Compounds to treat Alzheimer's disease

• US 7,034,182 B2
• Filed: 06/29/2001
• Issued: 04/25/2006
• Est. Priority Date: 06/30/2000
• Status: Expired due to Fees

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Inventors: John, Varghese, Fang, Lawrence Y.
• Primary Examiner(s): Kumar, Shailendra
• Application Number:
  US09/896,874
• Publication Number:
  US 20020016320A1
• Time in Patent Office: 1,761 Days
• Field of Search: 564/147, 514/614
• US Class Current: 564/147
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• 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 215/28 and containing six-membered aromatic rings
• CPC Class Codes: C07C 233/78 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
• CPC Class Codes: C07C 235/84 with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 239/20 having oxygen atoms of hydroxylamino groups etherified
• CPC Class Codes: C07C 243/22 having nitrogen atoms of hydrazine groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 243/28 to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
• CPC Class Codes: C07C 271/16 to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 271/18 to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
• CPC Class Codes: C07C 275/24 containing six-membered aromatic rings
• CPC Class Codes: C07C 311/03 having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 311/05 to acyclic carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
• CPC Class Codes: C07C 311/08 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: C07C 311/13 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 311/16 having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
• CPC Class Codes: C07C 311/37 : having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 317/44 : having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07C 323/60 : with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• CPC Class Codes: C07D 211/60 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 215/12 : with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 277/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 295/13 : to an acyclic saturated chain
• CPC Class Codes: C07D 303/36 : with hydrocarbon radicals, substituted by nitrogen atoms nitro, nitroso radicals C07D303/08
• CPC Class Codes: C07D 307/52 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/54 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/24 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The present invention is substituted amines of formula (XV)
useful in treating Alzheimer'"'"'s disease and other similar diseases.

Claims

1. A substituted amine of formula (XV)

or a salt thereof, where R₁ is —

(CH₂)_n1—

(R_1-aryl) where n₁ is zero or one and where R_1-aryl is phenyl, optionally substituted with one, two, or three of the following substituents

(A) C₁-C₆ alkyl optionally substituted with one, two or three substituents selected from the group consisting of C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b —

H or C₁-C₆ alkyl,

(D) —

F, Cl, —

Br or —

I,

(F) —

C₁-C₆ alkoxy optionally substituted with one, two, or three of;

—

F,

(G) —

NR_N-2R_N-3 where R_N-2 and R_N-3 are as defined below,

(H) —

OH,

(I) —

C≡

N,

(K) —

CO—

(C₁-C₄ alkyl),

where R₂ is;

—

H, or C₁-C₃ alkyl;

where R₃ is;

—

H or C₁-C₃ alkyl;

where R_N is R_N-1—

X_N—

where X_N is selected from the group consisting of;

(A) —

CO—

,

(B) —

SO₂—

,

(C) —

(CR′

R″

)_1-6 where R′ and

R″

are the same or different and are —

H or C₁-C₄ alkyl,

(E) a single bond;

where R_N-1 is R_N-aryl where R_N-aryl is phenyl, 1-naphthyl, or 2-naphthyl, each of which is optionally substituted with one, two or three of the following substituents which can be the same or different and are;

(1) C₁-C₆ alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b are as defined above,

(2) —

OH,

(3) —

NO₂,

(4) —

F, —

Cl, —

Br, or —

I,

(5) —

CO—

OH,

(6) —

C≡

N,

(7) —

(CH₂)_0-4—

CO—

NR_N-2R_N-3 where R_N-2 and R_N-3 are the same or different and are selected from the group consisting of;

(a) —

H,

(b) —

C₁-C₆ alkyl optionally substituted with one substitutent selected from the group consisting of;

(i) —

OH, and

(ii) —

NH₂,

(c) —

C₁-C₆ alkyl optionally substituted with one to three —

F, —

Cl, —

Br, or —

I,

(d) —

C₃-C₇ cycloalkyl,

(e) —

(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),

(f) —

(C₁-C₆ alkyl)-O—

(C₁-C₃ alkyl),

(8) —

(CH₂)_0-4—

CO—

(C₁-C₁₂ alkyl),

(11) —

(CH₂)_0-4—

CO—

(C₃-C₇ cycloalkyl),

(15) —

(CH₂)_0-4—

CO—

R_N-4 where R_N-4 is selected from the group consisting of morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where each group is optionally substituted with one, two, three, or four of C₁-C₆ alkyl,

(16) —

(CH₂)_0-4—

CO—

O—

R_N-5 where R_N-5 is selected from the group consisting of;

(a) C₁-C₆ alkyl,

(b) —

(CH₂)_0-2—

(R_1-aryl) where R_1-aryl is as defined above,

(e) C₃-C₇ cycloalkyl, and

(21) —

(CH₂)_0-4—

N(H or R_N-5)—

CO—

O—

R_N-5 where R_N-5 can be the same or different

(24) —

(CH₂)_0-4—

N(—

H or R_N-5)—

CO—

R_N-2 where R_N-5 and R_N-2 can be the same or different,

(25) —

(CH₂)_0-4—

NR_N-2R_N-3 where R_N-2 and R_N-3 can be the same or different,

(26) —

(CH₂)_0-4—

R_N-4,

(27) —

(CH₂)_0-4—

O—

CO—

(C₁-C₆ alkyl),

(29) —

(CH₂)_0-4—

O—

CO—

N(R_N-5)₂,

(31) —

(CH₂)_0-4—

O—

(R_N-5)₂

(34) —

(CH₂)_0-4—

O—

(C₁-C₆ alkyl optionally substituted with one, two, three, four, or five —

F),

(35) C₃-C₇ cycloalkyl,

(39) —

(CH₂)_0-4—

C₃-C₇ cycloalkyl,

where R_A is;

(I) —

C₁-C₁₀ alkyl optionally substituted with one, two or three substituents selected from the group consisting of C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₆ alkoxy, —

O-phenyl, —

NR_1-aR_1-b where R_1-a and R_1-b are as defined above, —

OC═

O NR_1-aR_1-b where R_1-a and R_1-b are as defined above, —

S(═

O)_0-2 R_1-a where R_1-a is as defined above, —

NR_1-aC═

O NR_1-aR_1-b where R_1-a and R_1-b are as defined above, —

C═

O NR_1-aR_1-b where R_1-a and R_1-b are as defined above, and —

S(═

O)₂ NR_1-aR_1-b where R_1-a and R_1-b are as defined above,

(III) —

(CR_A-xR_A-y)_0-4—

R_A-aryl where R_A-x and R_A-y are

(A) —

H,

(B) C₁-C₄ alkyl optionally substituted with one or two —

OH,

(C) C₁-C₄ alkoxy optionally substituted with one, two, or three of;

—

F,

(D) —

(CH₂)_0-4—

C₃-C₇ cycloalkyl,

(E) C₂-C₆ alkenyl containing one or two double bonds,

(F) C₂-C₆ alkynyl containing one or two triple bonds,

(G) phenyl,

(IV) -cyclopentyl, -cyclohexyl, or -cycloheptyl ring fused to R_A-aryl, where R_A-aryl is as defined above where one carbon of cyclopentyl, cyclohexyl, or -cycloheptyl is optionally replaced with NH, NR_N-5, O, or S(═

O)_0-2, and where cyclopentyl, cyclohexyl, or -cycloheptyl can be optionally substituted with one or two —

C₁-C₃ alkyl, —

F, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₆ alkoxy, ═

O, or —

NR_1-aR_1-b where R_1-a and R_1-b are as defined above,

(VI) —

H,

(VII)

—

C═

OR₇,

wherein R₇ is;

C₁-C₆ alkyl,

phenyl,

(aryl)alkyl,

cycloalkyl,

cycloalkylalkyl,

hydroxyalkyl,

alkoxyalkyl,

aryloxyalkyl,

haloalkyl,

carboxyalkyl,

alkoxycarbonylalkyl,

aminoalkyl,

alkylaminoalkyl,

dialkylaminoalkyl,

lower alkenyl,

where X is —

N, or —

O, with the proviso that when X is O, R_B is absent;

and when X is N,

R_B is;

—

C₁-C₁₀ alkyl optionally substituted with one, two or three substituents selected from the group consisting of C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, —

OH, —

SH, —

C≡

N, CF₃, C₁-C₆ alkoxy, —

O-phenyl, —

NR_1-aR_1-b —

OC═

O NR_1-aR_1-b —

C═

O NR_1-aR_1-b where R_1-a and R_1-b are as defined above, and S(═

O)₂ NR_1-aR_1-b;

(II) —

(CH₂)_0-3—

(C₃-C₈) cycloalkyl where cycloalkyl can be optionally substituted with one, two or three substituents selected from the group consisting of C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₆ alkoxy, —

O-phenyl, —

CO—

OH, —

CO—

O—

(C₁-C₄ alkyl), and NR_1-aR_1-b;

or —

H.

2. A substituted amine according to claim 1

where R₁ is:

—

(CH₂)_0-1-phenyl, wherein the phenyl group is optionally substituted with 1 or 2 groups that are F, Cl, Br, C₁-C₄ alkoxy, CF₃, C₁-C₆ alkyl optionally substituted with one or two substituents selected from the group consisting of C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

OH, —

C═

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b —

H or C₁-C₄ alkyl,

where R_N is;

R_N-1—

X_N—

where X_N is selected from the group consisting of;

—

CO—

, and

—

SO₂—

,

where R_N-1 is —

R_N-aryl;

where R_A is;

—

C₁-C₈ alkyl,

—

(CH₂)_0-3—

(C₃-C₇) cycloalkyl,

—

(CR_A-xR_A-y)_0-4—

R_A-aryl,

-cyclopentyl or -cyclohexyl ring fused to R_A-aryl, or

—

C═

OR₇, where R₇ is

C₁-C₆ alkyl,

phenyl,

phenylalkyl,

cycloalkyl,

cycloalkylalkyl,

hydroxyalkyl,

alkoxyalkyl,

phenyloxyalkyl

haloalkyl,

carboxyalkyl,

where X is —

N or —

O, with the proviso that when X is O, R_B is absent; and

when X is N,

R_B is;

—

C₁-C₆ alkyl.

3. A substituted amine according to claim 2 where R₁ is:

benzyl, wherein the phenyl portion is optionally substituted with 1 or 2 groups that are F, Cl, C₁-C₄ alkoxy, CF₃, C₁-C₄ alkyl optionally substituted with one substituent selected from the group consisting of C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

OH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b —

H or C₁-C₄ alkyl,

where R₂ is —

H;

where R₃ is —

H;

where R_N is;

R_N-1—

X_N—

where X_N is;

—

CO—

,

where R_N-1 is phenyl, substituted with one, two or three of the following substituents which can be the same or different and are C₁-C₄ alkyl, optionally substituted with one or two substituents selected from the group consisting of C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and NR_1-aR_1-b, —

OH, —

NO₂, —

F, —

Cl, —

Br, or —

I, —

CO—

OH, —

C≡

N, —

(CH₂)_0-4—

CO—

NR_N-2R_N-3, —

(CH₂)_0-4—

SO₂—

NR_N-2R_N-3, —

(CH₂)_0-4—

SO—

(C₁-C₆ alkyl), —

(CH₂)_0-4—

SO₂—

(C₁-C₆ alkyl), —

(CH₂)_0-4—

SO₂—

(C₃-C₇ cycloalkyl), —

(CH₂)_0-4—

O—

(C₁-C₆ alkyl optionally substituted with one, two, three, four, or five —

F), C₃-C₇ cycloalkyl, or —

(CH₂)_0-4—

C₃-C₇ cycloalkyl, where R_N-2 and R_N-3 are the same or different and are selected from the group consisting of H, and —

C₁-C₆ alkyl optionally substituted with one substituent selected from —

OH, and —

NH₂, —

C₁-C₆ alkyl optionally substituted with one to three —

F, —

Cl, —

Br, or —

I, —

C₃-C₇ cycloalkyl, —

(C₁-C₂alkyl)-(C₃-C₇, cycloalkyl), and —

(C₁-C₄ alkyl)-O—

(C₁-C₃ alkyl);

where R_A is;

—

C₁-C₈ alkyl,

—

(CH₂)_0-3—

(C₃-C₇) cycloalkyl,

—

(CR_A-xR_A-y)_0-4—

R_A-aryl,

-cyclopentyl or -cyclohexyl ring fused to R_A-aryl,

-cyclopentyl or -cyclohexyl ring fused to R_A-aryl,

—

C═

OR₇, where R₇ is

C₁-C₆ alkyl,

phenylalkyl,

cycloalkyl,

cycloalkylalkyl,

hydroxyalkyl,

alkoxyalkyl, or

haloalkyl,

where X is —

N or —

O, with the proviso that when X is O, R_B is absent;

and when X is N, and

R_B is;

H or —

C₁-C₆ alkyl.

4. A substituted amine according to claim 3, where R_A is:

—

(CR_A-xR_A-y)_0-4—

R_A-aryl, -cyclopentyl or -cyclohexyl ring fused to R_A-aryl, or —

C═

OR₇, where

R_A-aryl is phenyl, 1-naphthyl, or 2-naphthyl, substituted with one, two or three of the following substituents which can be the same or different and are C₁-C₄ alkyl, optionally substituted with one or two substituents selected from the group consisting of C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b, —

OH, —

NO₂, —

F, —

Cl, —

Br, or —

I, —

CO—

OH, —

C≡

N, —

(CH₂)_0-4—

CO—

NR_N-2R_N-3, —

(CH₂)_0-4—

SO₂—

NR_N-2R_N-3, —

(CH₂)_0-4—

SO—

(C₁-C₆ alkyl), —

(CH₂)_0-4—

SO₂—

(C₁-C₆ alkyl), —

(CH₂)_0-4—

SO₂—

(C₃-C₇ cycloalkyl), —

(CH₂)_0-4—

O—

(C₁-C₆ alkyl optionally substituted with one, two, three, four, or five —

F), C₃-C₇ cycloalkyl, or —

(CH₂)_0-4—

C₃-C₇ cycloalkyl, where

R_N-2 and R_N-3 are the same or different and are selected from the group consisting of H, and —

C₁-C₆ alkyl optionally substituted with one substituent selected from —

OH, and —

NH₂, —

C₁-C₆ alkyl optionally substituted with one to three —

F, —

Cl, —

Br, or —

I, —

C₃-C₇ cycloalkyl, —

(C₁-C₂alkyl)-(C₃-C₇ cycloalkyl), and —

(C₁-C₄ alkyl)-O—

(C₁-C₃ alkyl);

R₇ is C₁-C₆ alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, or haloalkyl,

R_A-x and R_A-y are —

H, C₁-C₄ alkyl optionally substituted with one or two —

OH, C₁-C₄ alkoxy optionally substituted with one, two, or three —

F, or phenyl;

where R_B is H or C₁-C₄ alkyl.

5. A substituted amine according to claim 4, where R₁ is benzyl substituted with 2 halogens.

6. A substituted amine according to claim 5 where R₁ is benzyl substituted with 2 fluorines.

7. A substituted amine according to claim 6 where R₁ is 3,5-difluorobenzyl.

8. A substituted amine according to claim 5 where R_N is —

C(O)-phenyl, wherein the phenyl is substituted with one —

CO—

NR_N-2R_N-3.

9. A substituted amine according to claim 8 where R_N-2 and R_N-3 are independently H or C₁-C₆ alkyl.

10. A substituted amine according to claim 5 where R_N is —

C(O)-phenyl, wherein the phenyl is substituted with one methyl group and with one —

CO—

NR_N-2R_N-3.

11. A substituted amine according to claim 10 where R_N-2 and R_N-3 are independently H or C₁-C₆ alkyl.

12. A substituted amine according to either claim 8 or 10 where R_A is:

—

(CR_A-xR_A-y)_0-4—

R_A-aryl where R_A-aryl is phenyl, which is optionally substituted with one or two substituents selected from the group consisting of C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b; and

wherein the phenyl is optionally fused to a cyclopentyl or cyclohexyl ring; and

R_A-x and R_A-y, if present, are both H.

13. A substituted amine according to claim 12 where R_A is phenyl.

14. A substituted amine according to claim 12 where phenyl is mono-substituted at the 3-position or disubstituted at the 3,5-positions.

15. A substituted amine according to claim 12 where R_A is:

-cyclohexyl ring fused to a phenyl ring.

16. A substituted amine according to claim 13, where R_B is H or C₁-C₄ alkyl.

17. A substituted amine according to claim 16 where R_B is H.

18. A substituted amine according to claim 16 where R_B is methyl.

19. A substituted amine according to claim 1, where X is oxygen and R_B is absent.

20. A substituted amine according to claim 1 chosen from the group consisting of:

N-[1-(3,5-Difluoro-benzyl)-2-hydroxy-3-(N′

-methyl-N′

-phenyl-hydrazino)-propyl]-5-methyl-N′

,N′

-dipropyl-isophthalamide,

N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[N′

-methyl-N′

-(4-methyl-pentanoyl)-hydrazino]-propyl}-5-methyl-N′

,N′

-dipropyl-isophthalamide, and

N-[1-(3,5-Difluoro-benzyl)-2-hydroxy-3-phenoxyamino-propyl]-5-methyl-N′

,N′

-dipropyl-isophthalamide.

21. A substituted amine according to claim 1 where the pharmaceutically acceptable salt is selected from the group consisting of salts of the following acids acetic, aspartic, benzenesulfonic, benzoic, bicarbonic, bisulfuric, bitartaric, butyric, calcium edetate, camsylic, carbonic, chlorobenzoic, citric, edetic, edisylic, estolic, esyl, esylic, formic, fumaric, gluceptic, gluconic, glutamic, glycollylarsanilic, hexamic, hexylresorcinoic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, maleic, malic, malonic, mandelic, methanesulfonic, methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic, p-nitromethanesulfonic, pamoic, pantothenic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, phthalic, polygalactouronic, propionic, salicyclic, stearic, succinic, sulfamic, sulfanilic, sulfonic, sulfuric, tannic, tartaric, teoclic and toluenesulfonic.

22. A composition comprising a compound of claim 1;

and an inert diluent or edible carrier.

23. The composition of claim 22, where said carrier is an oil.

24. A composition comprising a compound of claim 1;

and an binder, excipient, disintegrating agent, lubricant, or gildant.

25. A composition comprising a compound of claim 1, disposed in a cream, ointment, or patch.

26. A compound according to claim 9, wherein

R_N is of the formula

27. A compound according to claim 26, wherein R_N-2 and R_N-3 are both C₃ alkyl.

28. A compound according to claim 11, wherein

R_N is of the formula

29. A compound according to claim 28, wherein

R_N-2 and R_N-3 are both C₃ alkyl.

30. A compound according to claim 19, wherein

R₁ is benzyl, wherein the phenyl portion is optionally substituted with 1 or 2 groups that are F, Cl, C₁-C₄ alkoxy, CF₃, C₁-C₄ alkyl optionally substituted with one substituent selected from the group consisting of C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

OH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b —

H or C₁-C₄ alkyl,

R₂ is —

H;

R₃ is —

H;

R_N is R_N-1—

X_N—

where X_N is —

CO—

, and R_N-1 is phenyl substituted with one, two or three of the following substituents which can be the same or different and are C₁-C₄ alkyl, —

OH, —

NO₂, —

F, —

Cl, —

Br, or —

I, —

CO—

OH, —

C≡

N, —

(CH₂)_0-4—

CO—

NR_N-2R_N-3, where

R_N-2 and R_N-3 are the same or different and are selected from the group consisting of H, and —

C₁-C₆ alkyl optionally substituted with one substituent selected from —

OH, and —

NH₂, —

C₁-C₆ alkyl optionally substituted with one to three —

F, —

Cl, —

Br, or —

I, —

C₃-C₇ cycloalkyl, —

(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), and —

(C₁-C₄ alkyl)-O—

(C₁-C₃ alkyl).

31. A compound according to claim 30, wherein

R_A is —

(CR_A-xR_A-y)_0-4—

R_A-aryl, or —

C═

OR₇, where

R_A-aryl is phenyl, 1-naphthyl, or 2-naphthyl, substituted with one, two or three of the following substituents which can be the same or different and are C₁-C₄ alkyl optionally substituted with one or two substituents selected from the group consisting of C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and NR_1-aNR_1-b, —

OH, —

NO₂, —

F, —

Cl, —

Br, or —

I, —

CO—

OH, —

C≡

N, —

(CH₂)_0-4—

CO—

NR_N-2R_N-3, —

(CH₂)_0-4—

SO₂—

NR_N-2R_N-3, —

(CH₂)_0-4—

SO—

(C₁-C₆ alkyl), —

(CH₂)_0-4—

SO₂—

(C₁-C₆ alkyl), —

(CH₂)_0-4—

SO₂—

(C₃-C₇ cycloalkyl), —

(CH₂)_0-4—

O—

(C₁-C₆ alkyl optionally substituted with one, two, three, four, or five —

F), C₃-C₁ cycloalkyl, or —

(CH₂)_0-4—

C₃-C₇ cycloalkyl, where R_N-2 and R_N-3 are the same or different and are selected from the group consisting of H, and —

C₁-C₆ alkyl;

R₇ is C₁-C₆ alkyl;

R_A-x and R_A-y are —

H, C₁-C₄ alkyl, or phenyl.

32. A compound according to claim 31, wherein

R₁ is benzyl, wherein the phenyl portion is substituted with 1 or 2 groups that are F, Cl, C₁-C₄ alkoxy, CF₃, or C₁-C₄ alkyl;

R_A-aryl is phenyl substituted with one or two of the following substituents C₁-C₄ alkyl, optionally substituted with one or two substituents selected from the group consisting of C₁-C₃ alkyl, —

OH, —

NO₂, —

F, —

Cl, —

Br, or —

I, —

CO—

OH, —

C≡

N, —

(CH₂)_0-4—

CO—

NR_N-2R_N-3, and —

(CH₂)_0-4—

O—

(C₁-C₆ alkyl optionally substituted with one, two, three, four, or five —

F, where

R_N-2 and R_N-3 are the same or different and are selected from the group consisting of H, and —

C₁-C₆ alkyl.

33. A substituted amine according to claim 32 where R_N is —

C(O)-phenyl, wherein the phenyl is substituted with one —

CO—

NR_N-2R_N-3.

34. A substituted amine according to claim 33 where R_N-2 and R_N-3 are independently H or C₁-C₆ alkyl.

35. A compound according to claim 34, wherein R_N-2 and R_N-3 are both C₃ alkyl.

36. A substituted amine according to claim 32 where R_N is —

C(O)-phenyl, wherein the phenyl is substituted with one methyl group and with one —

CO—

NR_N-2R_N-3.

37. A substituted amine according to claim 36 where R_N-2 and R_N-3 are independently H or C₁-C₆ alkyl.

38. A compound according to claim 37, wherein R_N-2 and R_N-3 are both C₃ alkyl.

39. A compound according to claim 4, wherein

R₇ is C₁-C₆ alkyl;

R₁ is benzyl, wherein the phenyl portion is substituted with 1 or 2 groups that are F, Cl, C₁-C₄ alkoxy, CF₃, or C₁-C₄ alkyl; and

R_N is R_N-1—

X_N—

where XN is —

CO—

, and R_N-1 is phenyl substituted with one, two or three of the following substituents which can be the same or different and are C₁-C₄ alkyl, —

OH, —

NO₂, —

F, —

Cl, —

Br, or —

I, —

CO—

OH, —

C≡

N, —

(CH₂)_0-4—

CO—

NR_N-2R_N-3, where

R_N-2 and R_N-3 are the same or different and are selected from the group consisting of H, and —

C₁-C₆ alkyl optionally substituted with one substituent selected from —

OH, and —

NH₂, —

C₁-C₆ alkyl optionally substituted with one to three —

F, —

Cl, —

Br, or —

I, —

C₃-C₇ cycloalkyl, —

(C₁-C₂alkyl)-(C₃-C₇ cycloalkyl), and —

(C₁-C₄ alkyl)-O—

(C₁-C₃ alkyl).

40. A compound according to claim 39, wherein

R_N is —

C(O)-phenyl, wherein the phenyl is substituted with one —

CO—

NR_N-2R_N-3.

41. A substituted amine according to claim 40 where R_N-2 and R_N-3 are independently H or C₁-C₆ alkyl.

42. A compound according to claim 41, wherein R_N-2 and R_N-3 are both C₃ alkyl.

43. A substituted amine according to claim 39 where R_N is —

C(O)-phenyl, wherein the phenyl is substituted with one methyl group and with one —

CO—

NR_N-2R_N-3.

44. A substituted amine according to claim 43 where R_N-2 and R_N-3 are independently H or C₁-C₆ alkyl.

45. A compound according to claim 44, wherein R_N-2 and R_N-3 are both C₃ alkyl.