Pharmaceutical for treating of neurological and neuropsychiatric disorders

• US 6,001,854 A
• Filed: 05/30/1997
• Issued: 12/14/1999
• Est. Priority Date: 05/31/1996
• Status: Expired due to Fees

• Current Assignee: NPS Pharmaceuticals Incorporated (Shire plc)
• Original Assignee: Allelix Neuroscience, Inc. (Shire plc)
• Inventors: Zhang, Jing, Bell, Stanley Charles, Ognyanov, Vassil Iliya, Borden, Laurence A.
• Primary Examiner(s): Kight, John
• Assistant Examiner(s): AULAKH, CHARANJIT
• Application Number:
  US08/865,919
• Time in Patent Office: 928 Days
• Field of Search: 546/216, 546/221, 546/229, 546/233, 546/234, 546/239, 546/333, 546/342, 514/317, 514/327, 514/331, 514/357
• US Class Current: 514/317
• CPC Class Codes: C07D 207/06 with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 211/14 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/22 by oxygen atoms
• CPC Class Codes: C07D 211/42 attached in position 3 or 5
• CPC Class Codes: C07D 211/70 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 491/04 Ortho-condensed systems

Abstract

The invention provides a pharmaceutical for treatment of neurological and neuropsychiatric disorders comprising a compound of the following formulas I and II: ##STR1## or a pharmaceutically acceptable salt thereof.

Claims

1. A compound of formula I or II:

##STR57## or a pharmaceutically acceptable salt thereof, wherein;

(1) X is nitrogen or carbon, and R² is not present when X is nitrogen;

(2) R² (a) is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, cyano, (C2-C7) alkanoyl, aminocarbonyl, (C1-C6) alkylaminocarbonyl or dialkylaminocarbonyl wherein each alkyl is independently C1 to C6, (b) comprises (where R¹ is not --O--R⁸ or --S--R^8*) hydroxy, fluoro, chloro, bromo or (C2-C7) alkanoyloxy, (c) forms a double bond with an adjacent carbon or nitrogen from one of either R¹, R^xb or R^yb, (d) is oxygen forming an oxa linkage with R¹ or integrated into ring E (see, for example, Compound C6) or (e) is R^2a linked by R^2b to X;

(2ⁱ) R^x is a ring-containing structure R^xa linked by R^xb to X;

(2ⁱⁱ) R^y is a ring-containing structure R^ya linked by R^yb to X;

(2ⁱⁱⁱ) R^xa, R^ya and R^2a, are independently aryl, heteroaryl, adamantyl or a 5 to 7-membered non-aromatic ring having from 0 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein;

(a) aryl is phenyl or naphthyl,

(b) heteroaryl comprises a five-membered ring, a six-membered ring, a six-membered ring fused to a five-membered ring, a five-membered ring fused to a six-membered ring, or a six-membered ring fused to a six-membered ring, wherein the heteroaryl is aromatic and contains heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon,

(c) each of R^xa, R^ya and R^2a can be independently substituted with one of R^q, R^r O-- or R^s S--, wherein Rq, Rr and Rs are independently aryl, heteroaryl, adamantyl or a 5 to 7-membered non-aromatic ring as these structures are defined for R^xa, and

(d) R^xa, R^ya, R^2a, R^q, R^r and R^s can be substituted or additionally substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, hydroxy, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (C1-C6) N-alkyl substitutions, adamantyl, (C1-C12) alkyl, (C1-C12) alkenyl, amino, (C1-C6) alkylamino, dialkylamino wherein each alkyl is independently C1 to C6, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (C1-C6) alkylsulfonyl, amidino that can independently substituted with up to three (C1-C6) alkyl, or methylenedioxy or ethylenedioxy with the two oxygens bonded to adjacent positions on the aryl or heteroaryl ring structure, which methylenedioxy or ethylenedioxy can be substituted with up to two independent (C1-C6) alkyl, wherein;

(i) the substitutions of R^xa, R^ya and R^2a can be combined to form a second bridge between two of R^xa, R^ya and R^2a comprising (1) (C1-C2) alkyl or alkenyl, which can be independently substituted with one or more (C1-C6) alkyl, (2) sulfur, (3) oxygen, (4) amino, which can be substituted for hydrogen with one (C1-C6) alkyl, (5) carbonyl, (6) --CH₂ C(═

O)--, which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (7) --C(═

O)--O--, (8) --CH₂ --O--, which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (9) --C(═

O)--N(R²⁴)--, wherein R²⁴ is hydrogen or (C1-C6) alkyl, (10) --CH₂ --NH--, which can be substituted for hydrogen with up to three (C1-C6) alkyl, or (11) --CH═

N--, which can be substituted for hydrogen with (C1-C6) alkyl, or wherein two of R^xa, R^ya and R^2a can be directly linked by a single bond;

(2^iv) R^xb and R^2b are independently a single bond or (C1-C2) alkylene;

(2^v) R^yb is a single bond, oxa, (C1-C2) alkylene, ethenylene or --CH═

(where the double bond is with X), thia, methyleneoxy or methylenethio, or either --N(R⁶)-- or --CH₂ --N(R^6*)--, wherein R⁶ and R^6* are hydrogen or (C1-C6) alkyl, wherein when X is nitrogen X is not bonded to another heteroatom;

(3) R¹ comprises;

a single bond or double bond;

a straight-chained (C1-C3) aliphatic group;

or (where X is carbon and R^yb does not include a heteroatom attached to X) --O--R⁸ or --S--R^8*, wherein either R⁸ or R^8* is a single bond, (C1-C3) alkylene or (C2-C3) alkenylene and O or S is bonded to X;

wherein R¹ can be substituted with up to one hydroxy, up to one (C1-C6) alkoxy or up to one (C2-C7) alkanoyloxy, with up to two independent (C1-C6) alkyl, with up to one oxo, up to one (C2-C6) alkylidene, with the proviso that the hydroxy, alkoxy, alkanoyloxy, oxo substituents are not bonded to a carbon that is bonded to a nitrogen or oxygen, or (where R¹ is --O--R⁸ and X is carbon) an oxa linkage to X forming a 1,3-dioxolane,

wherein the alkyl or alkylidene substituents of R¹ can be linked to form a 3 to 7-membered non-aromatic ring, and

wherein if X is nitrogen, X is linked to R¹ by a single bond and the terminal carbon of R¹ that links R¹ to N is saturated;

(4) n is 0 or 1, and where if n is 1, R^3* is either (C1-C6) alkyl (with the attached nitrogen having a positive charge) or oxygen (forming an N-oxide) and X is carbon;

(5) wherein ring D is a 6-membered ring, a 6-membered ring substituted with a 3 to 6-membered spiro ring, or a 6-membered ring fused with a 5 to 6-membered ring, wherein the fused ring lacking the illustrated tertiary nitrogen can be aromatic, with the proviso that the ring atoms include no quaternary nitrogens;

wherein the carbon and nitrogen ring atoms of ring D can be substituted with substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, (C2-C7) alkyloxycarbonyl, (C1-C6) alkylidene, hydroxyl, (C1-C6) alkoxy, oxo, hydroxycarbonyl, aryl wherein the aryl is as defined for R^a or heteroaryl wherein the heteroaryl is as defined for R^a, with the proviso that ring atoms substituted with alkylidene, hydroxycarbonyl or oxo are carbon, with the further proviso that ring atoms substituted with hydroxyl or alkoxy are separated from other ring heteroatoms by at least two intervening carbon atoms; and

wherein R¹, R³ and G are such that at least two atoms separate X and the illustrated ring nitrogen;

(6) wherein ring E is a 6-membered ring, a 6-membered ring substituted with a 3 to 6-membered spiro ring, or a 6-membered ring fused with a 5 to 6-membered ring, wherein the fused ring lacking the illustrated tertiary nitrogen can be aromatic, with the proviso that the ring atoms include no quaternary nitrogens;

wherein the carbon and nitrogen ring atoms of ring E can be substituted with substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, (C2-C7) alkyloxycarbonyl, (C1-C6) alkylidene, hydroxyl (C-C6) alkoxy, oxo, hydroxycarbonyl, (C1-C6) alkoxycarbonyl, aryl wherein the aryl is as defined for R^a, or heteroaryl wherein the heteroaryl is as defined for R^a, with the proviso that ring atoms substituted with alkylidene, hydroxycarbonyl or oxo are carbon, with the further proviso that ring atoms substituted with hydroxyl or alkoxy are separated from other ring heteroatoms by at least two intervening carbon atoms; and

wherein G* and R¹⁸ are such that at least two atoms separate the illustrated ring nitrogen from the carbon linked to R^x and R^y ;

(7) R¹⁹ (a) forms a double bond with R¹, R³ or G, (b) is hydrogen (c) is (C1-C3) alkyl or alkylene, or (d) is incorporated into a fused ring;

(8) R⁴ and R^4* are independently hydrogen or (C1-C6) alkyl or one of R⁴ and R^4* can be (C1-C6) hydroxyalkyl; and

(9) R5 is (CO)NR¹³ R¹⁴, (CO)OR¹⁵, (CO)SR¹⁶, (SO₂)NR¹⁷ R¹⁸, (PO)(OR¹⁹)(OR²⁰), (CR²²)(OR²³)(OR²⁴), CN or tetrazol-5-yl, wherein R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ are independently hydrogen, (C1-C8) alkyl which can include a (C3-C8) cycloalkyl, wherein the carbon linked to the oxygen of R15 or the sulfur of R16 has no more than secondary branching and, (C2-C6) hydroxyalkyl, aminoalkyl where the alkyl is C2 to C6 and the amino can be substituted with up to two independent (C1-C6) alkyls, arylalkyl wherein the alkyl is C1-C6, heteroarylalkyl wherein the alkyl is C1 to C6, aryl or heteroaryl, R²² is hydrogen or OR²⁵ and R²³, R²⁴ and R²⁵ are (C1-C6) alkyl, phenyl, benzyl, acetyl or, where R²² is hydrogen, the alkyls of R²³ and R²⁴ can be combined to include 1,3-dioxylane or 1,3-dioxane;

wherein the aryl is phenyl or naphthyl and the heteroaryl is a five-membered ring, a six-membered ring, a six-membered ring fused to a five-membered ring, a five-membered ring fused to a six-membered ring, or a six-membered ring fused to a six-membered ring, wherein the heteroaryl is aromatic and contains heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon;

wherein the aryl, heteroaryl, aryl of arylalkyl or the heteroaryl of heteroarylalkyl can be substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (C1-C6) N-alkyl substitutions, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkylamine, dialkylamine wherein each alkyl is independently C1 to C6, amino, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be N-substituted with up to two independent (C1-C6) alkyl, (C1-C6) alkylsulfonyl, amidino that can substituted with up to three (C1-C6) alkyl, or methylenedioxy or ethylenedioxy with the two oxygens bonded to adjacent positions on the aryl or heteroaryl ring structure, which methylenedioxy or ethylenedioxy can be substituted with up to two independent (C1-C6) alkyl; and

wherein R¹³ and R¹⁴ together with the nitrogen can form a 5 to 7-membered ring that can contain one additional heteroatom selected from oxygen and sulfur;

wherein when (i) D is piperidine, (ii) R² is OH, (iii) R^x is R^xa, and (iv) R^y is R^ya, then R^xa and R^ya are not phenyl, phenyl substituted with fluoro, chloro, bromo, hydroxy, trifluoromethyl, C1-C8 alkyl, C1-C6 alkoxy, or not pyridyl, and R⁵ is not (CO)NR¹³ R¹⁴ or (CO)OR¹⁵ when R¹³, R¹⁴, and R¹⁵ are independently hydrogen, C1-C8 alkyl, phenyl, or phenyl substituted with fluoro, chloro, bromo, C1-C6 alkyl or C1-C6 alkoxy; and

wherein when (i) D is piperidine, (ii) X is carbon, (iii) R¹ is OR⁸, (iv) R⁵ is (CO)OR¹⁵, (v) R^x is R^xa and (vi) R^y is R^ya, then R^xa and R^ya are not both phenyl or phenyl substituted with fluoro, chloro, bromo, C1-C4 alkyl or C1-C4 alkoxy and R¹⁵ is not hydrogen or C1-C4 alkoxy.

2. The compound of claim 1, wherein (A) at least one of R^xa, R^ya and R^2a is substituted with fluoro, chloro, bromo, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, (C3-C8) alkyl, R^q, R^r O--, R^s S--, or (B) the ring structures of R^xa, R^ya and R^2a, including substituents thereto, otherwise include at least two aromatic ring structures that together include from 15 to 20 ring atoms.

3. The compound of claim 2, wherein at least one of R^xa, R^ya and R^2a is substituted with fluoro, trifluoromethyl, trifluoromethoxy, nitro, cyano, or (C3-C8) alkyl.

4. The compound of claim 1, wherein at least one of R^xa, R^ya and R^2a is substituted with R^q, R^r O--, or R^s S--.

5. The compound of claim 1, wherein an aryl or heteroaryl of at least one of R^xa, R^ya and R^2a is phenyl.

8. The compound of claim 1, wherein R⁵ is (CO)NR¹³ R¹⁴, (CO)OR¹⁵ or (CO)SR¹⁶.

9. The compound of claim 8, wherein R¹⁵ is (C2-C6) alkyl, (C2-C4) hydroxyalkyl, phenyl, phenylalkyl wherein the alkyl is C1-C3, or aminoalkyl where the alkyl is C2-C6 and the amino can be substituted with up to two independent (C1-C3) alkyls, wherein the phenyl or the phenyl of phenylalkyl can be substituted.

10. The compound of claim 8, wherein R¹⁵ is hydrogen.

11. The compound of claim 1, wherein R⁴ is hydrogen, methyl or hydroxymethyl and R^4* is hydrogen.

13. The compound of claim 1, wherein R¹ is --O--R⁸ or --S--R^8*.

14. The compound of claim 1, wherein said second bridge between two of R^xa, R^ya and R^2a is L, and satisfies the following formula:

##STR60## wherein A and B are aryl or heteroaryl groups of R^xa and R^ya, respectively, and wherein L is selected from the group consisting of;

(1) (C1-C2) alkyl or alkenyl which can be independently substituted with one or more (C1-C6) alkyl, (2) sulfur, (3) oxygen, (4) amino, which can be substituted for hydrogen with one (C1-C6) alkyl (5) carbonyl, (6) --CH₂ C(═

O)--, which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (7) --C(═

O)--O--, (8) --CH₂ --O--, which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (9) --C(═

O)--N(R²⁴)--, wherein R²⁴ is hydrogen or (C1-C6) alkyl, (10) --CH₂ --NH--, which can be substituted for hydrogen with up to three (C1-C6) alkyl, or (11) --CH═

N--, which can be substituted for hydrogen with (C1-C6) alkyl, or a single bond whereby two of R^xa, R^ya and R^2a are directly linked by the single bond.

15. The compound of claim 14, wherein R^xa --R^xb --, R^ya --R^yb -- and X form:

##STR61## wherein Y is a carbon bonded to R¹ by a single or double bond or a nitrogen that is bonded to R¹ and wherein R²¹ either (i) completes a single bond linking two aryl or heteroaryl rings of R^x and R^y, (ii) is (C1-C2) alkylene or alkenylene, (iii) is sulfur or (iv) is oxygen, and wherein R^x and R^y can be substituted as set forth above.

16. The compound of claim 15, wherein R²¹ is CH₂ CH₂ or CH═

CH.

17. The compound of claim 1, wherein the alkylenedioxy substitution of R^xa, R^ya or R^2a is as follows:

##STR62## wherein the alkylenedioxy can be substituted with up to two independent (C1-C3) alkyl.

18. The compound of claim 1, wherein ring D is according to one of formulas A'"'"' and B'"'"':

##STR63## wherein Z represents carbon, wherein for each of formulas A'"'"' and B'"'"' up to two of the bonds indicated with the hashed lines can be double bonds provided no two double bonds are adjacent, and wherein the ring of formulas A'"'"' and B'"'"' can be substituted as set forth above for ring D.

19. The compound of claim 1, wherein the ring system comprising G* is according to one of formulas C'"'"' and D'"'"' ##STR64## wherein Z represents carbon, wherein for formula C'"'"' up to one of the bonds indicated with the hashed lines can be double bond and for formula D'"'"' up to two of the bonds indicated with the hashed lines can be double bonds, and wherein the ring can be substituted as set forth above for ring E.

20. The compound of claim 1, wherein ring D or ring E is substituted with up to three substituents.

21. The compound of claim 1, wherein R^xa and R^ya together can be substituted with up to six substituents, R^2a, R^q, R^r and R^s can each be substituted with up to 3 substituents, and wherein the presence of each of R^q, R^r or R^s is considered a substitution to the respective ring structure of R^xa, R^ya and R^2a.

22. The compound of claim 1, wherein the aryl, heteroaryl, aryl of arylalkyl or the heteroaryl of heteroarylalkyl of R¹³, R¹⁴, R¹⁵, R¹⁶ R¹⁷, R¹⁸ R¹⁹ or R²⁰ is substituted with up to three substituents.

23. The compound of claim 1, wherein the compound is an optically pure enantiomer.

25. A compound of claim 1 according to the following formula ##STR66## wherein R²⁸ is the same as R¹ except that the bond to the ring is not a double bond, wherein ring C^ix is mono or di-unsaturated at one or more of the bonds indicated with the dashed lines with the double bonds formed between ring carbons and no two double bonds are adjacent, wherein ring C^ix can include a fused phenyl and can be substituted as follows

the carbon and nitrogen ring atoms of ring D can be substituted with up to 2 substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, and (C2-C7) alkyloxycarbonyl.

6. A compound of formula I or II:

##STR58## or a pharmaceutically acceptable salt thereof, wherein;

(1) X is nitrogen or carbon, and R² is not present when X is nitrogen;

(2) R² (a) is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, cyano, (C2-C7) alkanoyl, aminocarbonyl, (C1-C6) alkylaminocarbonyl or dialkylaminocarbonyl wherein each alkyl is independently C1 to C6, (b) comprises (where R¹ is not --O--R⁸ or --S--R^8*) hydroxy, fluoro, chloro, bromo or (C2-C7) alkanoyloxy, (c) forms a double bond with an adjacent carbon or nitrogen from one of either R¹, R^xb or R^yb, (d) is oxygen forming an oxa linkage with R¹ or integrated into ring E (see, for example, Compound C6) or (e) is R^2a linked by R^2b to X;

(2ⁱ) R^x is a ring-containing structure R^xa linked by R^xb to X;

(2ⁱⁱ) R^y is a ring-containing structure R^ya linked by R^yb to X;

(2ⁱⁱⁱ) R^xa, R^ya and R^2a, are independently aryl, heteroaryl, adamantyl or a 5 to 7-membered non-aromatic ring having from 0 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein;

(a) aryl is phenyl or naphthyl,

(b) heteroaryl comprises a five-membered ring, a six-membered ring, a six-membered ring fused to a five-membered ring, a five-membered ring fused to a six-membered ring, or a six-membered ring fused to a six-membered ring, wherein the heteroaryl is aromatic and contains heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon,

(c) each of R^xa, R^ya and R^2a can be independently substituted with one of R^q, R^r O-- or R^s S--, wherein Rq, Rr and Rs are independently aryl, heteroaryl, adamantyl or a 5 to 7-membered non-aromatic ring as these structures are defined for R^xa, and

(d) R^xa, R^ya, R^2a, R^q, R^r and R^s can be substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, hydroxy, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (C1-C6) N-alkyl substitutions, adamantyl, (C1-C12) alkyl, (C1-C12) alkenyl, amino, (C1-C6) alkylamino, dialkylamino wherein each alkyl is independently C1 to C6, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (C1-C6) alkylsulfonyl, amidino that can independently substituted with up to three (C1-C6) alkyl, or methylenedioxy or ethylenedioxy with the two oxygens bonded to adjacent positions on the aryl or heteroaryl ring structure, which methylenedioxy or ethylenedioxy can be substituted with up to two independent (C1-C6) alkyl wherein;

(i) the substitutions of R^xa, R^ya and R^2a can be combined to form a second bridge between two of R^xa, R^ya and R^2a comprising (1) (C1-C2) alkyl or alkenyl which can be independently substituted with one or more (C1-C6) alkyl (2) sulfur, (3) oxygen, (4) amino, which can be substituted for hydrogen with one (C1-C6) alkyl, (5) carbonyl, (6) --CH₂ C(═

O)--, which can be substituted for hydrogen with up to two independent (C1-C6) alkyl (7) --C(═

O)--O--, (8) --CH₂ --O--, which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (9) --C(═

O)--N(R²⁴)--, wherein R²⁴ is hydrogen or (C1-C6) alkyl, (10) --CH₂ --NH--, which can be substituted for hydrogen with up to three (C1-C6) alkyl, or (11) --CH═

N--, which can be substituted for hydrogen with (C1-C6) alkyl, or wherein two of R^xa, R^ya and R^2a can be directly linked by a single bond;

(2^iv) R^xb and R^2b are independently a single bond or (C1-C2) alkylene;

(2^v) R^yb is oxa, methyleneoxy, thia, methylenethia;

(3) R¹ comprises;

a single bond or double bond;

a straight-chained (C1-C3) aliphatic group;

or (where X is carbon and R^yb does not include a heteroatom attached to X) --O--R⁸ or --S--R^8*, wherein either R⁸ or R^8* is a single bond, (C1-C3) alkylene or (C2-C3) alkenylene and O or S is bonded to X;

wherein R¹ can be substituted with up to one hydroxy, up to one (C1-C6) alkoxy or up to one (C2-C7) alkanoyloxy, with up to two independent (C1-C6) alkyl, with up to one oxo, up to one (C1-C6) alkylidene, with the proviso that the hydroxy, alkoxy, alkanoyloxy, oxo substituents are not bonded to a carbon that is bonded to a nitrogen or oxygen, or (where R¹ is --O--R⁸ and X is carbon) an oxa linkage to X forming a 1,3-dioxolane,

wherein the alkyl or alkylidene substituents of R¹ can be linked to form a 3 to 7-membered non-aromatic ring, and

wherein if X is nitrogen, X is linked to R¹ by a single bond and the terminal carbon of R¹ that links R¹ to N is saturated;

(4) n is 0 or 1, and where if n is 1, R^3* is either (C1-C6) alkyl (with the attached nitrogen having a positive charge) or oxygen (forming an N-oxide) and X is carbon;

(5) wherein ring D is a 6-membered ring, a 6-membered ring substituted with a 3 to 6-membered spiro ring, or a 6-membered ring fused with a 5 to 6-membered ring, wherein the fused ring lacking the illustrated tertiary nitrogen can be aromatic, with the proviso that the ring atoms include no quaternary nitrogens;

wherein the carbon and nitrogen ring atoms of ring D can be substituted with substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, (C2-C7) alkyloxycarbonyl, (C1-C6) alkylidene, hydroxyl, (C1-C6) alkoxy, oxo, hydroxycarbonyl, aryl wherein the aryl is as defined for R^a or heteroaryl wherein the heteroaryl is as defined for R^a, with the proviso that ring atoms substituted with alkylidene, hydroxycarbonyl or oxo are carbon, with the further proviso that ring atoms substituted with hydroxyl or alkoxy are separated from other ring heteroatoms by at least two intervening carbon atoms; and

wherein R¹, R³ and G are such that at least two atoms separate X and the illustrated ring nitrogen;

(6) wherein ring E is a 6-membered ring, a 6-membered ring substituted with a 3 to 6-membered spiro ring, or a 6-membered ring fused with a 5 to 6-membered ring, wherein the fused ring lacking the illustrated tertiary nitrogen can be aromatic;

wherein the carbon and nitrogen ring atoms of ring E can be substituted with substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, (C2-C7) alkyloxycarbonyl, (C1-C6) alkylidene, hydroxyl, (C-C6) alkoxy, oxo, hydroxycarbonyl, (C1-C6) alkoxycarbonyl, aryl wherein the aryl is as defined for R^a or heteroaryl wherein the heteroaryl is as defined for R^a, with the proviso that ring atoms substituted with alkylidene, hydroxycarbonyl or oxo are carbon, with the further proviso that ring atoms substituted with hydroxyl or alkoxy are separated from other ring heteroatoms by at least two intervening carbon atoms; and

wherein G* and R¹⁸ are such that at least two atoms separate the illustrated ring nitrogen from the carbon linked to R^x and R^y ;

(7) R¹⁹ (a) forms a double bond with R¹, R³ or G, (b) is hydrogen (c) is (C1-C3) alkyl or alkylene, or (d) is incorporated into a fused ring;

(8) R⁴ and R^4* are independently hydrogen or (C1-C6) alkyl, or one of R⁴ and R^4* can be (C1-C6) hydroxyalkyl; and

(9) R5 is (CO)NR¹³ R¹⁴, (CO)OR¹⁵, (CO)SR¹⁶, (SO₂)NR¹⁷ R¹⁸, (PO)(OR¹⁹)(OR²⁰), (CR²²)(OR²³)(OR²⁴), CN or tetrazol-5-yl, wherein R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ are independently hydrogen, (C1-C8) alkyl which can include a (C3-C8) cycloalkyl, wherein the carbon linked to the oxygen of R15 or the sulfur of R16 has no more than secondary branching and, (C2-C6) hydroxyalkyl, aminoalkyl where the alkyl is C2 to C6 and the amino can be substituted with up to two independent (C1-C6) alkyls, arylalkyl wherein the alkyl is C1-C6, heteroarylalkyl wherein the alkyl is C1 to C6, aryl or heteroaryl, R²² is hydrogen or OR²⁵ and R²³, R²⁴ and R²⁵ are (C1-C6) alkyl, phenyl, benzyl, acetyl or, where R²² is hydrogen, the alkyls of R²³ and R²⁴ can be combined to include 1,3-dioxylane or 1,3-dioxane;

wherein the aryl is phenyl or naphthyl and the heteroaryl is a five-membered ring, a six-membered ring, a six-membered ring fused to a five-membered ring, a five-membered ring fused to a six-membered ring, or a six-membered ring fused to a six-membered ring, wherein the heteroaryl is aromatic and contains heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon;

wherein the aryl, heteroaryl, aryl of arylalkyl or the heteroaryl of heteroarylalkyl can be substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (C1-C6) N-alkyl substitutions, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkylamine, dialkylamine wherein each alkyl is independently C1 to C6, amino, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be N-substituted with up to two independent (C1-C6) alkyl, (C1-C6) alkylsulfonyl, amidino that can substituted with up to three (C1-C6) alkyl, or methylenedioxy or ethylenedioxy with the two oxygens bonded to adjacent positions on the aryl or heteroaryl ring structure, which methylenedioxy or ethylenedioxy can be substituted with up to two independent (C1-C6) alkyl; and

wherein R¹³ and R¹⁴ together with the nitrogen can form a 5 to 7-membered ring that can contain one additional heteroatom selected from oxygen and sulfur.

7. The compound of claim 6, wherein R^yb is oxa or thia.

12. A compound of FIG. I or II:

##STR59## or a pharmaceutically acceptable salt thereof, wherein;

(1) X is nitrogen or carbon, and R² is not present when X is nitrogen;

(2) R² (a) is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, cyano, (C2-C7) alkanoyl aminocarbonyl, (C1-C6) alkylaminocarbonyl or dialkylaminocarbonyl wherein each alkyl is independently C1 to C6, (b) comprises (where R¹ is not --O--R⁸ or --S--R^8*) hydroxy, fluoro, chloro, bromo or (C2-C7) alkanoyloxy, (c) forms a double bond with an adjacent carbon or nitrogen from one of either R¹, R^xb or R^yb, (d) is oxygen forming an oxa linkage with R¹ or integrated into ring E (see, for example, Compound C6) or (e) is R^2a linked by R^2b to X;

(2ⁱ) R^x is a ring-containing structure R^xa linked by R^xb to X;

(2ⁱⁱ) R^y is a ring-containing structure R^ya linked by R^yb to X;

(2ⁱⁱⁱ) R^xa, R^ya and R^2a, are independently aryl, heteroaryl, adamantyl or a 5 to 7-membered non-aromatic ring having from 0 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein;

(a) aryl is phenyl or naphthyl,

(b) heteroaryl comprises a five-membered ring, a six-membered ring, a six-membered ring fused to a five-membered ring, a five-membered ring fused to a six-membered ring, or a six-membered ring fused to a six-membered ring, wherein the heteroaryl is aromatic and contains heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon,

(c) each of R^xa, R^ya and R^2a can be independently substituted with one of R^q, R^r O-- or R^s S--, wherein Rq, Rr and Rs are independently aryl, heteroaryl, adamantyl or a 5 to 7-membered non-aromatic ring as these structures are defined for R^xa, and

(d) R^xa, R^ya, R^2a, R^q, R^r and R^s can be substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, hydroxy, cyano, trifluoromethyl amidosulfonyl which can have up to two independent (C1-C6) N-alkyl substitutions, adamantyl, (C1-C12) alkyl, (C1-C12) alkenyl amino, (C1-C6) alkylamino, dialkylamino wherein each alkyl is independently C1 to C6, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl aminocarbonyl that can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (C1-C6) alkylsulfonyl, amidino that can independently substituted with up to three (C1-C6) alkyl, or methylenedioxy or ethylenedioxy with the two oxygens bonded to adjacent positions on the aryl or heteroaryl ring structure, which methylenedioxy or ethylenedioxy can be substituted with up to two independent (C1-C6) alkyl, wherein;

(i) the substitutions of R^xa, R^ya and R^2a can be combined to form a second bridge between two of R^xa, R^ya and R^2a comprising (1) (C1-C2) alkyl or alkenyl, which can be independently substituted with one or more (C1-C6) alkyl, (2) sulfur, (3) oxygen, (4) amino, which can be substituted for hydrogen with one (C1-C6) alkyl, (5) carbonyl, (6) --CH₂ C(═

O)--, which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (7) --C(═

O)--O--, (8) --CH₂ --O--, which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (9) --C(═

O)--N(R²⁴)--, wherein R²⁴ is hydrogen or (C1-C6) alkyl, (10) --CH₂ --NH--, which can be substituted for hydrogen with up to three (C1-C6) alkyl, or (11) --CH═

N--, which can be substituted for hydrogen with (C1-C6) alkyl, or wherein two of R^xa, R^ya and R^2a can be directly linked by a single bond;

(2^iv) R^xb and R^2b are independently a single bond or (C1-C2) alkylene;

(2^v) R^yb is a single bond, oxa, (C1-C2) alkylene, ethenylene or --CH═

(where the double bond is with X), thia, methyleneoxy or methylenethio, or either --N(R⁶)-- or --CH₂ --N(R^6*)--, wherein R⁶ and R^6* are hydrogen or (C1-C6) alkyl, wherein when X is nitrogen X is not bonded to another heteroatom;

(3) R¹ comprises;

a single bond or double bond;

a straight-chained (C1-C3) aliphatic group;

or (where X is carbon and R^yb does not include a heteroatom attached to X) --O--R⁸ or --S--R^8*, wherein either R⁸ or R^8* is a single bond, (C1-C3) alkylene or (C2-C3) alkenylene and O or S is bonded to X;

wherein R¹ can be substituted with up to one hydroxy, up to one (C1-C6) alkoxy or up to one (C2-C7) alkanoyloxy, with up to two independent (C1-C6) alkyl, with up to one oxo, up to one (C1-C6) alkylidene, with the proviso that the hydroxy, alkoxy, alkanoyloxy, oxo substituents are not bonded to a carbon that is bonded to a nitrogen or oxygen, or (where R¹ is --O--R⁸ and X is carbon) an oxa linkage to X forming a 1,3-dioxolane,

wherein the alkyl or alkylidene substituents of R¹ can be linked to form a 3 to 7-membered non-aromatic ring, and

wherein if X is nitrogen, X is linked to R¹ by a single bond and the terminal carbon of R¹ that links R¹ to N is saturated;

(4) n is 0 or 1, and where if n is 1, R^3* is either (C1-C6) alkyl (with the attached nitrogen having a positive charge) or oxygen (forming an N-oxide) and X is carbon;

(5) wherein ring D is a 6-membered ring, a 6-membered ring substituted with a 3 to 6-membered spiro ring, or a 6-membered ring fused with a 5 to 6-membered ring, wherein the fused ring lacking the illustrated tertiary nitrogen can be aromatic, with the proviso that the ring atoms include no quaternary nitrogens;

wherein the carbon and nitrogen ring atoms of ring D can be substituted with substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, (C2-C7) alkyloxycarbonyl, (C1-C6) alkylidene, hydroxyl, (C1-C6) alkoxy, oxo, hydroxycarbonyl, aryl wherein the aryl is as defined for R^a or heteroaryl wherein the heteroaryl is as defined for R^a, with the proviso that ring atoms substituted with alkylidene, hydroxycarbonyl or oxo are carbon, with the further proviso that ring atoms substituted with hydroxyl or alkoxy are separated from other ring heteroatoms by at least two intervening carbon atoms; and

wherein R¹, R³ and G are such that at least two atoms separate X and the illustrated ring nitrogen;

(6) wherein ring E is a 6-membered ring, a 6-membered ring substituted with a 3 to 6-membered spiro ring, or a 6-membered ring fused with a 5 to 6-membered ring, wherein the fused ring lacking the illustrated tertiary nitrogen can be aromatic, with the proviso that the ring atoms include no quaternary nitrogens;

wherein the carbon and nitrogen ring atoms of ring E can be substituted with substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, (C2-C7) alkyloxycarbonyl, (C1-C6) alkylidene, hydroxyl, (C-C6) alkoxy, oxo, hydroxycarbonyl, (C1-C6) alkoxycarbonyl, aryl wherein the aryl is as defined for R^a or heteroaryl wherein the heteroaryl is as defined for R^a, with the proviso that ring atoms substituted with alkylidene, hydroxycarbonyl or oxo are carbon, with the further proviso that ring atoms substituted with hydroxyl or alkoxy are separated from other ring heteroatoms by at least two intervening carbon atoms; and

wherein G* and R¹⁸ are such that at least two atoms separate the illustrated ring nitrogen from the carbon linked to R^x and R^y ;

(7) R¹⁹ (a) forms a double bond with R¹, R³ or G, (b) is hydrogen (c) is (C1-C3) alkyl or alkylene, or (d) is incorporated into a fused ring;

(8) R⁴ and R^4* are independently hydrogen or (C1-C6) alkyl, or one of R⁴ and R^4* can be (C1-C6) hydroxyalkyl; and

(9) R5 is (CO)NR¹³ R¹⁴, (CO)OR¹⁵, (CO)SR¹⁶, (SO₂)NR¹⁷ R¹⁸, (PO)(OR¹⁹)(OR²⁰), (CR²²)(OR²³)(OR²⁴), CN or tetrazol-5-yl, wherein R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ are independently hydrogen, (C1-C8) alkyl which can include a (C3-C8) cycloalkyl, wherein the carbon linked to the oxygen of R15 or the sulfur of R16 has no more than secondary branching and, (C2-C6) hydroxyalkyl, aminoalkyl where the alkyl is C2 to C6 and the amino can be substituted with up to two independent (C1-C6) alkyls, arylalkyl wherein the alkyl is C1-C6, heteroarylalkyl wherein the alkyl is C1 to C6, aryl or heteroaryl, R²² is hydrogen or OR²⁵ and R²³, R²⁴ and R²⁵ are (C1-C6) alkyl, phenyl, benzyl, acetyl or, where R²² is hydrogen, the alkyls of R²³ and R²⁴ can be combined to include 1,3-dioxylane or 1,3-dioxane;

wherein the aryl is phenyl or naphthyl and the heteroaryl is a five-membered ring, a six-membered ring, a six-membered ring fused to a five-membered ring, a five-membered ring fused to a six-membered ring, or a six-membered ring fused to a six-membered ring, wherein the heteroaryl is aromatic and contains heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon;

wherein the aryl, heteroaryl, aryl of arylalkyl or the heteroaryl of heteroarylalkyl can be substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (C1-C6) N-alkyl substitutions, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkylamine, dialkylamine wherein each alkyl is independently C1 to C6, amino, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be N-substituted with up to two independent (C1-C6) alkyl, (C1-C6) alkylsulfonyl amidino that can substituted with up to three (C1-C6) alkyl, or methylenedioxy or ethylenedioxy with the two oxygens bonded to adjacent positions on the aryl or heteroaryl ring structure, which methylenedioxy or ethylenedioxy can be substituted with up to two independent (C1-C6) alkyl; and

wherein R¹³ and R¹⁴ together with the nitrogen can form a 5 to 7-membered ring that can contain one additional heteroatom selected from oxygen and sulfur and wherein at least one of R^xa, R^ya and R^2a is a heteroaryl comprising diazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiolyl, diazinyl, triazinyl, benzoazolyl, benzodiazolyl, benzothiazolyl, benzoxazolyl, benzoxolyl, benzothiolyl, quinolyl, isoquinolyl, benzodiazinyl, benzotriazinyl, thienyl, furanyl, pyrrolyl, indolyl, isoindoyl or pyrimidyl.

24. A pharmaceutical composition comprising an effective amount of a compound of formula I or II, and a pharmaceutically acceptable excipient:

##STR65## or a pharmaceutically acceptable salt thereof, wherein;

(1) X is nitrogen or carbon, and R² is not present when X is nitrogen;

(2) R² (a) is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, cyano, (C2-C7) alkanoyl, aminocarbonyl, (C1-C6) alkylaminocarbonyl or dialkylaminocarbonyl wherein each alkyl is independently C1 to C6, (b) comprises (where R¹ is not --O--R⁸ or --S--R^8*) hydroxy, fluoro, chloro, bromo or (C2-C7) alkanoyloxy, (c) forms a double bond with an adjacent carbon or nitrogen from one of either R¹, R^xb or R^yb, (d) is oxygen forming an oxa linkage with R¹ or integrated into ring E (see, for example, Compound C6) or (e) is R^2a linked by R^2b to X;

(2ⁱ) R^x is a ring-containing structure R^xa linked by R^xb to X;

(2ⁱⁱ) R^y is a ring-containing structure R^ya linked by R^yb to X;

(2ⁱⁱⁱ) R^xa, R^ya and R^2a, are independently aryl, heteroaryl, adamantyl or a 5 to 7-membered non-aromatic ring having from 0 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein;

(a) aryl is phenyl or naphthyl,

(b) heteroaryl comprises a five-membered ring, a six-membered ring, a six-membered ring fused to a five-membered ring, a five-membered ring fused to a six-membered ring, or a six-membered ring fused to a six-membered ring, wherein the heteroaryl is aromatic and contains heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon,

(c) each of R^xa, R^ya and R^2a can be independently substituted with one of R^q, R^r O-- or R^s S--, wherein Rq, Rr and Rs are independently aryl, heteroaryl, adamantyl or a 5 to 7-membered non-aromatic ring as these structures are defined for R^xa, and

(d) R^xa, R^ya, R^2a, R^q, R^r and R^s can be substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, hydroxy, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (C1-C6) N-alkyl substitutions, adamantyl, (C1-C12) alkyl, (C1-C12) alkenyl, amino, (C1-C6) alkylamino, dialkylamino wherein each alkyl is independently C1 to C6, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (C1-C6) alkylsulfonyl, amidino that can independently substituted with up to three (C1-C6) alkyl, or methylenedioxy or ethylenedioxy with the two oxygens bonded to adjacent positions on the aryl or heteroaryl ring structure, which methylenedioxy or ethylenedioxy can be substituted with up to two independent (C1-C6) alkyl, wherein;

(i) the substitutions of R^xa, R^ya and R^2a can be combined to form a second bridge between two of R^xa, R^ya and R^2a comprising (1) (C1-C2) alkyl or alkenyl, which can be independently substituted with one or more (C1-C6) alkyl, (2) sulfur, (3) oxygen, (4) amino, which can be substituted for hydrogen with one (C1-C6) alkyl, (5) carbonyl, (6) --CH₂ C(═

O)--, which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (7) --C(═

O)--O--, (8) --CH₂ --O--, which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (9) --C(═

O)--N(R²⁴)--, wherein R²⁴ is hydrogen or (C1-C6) alkyl, (10) --CH₂ --NH--, which can be substituted for hydrogen with up to three (C1-C6) alkyl, or (11) --CH═

N--, which can be substituted for hydrogen with (C1-C6) alkyl, or wherein two of R^xa, R^ya and R^2a can be directly linked by a single bond;

(2^iv) R^xb and R^2b are independently a single bond or (C1-C2) alkylene;

(2^v) R^yb is a single bond, oxa, (C1-C2) alkylene, ethenylene or --CH═

(where the double bond is with X), thia, methyleneoxy or methylenethio, or either --N(R⁶)-- or --CH₂ --N(R^6*)--, wherein R⁶ and R^6* are hydrogen or (C1-C6) alkyl, wherein when X is nitrogen X is not bonded to another heteroatom;

(3) R¹ comprises;

a single bond or double bond;

a straight-chained (C1-C3) aliphatic group;

or (where X is carbon and R^yb does not include a heteroatom attached to X) --O--R⁸ or --S--R^8*, wherein either R⁸ or R^8* is a single bond, (C1-C3) alkylene or (C2-C3) alkenylene and O or S is bonded to X;

wherein R¹ can be substituted with up to one hydroxy, up to one (C1-C6) alkoxy or up to one (C2-C7) alkanoyloxy, with up to two independent (C1-C6) alkyl, with up to one oxo, up to one (C1-C6) alkylidene, with the proviso that the hydroxy, alkoxy, alkanoyloxy, oxo substituents are not bonded to a carbon that is bonded to a nitrogen or oxygen, or (where R¹ is --O--R⁸ and X is carbon) an oxa linkage to X forming a 1,3-dioxolane,

wherein the alkyl or alkylidene substituents of R¹ can be linked to form a 3 to 7-membered non-aromatic ring, and

wherein if X is nitrogen, X is linked to R¹ by a single bond and the terminal carbon of R¹ that links R¹ to N is saturated;

(4) n is 0 or 1, and where if n is 1, R^3* is either (C1-C6) alkyl (with the attached nitrogen having a positive charge) or oxygen (forming an N-oxide) and X is carbon;

(5) wherein ring D is a 6-membered ring, a 6-membered ring substituted with a 3 to 6-membered spiro ring, or a 6-membered ring fused with a 5 to 6-membered ring, wherein the fused ring lacking the illustrated tertiary nitrogen can be aromatic, with the proviso that the ring atoms include no quaternary nitrogens;

wherein the carbon and nitrogen ring atoms of ring D can be substituted with substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, (C2-C7) alkyloxycarbonyl, (C1-C6) alkylidene, hydroxyl, (C1-C6) alkoxy, oxo, hydroxycarbonyl, aryl wherein the aryl is as defined for R^a or heteroaryl wherein the heteroaryl is as defined for R^a, with the proviso that ring atoms substituted with alkylidene, hydroxycarbonyl or oxo are carbon, with the further proviso that ring atoms substituted with hydroxyl or alkoxy are separated from other ring heteroatoms by at least two intervening carbon atoms; and

wherein R¹, R³ and G are such that at least two atoms separate X and the illustrated ring nitrogen;

(6) wherein ring E is a 6-membered ring, a 6-membered ring substituted with a 3 to 6-membered spiro ring, or a 6-membered ring fused with a 5 to 6-membered ring, wherein the fused ring lacking the illustrated tertiary nitrogen can be aromatic, with the proviso that the ring atoms include no quaternary nitrogens;

wherein the carbon and nitrogen ring atoms of ring E can be substituted with substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, (C2-C7) alkyloxycarbonyl, (C1-C6) alkylidene, hydroxyl, (C-C6) alkoxy, oxo, hydroxycarbonyl, (C1-C6) alkoxycarbonyl, aryl wherein the aryl is as defined for R^a or heteroaryl wherein the heteroaryl is as defined for R^a, with the proviso that ring atoms substituted with alkylidene, hydroxycarbonyl or oxo are carbon, with the further proviso that ring atoms substituted with hydroxyl or alkoxy are separated from other ring heteroatoms by at least two intervening carbon atoms; and

wherein G* and R¹⁸ are such that at least two atoms separate the illustrated ring nitrogen from the carbon linked to R^x and R^y ;

(7) R¹⁹ (a) forms a double bond with R¹, R³ or G, (b) is hydrogen (c) is (C1-C3) alkyl or alkylene, or (d) is incorporated into a fused ring;

(8) R⁴ and R^4* are independently hydrogen or (C1-C6) alkyl, or one of R⁴ and R^4* can be (C1-C6) hydroxyalkyl; and

(9) R5 is (CO)NR¹³ R¹⁴, (CO)OR¹⁵, (CO)SR¹⁶, (SO₂)NR¹⁷ R¹⁸, (PO)(OR¹⁹)(OR²⁰), (CR²²)(OR²³)(OR²⁴), CN or tetrazol-5-yl, wherein R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ are independently hydrogen, (C1-C8) alkyl which can include a (C3-C8) cycloalkyl, wherein the carbon linked to the oxygen of R15 or the sulfur of R16 has no more than secondary branching and, (C2-C6) hydroxyalkyl, aminoalkyl where the alkyl is C2 to C6 and the amino can be substituted with up to two independent (C1-C6) alkyls, arylalkyl wherein the alkyl is C1-C6, heteroarylalkyl wherein the alkyl is C1 to C6, aryl or heteroaryl, R²² is hydrogen or OR²⁵ and R²³, R²⁴ and R²⁵ are (C1-C6) alkyl, phenyl, benzyl, acetyl or, where R²² is hydrogen, the alkyls of R²³ and R²⁴ can be combined to include 1,3-dioxylane or 1,3-dioxane;

wherein the aryl is phenyl or naphthyl and the heteroaryl is a five-membered ring, a six-membered ring, a six-membered ring fused to a five-membered ring, a five-membered ring fused to a six-membered ring, or a six-membered ring fused to a six-membered ring, wherein the heteroaryl is aromatic and contains heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon;

wherein the aryl, heteroaryl, aryl of arylalkyl or the heteroaryl of heteroarylalkyl can be substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (C1-C6) N-alkyl substitutions, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkylamine, dialkylamine wherein each alkyl is independently C1 to C6, amino, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be N-substituted with up to two independent (C1-C6) alkyl, (C1-C6) alkylsulfonyl, amidino that can substituted with up to three (C1-C6) alkyl, or methylenedioxy or ethylenedioxy with the two oxygens bonded to adjacent positions on the aryl or heteroaryl ring structure, which methylenedioxy or ethylenedioxy can be substituted with up to two independent (C1-C6) alkyl; and

wherein R¹³ and R¹⁴ together with the nitrogen can form a 5 to 7-membered ring that can contain one additional heteroatom selected from oxygen and sulfur.