IL-8 receptor antagonists

• US 6,271,261 B1
• Filed: 12/17/1998
• Issued: 08/07/2001
• Est. Priority Date: 06/27/1996
• Status: Expired due to Fees

• Current Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Original Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Inventors: Widdowson, Katherine L
• Primary Examiner(s): Oswecki, Jane C.
• Application Number:
  US09/202,570
• Time in Patent Office: 964 Days
• Field of Search: 514/585, 514/586, 514/587, 514/596, 514/601, 558/411, 558/412, 564/26, 564/27, 564/29, 564/32, 564/80, 564/95
• US Class Current: 514/585
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 275/34 having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 275/42 being further substituted by carboxyl groups
• CPC Class Codes: C07C 311/21 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Novel IL-8 receptor antagonists and methods of using them are provided.

Claims

1. A method of treating a chemokine mediated disease state, wherein the chemokine binds to an IL-8 α

or β

receptor in a mammal, which comprises administering to said mammal an effective amount of a compound of the formula;

wherein

X is oxygen or sulfur;

R is hydroxy, carboxylic acid, thiol, SR₂, OR₂, —

NH—

C(O)R_a, —

C(O)NR₆R₇, —

NHS(O)₂R_b, —

S(O)₂NHR_c, NHC(X₂)NHR_b, or tetrazolyl;

wherein R₂ is a substituted aryl, heteroaryl, or heterocyclic ring which ring contains the functional moiety providing the ionizable hydrogen having a pKa of 10 or less;

R_a is an alkyl, aryl, aryl C_1-4alkyl, heteroaryl, heteroaryl C_1-4alkyl, heterocyclic, or a heterocyclic C_1-4alkyl moiety, all of which may be optionally substituted;

R_b is a NR₆R₇, alkyl, aryl, arylC_1-4alkyl, arylC_2-4alkenyl, heteroaryl, heteroarylC_1-4alkyl, heteroarylC_2-4 alkenyl, heterocyclic, heterocyclic C_1-4alkyl, heterocyclic C_2-4alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen;

nitro;

halosubstituted C_1-4 alkyl;

C_1-4 alkyl;

C_1-4 alkoxy;

NR₉C(O)R_a;

C(O)NR₆R₇, S(O)₃H, or C(O)OC_1-4 alkyl;

R₉ is hydrogen or a C_1-4 alkyl;

R_c is alkyl, aryl, arylC_1-4alkyl, arylC_2-4alkenyl, heteroaryl, heteroarylC_1-4alkyl, heteroarylC_2-4alkenyl, heterocyclic, heterocyclic C_1-4alkyl, or a heterocyclic C_2-4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro, halosubstituted C_1-4 alkyl, C_1-4 alkyl, C_1-4 alkoxy, NR₉C(O)R_a, C(O)NR₆R₇, S(O)₃H, or C(O)OC_1-4 alkyl; and

X₂ is oxygen or sulfur;

R₁ is independently selected from hydrogen;

halogen;

nitro;

cyano;

halosubstituted C_1-10 alkyl;

C_1-10 alkyl;

C_2-10 alkenyl;

C_1-10 alkoxy;

halosubstituted C_1-10 alkoxy;

azide;

(CR₈R₈)q S(O)_tR₄;

hydroxy;

hydroxy C_1-4alkyl;

aryl;

aryl C_1-4 alkyl;

aryloxy;

aryl C_1-4 alkyloxy;

heteroaryl;

heteroarylalkyl;

heterocyclic, heterocyclic C_1-4alkyl;

heteroaryl C_1-4 alkyloxy;

aryl C_2-10 alkenyl;

heteroaryl C_2-10 alkenyl;

heterocyclic C_2-10 alkenyl;

(CR₈R₈)qNR₄R₅;

C_2-10 alkenyl C(O)NR₄R₅;

(CR₈R₈)q C(O)NR₄R₅;

(CR₈R₈)q C(O)NR₄R₁₀;

S(O)₃H;

S(O)₃R₈;

(CR₈R₈)q C(O)R₁₁;

C_2-10 alkenyl C(O)R₁₁;

C_2-10 alkenyl C(O)OR₁₁(CR₈R₈)q C(O)OR₁₂;

(CR₈R₈)q OC(O) R₁₁;

(CR₈R₈)qNR₄C(O)R₁₁, (CR₈R₈)q NHS(O)₂R₁₇, (CR₈R₈)q S(O)₂NR₄R₅;

or two R₁ moieties together may form O—

(CH₂)_sO—

or a 5 to 6 membered unsaturated ring;

n is an integer having a value of 1 to 3;

m is an integer having a value of 1 to 3;

q is 0, or an integer having a value of 1 to 10;

t is 0, or an integer having a value of 1 or 2;

s is an integer having a value of 1 to 3;

v is an integer having a value of 1 to 4;

R₄ and R₅ are independently hydrogen, optionally substituted C_1-4 alkyl, optionally substituted aryl, optionally substituted aryl C_1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4alkyl, heterocyclic, heterocyclicC_1-4 alkyl, or R₄ and R₅ together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from oxygen, nitrogen or sulfur;

R₆ and R₇ are independently hydrogen or a C_1-4 alkyl group, or R₆ and R₇ together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;

Y is independently selected from hydrogen;

halogen;

nitro;

cyano;

halosubstituted C_1-10 alkyl;

C_1-10 alkyl;

C_2-10 alkenyl;

C_1-10 alkoxy;

halosubstituted C_1-10 alkoxy;

azide;

S(O)_tR₄;

hydroxy;

hydroxyC_1-4alkyl;

aryl;

aryl C_1-4 alkyl;

aryloxy;

arylC_1-4 alkyloxy;

heteroaryl;

heteroarylalkyl;

heteroaryl C_1-4 alkyloxy;

heterocyclic, heterocyclic C_1-4alkyl;

aryl C_2-10 alkenyl;

heteroaryl C_2-10 alkenyl;

heterocyclic C_2-10 alkenyl;

NR₄R₅;

C_2-10 alkenyl C(O)NR₄R₅;

C(O)NR₄R₅;

C(O)NR₄R₁₀;

S(O)₃H;

S(O)₃R₈;

C_1-10 alkyl C(O)R₁₁;

C_2-10 alkenyl C(O)R₁₁;

C_2-10 alkenyl C(O)OR₁₁;

C(O)R₁₁;

C(O)OR₁₂;

OC(O) R₁₁;

NR₄C(O)R₁₁;

or two Y moieties together may form O—

(CH₂)_sO—

or a 5 to 6 membered unsaturated ring;

R₈ is hydrogen or C_1-4 alkyl;

R₁₀ is C_1-10 alkyl C(O)₂R₈;

R₁₁ is hydrogen, C_1-4 alkyl, optionally substituted aryl, optionally substituted aryl C_1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC_1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC_1-4alkyl;

R₁₂ is hydrogen, C_1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;

R₁₃ and R₁₄ are independently hydrogen, optionally substituted C_1-4 alkyl or one of R₁₃ and R₁₄ may be optionally substituted aryl;

R₁₇ is C_1-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC_1-4alkyl, heterocyclic, or heterocyclicC_1-4alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted;

R_d is NR₆R₇, alkyl, arylC_1-4alklyl, arylC_2-4 alkenyl, heteroaryl, hetroaryl-C_1-4alkyl, heteroarylC_2-4 alkenyl, heterocyclic, heterocyclicC_1-4 alkyl, wherein the aryl, heteoaryl and heterocyclic rings may all be optionally substituted;

provided that

R₁ is not 3-phenyl, or 4-isopropyl, or 5-phenyl or 5-ethylsulfonyl, when R is OH, v is 1,

R₁₃ and R₁₄ are hydrogen, and Y is hydrogen;

or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 wherein the R₂ is optionally substituted one to three times by halogen, nitro, halosubstituted C_1-10 alkyl, C_1-10 alkyl, C_1-10 alkoxy, hydroxy, SH, —

C(O)NR₆R₇, —

NH—

C(O)R_a, —

NHS(O)₂R_b, S(O)NR₆R₇, C(O)OR₈, or a tetrazolyl ring.

3. The method according to claim 1 wherein R is OH, —

NHS(O)₂R_b or C(O)OH.

4. The method according to claim 1 wherein R₁ is halogen, cyano, nitro, CF₃, C(O)NR₄R₅, alkenyl C(O)NR₄R₅, C(O) R₄R₁₀, alkenyl C(O)OR₁₂, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(O)NR₄R₅.

5. The method according to claim 1 wherein Y is halogen, C_1-4 alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylene dioxy, NR₄R₅, thioC_1-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C_1-4alkyl, hydroxy alkyl.

6. The method according to claim 1 wherein R is OH, SH, or NHS(O)₂R_b and R₁ is substituted in the 3-position, the 4-position or di substituted in the 3,4-position by an electron withdrawing moiety.

7. The method according to claim 1 wherein the mammal is afflicted with a chemokine mediated disease selected from psoriasis, or atopic dermatitis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulo-nephritis, or thrombosis, alzheimers disease, graft vs. host reaction, or allograft rejections.

8. A compound of the formula:

wherein

X is oxygen or sulfur;

R is hydroxy, carboxylic acid, thiol, SR₂, OR₂, NH—

C(O)R_a, C(O)NR₆R₇, NHS(O)₂R_b, S(O)₂NHR_c, NHC(X₂)NHR_b, or tetrazolyl;

wherein R₂ is a substituted aryl, heteroaryl, or heterocyclic ring which ring contains the functional moiety providing the ionizable hydrogen having a pKa of 10 or less;

R_a is an alkyl, aryl, aryl C_1-4alkyl, heteroaryl, heteroaryl C_1-4alkyl, heterocyclic, or a heterocyclic C_1-4alkyl moiety, all of which may be optionally substituted;

R_b is a NR₆R₇, alkyl, aryl, arylC_1-4alkyl, arylC_2-4alkenyl, heteroaryl, heteroarylC_1-4alkyl, heteroarylC_2-4 alkenyl, heterocyclic, heterocyclic C_1-4alkyl, heterocyclic C_2-4alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen;

nitro;

halosubstituted C_1-4 alkyl;

C_1-4 alkyl;

C_1-4 alkoxy;

NR₉C(O)R_a;

C(O)NR₆R₇, S(O)₃H, or C(O)OC_1-4 alkyl;

R₉ is hydrogen or a C_1-4 alkyl;

R_c is alkyl, aryl, arylC_1-4alkyl, arylC_2-4alkenyl, heteroaryl, heteroarylC_1-4alkyl, heteroarylC_2-4alkenyl, heterocyclic, heterocyclic C_1-4alkyl, or a heterocyclic C_2-4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro, halosubstituted C_1-4 alkyl, C_1-4 alkyl, C_1-4 alkoxy, NR₉C(O)R_a, C(O)NR₆R₇, S(O)₃H, or C(O)OC_1-4 alkyl; and

X₂ is oxygen or sulfur;

R₁ is independently selected from hydrogen;

halogen;

nitro;

cyano;

halosubstituted C_1-10 alkyl;

C_1-10 alkyl;

C_2-10 alkenyl;

C_1-10 alkoxy;

halosubstituted C_1-10 alkoxy;

azide;

(CR₈R₈)q S(O)_tR₄;

hydroxy;

hydroxy C_1-4alkyl;

aryl;

aryl C_1-4 alkyl;

aryloxy;

aryl C_1-4 alkyloxy;

heteroaryl;

heteroarylalkyl;

heterocyclic, heterocyclic C_1-4alkyl;

heteroaryl C_1-4 alkyloxy;

aryl C_2-10 alkenyl;

heteroaryl C_2-10 alkenyl;

heterocyclic C_2-10 alkenyl;

(CR₈R₈)qNR₄R₅;

C_2-10 alkenyl C(O)NR₄R₅;

(CR₈R₈)q C(O)NR₄R₅;

(CR₈R₈)q C(O)NR₄R₁₀;

S(O)₃H;

S(O)₃R₈;

(CR₈R₈)q C(O)R₁₁;

C_2-10 alkenyl C(O)R₁₁;

C_2-10 alkenyl C(O)OR₁₁(CR₈R₈)q C(O)OR₁₂;

(CR₈R₈)q OC(O) R₁₁;

(CR₈R₈)qNR₄C(O)R₁₁, (CR₈R₈)q NHS(O)₂R₁₇, (CR₈R₈)q S(O)₂NR₄R₅;

or two R₁ moieties together may form O—

(CH₂)_sO—

or a 5 to 6 membered unsaturated ring;

n is an integer having a value of 1 to 3;

m is an integer having a value of 1 to 3;

q is 0, or an integer having a value of 1 to 10;

t is 0, or an integer having a value of 1 or 2;

s is an integer having a value of 1 to 3;

v is an integer having a value of 1 to 4;

R₄ and R₅ are independently hydrogen, optionally substituted C_1-4 alkyl, optionally substituted aryl, optionally substituted aryl C_1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4alkyl, heterocyclic, heterocyclicC_1-4 alkyl, or R₄ and R₅ together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from oxygen, nitrogen or sulfur;

R₆ and R₇ are independently hydrogen or a C_1-4 alkyl group, or R₆ and R₇ together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;

Y is independently selected from hydrogen;

halogen;

nitro;

cyano;

halosubstituted C_1-10 alkyl;

C_1-10 alkyl;

C_2-10 alkenyl;

C_1-10 alkoxy;

halosubstituted C_1-10 alkoxy;

azide;

(CR₈R₈)q S(O)_tR₄;

hydroxy;

hydroxyC_1-4alkyl;

aryl;

aryl C_1-4 alkyl;

aryloxy;

arylC_1-4 alkyloxy;

heteroaryl;

heteroarylalkyl;

heteroaryl C_1-4 alkyloxy;

heterocyclic, heterocyclic C_1-4alkyl;

aryl C_2-10 alkenyl;

heteroaryl C_2-10 alkenyl;

heterocyclic C_2-10 alkenyl;

(CR₈R₈)q NR₄R₅;

C_2-10 alkenyl C(O)NR₄R₅;

(CR₈R₈)q C(O)NR₄R₅;

(CR₈R₈)q C(O)NR₄R₁₀;

S(O)₃H;

S(O)₃R₈;

(CR₈R₈)q C(O)R₁₁;

C_2-10 alkenyl C(O)R₁₁;

C_2-10 alkenyl C(O)OR₁₁;

C(O)R₁₁;

(CR₈R₈)q C(O)OR₁₂;

(CR₈R₈)q OC(O) R₁₁;

(CR₈R₈)q NR₄C(O)R₁₁, (CR₈R₈)q NHS(O)₂R_d, (CR₈R₈)q S(O)₂NR₄R₅;

or two Y moieties together may form O—

(CH₂)_sO—

or a 5 to 6 membered unsaturated ring;

R₈ is hydrogen or C_1-4 alkyl;

R_1-10 is C_1-10 alkyl C(O)₂R_8;

R₁₁ is hydrogen, C_1-4 alkyl, optionally substituted aryl, optionally substituted aryl C_1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC_1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC_1-4alkyl;

R₁₂ is hydrogen, C_1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;

R₁₃ and R₁₄ are independently hydrogen, optionally substituted C_1-4 alkyl or one of R₁₃ and R₁₄ may be optionally substituted aryl;

R₁₇ is C_1-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC_1-4alkyl, heterocyclic, or heterocyclicC_1-4alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted;

R_d is NR₆R₇, alkyl, arylC1-4alklyl, arylC_2-4 alkenyl, heteroaryl, hetroaryl-C_1-4alkyl, heteroarylC_2-4 alkenyl, heterocyclic, heterocyclicC_1-4 alkyl, wherein the aryl, heteoaryl and heterocyclic rings may all be optionally substituted;

provided that

R₁ is not 3-phenyl, or 4-isopropyl, or 5-phenyl or 5-ethylsulfonyl, when R is OH, v is 1,

R₁₃ and R₁₄ are hydrogen, and Y is hydrogen;

or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8 wherein the R₂ is optionally substituted one to three times by halogen, nitro, halosubstituted C_1-10 alkyl, C_1-10 alkyl, C_1-10 alkoxy, hydroxy, SH, —

C(O)NR₆R₇, —

NH—

C(O)R_a, —

NHS(O)₂R_b, S(O)NR₆R₇, C(O)OR₈, or a tetrazolyl ring.

10. The compound according to claim 8 wherein R is OH, —

NHS(O)₂R_b or C(O)OH.

11. The compound according to claim 8 wherein R₁ is halogen, cyano, nitro, CF₃, C(O)NR₄R₅, alkenyl C(O)NR₄R₅, C(O) R₄R₁₀, alkenyl C(O)OR₁₂, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(O)NR₄R₅.

12. The compound according to claim 8 wherein Y is halogen, C_1-4 alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylene dioxy, NR₄R₅, thioC_1-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C_1-4alkyl, hydroxy alkyl.

13. The compound according to claim 8 wherein R is OH, SH, or NHS(O)₂R_b and R₁ is substituted in the 3-position, the 4-position or di substituted in the 3,4-position by an electron withdrawing moiety.

14. A pharmaceutical composition comprising an effective amount of a compound according to claim 8, and a phamaceutically acceptable carrier or diluent.

15. A compound of the formula:

wherein

X is oxygen or sulfur;

R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;

R₁ is independently selected from hydrogen;

halogen;

nitro;

cyano;

halosubstituted C_1-10 alkyl;

C_1-10 alkyl;

C_2-10 alkenyl;

C_1-10 alkoxy;

halosubstituted C_1-10 alkoxy;

azide;

(CR₈R₈)q S(O)_tR₄;

hydroxy;

hydroxy C_1-4alkyl;

aryl;

aryl C_1-4 alkyl;

aryloxy;

aryl C_1-4 alkyloxy;

heteroaryl;

heteroarylalkyl;

heterocyclic, heterocyclic C_1-4alkyl;

heteroaryl C_1-4 alkloxy;

aryl C_2-10 alkenyl;

heteroaryl C_2-10 alkenyl;

heterocyclic C_2-10 alkenyl;

(CR₈R₈)qNR₄R₅;

C_2-10 alkenyl C(O)NR₄R₅;

(CR₈R₈)q C(O)NR₄R₅;

(CR₈R₈)q C(O)NR₄R₁₀;

S(O)₃H;

S(O)₃R₈;

(CR₈R₈)q C(O)R₁₁;

C_2-10 alkenyl C(O)R₁₁;

C_2-10 alkenyl C(O)OR₁₁ (CR₈R₈)q C(O)OR₁₂;

(CR₈R₈)q OC(O) R₁₁;

(CR₈R₈)qNR₄C(O)R₁₁, (CR₈R₈)q NHS(O)₂R₁₇, (CR₈R₈)q S(O)₂NR₄R₅;

or two R₁ moieties together may form O—

(CH₂)_sO—

or a 5 to 6 membered unsaturated ring;

n is an integer having a value of 1 to 3;

m is an integer having a value of 1 to 3;

q is 0, or an integer having a value of 1 to 10;

t is 0, or an integer having a value of 1 or 2;

s is an integer having a value of 1 to 3;

v is an integer having a value of 1 to 4;

R₄ and R₅ are independently hydrogen, optionally substituted C_1-4 alkyl, optionally substituted aryl, optionally substituted aryl C_1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4alkyl, heterocyclic, heterocyclic C_1-4 alkyl, or R₄ and R₅ together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;

R₆ and R₇ are independently hydrogen or a C_1-4 alkyl group, or R₆ and R₇ together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;

Y is independently selected from hydrogen;

halogen;

nitro;

cyano;

halosubstituted C_1-10 alkyl;

C_1-10 alkyl;

C_2-10 alkenyl;

C_1-10 alkoxy;

halosubstituted C_1-10 alkoxy;

azide;

(CR₈R₈)q S(O)_tR₄;

hydroxy;

hydroxyC_1-4alkyl;

aryl;

aryl C_1-4 alkyl;

aryloxy;

arylC_1-4 alkyloxy;

heteroaryl;

heteroarylalkyl;

heteroaryl C_1-4 alkyloxy;

heterocyclic, heterocyclic C_1-4alkyl;

aryl C_2-10 alkenyl;

heteroaryl C_2-10 alkenyl;

heterocyclic C_2-10 alkenyl;

(CR₈R₈)q NR₄R₅;

C_2-10 alkenyl C(O)NR₄R₅;

(CR₈R₈)q C(O)NR₄R₅;

(CR₈R₈)q C(O)NR₄R₁₀;

S(O)₃H;

S(O)₃R₈;

(CR₈R₈)q C(O)R₁₁;

C_2-10 alkenyl C(O)R₁₁;

C_2-10 alkenyl C(O)OR₁₁;

C(O)R₁₁;

(CR₈R₈)q C(O)OR₁₂;

(CR₈R₈)q OC(O) R₁₁;

(CR₈R₈)q NR₄C(O)R₁₁, (CR₈R₈)q NHS(O)₂R_d, (CR₈R₈)q S(O)₂NR₄R₅;

or two Y moieties together may form O—

(CH₂)_sO—

or a 5 to 6 membered unsaturated ring;

R₈ is hydrogen or C_1-4 alkyl;

R₁₀ is C_1-10 alkyl C(O)₂R₈;

R₁₁ is hydrogen, C_1-4 alkyl, optionally substituted aryl, optionally substituted aryl C_1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC_1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC_1-4alkyl;

R₁₂ is hydrogen, C_1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;

R₁₃ and R₁₄ are independently hydrogen, optionally substituted C_1-4 alkyl, or one of R₁₃ and R₁₄ may be optionally substituted aryl;

R₁₇ is C_1-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC_1-4alkyl, heterocyclic, or heterocyclicC_1-4alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted;

R_d is NR₆R₇, alkyl, arylC1-4alklyl, arylC_2-4 alkenyl, heteroaryl, hetroaryl-C_1-4alkyl, heteroarylC_2-4 alkenyl, heterocyclic, heterocyclicC_1-4 alkyl, wherein the aryl, heteoaryl and heterocyclic rings may all be optionally substituted;

E is optionally selected from

 

the asterix * denoting point of attachment of the ring; and

Z is optionally selected from

 

the asterix * denoting point of attachment of the ring, with at least one E ring or Z ring being present;

or a pharmaceutically acceptably salt thereof.

16. The compound according to claim 15 wherein the ionizable hydrogen has a pKa of 3 to 10.

17. The method according to claim 15 wherein R is hydroxy, carboxylic acid, thiol, SR₂, OR₂, NH—

C(O)R_a, C(O)NR₆R₇, NHS(O)₂R_b, S(O)₂NHR_c, NHC(X₂)NHR_b, or tetrazolyl;

wherein R₂ is a substituted aryl, heteroaryl, or heterocyclic ring which ring contains the functional moiety providing the ionizable hydrogen having a pKa of 10 or less;

R_a is an alkyl, aryl, aryl C_1-4alkyl, heteroaryl, heteroaryl C_1-4alkyl, heterocyclic, or a heterocyclic C_1-4alkyl moiety, all of which may be optionally substituted;

R_b is a NR₆R₇, alkyl, aryl, arylC_1-4alkyl, arylC_2-4akenyl, heteroaryl, heteroarylC_1-4alkyl, heteroarylC_2-4 alkenyl, heterocyclic, heterocyclic C_1-4alkyl, heterocyclic C_2-4alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen;

nitro;

halosubstituted C_1-4 alkyl;

C_1-4 alkyl;

C_1-4 alkoxy;

NR₉C(O)R_a;

C(O)NR₆R₇, S(O)₃H, or C(O)OC_1-4 alkyl;

R₉ is hydrogen or a C_1-4 alkyl;

R_c is alkyl, aryl, arylC_1-4alkyl, arylC_2-4alkenyl, heteroaryl, heteroarylC_1-4alkyl, heteroarylC_2-4alkenyl, heterocyclic, heterocyclic C_1-4alkyl, or a heterocyclic C_2-4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro, halosubstituted C_1-4 alkyl, C_1-4 alkyl, C_1-4 alkoxy, NR₉C(O)R_a, C(O)NR₆R₇, S(O)₃H, or C(O)OC_1-4 alkyl; and

X₂ is oxygen or sulfur.

18. The compound according to claim 17 wherein the R₂ is optionally substituted one to three times by halogen, nitro, halosubstituted C_1-10 alkyl, C_1-10 alkyl, C_1-10 alkoxy, hydroxy, SH, C(O)NR₆R₇, NH—

C(O)R_a, NHS(O)₂R_b, S(O)NR₆R₇, C(O)OR₈, or a tetrazolyl ring.

19. The compound according to claim 17 wherein R is OH, NHS(O)₂R_b or C(O)OH.

20. The compound according to claim 15 wherein R₁ is halogen, cyano, nitro, CF₃, C(O)NR₄R₅, alkenyl C(O)NR₄R₅, C(O) R₄R₁₀, alkenyl C(O)OR₁₂, heteroaryl, heteroarylalyl , heteroaryl alkenyl, or S(O)NR₄R₅.

21. The compound according to claim 15 wherein Y is halogen, C_1-4 alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylene dioxy, NR₄R₅, thioC_1-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C_1-4alkyl, or hydroxy alkyl.

22. The compound according to claim 15 wherein R is OH, SH, or NHS(O)₂R_b and R₁ is substituted in the 3-position, the 4-position or di substituted in the 3,4-position by an electron withdrawing moiety.

23. A pharmaceutical composition comprising an effective amount of a compound according to claim 15, and a pharmaceutically acceptable carrier or diluent.