DNA, HIV-1 replication can be stopped.

A number of compounds that interfere with viral replication have been developed to treat AIDS. For example, nucleoside analogs, such as 3’-azido-3’-deoxythymidine (AZT), 2’,3’'-dideoxycytidine (ddc), 2’,3’'-dideoxythymidinene (d44T), 2',3’'-dideoxyinosine (ddI), and 2’,3'-dideoxy-3’-thia-cytidine (3TC) have been shown to be relatively effective in certain cases in halting HIV replication at the reverse transcriptase (RT) stage.

An active area of research is in the discovery of non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs). As an example, it has been found that certain

Dbenzoxazinones and quinazolinones are active in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of

AIDS.

U.S. 5,874,430 describes benzoxazinone non- nucleoside reverse transcriptase inhibitors for the treatment of HIV. U.S. 5,519,021 describe non- nucleoside reverse transcriptase inhibitors which are benzoxazinones of the formula:

x! R poe (@) wherein X is a halogen, Z may be O.

EP 0,530,994 and WO 93/04047 describe HIV reverse transcriptase inhibitors which are quinazolinones of the formula (A): rR! R® ww

EI zZ

La (A) wherein G is a variety of groups, R3 and R%4 may be H, Z may be O, R? may be unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycle, and optionally substituted aryl, and R! may be a variety of groups including substituted alkyl.

WO 95/12583 also describes HIV reverse transcriptase inhibitors of formula A. In this publication, G is a variety of groups, R3 and R% may be

H, Zz may be 0, R2 is substituted alkenyl or substituted alkynyl, and Rl is cycloalkyl, alkynyl, alkenyl, or cyano. WO 95/13273 illustrates the asymmetric synthesis of one of the compounds of WO 95/12583, (S)-(-)-6-chloro-4-cyclopropyl-3,4-dihydro-4 ((2-pyridy)e thynyl)-2 (1H) -quinazolinocne.

Synthetic procedures for making quinazolinones like those described above are detailed in the following references: Houpis et al., Tetr. Lett. 1994, 35(37), 6811-6814; Tucker et al., J. Med. Chem. 1994, 37,

2437-2444; and, Huffman et al., J. Org. Chem. 1995, 60, 1590-1594.

DE 4,320,347 illustrates quinazolinones of the formula:

R R’

Ng A

H x wherein R is a phenyl, carbocyclic ring, or a heterocyclic ring. Compounds of this sort are not considered to be part of the present invention.

Even with the current success of reverse transcriptase inhibitors, it has been found that HIV patients can become resistant to a given inhibitor.

Thus, there is an important need to develop additional inhibitors to further combat HIV infection.

SUMMARY QF THE INVENTION

Accordingly, one object of the present invention is to provide novel reverse transcriptase inhibitors.

It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention, including a pharmaceutically acceptable salt form thereof.

It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need thereof a therapeutically effective combination of (a) one of the compounds of the present invention and (b) one or more compounds selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

It is another object of the present invention to provide pharmaceutical compositions with reverse transcriptase inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.

It is another object of the present invention to provide novel tricyclic compounds for use in therapy.

It is another object of the present invention to provide the use of novel tricyclic compounds for the manufacture of a medicament for the treatment of HIV infection.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors’ discovery that compounds of formula (I):

R! R?

FEF

I" _ n

Y< 7 N

R8 (I) wherein RY, R2, R8, n, A, B, W, X, Y, and Z are defined below, including any stereoisomeric form, mixtures of stereoisomeric forms, complexes, prodrug forms or pharmaceutically acceptable salt forms thereof, are effective reverse transcriptase inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in a first embodiment, the present invention provides a novel compound of formula (I):

R! R2

WW.

XN B i n ~Z7°N

RS

(I) or a stereoisomeric form, mixtures of stereoisomeric forms, complexes, prodrug forms or pharmaceutically acceptable salt form thereof, wherein: n is selected from 0, 1, 2 and 3;

A is a ring selected from the group:

ODO

2 y » » and

SAN bY NZ ANN ~ N

IJ oo 1] x N wherein a ring nitrogen in ring A may optionally be in an N-oxide form; said ring A being substituted with 0-3 B, said substituent B being independently selected from the group Cj-4 alkyl, -OH, Ci_.4 alkoxy, -S-C;_szalkyl,

OCF3, CF3, F, Cl, Br, I, -NOp, -CN, and -NRS5RSa;

W is N or CR3;

X is N or CR3a;

Y is N or CR3b;

Z is N or CR3<; provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

Rl! is selected from the group Ci.3 alkyl substituted with 0-7 halogen, and cyclopropyl substituted with 0-5 halogen;

R2 is selected from the group -R2¢, -OH, -CN, -ORZC, -OCHRZ2aR2b, -QOCH,CHRZ23R2P, -0O(CHjy),CHR22R2D, -OCHR?aC (R22) =C (R2P) ,, -OCHRZ2aC (R22) =C(R2P),, -OCHR2aCc=C-R2b, -gR2¢, -SCHR22R2P, -SCH,CHR22R2D, -S (CHy) 2CHR22R2b, -SCHR22C (R22) =C(R2P) 5, 1s -SCHR2aC (R2a) = (R2P) ,, -SCHR22C=C-R2b, -NR2aRr2c, -NHCHR22R2b, _-NHCH,CHR22R2P, -NH (CHj),CHR22aR2b, -NHCHR2aC (R22) =C (R2b),, -NHCHRZ22C (R22) =(R2P),, and -NHCHR2aC=C-R2b;

R22 jis selected from the group H, CH3, CH,CHi, CH(CH3);, and CHCH;CH3;

R2P is H or R2c;

R2¢ is selected from the group methyl substituted with 0-3 R3f, C;_¢ alkyl substituted with 0-3 R%, C,_g alkenyl substituted with 0-2 R%, Cy.5 alkynyl substituted with 0-1 R4, C3_¢ cycloalkyl substituted with 0-2 R34, phenyl substituted with 0-2 R34, and 3-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group

O, N, and S, substituted with 0-2 R34;

alternatively, the group -NR23R2C represents a 4-7 membered cyclic amine, wherein 0-1 carbon atoms are replaced by O or NR3;

R3 is selected from the group H, Ci_4 alkyl, -OH, Ci-4 alkoxy, OCF3, F, Cl, Br, I, -NR°R52, -NO,, -CN, -C(O)R®, -NHC(O)R7, -NHC(O)NRSR52, -NHSO,R10, -SO;NR5R52, and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group

O, N, and S;

R32 is selected from the group H, Cj-4 alkyl, -OH, Cj_4 alkoxy, OCF3, F, C1, Br, I, -NRS5R52, -NO,, -CN, -C(O)R®, -NHC(O)R7, -NHC(O)NRSR52, -NHSO,R10, ~SO2NRSR32, and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group

O, N, and S; alternatively, R3 and R32 together form -OCH,0-;

R3b is selected from the group H, C3. alkyl, -OH, Ci-4 alkoxy, OCF3, F, Cl, Br, I, -NR5R52, -NO,, -CN, -C(O)RS, -NHC(O)R7, -NHC(O)NRSR5a, -NHSO,R19, and -SO,NR5R5a; alternatively, R32 and R3P together form -OCH,0-;

R3¢ is selected from the group H, Cj_4 alkyl, -OH, Cj_g alkoxy, OCF3, F, Cl, Br, I, -NR5R5a, -NO,, -CN, -C(0)R®, -NHC(O)R7, -NHC(O)NRSRSa, -NHSO,R10, and -SO3NROR54;

alternatively, R3P and R3¢ together form -OCH0-;

R34, at each occurrence, is independently selected from the group H, C3-4 alkyl, -OH, Ci_4 alkoxy, OCF3, F, cl, Br, I, -NR°R5a, -NO;, -CN, -C(O)R®, -NHC(O)R7, -NHC (O)NRS5R52, -NHSO3R19, and -SO,;NR5R52;

R3e, at each occurrence, is independently selected from the group H, Ci-4 alkyl, -OH, C3-4 alkoxy, OCF3, F,

Cl, Br, I, -NR®R®2, -NO;, -CN, -C(O)R®, -NHC(O)R7, -NHC (O)NRSR52, -NHSO,R10, and -SO;NRSR53;

R3f, is selected from the group group H, F, Cl, Br, I, -OH, -O0-R11l, -0-C3_;, carbocycle substituted with 0- 2 R3e, -0(CcO)-R3, -0S(0),C;_4alkyl, -NR12rl2a, -C(O)R13, -NHC(O)R13, -NHSO,R10, and -SO,NR12R12a;

R%¢ is selected from the group H, F, Cl, Br, I, -OH, -0-R11, -0-C;_,¢ carbocycle substituted with 0-2

R3e, -0S(0),C;_salkyl, -NRI2RI1Z2a, (,_ alkyl substituted with 0-2 R3e, C3.1¢ carbocycle substituted with 0-2 R3e, phenyl substituted with 0-5 R3®, and a 5-10 membered heterocyclic system containing 1-3 heteroatoms selected from the group

O, N, and S, substituted with 0-2 R3e;

R> and R°2 are independently selected from the group H and Cj_4 alkyl;

alternatively, R3 and R33, together with the nitrogen to which they are attached, combine to form a 5-6 membered ring containing 0-1 OQ or N atoms;

S R6 is selected from the group H, OH, Ci_g alkyl, C;_; alkoxy, and NRSR52;

R7 is selected from the group H, Cj;.3 alkyl and Ci_3 alkoxy;

R8 is selected from the group H, (Ci-g alkyl)carbonyl,

Ci-6¢ alkoxyalkyl, (Ci-4 alkoxy)carbonyl, Cg-10 aryloxyalkyl, (Cg-190 aryl)oxycarbonyl, (Ceg-10 aryl)methylcarbonyl, (C;_4 alkyl)carbonyloxy(Ci_4 alkoxy) carbonyl, Ce-190 arylcarbonyloxy (Cj_4 alkoxy) carbonyl, Cj3-.g alkylaminocarbonyl, phenylaminocarbonyl, phenyl(Cj;-4 alkoxy)carbonyl, and (Ci-g alkyl substitued with NRSR52)carbonyl; and

RY is selected from the group Cj;-4 alkyl and phenyl

R11 is selected from C;_g alkyl, C;_¢ haloalkyl, C;_¢ alkyl substituted with C3_gcycloalkyl, C,_g alkenyl,

Cu. alkynyl, C5_g cycloalkyl;

R12 and R!22 are independently selected from H, Ci-6 alkyl, and C3_g cycloalkyl; alternatively, R!2 and R22 can join to form 4-7 membered ring; and

R13 is selected from the group H, Ci_¢ alkyl, C;_g haloalkyl, Ci_g alkoxy, Ci. alkenyl, Cy;_¢ alkynyl, -0-Cy-¢ alkenyl, -0-Cz.g alkynyl, NR12rR12a,

Cy_gcarbocycle, and -0-Cj3_gcarbocycle. {2]) In another embodiment, the present invention provides compounds of formula (I) as set forth above, wherein:

Rl is selected from the group Ci.3 alkyl substituted with 1-7 halogen, and cyclopropyl;

R2 is selected from the group -R2¢, -0OH, -CN, -ORZ2c, -OCHRZ22R2b, -QCH;CHRZ?aR2b, -0(CH;),CHR22R2Db, ~-OCHR2aCH=CHR2P, -OCHR2aCH=CHR2¢, -OCHR2aC=CR2P, -NR2aRZ¢, -SR2¢, -SCHR2aR2b, -SCH;CHRZ2R2b, -SCHR23CH=CHR?P, -SCHR22CH=CHR2¢, and -SCHR2aC=CR2b;

R22 js selected from the group H, CHz, CH>CH3, CH(CH3)3, and CH,CH3CHj3;

R2P is H or R2°;

R2¢ is selected from the group methyl substituted with 0-3 R3f, Ci_5 alkyl substituted with 0-3 R%, C,.g alkenyl substituted with 0-2 R%, Cy_.5 alkynyl substituted with 0-1 R%, C3.g¢ cycloalkyl substituted with 0-2 R34, and phenyl substituted with 0-2 R34;

R3 and R32, at each occurrence, are independently selected from the group H, Ci-4 alkyl, OH, Ci-4 alkoxy, F, C1, Br, I, NR5R52, NO,, -CN, C(O)RS,

NHC (O)R7, NHC(O)NR°R32, and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group O, N, and S; alternatively, R3 and R32 together form -OCH,0-;

R3P and R3¢, at each occurrence, are independently selected from the group H, Cj;-4 alkyl, OH, Cj-_4 alkoxy, F, Cl, Br, I, NR®R52, NO,, -CN, C(O)RS,

NHC (O)R7, and NHC (O)NRSR523; alternatively, R32 and R3P together form -OCH;0-;

R% is selected from the group H, Cl, F., -OH, -0-C;_galkyl, -0-C;_g5 carbocycle substituted with 0- 2 R3e, -0S(0),C,_4alkyl, -NR12R12a, C;_4 alkyl substituted with 0-2 R3e, C3_g carbocycle substituted with 0-2 R3e, phenyl substituted with 0-5 R3e, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group 0, N, and S, substituted with 0-2 R3e;

R> and R52 are independently selected from the group H,

CH3 and CzHs;

R6 is selected from the group H, OH, CH3, C,Hs, OCHj,

OC,Hs, and NR5R32; and

R7 is selected from the group CH3, C,Hs, CH(CH3)2, OCHj,

OC3H,, and OCH(CH3) 3.

(31 In an alternative embodiment the present invention also provides compounds of formula (I) as described above, wherein: ring A is selected from v

AN ESN ~ ~ 00 To

N N FENN HN

) , and 1) id SSN 0]

Rl is selected from the group CF3, CFs, CHF,, CF,CH; and cyclopropyl;

R2 is selected from the group -R2?¢, -OH, -CN, -OR2c, -OCHR22R2b, -OCH,CHR22R2P, -OCHR22CH=CHR?2V, -OCHR22CH=CHR2¢, -0QCHRZ22C=CR2?P, and -NRZaRZ¢;

R22 is selected from the group H, CH3, CHyCH3, CH(CHj3)3, and CH,CHCHj;

R2b is H or R2c;

R2¢ is selected from the group methyl substituted with 0-3 R3f, C;_3 alkyl substituted with 0-3 R%, Cy_3 alkenyl substituted with 0-2 R%, C;.3 alkynyl substituted with 0-1 R4, and Ci_g cycloalkyl substituted with 0-2 R39;

R3, R32, R3P, and R3¢, at each occurrence, are independently selected from the group H, Ci-3 alkyl, OH, Ci.3 alkoxy, F, C1, Br, I, NRS5R52, NO,, -

CN, C(O)Ré, NHC(O)R7, and NHC (O)NRSRS5a; alternatively, R3 and R32 together form -OCH,0-;

R3¢, at each occurrence, is independently selected from the group H, Ci-4 alkyl, -OH, Cj-4 alkoxy, OCF3, F,

Cl, -NR°R52, -C(O)R®, and -SO,NRSRS53;

R3f is selected from the group group H, F, Cl, Br, -OH, -0-R11, -O-cyclopropyl substituted with 0-2 R3e, -

O-cyclobutyl substituted with 0-2 R3e, -0O-phenyl substituted with 0-2 R3e, -0(CO)-R!3, -0S(0),C,_ salkyl, -NR12Rl2a, _c(0)R13, -NHC(O)R13, -NHSO,R!O, and -SO;NR12Rl2a;

R% is selected from the group H, Cl, F, -OH, -0-C;_galkyl, -0-C3.,¢ carbocycle substituted with 0-2 R3®, -0S(0),Cy_zalkyl, -NR12R12a C;_, alkyl substituted with 0-1 R3®, C3_g5 carbocycle substituted with 0-2 R3®, phenyl substituted with 0-2 R3®, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group 0, N, and S, substituted with 0-1 R3e;

R> and R®2 are independently selected from the group H,

CH3 and CzHs;

R® is selected from the group H, OH, CH3, CyHs, OCHj3,

OC2Hs5, and NR°R52; and

R7 is selected from the group CH3, CyHs, OCH3, and OCyHs;

Rll js selected from methyl, ethyl, propyl, i-propyl, butyl, pentyl, hexyl, CFj, CH,CF3, CH,CH,CF3, -CH,-cyclopropyl, and cyclopropyl;

R12 and R122 are independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, pentyl, and cyclopropyl;

R13 ig selected from the group H, methyl, ethyl, propyl, i-propyl, butyl, pentyl, hexyl, C;_¢ haloalkyl, methoxy, ethoxy, propoxy, i-propoxy, butoxy,

NR12R12a, cyclopropyl, cyclobutyl, cyclopropoxy, and cyclobutoxy.

[4] Another embodiment of the present invention include compounds of formula (I) as described above, wherein:

Rl is CF3, CF,CH;, or CHF,;

R2 is selected from the group -R2¢, -OH, -CN, -OCHRZ2b, -OCH3CHoR2P, -OCH,CH=CHRZ2P, -OCH,C=CR?P, and -

NRZ2aR2c;

R2?b is H or R2¢;

R2¢ jis selected from the group methyl substituted with 0-3 R3f, C;.3 alkyl substituted with 0-3 R%, Cj_3 alkenyl substituted with 1 R%4, and C;.3 alkynyl substituted with 1 R%;

R3, R32, R3P, and R3¢, at each occurrence, are independently selected from the group H, Cji-3 alkyl, OH, Cj.3 alkoxy, F, Cl, NRSR5a, NO,, -CN,

C(O)R®, NHC(O)R7, and NHC (O)NRSR52; alternatively, R3 and R32 together form -OCH,0-;

R3e, at each occurrence, is independently selected from the group CH;3, -OH, OCH3, OCF3, F, Cl, and -NRSR52;

R3f, is selected from the group group H, F, Cl, -OH, -0-R11, -0(C0)-R13, -0S(0),C;_4alkyl, -NRL2R12a, and ~NHC (0) NR12R12a;

R% is selected from the group H, Cl, F, CH3, CH,CHs, cyclopropyl substituted with 0-1 R3e, 1-methyl- cyclopropyl substituted with 0-1 R3e, cyclobutyl substituted with 0-1 R3e, phenyl substituted with 0-2 R3e, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group

O, N, and S, substituted with 0-1 R3e, wherein the heterocyclic system is selected from the group 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, 2-imidazolyl, morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl;

R> and R52 are independently selected from the group H,

CH3 and C3Hs;

R® is selected from the group H, OH, CH3, CaHs, OCH;, 0CyHsg, and NR3R32; and

R? is selected from the group CH3, C3Hs, OCH3, and CC3Hs.

[5] Another embodiment of the present invention include compounds of formula (I) as described above, wherein: 5) n is 0 or 1; ring A is optionally in an N-oxide form;

Rl is CF3, CHF,, or CF,CHj;

R? is selected from the group -R2¢, -0OR2¢, -OH, -CN, -OCH3R2P, -OCH,;CHR2P, -OCH,C=C-R2P, -OCH,C=C-RZ2Pb, -NR2@R2¢, -SR2¢, -SCHR2?P, -SCH,CH,R2b, —-SCH,CH=CHR?YP, and -SCH,C=CRZ2b;

R2P is H or RZ2c;

R2¢ is selected from the group methyl substituted with 0-2 R3f, ethyl substituted with 0-3 R%4, propyl substituted with 0-2 R4, ethenyl substituted with 0-2 R%?, 1-propenyl substituted with 0-2 R#%, 2-propenyl substituted with 0-2 R%, ethynyl substituted with 0-2 R%4, 1-propynyl substituted with 0-2 R%, 2-propynyl substituted with 0-2 R%, and cyclopropyl substituted with 0-1 R34;

R3e, at each occurrence, is independently selected from the group CH;, -OH, OCH, OCF3, F, Cl, and -NRSR5a;

R3f, is selected from the group group H, F, Cl, -OH, -0-R11, -0(co)-R13, -0S(0),C; salkyl, -NRI12R12a, and -NHC (0) NR12R12a;

RY is selected from the group H, Cl, F, CH, CH,CHi, cyclopropyl substituted with 0-1 R3®, 1-methyl- cyclopropyl substituted with 0-1 R3e, cyclobutyl substituted with 0-1 R3e, phenyl substituted with 0-2 R3®, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group 0, N, and S, substituted with 0-1 R3e, wherein the heterocyclic system is selected from the group 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, 2-imidazolyl, morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl;

RS and R52 are independently selected from the group H,

CH3 and CjHs;

R6 is selected from the group H, OH, CH3, CyHs, OCHj,

OC3Hs, and NRSR5a;

R7 is selected from the group CH3, CzHs, OCH3, and OCyHs;

R8 is H.

[6] Another embodiment of the present invention include compounds of formula (I) as described above, wherein: n is selected from 0 or 1;

A 1s selected from

00-5

Bi NG ' BY 7 . and x 7 o ;

B is selected from methyl, ethyl, propyl, -OH, Cl, Br, -S-CHy,

W is CR3;

X is CR3e;

Y is CR3a;

Z is N or CR33;

Rl is selected from CF;, CHF,, and CF,CHj,

R? is selected from -R2¢, -0OH, -CN, -OR2¢, -OCH,C=C-R2b, -OCH,C=C-R2?P, and -NR2aR2c;

R22 is H;

R2b is H;

R2¢ is selected from the group methyl substituted with 0-3 R3f, ethyl substituted with 0-3 R%, propyl substituted with 0-3 R4, i-propyl substituted with 0-3 R%, butyl substituted with 0-3 R%, 1l-propenyl substituted with 0-2 R4, 2-propenyl substituted with 0-2 R4, l-propynyl substituted with 0-2 R%, 2-propynyl substituted with 0-2 Ré%;

R3 is H;

R32 is H, F, Cl, or Br;

RI is H;

R3¢ is H;

R3e, at each occurrence, is independently selected from the group H, methyl, and ethyl, -OH, Cj_4 alkoxy,

OCF3, F, Cl, Br, I, -NR®R52, -NO;, -CN, -C(O)RS, -NHC (O)R7, -NHC(O)NRSR52, -NHSO,R10, and -SO,NRSRS52;

R3 is selected from H, F, Cl, OH, -OR!l, -0SO,methyl, -

NR12R12a, and -NHC(O)NRSR53;

RY is selected from H, F, -OH, -O-i-propyl, -0S(0),CHj, cyclopropyl substituted with 0-1 R3e, cyclobutyl substituted with 0-1 R3e, phenyl, N-morpholinyl, 2- pyridyl, 3-pyridyl, 4-pyridiyl, N2-methyl-N1- piperidinyl, N-piperidinyl, N-pyrrolidinyl, and N- piperazinyl;

R8 is H;

R11 is selected from H, methyl, ethyl, propyl, i-propyl,

CHycyclopropyl, and cyclopropyl; and

R12 and R122 are independently selected from H, methyl, ethyl, propyl, i-propyl, and cyclopropyl.

[7] Another embodiment of the present invention includes those compounds wherein the compound is of formula (Ic):

R! FR

W. :

XX

J °n

LZ

~Z7°N

RS

(Ic)

[8] Another embodiment of the present invention includes those compounds wherein the compound is of formula (Id):

RZ \R'

W. 3

AN

SOG

~ = n

Zz N

Re (Id)

Another embodiment of the present invention include compounds of formula (I) wherein: ring A is selected from: ~ ~ ~

AS, AS TN NAN

Xx J° 3. o B, 2 _N 1 JB ~~

N N N d N ; and ring A is optionally in an N-oxide form.

Another embodiment of the present invention include compounds of formula (I) wherein: ring A is selected from: [4 —

J : 2B, % N Be N ; and ring A is optionally in an N-oxide form.

In another embodiment, the present invention provides ring A is ~

Y co

In another embodiment, the present invention provides ring A is 0 lL.

XN

In another embodiment, the present invention provides ring A is ~ ~

Ov oo oo . py 1] »

AON 5 N Bite 7 BA

Oo

HO ) KO lo] » an b

HN AN

0 .

In another embodiment, the present invention provides the N on ring A is in the N-oxide form.

In another embodiment, the present invention provides the N on ring A is not in the N-oxide form.

Another embodiment of the present invention include compounds of formula (I) wherein:

W is CR3;

X is CR3a;

Y is CR3P; and

Z is CR3c.

W is CR3; :

X is CR32;

Y is CR3P; and 7 is selected from N and CR3c.

R? is selected from the group -R2€, -OH, -CN, -OR2°c, ~OCHR22R2P, -OCH;CHR2aR2b, -0(CH;)CHR22R2Db, -OCHR23CH=CHR2P, -OCHR22CH=CHR2¢, -OCHR2aC=CR2b, -NR23R2¢, -SR2C¢, -SCHR22R2P, -SCH,CHR2aR2b, -SCHR22CH=CHR2P, -SCHR2aCH=CHR2¢, and -SCHR22C=CR2b,

R? is selected from the group -R2¢, -OH, -CN, -OR2c, -OCHR2aR2P, -QCH,CHR22R2P, -OCHR22CH=CHRZ2b, -OCHR2?2CH=CHR2¢, -0OCHR22C=CR2P, and -NR2aRr2c,

R? is selected from the group -R2¢, -OR2C, -QCHRZ2aR2b, -OCH,CHR22R2b, -QCHR22CH=CHR2P, -OCHR2aCH=CHR2c, -OCHR?aC=CR?P, and -NRZ2aR2c,

R2¢ is selected from the group methyl substituted with 0-3 R3f, Cc; 5 alkyl substituted with 0-3 R4, C,_s alkenyl substituted with 0-2 R4, Cy_5 alkynyl substituted with 0-1 R%, C3.g cycloalkyl substituted with 0-2 R34, and phenyl substituted with 0-2 R34.

R2¢ is selected from the group methyl substituted with 0-3 R3f, C1.3 alkyl substituted with 0-3 R%, Cj_3 alkenyl substituted with 1 R%4, and Cz_3 alkynyl substituted with 1 R%.

RC is selected from the group methyl substituted with 0-2 R3f, ethyl substituted with 0-3 R%, propyl substituted with 0-2 R4, ethenyl substituted with 0-2 R%, l1l-propenyl substituted with 0-2 RY, 2-propenyl substituted with 0-2 R¢, ethynyl substituted with 0-2 R%, l-propynyl substituted with 0-2 R%4, 2-propynyl substituted with 0-2 R%, and cyclopropyl substituted with 0-1 R3d,

R4 is selected from the group H, Cl, F, CHz, CH;CHs, cyclopropyl substituted with 0-1 R3e, l-methyl- cyclopropyl substituted with 0-1 R3e, cyclobutyl substituted with 0-1 R3e, phenyl substituted with 0-2 R38, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group 0, N, and S, substituted with 0-1 R3®, wherein the heterocyclic system is selected from the group 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, 2-imidazolyl,

morpholiny>, piperidinyl, pyrrolidinyl, and piperazinyl.

R8 is H.

Another embodiment of the present invention include compounds of fomula (I) wherein:

R* is selected from H, F, -OH, -O-i-propyl, -0S(0O),CHj, cyclopropyl substituted with 0-1 R3e, cyclobutyl substituted with 0-1 R3e, phenyl, N-morpholinyl, 2- pyridyl, 3-pyridyl, 4-pyridiyl, N2-methyl-N1- piperidinyl, N-piperidinyl, N-pyrrolidinyl, and N- piperazinyl; and

[7] Compounds of the present invention include compounds of formula (I), or a stereoisomeric form, mixtures of stereoisomeric forms, complexes, prodrug forms or pharmaceutically acceptable salt form thereof, or N-oxide forms thereof, wherein the compound of formula (I) is selected from: the compounds of the Examples, Table 1, Table 2, Table 3, Table 4, and 7-Chloro-5-(cyclopropylmethoxy)-5,10-dihydro-5- (trifluoromethyl)benzo[b] [1, 8lnaphthyridine, 7-Chloro-5-(benzyloxy)-5,10-dihydro-5- (trifluoromethyl)benzo[b] (1, 8] naphthyridine,

7-Chloro-5- (cyclobutylmethoxy)-5, 10-dihydro-5- (trifluoromethyl)benzo(b] [1, 8]naphthyridine, 7-Chloro-5- (ethoxy) -5,10-dihydro-5~ (trifluoromethyl)benzo(b][1l, 8]naphthyridine, 7-Chloro-5- (hydroxy) -5,10-dihydro-5- (trifluoromethyl)benzo(b] (1, 8)naphthyridine,

7-Chloro-5- (n-propoxy) -5, 10-dihydro-5- (trifluoromethyl)benzo[b] [1, 8] naphthyridine, 7-Chloro-5-(i-propoxy) -5,10-dihydro-5- (trifluoromethyl )benzo(b] (1, 8] naphthyridine, 7-Chloro-5- (butyl) -5,10-dihydro-5- oe (trifluoromethyl)benzo([b] [1, 8] naphthyridine, 7-Chloro-5- (methoxy) -5,10-dihydro-5- (trifluoromethyl) benzo(l[b] {1, 8]naphthyridine, 7-Chloro-5(S)- (cyclopropylmethoxy)-5,10-dihydro-5- (trifluoromethyl )benzo[b] [1, 8] naphthyridine,

7-Chloro-5(R) -(cyclopropylmethoxy)-5,10-dihydro-5- (trifluoromethyl)benzo[b] [1,81 naphthyridine, 7-Chloro-5-(2-cyclopropylethyl)-5,10-dihydro-5- (trifluoromethyl) benzo[b] [1, 8]naphthyridine, 7-Chloro-5-(2,2,2-trifluoroethoxy)-5,10-dihydro-5- (crifluoromethyl)benzo(b] [1, 8]Jnaphthyridine,

7-Chloro-5- (propargoxy) -5, 10-dihydro-5- (crifluoromethyl)benzo([b) [1,8]naphthyridine, 7-Chloro-5- (ethyl) -5,10-dihydro-5- (trifluoromethyl)benzo(b] [1,8)naphthyridine, 7-Chloro-5-(cyclopropylmethoxy)-2-methyl-5,10-dihydro-5- (trifluoromethyl)benzo([b] [1, 8) naphthyridine, 7-Chloro-5- (n-butyl) -2-methyl-5,10-dihydro-5- (trifluoromethyl)benzo(b] [1, 8lnaphthyridine, 7-Chloro-5-(2-cyclopropylethyl) -2-methyl-5, 10-dihydro-5- (trifluoromethyl)benzo[b] [1, 8] naphthyridine,

7-Chloro-5-(cyclopropylmethoxy)-5, 10-dihydro-2- (methylthio)-5-(trifluoromethyl)pyrimido[4, 5- bljgquinoline,

7-Chloro-5-(i-butoxy)-5,10-dihydro-2- (methylthio)-5- {trifluoromethyl )pyrimido[4,5-blquinoline, 7-Chloro-5- (benzyloxy) -5, 10-dihydro-2- (methylthio) -5- (trifluoromethyl )pyrimido[4,5-blquinoline,

7-Chloro-5-(2-pyridylmethoxy)-5,10-dihydro-2- {methylthio)~-5-(trifluoromethyl)pyrimido|[4, 5- blquinoline, 7-Chloro-5-(cyclopropylmethoxy)-5,10-dihydro-5- (trifluoromethyl)pyrimido(4,S5-bljquinoline, 7-Chlorc-5-(cyclopropylamino) -5, 20-dihydro-5- (trifluoromethyl)benzo(b} (1, 8] naphthyridine,

7-Chloro-5- (i-propylamino)-5,10-dihydro-5- (trifluoromethyl)benzo(b] [1, 8) naphthyridine, 7-Chloro-5- (N,N-dimethylaminoethoxy) -5, 10-dihydro-5- (trifluoromethyl)benzo{b]} (1, 8] naphthyridine, 7-Chloro-5- (N-morpholinylethylamino)-5,10-dihydro-5- (trifluoromethyl)benzo([b] [1, 8) naphthyridine, 7-Chloro-5-((l-methylcyclopropyl)methoxy)-5,10-dihydro- 5-(trifluoromethyl)benzolb] [1,8]lnaphthyridine, 7-Chloro-5-(3,3,3-trifluoroprop-l-oxy)-5,10-dihydro-5- (trifluoromethyl )benzo([b] [1,8] naphthyridine,

7-Chloro-5-(cyclopropylmethylamino)-5, 10-dihydro-5- (trifluoromethyl )benzo[b] [1,8] naphthyridine, 7-Chloro-5- (methylamino)-5, 10-dihydro-5- (trifluoromethyl )benzo[b] [1l,8]naphthyridine, 7-Chloro-5-{ethylamino)-5,10-dihydro-5- (trifluoromethyl )benzo([b] [1,8]1naphthyridine, (S)-7-Chloro-5- (cyclopropylethyl)-5,10-dihydro-5- (trifluoromethyl) benzo[b] (1, 8)naphthyridine, (R)-7-Chloro-5- (cyclopropylethyl)-5,10-dihydro-5- (trifluoromethyl)benzo l(b] [1, 8)naphthyridine,

7-Fluoro-5-(cyclopropylmethoxy)-5,10-dihydro-5- (trifluoromethyl)benzo[b] [1,8] naphthyridine, 7-Fluoro-5- (cyclopropylethoxy)-5,10-dihydro-5- (trifluoromethyl) benzolb] [1,8)naphthyridine,

7-Fluoro-5-(allyloxy)-5,10-dihydro-5- (trifluoromethyl)benzo(b] [1, 8) naphthyridine, 7-Chloro-5- (phenylamino)-5,10-dihydro-5- (trifluoromethyl)benzo(b] [1, 8] naphthyridine, 7-Chloro-5-(cyclopropylmethoxy) -2-methyl-5,10-dihydro-5- (trifluoromethyl)benzo[b] [1, 8 naphthyridine,

7-Chloro-5- (n-butyl) -2-methyl-5, 10-dihydro-5- (trifluoromethyl)benzo([b] [1, 8] naphthyridine, 7-Chloro-5-(cyclopropylethyl) -2-methyl-5, 10-dihydro-5- (trifluoromethyl)benzo(b] [1, 8) naphthyridine, 7-Chloro-5-(cyclobutylmethoxy) -5,10-dihydro-5- (trifluoromethyl)pyrimido[4,5-b)Jquinoline, 7-Chloro-5- (methoxy) -5,10-dihydro-5- (trifluoromethyl)pyrimido[4,5-blquinoline, (S)-7-Chloro-5-(cyclopropylmethoxy)-5, 10-dihydro-5- (trifluoromethyl )pyrimido(4,5-b)quinoline,

(R)-7-Chloro-5-(cyclopropylmethoxy) -5, 10-dihydro-5- (trifluoromethyl)pyrimido[4,5-blquinoline, 7-Chloro-5-(N-piperidinylethoxy)-5,10-dihydro-5- (trifluoromethyl) pyrimido(4,5-blquinoline, 7-Chloro-5- (N-pyrrolidinylethoxy)-5, 10-dihydro-5- (trifluoromethyl) pyrimido(4,5-b]Jquinoline,

7-Chloro-5-((4-methylpiperazin-1-yl)prop-1-oxy)-5,10- dihydro-5- (trifluoromethyl) pyrimido[4, 5- blgquinoline, 7-Chloro-5-(prop-1l-oxy)-5,10-dihydro-5- (trifluoromethyl) pyrimido[4, 5-blgquinoline, 7-Chloro-5-(N,N-dimethylaminoprop-1-yl)-5, 10-dihydro-5- (trifluoromethyl)pyrimido([4,5-blquinoline,

7-Chloro-5- (benzyloxy) -5,10-dihydro-5- (trifluoromethyl) pyrimido[4, 5-blgquinoline, 7-Chloro-5-(3-pyridinylmethyl)-5,10-dihydro-5- (trifluoromethyl )pyrimido[4,5-blquinoline, 7-Chloro-5-(allyloxy)-5,10-dihydro-5- (trifluoromethyl)pyrimido[4,5-blquinoline, 7-Chloro-5- (propargoxy)-5,10-dihydro-5- (trifluoromethyl )pyrimido[4,5-blquinocline, and 7-Chloro-5-(N,N-dimethylaminoethyl) -5, 10-dihydro-5- (trifluoromethyl )pyrimido{4,5-blJquinoline;

7-Chloro-5-cyclopropylmethoxy-5-trifluoromethyl-5,10- dihydro-benzo[b] [1, 8) naphthyridine 1l-oxide; 5-Allyloxy-7-fluoro-5-trifluoromethyl-5, 10-dihydro- benzo[b][1l, 8) naphthyridine; 7-Fluoro-5-trifluoromethyl-5,10-dihydro- benzo [bl (1, 8lnaphthyridine-5-carbonitrile;

7-Fluoro-5-trifluoromethyl-5,10 dihydro- benzo [b] [1, 8]naphthyridin-5-0l; 5-Cyclopropylmethoxy-7-fluoro-5-trifluoromethyl-5,10- dihydro-benzo(b] [1, 8)naphthyridine 1 oxide; 7-Chloro-5-prop-2-ynyloxy-5-trifluoromethyl-5,10- dihydro-benzo(b] (1, 8]naphthyridine l-oxide; 7-Chloro-5-(1l-methyl-cyclopropylmethoxy)-5- trifluoromethyl-5,10-dihydro- benzo [bl] (1, 8lnaphthyridine l-oxide; 7-Chloro-5-(2-cyclopropyl-ethoxy)-5-trifluoromethyl- 5,10-dihydro-benzo{b] [1, 8] naphthyridine l-oxide; (7-Chloro-5~-trifluoromethyl-5, 10-dihydro- benzo [b] [1, 8] naphthyridin-5-yl) -isopropyl-amine; (7-Chloro-5-trifluoromethyl-5, 10-dihydro- benzo[b] [1,8] naphthyridin-5-yl) -cyclobutylmethyl- amine; 7-Chloro-5-(2-cyclopropyl-ethyl)-5-trifluoromethyl-5,10- dihydro-benzo[b] [1, 8] naphthyridine l-oxide; 5-Cyclobutylmethoxy-7-fluoro-5S-trifluoromethyl-5, 10- dihydro-benzo[b] [1, 8] naphthyridine l-oxide; (7-Fluoro-l-oxy-5-trifluoromethyl-5S, 10-dihydro- benzo [b] [1, 8) naphthyridin-5-yl) -isopropyl-amine;

5-Cyclobutylmethoxy-7-fluoro-5-trifluoromethyl-5,10- dihydro-benzol(b] [1, 8) naphthyridin-2-o01l; 7-Chloro-5- (pyridin-2-ylmethoxy) -5-trifluoromethyl-5,10- dihydro-benzo(b] [1, 8) naphthyridine; 5-Butyl-7-fluoro-5-trifluoromethyl-5,10-dihydro- benzo([b] [{1, 8) naphthyridine; 7-Chloro-l-oxy-5-trifluoromethyl-5,10-dihydro- benzo (b] [1,8]naphthyridin-5-o0l; 7-Chloro-5-cyclopropylmethoxy-5-trifluoromethyl-5,10- dihydro-benzo([b] [1, 8]naphthyridine l-oxide; 7-Chloro-5-pyridin-2-ylmethyl-5-trifluoromethyl-5,10- dihydro-benzo([b] [1, 8]naphthyridine 1l-oxide; 7-Fluoro-5-pyridin-2-ylmethyl-5-trifluoromethyl-5,10- dihydro-benzo[b] [1, 8]naphthyridine;

S-Cyclopropylmethoxy-7-fluoro-5-trifluoromethyl-5,10- dihydro-benzo[b] [1, 8lnaphthyridine l-oxide; 7-Chloro-5-pyridin-2-ylmethyl-5-trifluoromethyl-5,10- dihydro-benzo(b]} [1, 8)naphthyridine; 3,7-Dichloro-5-cyclopropylmethoxy-5-trifluoromethyl- 5,10-dihydro-benzo([b] [1, 81 naphthyridine; 3,7-Dichloro-5-cyclopropylmethoxy-5-trifluoromethyl- 5,10-dihydro-benzo(b] [1,8]naphthyridine l-oxide;

3,7-Dichloro-5-pentyl-5-trifluoromethyl-5,10-dihydro- benzo ([b] (1, 8)Jnaphthyridine l-oxide; 5-(2-Cyclopropyl-ethyl)-7-fluoro-5-trifluoromethyl-5,10- dihydro-benzo(b] [1, 8) naphthyridine; 5-(2-Cyclopropyl-ethyl)-7-fluoro-5-trifluoromethyl-5,10- dihydro-benzo[b] [1, 8) naphthyridine 1l-oxide;

3,7-Dichloro-5-cyclopropylmethoxy-5-trifluoromethyl- 5,10-dihydro-benzo[b] [1, 8]naphthyridine l-oxide;

5-(2-Cyclopropyl-ethyl) -7-fluoro-5-trifluoromethyl-5, 10- dihydro-benzol[b) [1,8]naphthyridine l-oxide;

3-Chloro-5-cyclopropylmethoxy-7-fluoro-5- ’ trifluoromethyl-5,10-dihydro- benzo ([b] [1, 8}naphthyridine;

3-Chloro-5-cyclopropylmethoxy-7-fluoro-5- trifluoromethyl-5,10-dihydro- benzo(b] [1,8)naphthyridine l-oxide;

7-Chloro-5-isobutoxy-5-trifluoromethyl-5,10-dihydro-

benzo(b] [1,8)naphthyridine l-oxide;

5-Butyl-7-chloro-5-trifluoromethyl-5, 10-dihydro- benzo [bl] [1, 8]lnaphthyridine l-oxide;

(S) 3-Chloro-5-cyclopropylmethoxy-7-fluoro-5- trifluoromethyl-5,10-dihydro- benzo(b] [1, 8) naphthyridine 1l-oxide;

(7-Chloro-5-trifluoromethyl-5,10-dihydro- benzo [b][1l, 8lnaphthyridin-5-yl)-methanol; 7-Fluoro-5-isobutoxy-5-trifluoromethyl-5,10-dihydro- benzo [b] [1,8)naphthyridine l-oxide; 7-Fluoro-5-isopropoxy-5-trifluoromethyl-5,10-dihydro- benzo[b] [1,8] naphthyridine l-oxide;

Methanesulfonic acid 7-chloro-5-trifluocromethyl-5,10- dihydro-benzo[b] [1l, 8) naphthyridin-5-ylmethyl ester; 7-Chloro-5-isopropoxy-5-trifluoromethyl-5,10-dihydro- benzo([b) (1, 8lnaphthyridine l-oxide; (7-Fluoro-5-trifluoromethyl-5, 10-dihydro- benzo[b] [1, 8)naphthyridin-5-yl)-acetonitrile; 7-Fluoro-5-trifluoromethyl-5,10-dihydro- benzo [b] [1,8] naphthyridine-5-carbaldehyde; 3-Bromo-5-cyclopropylmethoxy-7-fluoro-5-trifluoromethyl- 5,10-dihydro-benzo{b] [1, 8] naphthyridine l-oxide;

S-Butyl-7~-fluoro-5-trifluoromethyl-5,10-dihydro- benzo ([(b] [1,8 ]lnaphthyridine l-oxide; 5-Diisopropoxymethyl-7-fluoro-5-trifluoromethyl-5,10- dihydro-benzo[b] [1,8] naphthyridine; 7-Fluoro-5-isopropoxymethyl-5S-trifluoromethyl-5,10- dihydro-benzo[b] (1, 8]lnaphthyridine l-oxide;

7-Chloro-5-isobutyl-5-trifluoromethyl-5, 10-dihydro- benzo (bl [1, 8)naphthyridine 1l-oxide; 7-Chloro-5-propoxy-5-trifluoromethyl-5, 10-dihydro- benzo {b] [1, 8)naphthyridine 1-oxide; (S) 7-Fluoro-5-isobutoxy-5-trifluoromethyl-5,10-dihydro- benzo[b] (1, 8)naphthyridine l-oxide; (R) 7-Fluoro-5-isobutoxy-5-trifluoromethyl-5,10-dihydro- benzol[b] [1, 8) naphthyridine l-oxide; (7-Chloro-5-trifluoromethyl-5,10-dihydro- benzol[b] [1,8lnaphthyridin-5-yl)-acetaldehyde;

7-Chloro-5-(2,2-diisopropoxy-ethyl) -5-trifluoromethyl- 5,10-dihydro-benzo[b]l [1, 8] naphthyridine; 7-Chloro-5-(2-isopropoxy-ethyl)-5-trifluoromethyl-5,10- dihydro-benzo [bl [1, 8] naphthyridine; 2-(7-Chloro-5-trifluoromethyl-5,10-dihydro- benzo[b] [1,8]naphthyridin-5-yl)-ethanol; 7-Chloro-5-(2-isopropoxy-ethyl)-5-trifluoromethyl-5,10- dihydro-benzo[b] [1, 8] naphthyridine l-oxide; (R) 7-Fluoro-5-(2-isopropoxy-ethyl)-S-trifluoromethyl- 5,10-dihydro-benzo[b] (1, 8Jnaphthyridine l-oxide;

(7-Fluoro-5-trifluoromethyl-5,10-dihydro- benzc[b] (1, 8lnaphthyridin-5-yl)-acetic acid tert- butyl ester;

(7-Fluoro~l-oxy-5-trifluoromethyl-5,10-dihydro- benzo [b] (1, 8] naphthyridin-5-yl) -acetic acid tert- butyl ester;

(7-Fluoro-5-trifluoromethyl-5, 10-dihydro- benzo [b] [1,8] naphthyridin-5-yl) -acetic acid; 7-Chloro-5-cyclopropylmethoxy-2-methylsulfanyl-5- trifluoromethyl-5,10-dihydro-pyrimido[4, 5- blquinoline; 7-Chloro-5-isobutoxy-2-methylsulfanyl-5-trifluoromethyl- 5,10-dihydro-pyrimido(4,5-blgquinoline;

5-Benzyloxy-7-chloro-2-methylsulfanyl-5-trifluoromethyl- 5,10-dihydro-pyrimido(4,5-blquinoline; 7-Chloro-2-methylsulfanyl-5- (pyridin-2-ylmethoxy)-5- trifluoromethyl-5,10-dihydro-pyrimido(4,5- blgquinoline; 7-Chloro-5-cyclopropylmethoxy-5-trifluoromethyl-5,10- dihydro-pyrimido(4,5-blquinoline l-oxide;

7-Chloro-5-cyclopropylmethoxy-5-(1,1-difluoro-ethyl) - 5,10-dihydro-benzo[b] [1, 8lnaphthyridine l-oxide; 5-Cyclopropylmethoxy-5-(1, 1-difluoro-ethyl)-7-fluoro- 5,10-dihydro-benzo(bl (1, 8) naphthyridine; 5-Cyclopropylmethoxy-5-(1,1-difluoro-ethyl)-7-fluoro- 5,10-dihydro-benzo[b] [1,8] naphthyridine 1l-oxide;

7-Chloro-5-(1,1-difluoro-ethyl)-5-isobutoxy-5,10- dihydro-benzo(b} (1, 8] naphthyridine;

7-Chloro-5-(1,1-difluoro-ethyl)-5-isobutoxy-5, 10-

dihydro-benzo!b] [1, 8] naphthyridine 1l-oxide;

(R) 7-Chloro-5-cyclopropylmethoxy-5-(1,1-difluoro- ethyl) -5,10-dihydro-benzo(b] (1, 8) naphthyridine 1- oxide;

(S) 7-Chloro-5-cyclopropylmethoxy-5-(1,1-difluoro- ethyl) -5, 10-dihydro-benzo[b] [1, 8} naphthyridine 1- oxide;

3-Chloro-10-cyclopropylmethoxy-10-trifluoromethyl-9,10- dihydro-1, 8,9-triaza-anthracene; 3-Chloro-10-cyclopropylmethoxy-10-trifluoromethyl-9,10- dihydro-1, 8, 9-triaza-anthracene 8-oxide;

3,6-Dichloro-10-cyclopropylmethoxy-10-trifluoromethyl- 9,10-dihydro-1,8,9-triaza-anthracene;

3-Chloro-10-isobutoxy-10-trifluoromethyl-9,10-dihydro-

1,8,9-triaza-anthracene; 3-Chloro-10-isobutoxy-10-trifluoromethyl-9,10-dihydro- 1,8,9-triaza-anthracene 8-oxide; 7-Chloro-5-difluoromethyl-5-isopropoxymethyl-5,10- dihydro-benzo([b) [1, 8) naphthyridine; 7-Chloro-5-difluoromethyl-5-isopropoxymethyl-5,10- dihydro-benzo([b] {1, 8lnaphthyridine 1l-oxide:

7-chloro-1,5-dihydro-5- (N-ethylaminomethyl) -5- (trifluoromethyl)benzo(b] (1, 8)napthyridine; 7-chloro-5,10-dihydro-5- (N-isopropylaminomethyl) -5- (trifluoromethyl )benzo([b] {1,8]napthyridine; 7-chloro-5,10-dihydro-5- (N-isopropyl-N- ethylaminomethyl) -5- (trifluoromethyl )benzol[b] [1,8]napthyridine;

7-chloro-5-(N,N-diethylaminomethyl)}-5, 10-dihydro-5- (trifluoromethyl )benzolbl [1,8lnapthyridine; 5-(acetamidomethyl)-7-chloro-5,10-dihydro-5- (trifluoromethyl) [b}[1l, 8lnapthyridine; 5,10-dihydro-7-fluoro-5- (N-methylsulfonylmethyl)-5- (trifluoromethyl) [b] [1, 8] napthyridine; 5,10-dihydro-7-fluoro-5- (isopropylamidomethyl) -5- (trifluoromethyl) [b] [1, 8) napthyridine; 5,10-dihydro-7-£fluoro-5- (isopropylguanadinomethyl)-5- (trifluormethyl) [bl [1l, 8] napthyridine;

1,5-dihydro-7-fluoro-5- (N-isopropylmethyl)-5- (trifluoromethyl) [b] (1, 8lnapthyridine-1- (N-oxide) ; 5-(N,N-diethylaminomethyl)-5,10-dihydro-7-fluoro-5- (trifluoromethyl) [b]) [1, 8] napthyridine-1- (N-oxide); 5,10-dihydro-5-(N,N-dimethylaminomethyl) -7-fluoro-5- (trifluoromethyl) [b] [1,8] napthyridine-1- (N-oxide);

7-chloro-5,10-dihydro-5- (N-isopropylaminomethyl) -5- (trifluoromethyl) [bl [1, 8] napthyridine-1- (N-oxide); 7-chloro-5-(N,N-diethylaminomethyl)}-5,10-dihydro-5- (trifluoromethyl) (b] [1, 8) napthyridine-1- (N-oxide) ; and 7-chloro-5,10-dihydro-5- (N,N-dimethylaminomethyl)-5- (trifluoromethyl) [b] [1, 8) napthyridine-1- (N-oxide.

Another embodiment of the present invention are those compounds wherein the heterocyclic ring A is in an

N-oxide form.

The present invention also provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof

The compositions and methods of use comprising the compounds of the present invention include compositions and methods of use comprising the compounds of the present invention and stereoisomeric forms thereof, mixtures of stereoisomeric forms thereof, complexes thereof, crystalline forms thereof, prodrug forms thereof and pharmaceutically acceptable salt forms thereof

In another embodiment, the present invention provides a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof

In another embodiment, the present invention provides a novel method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of: (a) a compound of formula (I); and (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and

HIV protease inhibitors.

Preferred reverse transcriptase inhibitors useful in the above method of treating HIV infection are selected from the group AZT, d4ddC, ddI, d44T, 3TC, delavirdine, efavirenz, nevirapine, Ro 18,893, trovirdine, MKC-442, HBY 097, HBY1293, GW867, ACT,

UCc-781, UC-782, RD4-2025, MEN 10979, and AG1549 (S1153).

Preferred protease inhibitors useful in the above method of treating HIV infection are selected from the group saquinavir, ritonavir, indinavir, amprenavir, nelfinavir, palinavir, BMS-232623, GS3333, KNI-413,

KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-140690, and ABT-378.

In another embodiment, the reverse transcriptase inhibitor is selected from the group AZT, efavirenz, and 3TC and the protease inhibitor is selected from the group saquinavir, ritonavir, nelfinavir, and indinavir.

In another embodiment, the reverse transcriptase inhibitor is AZT.

In another embodiment, the protease inhibitor is indinavir.

In another embodiment, the present invention provides a pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of: (a) a compound of formula (I); and, (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and

HIV protease inhibitors, in one or more sterile containers.

In another embodiment, the present invention provides novel tricyclic compounds for use in therapy.

In another embcdiment, the present invention provides the use of novel tricyclic compounds for the manufacture of a medicament for the treatment of HIV infection.

The invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention also encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional embodiments of the present invention. Furthermore, any elements of an embodiment are meant to be combined with any and all other elements from any of the embodiments to describe additional embodiments.

DEFINITIONS

It will be appreciated that the compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.

The present invention is intended to include all isotopes of atoms occurring on the present compounds.

Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

As used herein, the following terms and expressions have the indicated meanings.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. By way of illustration, the term "Cj;_j0 alkyl" or "C1-Cip alkyl" is intended to include C;, Cz, C3, Cg,

Cs, Cg, C7, Cg, Cg, and Cig alkyl groups. "Ci_g4 alkyl" is intended to include Cj, C3, C3, and C4 alkyl groups.

Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example -CyF, where v = 1 to 3 and w = 1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, 2,2, 2- trifluoroethyl, 3,3,3-trifluoropropyl,pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Cj_1g alkoxy, is intended to include C3, Cz, C3, C4, Cs, Cg,

C7, Cg, Cg, and Cyjp alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. "Cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl, is intended to include C3, C4, Cs, Cg, and Cy cycloalkyl groups. “Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like. Cz_jp alkenyl, is intended to include Cz, C3, Cs, Cs, Cg, C7, Cg, Cg, and

C10 alkenyl groups. "Alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. Cz.1p alkynyl, is intended to include Cj, C3, C4, Cs, Cg, C7, Cg, Cg, and Cig alkynyl groups. "Halo" or "halogen" as used herein refers to fluoro, chloro, bromo and iodo. "Counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.

As used herein, "aryl" or "aromatic residue” is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as phenyl or naphthyl. As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12 or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic.

Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0])bicyclooctane, [4.3.0}bicyclononane, [4.4.0])bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl.

As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10- membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, 0 and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. An oxo group may be a substituent on a nitrogen heteroatom to form an N-oxide. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.

If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or l0-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 hetercatoms independently selected from the group consisting of N, 0 and 8S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro(2,3-b]tetrahydrofuran, 5,10-dihydro- benzo (bl [1l, 8lnaphthyridinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, 1isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole,

pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrimido([4,5-bjquinolinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, gquinazolinyl, quinolinyl, 4H-gquinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

As used herein, "HIV reverse transcriptase inhibitor" is intended to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT) . Examples of nucleoside RT inhibitors include, but are not limited to, AZT, d4ddC, ddI, d4T, and 3TC.

Examples of non-nucleoside RT inhibitors include, but are no limited to, delavirdine (Pharmacia and Upjohn

U901528), efavirenz (DuPont), nevirapine (Boehringer

Ingelheim), Ro 18,893 (Roche), trovirdine (Lilly),

MKC-442 (Triangle), HBY 097 (Hoechst), HBY1293 (Hoechst), GWB867 (Glaxo Wellcome), ACT (Korean Research

Institute), UC-781 (Rega Institute), UC-782 (Rega

Institute), RD4-2025 (Tosoh Co. Ltd.), MEN 10979 (Menarini Farmaceutici) and AG1549 (S1153; Agouron).

As used herein, "HIV protease inhibitor" is intended to refer to compounds which inhibit HIV protease. Examples include, but are not limited, saquinavir (Roche, Ro31-8959), ritonavir (Abbott,

ABT-538), indinavir (Merck, MK-639), amprenavir (Vertex/Glaxo Wellcome), nelfinavir (Agouron, AG-1343), palinavir (Boehringer Ingelheim), BMS-232623 (Bristol-Myers Squibb), GS3333 (Gilead Sciences),

KNI-413 (Japan Energy), KNI-272 (Japan Energy), LG-71350 (LG Chemical), CGP-61755 (Ciba-Geigy), PD 173606 (Parke

Davis), PD 177298 (Parke Davis), PD 178390 (Parke

Davis), PD 178392 (Parke Davis), U-140690 (Pharmacia and

Upjohn), and ABT-378. Additional examples include the cyclic protease inhibitors disclosed in W093,/07128, WO 94/19329, WO 94/22840, and PCT Application Number

US96/03426.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical

Sciences, 17th ed., Mack Publishing Company, Easton, Pa, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject.

Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.

Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.

Examples of prodrugs at R® are Cj;.g alkylcarbonyl, Ci-¢ alkoxy, Cj-4 alkoxycarbonyl, Cg-19 aryloxy, Ce-10 aryloxycarbonyl, Ce-19 arylmethylcarbonyl, Cj_-4 alkylcarbonyloxy Cji-4 alkoxycarbonyl, Cg-10 arylcarbonyloxy Cj;-4 alkoxycarbonyl, Cj_g alkylaminocarbonyl, phenylaminocarbonyl, and phenyl Ci-a alkoxycarbonyl. "Stable compound” and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contemplated by the present invention. "Substituted" is intended to indicate that one or more hydrogens on the atom indicated in the expression using "substituted" is replaced with a selection from the indicated group(s), provided that the indicated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =0) group, then 2 hydrogens on the atom are replaced. "Therapeutically effective amount” is intended to include an amount of a compound of the present invention alone or in combination with other active ingredients or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination.

Synergy, as described for example by Chou and Talalay,

Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.

Synthesis

The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art.

Preferred methods include but are not limited to those methods described below. Each of the references cited below are hereby incorporated herein by reference. In the Schemes which follow, R! is shown as a CF3 group, but could be any one of the presently described R1 groups.

Scheme 1

Ww HO,C

I x W_ H

X OC

+ re.

YF F

NH, CI N NF AN 2 N N

H

A

(o] 0

XN = \

X x” AN = lA A) — z N N NF x z N N

H

SEM Cc B

F3C OH FaC A w 0 x” EN =z x” A =

I — 1 ~~; i N ~~; N N

D SEM L, E

FaC A

Ww,

I TI

Y. = nn

Nz N N

H

F

Scheme 1 illustrates the reaction between an aryl/heterocyclic amine with 2-chloronicotinic acid to obtain the di-substituted amine A which can be cyclized using PPA to give B. Protection of the amine, followed by reaction with TMSCF3 in the presence of TBAF gives D, which can be alkylated using a base and an alkylhalide and then deprotected to give F.

Scheme 2

CF5 xa INN

DF —_— I"

Ya_2o = V

A N N

G

FsC. R?

W

XT NX

G _— i

YZ =

Zz N N

H

Scheme 2 illustrates the aromatization of either D or FP to give the compound G. The compound G can then be alkylated either through reaction with a Grignard reagent, or alternatively, by reaction with an organometalic reagent to give H.

When required, separation of the diasteriomeric material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Thomas J. Tucker, et al, J. Med. Chem. 1994, 37, 2437-2444. A chiral compound of formula (I) may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g. Mark A. Huffman, et al, J. Org.

Chem. 1995, 60, 1590-1594.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

Examples

Abbreviations used in the Examples are defined as follows: "°C" for degrees Celsius, "d" for doublet, "dd" for doublet of doublets, "eg" or “equiv” for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "mL" for milliliter or milliliters, "H" for hydrogen or hydrogens, "hr" for hour or hours, "m" for multiplet, "M" for molar, "min" for minute or minutes, "MHz" for megahertz, “mp” for melting point, "MS" for mass spectroscopy, "nmr" or "NMR" for nuclear magnetic resonance spectroscopy, "t" tor triplet, "TLC" for thin layer chromatography, "CDI" for carbonyl diimidazole, "DIEA" for diisopropylethylamine, *"DIPEA" for diisopropylethylamine, "DMAP" for dimethylaminopyridine, "DME" for dimethoxyethane, "EDAC" for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, "LAH" for lithium aluminium hydride, “"MCPBA" is meta-chloroperbenzoic acid, "TBAF" for tetrabutylammonium fluoride, "TBS-Cl" for t-butyldimethylsilyl chloride, "TEA" for triethylamine,

“PPA” for polyphosphoric acid, “SEM-Cl” for 2- (trimethylsilyl) ethoxymethyl chloride, “TMS-CF3” for trifluoromethyltrimethylsilane, “THF” for tetrahydrofuran, “DMF” for dimethylformamide, “TFA” for trifluoroactic acid, “NCS” for N-chlorosuccinimide, “EtOAc” for ethyl acetate, and “LDA” for lithium diisopropylamide.

All reactions were run under a nitrogen atmosphere at room temperature and most were not optimized. The reactions were followed by TLC. Reactions run overnight were done so for adequate time. Reagents were used as received. Dimethylformamide, tetrahydrofuran and acetonitrile were dried over molecular sieves. All other solvents were reagent grade. Ethanol and methanol were absolute and water was deionized. Melting points were determined in open capillary tubes on a Mel-Temp apparatus and are uncorrected. Column chromatographies were done on flash silica gel. Exceptions to any of the conditions above are noted in the text. Chiral HPLC separations were done using chiral columns which gave the enantiomers in >99% EE.

The following methods are illustrated in the synthetic schemes which follow the methods. While the examples are described for specific compounds, the same methods were employed to synthesize the other compounds which are listed in the table of examples.

Example 1

Synthesis of 7-Chloro-5-(cvcloproppylmethoxy)-5,10- dihydro-5-(trifluoromethyl)benzo[b] [1,6 8lnaphthyridine.

Method A. A mixture of the 4-chlorocaniline (18.3 g, 144 mmol) and 2-chloronicotinic acid (24.6 g, 144 mmol) in toluene (250 mL) was refluxed for 3 hours. The reaction was poured into a mixture of hexane and saturated NaHCO3 (200 mL and 500 mL) and it was stirred vigorously for 30 minutes. Filtration gave 1 as a light creamy white powder that was used without further purification, 22 g (85%).

Method B. A mixture of 1 (30 g, 114 mmol) in PPA (35 mL) was stirred at 170 degrees C for 1.5 hours. The reaction was diluted with 1 N NaOH (400 mL) and the pH was adjusted to 2 with 50% NaOH then filtered. The solid cake was re-suspended in water (400 mL) and the pH adjusted to 8 with 1N NaOH. Filtration gave 2 as a light tan powder that was used without further purification, 22.8 g (82%).

Method C. To a mixture of 2 (8.31 g, 36.1 mmol) and .

SEM-Cl (9.55 mL, S4.2 mmol) in DMF (100 mL) was added

NaH (60%, 2.89 g, 72.3 mmol). After stirring overnight, the reaction was diluted with ethyl acetate (200 mL), washed with saturated NaHCO; (3x200 mL) and saturated

NaCl (50 mL), dried (MgSO,) and evaporated at reduced pressure. Chromatography of the residue (hexane/ethyl acetate, 5-10%) gave a creamy foam on evaporation. It was crystallized from hexane giving 3 as creamy white needles, 9.02 g (69%).

Method D. To a solution of 3 (7.84 g, 21.8 mmol) and TMS-CF3 (4.82 mL, 32.7 mmol) in chilled THF (0 degrees C, 150 mL) was added TBAF (1N in THF, 16.3 mL).

After stirring for 10 minutes, the reaction was diluted with ethyl acetate (100 mL), washed with saturated

NaHCO; (3x150 mL) and saturated NaCl (50 mL), dried (MgSO4) and evaporated at reduced pressure giving a reddish brown powder. It was crystallized from hexane giving 4 as a light tan powder, 8.09 g (86%).

Method E. To a solution of 4 (4.00 g, 9.30 mmol) and cyclopropylmethylbromide (1.08 mL, 11.2 mmol) in DMF

(50 mL) was added NaH (0.63 g, 15.7 mmol). After stirring overnight, the reaction was diluted with ethyl acetate (100 mL), washed with saturated NaHCO; (3x70 mL) and saturated NaCl (20 mL), dried (MgSO;) and evaporated at reduced pressure which gave 5 as a thick light brown oil that was used without further purification.

Method F. A solution of 5 (~9.30 mmol} and TFA (5 mL) in dichloromethane (40 mL) was stirred under a glass stopper for one hour. The reaction was diluted with ethyl acetate (100 mL), washed with saturated NaHCO; (3x70 mL) and saturated NaCl (20 mL), dried (MgSO,) and evaporated at reduced pressure giving a brown foam.

Chromatography (hexane/ethyl acetate, 20%) gave a light yellow foam on evaporation. It was crystallized from hexane giving 6 as creamy white micro-needles, 2.06 ¢g (63% for steps E and F).

Cl HO,C

XY aC HOLC, Z + — —p

NH

H 1 le o 0

CLO) = Cr)

N

NN NSN

Jo SEM 3 2 H

FsC_ OH F4C oN, “CL =" Cro

S <

N N N N

4 SEM IF SEM

F;C oF “CL

N™ °N

H

6

Example 2

Synthesis of 7-Chloro-5-trifluoromethyl- benzo[b]l [1,8]1naphthyridine

CF,

NZ Ng

Method G. A solution of 6 (1.41 g, 3.98 mmol) in

TFA (14 mL) was stirred overnight. The reaction was evaporated at reduced pressure and the residue was dissolved in dichloromethane (35 mL), washed with saturated NaHCO; (3x20 mL) and saturated NaCl (5 mL), dried (MgSO4) and evaporated at reduced pressure giving a tan crystalline powder. It was triturated in hexane giving 7 as a light tan powder, 1.01 g (90%).

Example 3

Synthesis of 7-Chloro-5- (ethoxy) -5,10~-dihydro-5- (trifluoromethyl )benzo(bl[1,8]lnaphthyridine.

Method H. A solution of 6 (31 mg, 0.088 mmol) and

THF (0.2 mL) in ethanol (3 ml) was refluxed for 4 hours.

The reaction was diluted with ethyl acetate (30 mL), washed with saturated NaHCO; (3x25 mL) and saturated

NaCl (5 mL), dried (MgS0O4) and evaporated at reduced pressure giving a white powder. Chromatography (ether /hexane, 20%) gave a white powder, which was crystallized from dichloromethane and hexane giving 8 as a white crystalline powder, 18 mg (63%).

Example 4

Synthesis of 7-Chloro-5-(n-butyl)-5,10-dihydro-5- (trifluoromethyl)benzo {bl (1, 8lnaphthyridine.

Method I. To a chilled (0 degree C) solution of 7 (86 mg, 0.304 mmol) in THF (3 mL) was added butylmagnesium chloride (0.460 mL, 0.915 mmol). After stirring for 10 minutes, the reaction was diluted with ethyl acetate (30 mL), washed with saturated NaHCO; (3x25 mL) and saturated NaCl (5 mL), dried (MgSO,) and evaporated at reduced pressure giving clear brown film.

Chromatography (hexane/ethyl acetate, 20%) gave a white powder, which was crystallized from hexane giving 9 as a white crystalline powder, 24 mg (23%).

Example 5

Synthesis of 7-Chloro-5-(ethyl)-5,10-dihydro-5- (trifluoromethyl )benzo[bl[1,8]naphthyridine.

Method J. To a chilled (15 degree C) solution of 7 (30.0 g, 0.106 mmol) in benzene (3 mL) was added diethyl zinc (1N in hexane, 0.530 mL). After stirring - 20 overnight, the reaction was diluted with ethyl acetate (20 mL), washed with saturated NaHCO; (3x15 mL) and saturated NaCl (5 mL), dried (MgSO,;) and evaporated at reduced pressure giving a light brown film.

Chromatography (hexane/ethyl acetate, 20%) gave a white powder, which was crystallized from hexane giving 10 as a white microcrystalline powder, 12 mg (34%).

Method K. A mixture of 37 (1.96 g, 4.80 mmol, synthesized by route A, B & C starting with ethyl 4- chloro-2-methylthio-5-pyrimidine carboxylate instead of 2-chloronicotinic acid) and Raney Nickel (excess) was refluxed in ethanol (15 mL) for 30 minutes. The reaction was filtered through celite and evaporated at reduced pressure giving a yellow solid. Chromatography

(hexane/ethyl acetate, 20%) gave 3” as a yellow powder on evaporation, 580 mg (33%).

CF;

Cl

Xr woe SOLD

A 2

N™ °N

Fic. o-Me

Cl gr.

N N

H

FiC Me

Cl x 7 —_— | _ 9

N™ °N

H

F5C ; cl Me 10 7 —

N N

H

0] 0]

REST oH: = -_— p>

N N= “SMe N N

SEM SEM

3 3"

Example 6

Synthesis of Cvyclopropvlethyl magnesium bromide.

Method L. To a chilled (0 degree C) solution of cyclopropylacetic acid (5.0 g, 50 mmol) in THF (50 mL) was added BH;3.THF (1N in THF, 70 mL). After stirring overnight at room temperature, the reaction was quenched with water. It was then diluted with ethyl acetate (50 mL), washed with 1N HCl (3x30 mL) and saturated NaCl (10 mL), dried (MgSO4) and evaporated at reduced pressure giving 11 as a colorless oil that was used without further purification, 4.3 g.

Method M. A mixture of 11 (4.3 g, 50 mmol), I, (12.7 g, 50 mmol), PhyP (13.1 g, 50 mmol) and imidazole {3.41 g, 50 mmol) in dichloromethane (140 mL) was stirred for two hours. The reaction was evaporated at reduced pressure and chromatography (hexane) gave 12 as a brown oil on evaporation, 6.3 g (64%).

Method N. To a chilled (-78 degree C)} solution of 12 (0.245 mL, 1.06 mmol) in THF (5 mL) was added t-butyl lithium (1.25 mL, 2.13 mmol). After warming to room temperature and stirring for one hour, the solution was re-chilled (to -78 degree C) and MgBr, was added (1N in ether/benzene, 1.06 mL). The reaction was then allowed to warm to room temperature and then it was stirred for one hour affording a solution of 13.

CoH og 1” BrMg 1 12 13

Example 7

Synthesis of 7-Chloro-5-(cvclopropylmethylamino)-5,10- dihydro-5-(trifluoromethyllbenzo{bl[1,8lnaphthyridine.

Method O. A solution of 7 (50 mg, 0.177 mmol) cyclopropylmethylamine (0.031 mL, 0.355 mmol) in DMF (2 mL) was stirred for 1 hour. The reaction was diluted with ethyl acetate (20 mL), washed with saturated NaHCO; {3x15 mL) and saturated NaCl (5 mL), dried (MgSO,) and evaporated at reduced pressure giving a yellow film.

Chromatography (hexane/ethyl acetate, 30%) gave a white powder, which was crystallized from hexane giving 14 as a white crystalline powder, 26 mg (42%).

Example 8

Synthesis of 7-Chloro-5-(phenylamino)-5,10-dihydro-5- {trifluoromethyl )benzo[bl [1,81naphthyridine.

Method P. To a solution of 7 (50 mg, 0.177 mmol) and aniline (0.024 mL, 0.266 mmol) in DMF (3 mL) was added NaH (excess). After stirring 15 minutes, the reaction was diluted with ethyl acetate (20 mL), washed with saturated NaHCO3 (3x15 mL) and saturated NaCl (5 mL), dried (MgSO,) and evaporated at reduced pressure which gave a brown film. Chromatography (hexane/ethyl acetate, 30%) gave a yellow film, which was crystallized from hexane and dichloromethane giving 15 as a creamy white crystalline powder, 27 mg (41%).

Example 9

Synthesis of 7-Chloro-5-(3,3,3-trifluoroprop-l-oxy)- 5,10-dihvydro-5- (trifluoromethvl)benzo[b][1, 8])naphthyridine

Method Q. To a solution of 7 (50 mg, 0.177 mmol) and 3,3,3-trifluoropropanol (0.040 mL, 0.355 mmol) in

DMF (3 mL) was added NaH (excess). After stirring 15 minutes, the reaction was quenched with saturated NH,C1, diluted with ethyl acetate (20 mL), washed with saturated NaHCO; (3x15 mL) and saturated NaCl (5 mL), dried (MgSO4) and evaporated at reduced pressure which gave a yellow film. It was crystallized from hexane giving 16 as a tan crystalline powder, S54 mg (77%).

CF, FC. NH

Cl v7 —_— ~

N N

N™ °N H 7 14 B

FaC. NH 7 —_— . Ps

N™ °N

H

15

CF.

FC oY 3

Q dC -

FOOD

A

N N

H

16

Example Sa

Synthesis of 7-Chloro-5-pyridin-2-vimethyl-5- trifluoromethyl-5,10-dihydro-benzo[b][1,8]lnaphthvyridine.

Method R; A solution of 2-picoline (5.0 mL, 51 mmol) and LDA (50 mmol) in THF (50 mL) was stirred for 3 hours under nitrogen at -78°C. The azaacridine 7 was added and the reaction was stirred at -78°C for 30 minutes then it was allowed to warm to room temperature over 30 minutes. The reaction was quenched with saturated NH4Cl then diluted with ethyl acetate (50 mL), washed with saturated NaHCO; (3x30 mL) and saturated

NaCl (5 mL), dried (MgSO4) and evaporated at reduced pressure giving a brown syrup. Chromatography (ethyl acetate/hexane, 40%) gave a creamy film, which was crystallized from dichloromethane and hexane giving 19 as a creamy white crystalline powder, 645 mg (20%).

Example Sb

Synthesis of 3,7 Dichloro 5 triflucromethyl-5,10- dihydro-benzo[b] [1, 8} naphthyridin-5-0l.

Method S; A solution of the azaacridine hydrate 20 (100 mg, 0.33 mmol) and NCS (49 mg, 0.37 mmol) in isopropanol (5 mL) was refluxed for 15 minutes under nitrogen. The reaction was diluted with ethyl acetate (20 mL), washed with 1N HCl (3x10 mL) and saturated NaCl (5 mL), dried (MgSO4) and evaporated at reduced pressure giving a yellow powder. Trituration from dichloromethane and gave the 3-chloroazaacridine 21 as a creamy white crystalline powder, 102 mg (92%). — \ _N

FaC

Cla N 7 BR ps

N N ig H

FsC. OH o. Fo oH ol 3 ol xy S ~ ) — Ll _ ~

NN N° N

H 21 20

Example 10

Synthesis of 7-chloro-5-(cyclopropylmethoxy)-5,10- dihydro-1N-ox0-5- (trifluoromethyl )benzo!bl!1, 8lnaphthyridine.

Method U. A solution of 17 (150 mg, 0.424 mmol) mCPBA (3-chloroperbenzoic acid) (91 mg, 0.424 mmol) in dichloromethane (3 mL) was stirred for 2 hours. The reaction was diluted with ethyl acetate (10 mL), washed with 1N NaOH (3x10 mL) and saturated NaCl (5 mL), dried (MgS0,) and evaporated at reduced pressure giving a brown film. Chromatography (ethyl acetate) gave a colorless film, which was crystallized from dichloromethane and hexane giving 18 as a creamy white crystalline powder, 56 mg (36%).

FC, oN, FsC oF

N Nig N N”

H H S

17 18

Method Z. Chiral HPLC separation was performed using chiral columns which gave the (R) and (5S) enantiomers in >99% EE.

Example 11

Synthesis of 7-Chloro-5-cyclopropylmethoxy-5- difluoromethyl-5, 10-dihydro-benzo{b] [1, 8] naphthyridine (X = Cl in Scheme 5, below).

Method AA. Preparation of 2-Chloro-3- difluoroacetylpyridine. To a 1000 mL 3-necked round bottom flask equipped with a magnetic stirrer, cooling bath, thermometer, addition funnel, septum and a nitrogen inlet was added diisopropylamine (20.2 g, 30 mL, d=0.722, 0.21 moles) and THF (200.0 mL). The solution was cooled to -20 °C. np-Butyl lithium in hexane (2.5 M, 86 mL, 0.20 mole) was added over 30 min.

The reaction mixture was stirred at -20 °C for 30 min and then cooled to -78 °C. 2-Chloropyridine (11.3 gq, 9.4 mL, 0.1 moles) was aded dropwise over $5 min and the reaction mixture was stirred at -78 °C for 4 h. Ethyl difluoroacetate (24.8 g, 0.01 moles) was added dropwise over 15 min and the reaction mixture was stirred at -78 °C. After 2 h, the reaction mixture was quenched with sat. ammonium chloride solution (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organics were washed with brine, dried (MgSO,) and concentrated to afford a brown vellow oil. Column chromatography (SiO,, 15-30 % EtOAc-hexane, gradient elution) afforded the desired material 23 (11.6 g, 61 % ) as brown vellow oil.

Method BB Preparation of 2-amino-N-(4- chlorophenyl)-3-difluorocacetylpyridine: In a 100.0 mL round bottom flask equipped with a magnetic stirrer, oil bath, thermometer, reflux condenser and a nitrogen inlet, 2-chloro-3-difluoroacetylpyridine 23 (2.75 g, 14.4 mmol) and 4-chloroaniline were dissolved in 3% H,0-

AcOH and were heated to reflux for 14 h. The reaction mixture was cooled and concentrated by rotary evaporation. The resulting brown residue was diluted with water, neutralized with NaHCO;, and extracted with

EtOAc (3 x 150 mL). The combined organic layers were washed with brine and dried. Column chromatography (8i0,, 10 % EtOAc-hexane) provided the desired material 24 (2.15 g, mp 73-74 °C, 53 % yield) as yellow solid.

Method CC: Preparation of 4-aza-7-chloro-9- diflucromethylacridine. To a 50.0 mL round bottom flask equipped with a magnetic stirrer and nitrogen inlet was added conc. H;S0, followed by 2-amino-N-(4- chlorophenyl)-3-difluorocacetylpyridine (2.5 g, 8.8 mmol) in portions over 15 min. The reaction mixture became an orange yellow homogeneous solution and was stirred at 23 °C for 48 h. The reaction was quenched with ice (250 gq) and neutralized carefully with NaHCO; (30-32 g). The cream precipitate was filtered, washed with water and dried in vacuum to afford 2.3 g (98 %) of the desired product 25 which was used without further purification (mp 232-233 °C).

Method DD: Preparation of 7-Chloro-9-

Cyclopropylmethoxy-9-difluoromethyl-4-azaacridine. To a 250.0 mL round bottom equipped with a magnetic stirrer, a cooling bath, and nitrogen inlet was added 4-aza-7- chloro-9-difluoromethylacridine (2.0 g, 7.56 mmol), cyclopropyl carbinol (0.82 g, 11.4 mmol, 1.5 equiv) and anhydrous DMF (50 mL). The cream colored suspension was cooled to -10 °C under N, and then NaH (60% oil dispersion) was added in portions over 10 min. The reaction mixture was stirred for 3 h at 0-5 °C before quenching with ice. The resulting mixture was extracted with EtOAc (3 x 200 mL), washed with brine, dried and concentrated. Column chromatography (SiO,, 25 % EtOAc- hexane-1 % EtsN) afforded 1.4 g of the desired product 26 as a cream colored solid (mp 83-84 °C, 55 %).

Scheme 5 : Q CHF, __O 1.) LDA (2 equiv) x_n 2

L) "eX — EE oO” SN” THF-78°C 0” SN” AcOH-HO oy FS 2.) F,CHCO,E reflux NA 61% 23 24

CHF, \/~ “Ona CHF, FP conc. HaSO,4 Cr (1.5 equiv) CL

To —> 23°C SN SNF DMF-0°C NT NT 25 26

CHF. A

MCPBA 2° ——— AN

CHuClp - 1t Zz

NT oO 27

Examples 12-14 were prepared according to the procedure described in Example 11:

Example 12 7-Fluoro-5-cyclopropylmethoxy-5-difluoromethyl - 5,10-dihydro-benzo([b] [1, 8]naphthyridine, 900 mg, mp 137- 138 oC.

Example 13 7-Chloro-5-(2-cyclopropyl-ethoxy) -5-difluoromethyl- 5,10-dihydro-benzo({b] [1,8] naphthyridine, 274 mg, mp 148- 149 °C.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (I): R\ R?

W. XX B

'. R® (I) or a stereoisomeric form or mixture of stereocisomeric forms or a pharmaceutically acceptable salt form thereof, wherein: n is selected from 0, 1, 2 and 3; A is a ring selected from the group: HOI SIE 2 , ) , and 2 N 2 NZ 2 Nd HS () 2, N wherein a ring nitrogen in ring A may optionally be in an N-oxide form; said ring A being substituted with 0-3 B, said substituent B being independently selected from the group C34 alkyl, -OH, C;.4 alkoxy, -S-C;_salkyl, OCF3, CF3, F, Cl, Br, I, -NO;, -CN, and -NRSR5a; W is N or CR3;

WO (1/29037 PCT/US00/28824 X is N or CR3a; Y is N or CR3b; 2 is N or CR3c; provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

Rl is selected from the group C;_3 alkyl substituted with 0-7 halogen, and cyclopropyl substituted with 0-5 halogen; ’

R? is selected from the group -R2¢, -OH, -CN, -OR2¢<,

-OCHR?2R2b, -OCH,CHR22R2P, -0(CH;),CHR2aR2b, -OCHR?aC (R22) =C(R2b),, -OCHRZ22C (R22) =C (R2D),, -OCHR2aC=C-R2b, -8R2¢, -SCHR2aR2b, -SCH,CHR22R2Db, -S (CH) ;CHR22R2b, _gCHR2aC (R22) =C (R2P) ,,

-SCHR22aC (R28) = (R2P) ,, -SCHR2aC=C-R2P, -NR2aR2c,

-NHCHR2aR2b, -NHCH,CHRZ22R2b, _NH(CH,),CHR2aR2b, -NHCHR22aC (R22) =C (R2P) 5, -NHCHR22C (R22) =(R2?P),, and -NHCHR2aC=C-R2b;

R22 is selected from the group H, CH, CHyCH3, CH(CH3)a,

and CH,CH,CHj3;

R2b is H or RZ2c; R2¢ is selected from the group methyl substituted with

0-3 R3f, C;_¢ alkyl substituted with 0-3 R%, C,_s alkenyl substituted with 0-2 R%, Cy.5 alkynyl substituted with 0-1 R4, C3.g cycloalkyl substituted with 0-2 R34, phenyl substituted with 0-2 R34, and 3-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R34;

alternatively, the group -NR22R2C represents a 4-7 membered cyclic amine, wherein 0-1 carbon atoms are replaced by O or NR5;

R? is selected from the group H, Cj_4 alkyl, -OH, Cj_4 alkoxy, OCF3;, F, Cl, Br, I, -NRSR52, -NO,, -CN, -C(O)R®, -NHC(O)R7, -NHC(O)NRS5R52, -NHSO,R10, -SO;NR®R%2, and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group 0, N, and S;

R32 is selected from the group H, Ci;_s alkyl, -OH, Ci_a alkoxy, OCF3, F, C1, Bx, I, -NRSR53, -NO,, -CN, ~C(0)R®, -NHC(O)R7, -NHC(O)NRSR52, -NHSO,R10,

-SO2NR5R52, and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group O, N, and S; alternatively, R3 and R32 together form -OCH,0-;

R3P is selected from the group H, Cj-4 alkyl, -OH, Ci_a alkoxy, OCF3, F, Cl, Br, I, -NRS5R52, -NO,, -CN, -C(O)RS, -NHC(O)R7, -NHC(O)NRSR52, -NHSO,R1®, and -SO3NR5R52;

alternatively, R32 and R3P together form -OCH,0-;

R3¢ is selected from the group H, Ci-4 alkyl, -OH, Ci-4 alkoxy, OCF3, F, Cl, Br, I, -NR5R52, -NO,, -CN, -C(O)R®, -NHC(O)R7, -NHC(O)NR5R52, -NHSO,R10, and -SO,NRSR52;

alternatively, R3P and R3¢ together form -OCH30-; R34, at each occurrence, is independently selected from the group H, Cj-4 alkyl, -OH, Ci-4 alkoxy, OCF3, F, cl, Br, I, -NR5R52, -NO3, -CN, -C(0)R®, -NHC(O)R7, -NHC (0) NR5R52@, -NHSO,R10, and -SO,NR5R%2; R3e, at each occurrence, is independently selected from the group H, Cj-4 alkyl, -OH, Cj_4 alkoxy, OCF3, F, Cl, Br, I, -NR®R52, -NO;, -CN, -C(O)R®, -NHC(O)R7, -NHC (O)NR®R%2, -NHSOR10, and -SO,;NRSR32; R3f, is selected from the group group H, F, Cl, Br, I, -OH, -0-R11, -0-C5_;o carbocycle substituted with 0- 2 R3e, -0(CO)-R13, -05(0),C;_4alkyl, -NR12Rl2a, -C(O)R13, -NHC(O)R13, -NHSO2R10, and -SO,;NR12R12a; R4 is selected from the group H, F, Cl, Br, I, -OH, -0-R1, -0-C3_i9 carbocycle substituted with 0-2 R3e, -0S(0),Cy_zalkyl, -NRI12Rl2a, (Cc; . alkyl substituted with 0-2 R3®, (Cs. carbocycle substituted with 0-2 R3e, phenyl substituted with 0-5 R3e, and a 5-10 membered heterocyclic system containing 1-3 heteroatoms selected from the group 0, N, and S, substituted with 0-2 R3e;

R> and R52 are independently selected from the group H and Cy.4 alkyl; alternatively, R> and R52, together with the nitrogen to which they are attached, combine to form a 5-6 membered ring containing 0-1 O or N atoms; R® is selected from the group H, OH, C;_4 alkyl, Ci_g alkoxy, and NRSR3a; R7 is selected from the group H, Ci_3 alkyl and Ci_3 alkoxy; R8 is selected from the group H, (Cj3-g alkyl)carbonyl, Ci-¢ alkoxyalkyl, (Ci-4 alkoxy)carbonyl, Cg-19 aryloxyalkyl, (Ce¢-10 aryl)oxycarbonyl, (Cg-10 aryl)methylcarbonyl, (Ci-g4 alkyl) carbonyloxy(Ci-4 alkoxy) carbonyl, Cg-10 arylcarbonyloxy(Ci_4 alkoxy) carbonyl, Ci-g¢ alkylaminocarbonyl, phenylaminocarbonyl, phenyl (Ci_g4 alkoxy) carbonyl, and (Ci-s alkyl substitued with NRSR52)carbonyl; and R10 is selected from the group Ci-4 alkyl and phenyl RI! is selected from C;.¢ alkyl, C;.¢ haloalkyl, Cj ¢ alkyl substituted with Cj_gcycloalkyl, C,_¢ alkenyl,

Co. alkynyl, C;_g cycloalkyl; R12 and R122 are independently selected from H, C;_g alkyl, and C;3.¢ cycloalkyl;

alternatively, R!? and Rl22 can join to form 4-7 membered ring; and R13 jis selected from the group H, Cj.g alkyl, C;_g haloalkyl, Ci-¢ alkoxy, Cs. alkenyl, Ca_g alkynyl, -0-Cy_g alkenyl, -0-Cy_¢ alkynyl, NR12Rl2a, C3 _gcarbocycle, and -0-Cy_gcarbocycle.

2. A compound of claim 1 or pharmaceutically acceptable salt forms thereof, wherein: Rl is selected from the group C;-3 alkyl substituted with 1-7 halogen, and cyclopropyl; R2? is selected from the group -R2¢, -OH, -CN, -ORZ2c, -OCHR2aR2b, _-QCH,CHR2aR2b, -0O(CHj),CHR2aR2b, -OCHRZ22CH=CHR2P, -OCHR2aCH=CHR2¢, -OCHR2aC=CR2P, -NR2aR2¢, -gR2c¢, -SCHR2aR2b, -SCH,CHR2aR2b, -SCHR2aCH=CHR2P, -SCHR2aCH=CHRZ¢, and -SCHR22C=CRZ2b; R22 is selected from the group H, CH3, CH,CH3, CH(CH3)3, and CH,;CHoCHj; R2b is H or RZ2c; R2¢ is selected from the group methyl substituted with 0-3 R3f, Ci1.5 alkyl substituted with 0-3 R%, Ca_s alkenyl substituted with 0-2 R%, Cy_.5 alkynyl substituted with 0-1 R%, C3.g cycloalkyl substituted with 0-2 R34, and phenyl substituted with 0-2 R34;

R3 and R33, at each occurrence, are independently selected from the group H, Cj3_4 alkyl, OH, Cj.4 alkoxy, F, Cl, Br, I, NRSR53, NO;, -CN, C(O)RS, NHC (O)R7, NHC (O)NRSR52, and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group O, N, and S;

alternatively, R3 and R32 together form -OCH,O-;

R3b and R3¢, at each occurrence, are independently selected from the group H, Cj3-4 alkyl, OH, Cis alkoxy, F, Cl, Br, I, NRSR52, NO,, -CN, C(O)RS, NHC (0)R7, and NHC (O)NRSR52;

alternatively, R32 and R3P together form -OCH;0-;

RY is selected from the group H, Cl, F, -OH, -0-Cy_galkyl, -0-C;3_s carbocycle substituted with 0- 2 R3®, -0S(0),C;_salkyl, -NRI2R12a, C;_4 alkyl substituted with 0-2 R3®, C3.5 carbocycle substituted with 0-2 R3e, phenyl substituted with 0-5 Re, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group 0, N, and S, substituted with 0-2 R3e;

R3> and R33 are independently selected from the group H, CH3 and C3Hs; R6 is selected from the group H, OH, CH;, CyHs, OCHj3,

OC3Hs, and NR5R52; and

R7 is selected from the group CH3, CyHs, CH(CH3),, OCHj3, OC3Hs, and OCH(CH3) 3.

3. A compound of claim 2, wherein: ring A is selected from ~ IN ~ ~ 00 fy rs ’ — » » “%N KY N Pils NZ pit nv HD 0 ¥ Na (0) and 1) So bd x; N 2 hg 0) Rl is selected from the group CF3, C3Fs, CHF,, CF,CH; and cyclopropyl; R2 is selected from the group -R2¢, -~-0OH, -CN, -OR2c, ~OCHR22R2b, -OCH,CHR22R2P, -OCHR2aCH=CHRZ2b, -OCHR22CH=CHR2¢, -OCHR22C=CR?P, and -NRZ22R2c; R22 is selected from the group H, CH3, CH,CH3, CH(CH3)j, and CH,CHCHj; R2P is H or R2c; R2¢ is selected from the group methyl substituted with 0-3 R3f, C;.3 alkyl substituted with 0-3 R%, Cjy.3 alkenyl substituted with 0-2 R%, Cy_3 alkynyl substituted with 0-1 R%, and Ci_g cycloalkyl substituted with 0-2 R34;

R3, R3a, R3P, and R3¢, at each occurrence, are independently selected from the group H, Ci_.3 alkyl, OH, C;.3 alkoxy, F, Cl, Br, I, NRSR%2, NO,, - CN, C(O)R®, NHC(O)R7, and NHC (0)NRS5R5a;

alternatively, R3 and R32 together form -OCH,0-;

R3e, at each occurrence, is independently selected from the group H, C;-4 alkyl, -OH, Ci_4 alkoxy, OCF3, F,

Cl, -NRSR%2, -C(O)R%, and -SO;NRSR52;

R3f is selected from the group group H, F, Cl, Br, -OH, -0-R11, -O-cyclopropyl substituted with 0-2 R3e, - O-cyclobutyl substituted with 0-2 R3e, -O-phenyl substituted with 0-2 R3¢, -0(CO)-R13, -0S5(0),C;_ salkyl, -NR12R12a, -c(0)R13, -NHC(O)R13, -NHSO,R10, and -SO;NRI12R12a;

R? is selected from the group H, Cl, F, -OH,

-0-C;_galkyl, -0-C3_;o carbocycle substituted with 0-2 R3e, -0S(0),Cy_4alkyl, -NR12R122 C;_, alkyl substituted with 0-1 R3®, C3.5 carbocycle substituted with 0-2 R3e, phenyl substituted with 0-2 R3e, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-1 R3e;

R5 and R52 are independently selected from the group H, CH3 and C3Hs;

R6 is selected from the group H, OH, CH3, CyHy, OCHj, OC2Hs, and NR°R5%4; and

R’7 is selected from the group CHj3, C3Hs, OCH3, and OC3Hs; Rll is selected from methyl, ethyl, propyl, i-propyl, butyl, pentyl, hexyl, CF3, CH,CF3, CH,CH,CFj, -CH,-cyclopropyl, and cyclopropyl; R12 and R22 are independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, pentyl, and cyclopropyl; R13 is selected from the group H, methyl, ethyl, propyl, i-propyl, butyl, pentyl, hexyl, C;_¢ haloalkyl, methoxy, ethoxy, propoxy, i-propoxy, butoxy, NR12R12a, cyclopropyl, cyclobutyl, cyclopropoxy, and cyclobutoxy.

4. A compound of claim 3, or a pharmaceutically acceptable salt form thereof, wherein: Rl! is CF3, CF,CH3, or CHFy; R2 is selected from the group -R2¢, -0OH, -CN, -0CH3RZ2b, -OCH,CH3R2P, -OCH,CH=CHR2P, -OCH,C=CR2P, and - NR2aR2c; R2b is H or RZ2c; R2¢ is selected from the group methyl substituted with 0-3 R3f, C;_.3 alkyl substituted with 0-3 R4, Ca_3 alkenyl substituted with 1 R%4, and C,.3 alkynyl substituted with 1 R#%;

R3, R3a, R3P, and R3¢, at each occurrence, are independently selected from the group H, Cj 3 alkyl, OH, Cj-3 alkoxy, F, Cl, NR°R52, NO,, -CN, C(O)R®, NHC(O)R’7, and NHC (O)NRSRS53;

alternatively, R3 and R32 together form -OCH,0-;

R3e, at each occurrence, is independently selected from the group CH3, -OH, OCH3, OCF3, F, Cl, and -NRSR®3;

R3f, is selected from the group group H, F, Cl, -OH, -0-R11, -0(c0)-R13, -0S(0),C;_y4alkyl, -NR12R12a, and -NHC (0) NR12Rr12a,;

RH? is selected from the group H, Cl, F, CH3, CH,CHj, cyclopropyl substituted with 0-1 R3e, l-methyl- cyclopropyl substituted with 0-1 Rie, cyclobutyl substituted with 0-1 R3e, phenyl substituted with 0-2 R3®, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-1 R3e, wherein the heterocyclic system is selected from the group 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl,

2-thiazolyl, 4-isoxazolyl, 2-imidazolyl, morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl;

R> and Ra are independently selected from the group H,

CH3 and CjHg;

Ré is selected from the group H, OH, CH3, CyHs, OCHj3, CC3Hs, and NRSR52; and

R7 is selected from the group CH3, C3Hs, OCH3, and OCyHs.

5S. A compound of claim 1, or a pharmaceutically acceptable salt form thereof, wherein: n is 0 or 1; ring A is optionally in an N-oxide form; Rl is CF3, CHF,, or CF,CHj; R2 is selected from the group -R2¢, -OR2¢, -QH, -CN, -OCHzR?P, -OCHCHaR2?P, -OCH,C=C-R2P, -OCH,C=C-RZ2b, -NR2aR2¢, -SR2¢, -SCH,R2P, -SCH,CH,R2b, -SCH,CH=CHR?P, and -SCH,C=CR2b; R2P is H or R2c; R2¢ jis selected from the group methyl substituted with 0-2 R3f, ethyl substituted with 0-3 R%, propyl substituted with 0-2 R%, ethenyl substituted with 0-2 R%, l-propenyl substituted with 0-2 R%, 2-propenyl substituted with 0-2 R%, ethynyl substituted with 0-2 R%, 1-propynyl substituted with 0-2 R4, 2-propynyl substituted with 0-2 R%, and cyclopropyl substituted with 0-1 R34; R3e, at each occurrence, is independently selected from the group CH3, -OH, OCH3, OCF3, F, Cl, and -NR°R%2;

R3f, is selected from the group group H, F, Cl, -OH, -0-R1l, -0(CO)-R13, -0S(0),Cy_4alkyl, -NR12R12a, ang -NHC (0) NR12R12a; R*% is selected from the group H, Cl, F, CHj, CH,CH3, cyclopropyl substituted with 0-1 R3e, 1l-methyl- cyclopropyl substituted with 0-1 R3e, cyclobutyl substituted with 0-1 R3e, phenyl substituted with 0-2 R3¢, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group 0, N, and S, substituted with 0-1 R3e, wherein the heterocyclic system is selected from the group 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, 2-imidazolyl, morpholinyl, piperidinyl, pyrrolidinyl, and pPiperazinyl; R> and R®2 are independently selected from the group H, CH3 and CjHs; Ré is selected from the group H, OH, CH3, CyHs, OCH3, OC3Hg, and NRSR33; R7 is selected from the group CHi, CyHs, OCH3, and OC,Hs; R8 is H.

6. A compound of claim 4, or a pharmaceutically acceptable salt form thereof, wherein: n is selected from 0 or 1;

A is selected from DL

’ . and co; B is selected from methyl, ethyl, propyl, -0H, Cl, Br, -S-CHj, W is CR3; X is CR3a; Y is CR32a; Z is N or CR3a; R! is selected from CF, CHF,, and CF,CH3, R? is selected from -R2¢, -0OH, -CN, -OR2¢, -0CH,C=C-R2b, -OCH,C=C-R2P, and -NR2aR2c; R?a is H; R2b ig H; R2¢ is selected from the group methyl substituted with 0-3 R3f, ethyl substituted with 0-3 R%, propyl substituted with 0-3 R%, i-propyl substituted with 0-3 R4, butyl substituted with 0-3 R4, l-propenyl substituted with 0-2 R%4, 2-propenyl substituted with 0-2 R4, l-propynyl substituted with 0-2 R#%, 2-propynyl substituted with 0-2 R%;

R3 is H; R32 is H, F, Cl, or Br; R3b is H; R3¢ is H; R3e, at each occurrence, is independently selected from the group H, methyl, and ethyl, -OH, Cj_4 alkoxy, OCF3, F, Cl, Br, I, -NR®R®3, -NOz, -CN, -C(O)RS, -NHC (0)R7, -NHC(O)NRSR52, -NHSO,R10, and -SO,NRSR5a; R3f is selected from H, F, Cl, OH, -OR!l, -0SO,methyl, - NR12R122, and -NHC (O)NRSRS52; R4 is selected from H, F, -OH, -O-i-propyl, -0S(0),CHs, cyclopropyl substituted with 0-1 R3e, cyclobutyl substituted with 0-1 R3e, phenyl, N-morpholinyl, 2- pyridyl, 3-pyridyl, 4-pyridiyl, N2-methyl-N1- piperidinyl, N-piperidinyl, N-pyrrolidinyl, and N- piperazinyl; R® is H; R11 is selected from H, methyl, ethyl, propyl, i-propyl, CHycyclopropyl, and cyclopropyl; and R!? and R122 are independently selected from H, methyl, ethyl, propyl, i-propyl, and cyclopropyl.

2.3

7. A compound of claim 1, or a pharmaceutically acceptable salt form thereof, wherein the compound is of formula (Ic): R! R?

W. $ IN £1» He). 2 ~Z7°N RS (Ic)

8. A compound of claim 1, or a pharmaceutically acceptable salt form thereof, wherein the compound is of formula (Id):

W. 3 < Lx He) = n ~Z7°N Re (14)

9. A compound of claim 1, or a pharmaceutically acceptable salt form thereof or an N-oxide form thereof, wherein the compound of formula (I) is selected from: 7-Chloro-5-(cyclopropylmethoxy)-5,10-dihydro-5- (trifluoromethyl)benzo[b] [1l, 8] naphthyridine, 7-Chloro-5- (benzyloxy)-5,10-dihydro-5- {trifluoromethyl )benzo[b][1l, 8]lnaphthyridine, 7-Chloro-5-(cyclobutylmethoxy)-5,10-dihydro-5- (trifluoromethyl)benzo[b] [1,8)naphthyridine,

7-Chloro-5- (ethoxy) -5,10 dihydro 5S (trifluoromethyl)benzo{b] (1, 8lnaphthyridine, 7-Chloro-5- (hydroxy) -5, 10-dihydro-5- (trifluoromethyl) benzo(b] {1, 8lnaphthyridine, 7-Chloro-5- (n-propoxy) -5, 10-dihydro-5- (trifluoromethyl)benzo([b] [1, 8) naphthyridine, 7-Chloro-5-(i-propoxy)-5,10-dihydro-5- (trifluoromethyl )benzo([b] [1, 8] naphthyridine, 7-Chloro-5- (butyl) -5,10-dihydro-5- (trifluoromethyl)benzo([b] [1, 8) naphthyridine,

7-Chloro-5- (methoxy) -5,10-dihydro-5- (trifluoromethyl)benzo[b] (1, 8] naphthyridine, 7-Chloro-5(S) - (cyclopropylmethoxy) -5, 10-dihydro-5- (trifluoromethyl)benzo([b] (1, 8) naphthyridine, 7-Chloro-5 (R) - (cyclopropylmethoxy) -5, 10-dihydro-5- (trifluoromethyl)benzo[b] (1, 8) naphthyridine, 7-Chloro-5-(2-cyclopropylethyl)-5,10-dihydro-5- (trifluoromethyl)benzo[b] [1, 8] naphthyridine, 7-Chloro-5-(2,2,2-trifluoroethoxy)-5,10-dihydro-5- (trifluoromethyl)benzo(b] [1, 8] naphthyridine,

7-Chloro-5- (propargoxy)-5, 10-dihydro-5- (trifluoromethyl)benzo[b] [1, 8) naphthyridine, 7-Chloro-5- (ethyl) -5,10-dihydro-5- (trifluoromethyl)benzo(b] [1, 8] naphthyridine,

7-Chloro-5-(cyclopropylmethoxy)-2-methyl-5,10-dihydro-5-

{(trifluoromethyl)benzo([b] [1, 8} naphthyridine, 7-Chloro-5- (n-butyl) -2-methyl-5,10-dihydro-5-

(trifluoromethyl)benzo{b] (1, 8lnaphthyridine,

7-Chloro-5-(2-cyclopropylethyl)-2-methyl-5,10-dihydro-5- (trifluoromethyl)benzo[b] [1, 8] naphthyridine,

7-Chloro-5-(cyclopropylmethoxy)-5,10-dihydro-2- {methylthio)-5- (trifluoromethyl )pyrimido(4,5- bjquinoline,

7-Chloro-5-(i-butoxy)-5,10-dihydro-2- (methylthio)-5- (trifluoromethyl) pyrimido[4, 5-blquinoline, 7-Chloro-5-(benzyloxy)-5,10-dihydro-2- (methylthio) -5- (trifluoromethyl) pyrimido[4,5-b]quinoline,

7-Chloro-5-(2-pyridylmethoxy}-5, 10-dihydro-2- {methylthio)-5- (trifluoromethyl )pyrimido[4, 5- blquinoline, 7-Chloro-5-(cyclopropylmethoxy)-5,10-dihydro-5- (trifluoromethyl) pyrimido({4,5-blgquincline, 7-Chloro-5-(cyclopropylamino)-5,10-dihydro-5- (trifluoromethyl)benzo[b] [1, 8] naphthyridine,

7-Chloro-5-(i-propylamino)-5,10-dihydro-5- (trifluoromethyl)benzo[b] [1l, 8] naphthyridine, 7-Chloro-5-(N,N-dimethylaminoethoxy)-5, 10-dihydro-5- {trifluoromethyl)benzo([b] [1, 8] naphthyridine,

7-Chloro-5- (N-morpholinylethylamino)-5,10-dihydro-5- (trifluoromethyl)benzo([b] [1, 8) naphthyridine, 7-Chloro-5-((1-methylcyclopropyl)methoxy)-5,10-dihydro- 5-(trifluoromethyl)benzo[b] [1, 8) naphthyridine, 7-Chloro-5-(3,3,3-trifluoroprop-1-oxy)-5,10-dihydro-5- (trifluoromethyl)benzo(b] [1, 8)naphthyridine,

7-Chloro-5- (cyclopropylmethylamino)-5, 10-dihydro-5- (trifluoromethyl) benzo([b] [1, 8] naphthyridine, 7-Chloro-5- (methylamino)-5,10-dihydro-5- (trifluoromethyl)benzo[b] [1, 8] naphthyridine, 7-Chloro-5-(ethylamino) -5,10-dihydro-5- (trifluoromethyl)benzo(b] [1, 8) naphthyridine, (S)-7-Chloro-5-(cyclopropylethyl)-5, 10-dihydro-5- (trifluoromethyl)benzo([b] [1, 8] naphthyridine, (R)-7-Chloro-5-(cyclopropylethyl)-5,10-dihydro-5- (trifluoromethyl)benzo([b] [1, 8]naphthyridine,

7-Fluoro-5- (cyclopropylmethoxy) -5,10-dihydro-5- (trifluoromethyl)benzo[b] [1, 8]naphthyridine, 7-Fluoro-5-(cyclopropylethoxy)-5, 10-dihydro-5- (trifluoromethyl)benzo(b] [1, 8) naphthyridine, 7-Fluoro-5-(allyloxy}-5,10-dihydro-5- (trifluoromethyl)benzo[b] (1, 8lnaphthyridine,

7-Chloro-5-{phenylamino) -5, 10-dihydro-5- (trifluoromethyl) benzo([b] [1,8] naphthyridine, 7-Chloro-5- (cyclopropylmethoxy)-2-methyl-5, 10-dihydro-5- (trifluoromethyl)benzo[b] [1, 8] naphthyridine, 7-Chloro-5- (n-butyl) -2-methyl-5,10-dihydro-5- (trifluoromethyl)benzo [kb] {1, 8] naphthyridine, 7-Chloro-5-(cyclopropylethyl)-2-methyl-5,10-dihydro-5- (trifluoromethyl) benzo [b] [1, 8] naphthyridine, 7-Chloro-5-(cyclobutylmethoxy)-5,10-dihydro-5- (trifluoromethyl) pyrimido(4,5-b]Jquinocline,

7-Chloro-5- (methoxy) -5,10-dihydro-5- {trifluoromethyl)pyrimido[4,5-b]lquinoline, (S)-7-Chlorc-5- (cyclopropylmethoxy) -5, 10-dihydro-5- (trifluoromethyl) pyrimido([4,5-blquinoline, (R)-7-Chloro-5- (cyclopropylmethoxy)-5,10-dihydro-5- (trifluoromethyl) pyrimido([4,5-b]quinoline, 7-Chloro-5- (N-piperidinylethoxy)-5,10-dihydro-5- (trifluoromethyl) pyrimido[4,5-blquinoline, 7-Chloro-5~ (N-pyrrolidinylethoxy)-5,10-dihydro-5- (trifluoromethyl )pyrimido[4,5-b]Jquinoline,

7-Chloro-5-({4-methylpiperazin-1l-yl)prop-l-oxy)-5,10- dihydro-5- (trifluoromethyl)pyrimido(4, 5- blquinoline,

7-Chloro-5- (prop-l-oxy)-5,10-dihydro-5- (trifluoromethyl)pyrimido(4,5-blquinoline, 7-Chloro-5- (N,N-dimethylaminoprop-1-y1l)-5,10-dihydro-5- (trifluoromethyl)pyrimido(4, S-b]quinoline, 7-Chloro-5-(benzyloxy)-5,10-dihydro-5- (trifluoromethyl) pyrimido(4,S5-blquinoline, 7-Chloro-5-(3-pyridinylmethyl)-5,10-dihydro-5- (trifluoromethyl)pyrimido(4,5-blquinoline, 7-Chloro-5-(allyloxy)-5,10-dihydro-5- (crifluoromethyl)pyrimido[4,5-blquinoline,

7-Chloro-5- (propargoxy) -5, 10-dihydro-5- (trifluoromethyl)pyrimido(4,S-blquinoline, and 7-Chloro-5-(N,N-dimethylaminoethyl) -5, 10-dihydro-5- (trifluoromethyl )pyrimido[4,S-blquinoline; 7-Chloro-5-cyclopropylmethoxy-5-trifluoromethyl-5S, 10- dihydro-benzo([b] [1, 8]naphthyridine l-oxide; 5-Allyloxy-7-fluoro-5-trifluoromethyl-5, 10-dihydro- benzo({b] [1, 8]naphthyridine; 7-Fluoro-5S-trifluoromethyl-S, 10-dihydro- benzo (bl[1, 8]lnaphthyridine-5-carbonitrile;

7-Fluoro-5-trifluoromethyl-5,10-dihydro- benzo(b] (1, 8]naphthyridin-5-01;

5-Cyclopropylmethoxy-7-fluoro-5-trifluoromethyl-5,10- dihydro-benzo(b][1l, 8]naphthyridine l-oxide; 7-Chloro-5-prop-2-ynyloxy-5-trifluoromethyl-5, 10- S dihydro-benzo[b] [1, 8lnaphthyridine 1l-oxide; 7-Chloro-5-(l-methyl-cyclopropylmethoxy) -5- trifluoromethyl-5,10-dihydro- benzo[b][1l, 8lnaphthyridine l-oxide;

7-Chloro-5-(2-cyclopropyl-ethoxy)-5-trifluoromethyl- 5,10-dihydro-benzo[b]} [1,8]lnaphthyridine l-oxide; (7-Chloro-5-trifluoromethyl-5, 10-dihydro- benzo([b] [1l,8]lnaphthyridin-5-yl) -isopropyl-amine; (7-Chloro-5-trifluoromethyl-5, 10-dihydro- benzo [b] [1,8 naphthyridin-5-yl) -cyclobutylmethyl- amine;

7-Chloro-5-(2-cyclopropyl-ethyl}-5-trifluoromethyl-5,10- dihydro-benzol[b] [1,8]naphthyridine l-oxide; 5-Cyclobutylmethoxy-7-fluoro-5-trifluoromethyl-5,10- dihydro-benzo(b]l [1,8] naphthyridine l-oxide; (7-Fluoro-l-oxy-5-trifluoromethyl-5, 10-dihydro- benzo [b] [1, 8) naphthyridin-5-yl)-isopropyl-amine; 5-Cyclobutylmethoxy-7-fluoro-5-triflucromethyl-5,10- dihydro-benzo([b] (1, 8}naphthyridin-2-o0l;

7-Chloro-5-(pyridin-2-ylmethoxy) -5-trifluoromethyl-5, 10- dihydro-benzo[b] (1, 8)Jnaphthyridine; 5-Butyl-7-fluoro-5-trifluoromethyl-5, 10-dihydro- benzo(b]{i, 8]naphthyridine; 7-Chloro-l-oxy-5-trifluoromethyl-5,10-dihydro- benzo[bl[1, 8lnaphthyridin-5-01l; 7-Chloro-5-cyclopropylmethoxy-5-trifluoromethyl-S,10- dihydro-benzo(b} (1, 81 naphthyridine 1l-oxide; 7-Chloro-5-pyridin-2-ylmethyl-5-trifluoromethyl-5,10- dihydro-benzo[b] {1, 8] naphthyridine l-oxide;

7-Fluoro-5-pyridin-2-ylmethyl-5-trifluoromethyl-5,10- dihydro-benzo[b] (1, 8]naphthyridine; 5-Cyclopropylmethoxy-7-fluoro-5-trifluoromethyl-5,10- dihydro-benzo[b] [1,8] naphthyridine 1-oxide; 7-Chloro-5-pyridin-2-ylmethyl-5-trifluoromethyl-5,10- dihydro-benzo([b] [1, 81 naphthyridine; 3,7-Dichloro-5-cyclopropylmethoxy-5-trifluoromethyl- 5,10-dihydro-benzo(b] [1, 81 naphthyridine; 3,7-Dichloro-5-cyclopropylmethoxy-5-trifluoromethyl- 5,10-dihydro-benzo[b] [1,8] naphthyridine l-oxide;

3,7-Dichloro-5-pentyl-5-trifluoromethyl-5, 10-dihydro- benzo![b] [1, 8]naphthyridine 1l-oxide;

5-(2-Cyclopropyl-ethyl)-7-fluoro-5-trifluoromethyli-5,10- dihydro-benzo[b] (1, 8) naphthyridine; 5-(2-Cyclopropyl-ethyl)-7-fluoro-5-trifluoromethyl-5,10- S dihydro-benzo{b][1l, 8lnaphthyridine 1l-oxide; 3,7-Dichloro-5-cyclopropylmethoxy-5-trifluoromethyl- 5,10-dihydro-benzo[b] [1,8] naphthyridine l-oxide; 5-(2-Cyclopropyl-ethyl)-7-fluoro-5-trifluoromethyl-5,10- dihydro-benzo(b] [1, 8] naphthyridine l-oxide; 3-Chloro-5-cyclopropylmethoxy-7-fluoro-5- trifluoromethyl-5,10-dihydro- benzo[b] [1, 8] naphthyridine; 3-Chloro-5-cyclopropylmethoxy-7-fluoro-5- trifluoromethyl-5,10-dihydro- benzo[b]l [1, 8]naphthyridine 1l-oxide;

7-Chloro-5-isobutoxy-5-trifluoromethyl-5,10-dihydro- benzo[b] [1,8] naphthyridine l-oxide; S-Butyl-7-chloro-5-trifluoromethyl-5,10-dihydro- benzo ([b] [1, 8]naphthyridine l-oxide; (S) 3-Chloro-5-cyclopropylmethoxy-7-fluoro-5- trifluoromethyl-5,10-dihydro- benzo [b] [1, 8] naphthyridine 1-oxide;

(7-Chloro-5-trifluoromethyl-5,10-dihydro- benzo [b] (1, 8] naphthyridin-5-y1)-methanol;

7-Fluoro-5-isobutoxy-5-trifluoromethyl1-5, 10-dihydro- benzo (b] [1, 8] naphthyridine 1-oxide; 7-Fluoro-5-isopropoxy-5-trifluoromethyl-5, 10-dihydro- benzo [b} {1, 8]Jnaphthyridine 1-oxide; Methanesulfonic acid 7-chloro-5-trifluoromethyl-5,10- dihydro-benzo(b] [1, 8]naphthyridin-5-ylmethyl ester; 7-Chloro-5-isopropoxy-5-trifluoromethyl-5,10-dihydro- benzo [b] [1, 8) naphthyridine l-oxide; (7-Fluoro-5-trifluoromethyl-5,10-dihydro- benzo (b] (1, 8)naphthyridin-5-yl)-acetonitrile; is 7~Fluoro-5-trifluoromethyl-5,10-dihydro- benzo[b] [1, 8)naphthyridine-5-carbaldehyde; 3-Bromo-5-cyclopropylmethoxy-7-fluoro-5-trifluoromethyl- 5,10-dihydro-benzo([b] [1, 8] naphthyridine l-oxide; 5-Butyl-7-fluoro-5~trifluoromethyl-5, 10-dihydro- benzo([b] [1,8]lnaphthyridine l1-oxide; 5-Diisopropoxymethyl-7-fluoro-5-trifluoromethyl-5,10- dihydro-benzo{b] [1, 8) naphthyridine; 7-Fluoro-5-isopropoxymethyl-5-trifluoromethyl-5,10- dihydro-benzo[b]) [1, 8] naphthyridine 1l-oxide;

7-Chloro-5-isobutyl-5-trifluoromethyl-5, 10-dihydro- benzo[b]l[1,8]naphthyridine 1l-oxide;

7-Chloro-5-propoxy~5-trifluoromethyl-5,10-dihydro- benzo(b] (1, 8lnaphthyridine l-oxide; (S) 7-Fluoro-5-isobutoxy-5-trifluoromethyl-5,10-dihydro- benzo (b] 1, 8)naphthyridine l-oxide; (R) 7-Fluoro-5-isobutoxy-5-trifluoromethyl-5,10-dihydro- benzo(b]{1l, 8] naphthyridine l-oxide; {7-Chloro-5-trifluoromethyl-5,10-dihydro- benzo[b] (1, 8lnaphthyridin-5-yl) -acetaldehyde; 7-Chloro-5-(2,2-diisopropoxy-ethyl)-5-trifluoromethyl- 5,10-dihydro-benzo[b] (1, 8] naphthyridine;

7-Chloro-5-(2-isopropoxy-ethyl)-5-trifluoromethyl-5,10- dihydro-benzo([b] [1l, 8lnaphthyridine; 2-(7-Chloro-5-trifluoromethyl-5,10-dihydro- benzo ([b] [1,8]naphthyridin-5-yl) -ethanol; : 7-Chloro-5-(2-isopropoxy-ethyl)-5-trifluoromethyl-5,10- dihydro-benzo[b] {1, 8]lnaphthyridine 1l-oxide; (R) 7-Fluoro-5-(2-isopropoxy-ethyl)-5-trifluoromethyl- 5,10-dihydro-benzo(b] (1, 8) naphthyridine l-oxide; (7-Fluoro-5-trifluoromethyl-5, 10-dihydro- benzo[b] [1,8] naphthyridin-5-yl) -acetic acid tert- butyl ester;

(7-Fluoro-1-oxy-5-trifluoromethyl-5, 10-dihydro- benzo[b] [1, 8]naphthyridin-5-yl) -acetic acid tert- butyl ester; (7-Fluoro-5-trifluoromethyl-5,10-dihydro- benzo(b] [1, 8]naphthyridin-5-yl) -acetic acid; 7-Chloro-5-cyclopropylmethoxy-2-methylsul fanyl-5- trifluoromethyl-5, 10-dihydro-pyrimido[4, 5- blquinoline; 7-Chloro-5-isobutoxy-2-methylsulfanyl-5-trifluoromethyl- 5,10-dihydro-pyrimido(4,5-blquinoline; 5-Benzyloxy-7-chloro-2-methylsulfanyl-5-trifluoromethyl- 5,10-dihydro-pyrimido(4,5-blguinoline; 7-Chloro-2-methylsulfanyl-5- (pyridin-2-ylmethoxy) -5- trifluoromethyl-5,10-dihydro-pyrimido(4, 5- blquinoline; 7-Chloro-5-cyclopropylmethoxy-5-trifluoromethyl-5,10- dihydro-pyrimido(4,5-blquinoline l-oxide; 7-Chloro-5-cyclopropylmethoxy-5-(1,1-difluoro-ethyl)- 5,10-dihydro-benzo([b]l[1,8)naphthyridine l-oxide; 5-Cyclopropylmethoxy-5-(1,1-difluoro-ethyl)-7-fluoro- 5,10-dihydro-benzo [bl] (1, 8Jnaphthyridine;

5-Cyclopropylmethoxy-5-(1,1-difluoro-ethyl)-7-fluoro- 5,10-dihydro-benzo([b] [1, 8] naphthyridine 1-oxide;

7-chloro-1, 5-dihydro-5- (N-ethylaminomethyl) -5- (trifluoromethyl)benzo[b] [1,8] napthyridine; 7-chloro-5,10-dihydro-5- (N-isopropylaminomethyl) -5- (trifluoromethyl) benzo[b] [1,8]napthyridine; 7-chloro-5,10~-dihydro-5- (N-isopropyl-N- ethylaminomethyl) -5- (trifluoromethyl) benzo(b] [1l, 8lnapthyridine;

7-chloro-5-(N,N-diethylaminomethyl)-5, 10-dihydro-5- (trifluoromethyl )benzo[b] [1,8] napthyridine; 5- (acetamidomethyl)-7-chloro-5,10-dihydro-5- (trifluoromethyl) (b} (1, 8)napthyridine; 5,10-dihydro-7-fluoro-5- (N-methylsulfonylmethyl)-5- (trifluoromethyl) (bl (1,8) napthyridine; 5,10-dihydro-7-fluoro-5-(isopropylamidomethyl)-5- (trifluoromethyl) (b] [1,8] napthyridine; 5,10-dihydro-7-fluoro-5- (isopropylguanadinomethyl) -5- (trifluormethyl) [bl] [1, 8] napthyridine;

1,5-dihydro-7-fluoro-5- (N-isopropylmethyl)-5- (trifluoromethyl) (b] [1,8] napthyridine-1- (N-oxide); 5-(N,N-diethylaminomethyl) -5,10-dihydro-7-fluoro-5- (trifluoromethyl) [b] [1,8] napthyridine-1- (N-oxide) ; 5,10-dihydro-5-(N,N-dimethylaminomethyl)-7-fluoro-5- (trifluoromethyl) [b] [1, 8) napthyridine-1- (N-oxide);

7-Chloro-5-(1,1-difluoro-ethyl)-5-isobutoxy-5, 10- dihydro-benzo(b] [1,8] naphthyridine;

7-Chloro-5-(1,1-difluoro-ethyl) -5-isobutoxy-5,10-

dihydro-benzo(b] (1, 8]naphthyridine l-oxide;

(R) 7-Chloro-5-~cyclopropylmethoxy-5-(1,1-difluoro- ethyl) -5,10-dihydro-benzo(b] (1, 8lnaphthyridine 1- oxide;

(S) 7-Chloro-5-cyclopropylmethoxy-5-(1,1l-difluoro- ethyl) -5,10-dihydro-benzo({b] [1, 8] naphthyridine 1- oxide;

3-Chloro-10-cyclopropylmethoxy-10-trifluoromethyl-9,10- dihydro-1,8,9-triaza-anthracene; 3-Chloro-10-cyclopropylmethoxy-10-trifluoromethyl-9,10- dihydro-1,8,9-triaza-anthracene 8-oxide;

3,6-Dichloro-10-cyclopropylmethoxy-10-trifluoromethyl- 9,10-dihydro-1, 8,9-triaza-anthracene;

3-Chloro-10-isobutoxy-10-trifluoromethyl-9, 10-dihydro-

1,8,9-triaza-anthracene; 3-Chloro-10-isobutoxy-10-trifluoromethyl-9, 10-dihydro- 1,8,9-triaza-anthracene 8-oxide; 7-Chloro-5-difluoromethyl-5-isopropoxymethyl-5,10- dihydro-benzo[b] [1, 8 naphthyridine; 7-Chloro-5-difluoromethyl-5-isopropoxymethyl-5,10- dihydro-benzo(b] [1, 8lnaphthyridine l-oxide;

7-chloro-5, 10-dihydro-5- (N-isopropylaminomethyl)-5 (trifluoromethyl) [b] [1,8]napthyridine-1-(N-oxide}; 7-chloro-5-(N, N-diethylaminomethyl)-5,10-dihydro-5 (trifluoromethyl) [b] (1,8]napthyridine-1- (N-oxide); and 7-chloro-5,10-dihydro-5-(N, N-dimethylaminomethyl)-5 (trifluoromethyl) [b] [1,8] napthyridine-1- (N-oxide).

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of claims 1-9 or pharmaceutically acceptable salt form thereof.

11. A compound of any one of claims 1-9 or pharmaceutically acceptable salt form thereof for use in a method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of the compound.

12. A combination of: (a) compound of any one of claims 1-9; and, (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors for use in a method of treating HIV infection which comprises administering to a host in need thereof a therapeutically effective amount of the combination.

13. A combination of claim 12, wherein the reverse transcriptase inhibitor is selected from the group AZT, ddC, ddI, d4T, 3TC, delavirdine, efavirenz, 228 Amended Sheet 23/06/20C3 nevirapine, Ro 18,893, trovirdine, MKC-442, HBY 097,

. HBY1293, GW867, ACT, UC-781, UC-782, RD4-2025, MEN 10979 and AG1549 (S1153), and the protease inhibitor is selected from the group saquinavir, ritonavir, indinavir, amprenavir, nelfinavir, palinavir, BMS- 232623, GS3333, KNI-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-140690, and ABT-378.

14. A combination of claim 13, wherein the reverse transcriptase inhibitor is selected from the group AZT, efavirenz, and 3TC and the protease inhibitor is selected from the group saquinavir, ritonavir, nelfinavir, and indinavir.

15. A combination of claim 14, wherein the reverse transcriptase inhibitor is AZT.

16. A combination of claim 14, wherein the protease inhibitor is indinavir.

17. A pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of: (a) a compound of any one of claims 1-9; and, (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers.

18. A compound of any one of claims 1-9 for use in therapy. 229 Amended Sheet 20/06/2523

19, The use of a compound of any one of claims 1-9 for the manufacture of a medicament for the treatment of HIV infection.

20. A compound of claim 1, other than the compounds of claim 9, as specifically described herein.

21. A composition of claim 10, substantially as herein described. 2370 Amended Sheet 20/06/20C3