Imidazolyl derivatives

• US 6,420,555 B1
• Filed: 05/22/2001
• Issued: 07/16/2002
• Est. Priority Date: 06/16/1998
• Status: Expired due to Fees

• Current Assignee: Ipsen Pharma Sas (Ipsen Sa)
• Original Assignee: Societe de Conseils de Recherches et d'Applications Scientifiques
• Inventors: Dong, Zheng Xin, Shen, Yeelana
• Primary Examiner(s): Higel, Floyd D.
• Assistant Examiner(s): SAEED, KAMAL A
• Application Number:
  US09/719,720
• Time in Patent Office: 420 Days
• Field of Search: 544/139, 544/370, 546/154, 546/157, 548/312.4, 514/397, 514/235.8
• US Class Current: 544/139
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/14 containing three or more hetero rings

Abstract

The present invention is directed to imidazolyl derivatives of formula (I), wherein the variables are defined in the specification, which are useful as prenyl transferase inhibitors.

Claims

1. A compound of formula (I),

or a pharmaceutically acceptable salt thereof,

wherein

- - - represents an optional bond;

m, n, p, and q are each independently 0 or 1;

T for each occurrence is independently selected from the group consisting of CR²⁶R²⁷, S, O, C(O), S(O)₂ and NR²⁸;

X is N—

Y, O or S where Y is selected from the group consisting of H, CR¹⁴R¹⁵R¹⁶, S(O)R¹⁷, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹, C(S)NR²²R²³, C(O)OR²⁴, C(S)OR²⁵, S(O)NR²⁹R³⁰ and S(O)₂NR³¹R³²;

Z is selected from the group consisting of H, cyano, halo, CR¹⁴R¹⁵R¹⁶, S(O)R¹⁷, S(O)₂R¹⁸ and C(O)R¹⁹;

R¹, R², R³, R⁴, R⁵, R⁶, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R²⁶ and R²⁷ are each independently selected from the group consisting of H, halo, hydroxy, thio and cyano, or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino and alkyl carbonyl amino;

or R¹ and R² when on adjacent positions, or R⁴ and R⁵, or R¹¹ and R¹², are taken together to form a bivalent radical selected from the group consisting of —

O—

CH₂—

O—

, —

O—

CH₂—

CH₂—

O—

, —

O—

CH═

CH—

, —

O—

CH₂—

CH₂—

, —

O—

CH₂—

CH₂—

CH₂— and

—

CR³³═

CR³⁴—

CR³⁵═

CR³⁶—

;

R⁷, R⁸ and R⁹ are each independently selected from the group consisting of H, halo, aryl, alkyl, substituted alkyl, alkyloxy, alkylthio, aryloxy, arylthio amino, mono- or di-alkylamino, hydroxycarbonyl, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)₂-alkyl, cyanoarylalkyl, arylalkyl and substituted arylakyl;

R¹⁰ is selected from the group consisting of H, amino, azido, hydroxy, halo, alkyl, substituted alkyl, cyano, hydroxyalkyl, hydroxycarbonyl, aminoalkyl, mono- or di-alkylaminoalkyl, mono- or di-alkylamino, alkoxy, alkylcarbonylalkyl, cyanoalkyl, alkyloxy-carbonylalkyl, carboxyalkyl, cycloalkyl, cycloalkylamino, cycloalkylhydroxy, imidazoyl, substituted imidazoyl, aminocarbonylalkyl, aryloxy, thio, alkylthio, OS(O₂)R¹⁸, OC(O)R¹⁹, OC(O)NR²⁰R²¹, OC(S)NR²²R²³, OS(O)NR²⁹R³⁰, OSO)₂NR³¹R³² and arylthio;

and R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁸, R²⁹, R³⁰, R³¹, R³² and R³⁷ for each occurrence are each independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl and arylalkyl;

or R²⁰ and R²¹, or R²² and R²³, or R²⁹ and R³⁰, or R³¹ and R³² are taken together to form a bivalent radical selected from the group consisting of —

(CH₂)_r—

NR³⁷—

(CH₂)_s—

, —

(CH₂)_r—

O—

(CH₂)_s— and

—

(CR³⁸R³⁹)_t—

, where r and s are each independently 1 to 3 and t is 2 to 6;

R³³, R³⁴, R³⁵, R³⁶, R³⁸ and R³⁹ are each independently selected from the group consisting of H, halo, cyano, alkyl, substituted alkyl, aryl, substituted aryl, alkyloxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, hydroxy and thio.

2. A compound according to claim 1, wherein m, n, p and q are each 0.

3. A compound according to claim 2, wherein R¹, R², R³, R⁴, R⁵, R⁶, R¹¹, R¹² and R¹³ are each H, halo, alkyl, substituted alkyl, cyano or alkyloxy.

4. A compound according to claim 3, wherein R¹⁰ is OH, H, halo, azido, amino, mono- or di-alkylamino, OS(O₂)R¹⁸, OC(O)NR²⁰R²¹ or OS(O)₂NR³¹R³².

5. A compound according to claim 4, wherein R⁷, R⁸ and R⁹ are each H, alkyl, substituted alkyl, amino or cyanoarylalkyl.

6. A compound according to claim 5, wherein X is N—

Y and Y is H, CR¹⁴R¹⁵R¹⁶, S(O)₂R¹⁸, C(O)NR²⁰R²¹ or S(O)₂NR²⁹R³⁰.

7. A compound according to claim 6, wherein R¹, R², R³, R¹¹, R¹² and R¹³ are each halo or hydrogen.

8. A compound according to claim 7, wherein R¹, R², R³, R¹¹, R¹² and R¹³ are each chloro or hydrogen.

9. A compound according to claim 8, wherein R⁷, R⁸, and R⁹ are each (C₁-C₄)alkyl or hydrogen.

10. A compound according to claim 9 wherein, R⁷, R⁸, and R⁹ are each methyl or hydrogen.

11. A compound according to claim 10, wherein R¹⁰ is OH, amino, OS(O₂)R¹⁸, or OC(O)NR²⁰R²¹.

12. A compound according to claim 11, wherein R⁴, R⁵ and R⁶ are each H.

13. A compound according to claim 12, wherein Z is hydrogen.

14. A compound according to claim 13, wherein Y is H, methyl, S(O)₂R¹⁸, C(O)NR²⁰R²¹ or S(O)₂R²⁹R³⁰.

15. A compound according to claim 14, wherein said compound is of the formula

wherein

R¹⁰ is OH and Y is H;

R¹⁰ is NH₂ and Y is —

S(O)₂—

CH₃;

R¹⁰ is OH and Y is —

S(O)₂—

CH₃;

R¹⁰ is OH and Y is —

C(O)—

N(CH₃)₂;

R¹⁰ is NH₂ and Y is —

C(O)—

N(CH₃)₂;

R¹⁰ is NH₂ and Y is H;

R¹⁰ is OH and Y is

R¹⁰ is NH₂and Y is

R¹⁰ is OH and Y is —

S(O)₂-Phenyl;

R¹⁰ is NH₂ and Y is —

S(O)₂-Phenyl;

R¹⁰ is OH and Y is —

C(O)—

N(CH₂CH₃)₂;

R¹⁰ is NH₂ and Y is —

C(O)—

N(CH₂CH₃)₂;

R¹⁰ is OH and Y is —

CH₃;

or

R¹⁰ is NH₂ and Y is —

CH₃.

16. A compound according to claim 15, wherein said compound is of the formula

wherein

R¹⁰ is OH and Y is H;

R¹⁰ is NH₂ and Y is —

S(O)₂—

CH₃;

R¹⁰ is OH and Y is —

S(O)₂—

CH₃;

or

R¹⁰ is OH and Y is —

C(O)—

N(CH₃)₂.

17. A compound according to claim 16, wherein said compound is of the formula

wherein

R¹⁰ is OH and Y is H;

or

R¹⁰ is OH and —

S(O)₂—

CH₃.

34. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

35. A method of inhibiting prenyl transferase in a subject in need thereof, which comprises administering to said subject an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

18. A compound of formula (II),

or a pharmaceutically acceptable salt thereof,

wherein

- - - represents an optional bond, provided that only one of the optional bonds is present in a compound of formula (I);

m, n, p, and q are each independently 0, 1 or 2;

T¹, T², T³ and T⁴ for each occurrence are each independently selected from the group consisting of CR²⁶R²⁷, S, O, C(O), S(O)₂ and NR²⁸;

X is N—

Y, O or S where Y is selected from the group consisting of H, CR¹⁴R¹⁵R¹⁶, S(O)R¹⁷, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹, C(S)NR²²R²³, C(O)OR²⁴, C(S)OR²⁵, S(O)NR²⁹R³⁰ and S(O)₂NR³¹R³²;

Z is selected from the group consisting of H, hydroxy, alkoxy, aryloxy, cyano, halo, CR¹⁴R¹⁵R¹⁶, S(O)R¹⁷, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹, C(O)OR²⁴, C(S)NR²²R²³, C(S)OR²⁵, S(O)NR²⁹R³⁰ and S(O)₂NR³¹R³², provided that when the optional bond connected to Z is present then Z is oxygen or sulfur;

R¹, R², R³, R⁴, R⁵, R⁶, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R²⁶ and R²⁷ for each occurrence are each independently selected from the group consisting of H, halo, hydroxy, thio and cyano, or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino and alkyl carbonyl amino;

or each pair of R¹ and R², R⁴ and R⁵, and R¹¹ and R¹² when on adjacent positions, is independently taken together to form a bivalent radical selected from the group consisting of —

O—

CH₂—

O—

, —

O—

CH₂—

CH₂—

O—

, —

O—

CH═

CH—

, —

O—

CH₂—

CH₂—

, —

O—

CH₂—

CH₂—

CH₂—

and —

CR³³═

CR³⁴—

CR³⁵═

CR³⁶—

;

R⁷, R⁸ and R⁹ are each independently H, halo, amino, cyano, hydroxycarbonyl, or an optionally substituted moiety selected from the group consisting of aryl, alkyl, alkyloxy, alkylthio, aryloxy, arylthio, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)₂-alkyl, cyanoarylalkyl and arylalkyl, provided that when R⁷, R⁸ or R⁹ is bound to one of the nitrogen atoms of the imidazolyl ring, R⁷, R⁸ or R⁹ is H or an optionally substituted moiety selected from the group consisting of aryl, alkyl, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)₂-alkyl, cyanoarylalkyl and arylalkyl;

R¹⁰ is selected from the group consisting of H, amino, azido, hydroxy, halo, alkyl, substituted alkyl, cyano, hydroxycarbonyl, mono- or di-alkylamino, alkyloxy, cycloalkyl, cycloalkylamino, cycloalkyloxy, imidazolyl, substituted imidazolyl, aryloxy, thio, alkylthio, arylthio, OS(O)₂R¹⁸, OC(O)R¹⁹, OC(O)NR²⁰R²¹, OC(S)NR²²R²³, OS(O)NR²⁹R³⁰ and OS(O)₂NR³¹R³²;

R¹⁷ and R¹⁸, for each occurrence are each independently H, OH or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;

R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁸, R²⁹, R³⁰, R³¹ and R³² for each occurrence are each independently H or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;

or each pair of R²⁰ and R²¹, R²² and R²³, R²⁹ and R³⁰, and R³¹, and R³² is independently taken together to form a bivalent radical selected from the group consisting of —

(CH₂)_r—

NR⁴⁰—

(CH₂)_s—

, —

(CH₂)_r—

O—

(CH₂)_s—

, —

(CR³⁸R³⁹)_t— and

—

(CH₂)_r—

NR⁴⁰—

(C(O))_u—

, where r and s are each independently 1 to 3, t is 2 to 6 and u is 1 or 2;

R³³, R³⁴, R³⁵, R³⁶, R³⁸ and R³⁹ for each occurrence are each independently selected from the group consisting of H, amino, halo, cyano, alkyl, substituted alkyl, aryl, substituted aryl, alkyloxy, aryloxy, alkylthio, arylthio, mono- or di-alkylamino, arylamino, hydroxy, heterocyclyl and thio;

and R⁴⁰ is H, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹, C(S)NR²²R²³, C(O)OR²⁴, C(S)OR²⁵, S(O)₂NR³¹R³² or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl.

19. A compound according to claim 18 wherein m, n, p and q are each 0.

20. A compound according to claim 19 wherein R¹, R², R³, R⁴, R⁵, R⁶, R¹¹, R¹² and R¹³ are each H, halo, alkyl, substituted alkyl, cyano or alkyloxy.

21. A compound according to claim 20 wherein R¹⁰ is OH, H, halo, azido, amino, mono- or di-alkylamino, OS(O)₂R¹⁸, OC(O)NR²⁰R²¹ or OS(O)₂NR³¹R³².

22. A compound according to claim 21 wherein R⁷, R⁸ and R⁹ are each H, alkyl, substituted alkyl or cyanoarylalkyl.

23. A compound according to claim 22 wherein X is N—

Y and Y is H, CR¹⁴R¹⁵R¹⁶, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹, C(O)OR²⁴ or S(O)₂NR³¹R³².

24. A compound according to claim 23 wherein R¹, R², R³, R¹¹, R¹² and R¹³ are each halo or H.

25. A compound according to claim 24 wherein R¹, R², R³, R¹¹, R¹² and R¹³ are each chloro or H.

26. A compound according to claim 25 wherein R⁷, R⁸, and R⁹ are each (C₁-C₄)alkyl or H.

27. A compound according to claim 26 wherein R⁷, R⁸, and R⁹ are each methyl or H.

28. A compound according to claim 27 wherein R¹⁰ is OH, amino, OS(O)₂R¹⁸, OC(O)NR²⁰R²¹ or OS(O)₂NR³¹R³².

29. A compound according to claim 28 wherein R⁴, R⁵ and R⁶ are each H.

30. A compound according to claim 29 wherein Z is hydrogen, halo or C(O)NR²⁰R²¹.

31. A compound according to claim 30 wherein Y is H, methyl, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹, C(O)OR²⁴ or S(O)₂NR³¹R³².

32. A compound according to claim 31 wherein said compound is of the formula:

wherein

Z is H, R¹⁰ is OH and Y is H;

Z is H, R¹⁰ is NH₂ and Y is —

S(O)₂—

CH₃;

Z is H, R¹⁰ is OH and Y is —

S(O)₂—

CH₃;

Z is H, R¹⁰ is OH and Y is —

C(O)—

N(CH₃)₂;

Z is H, R¹⁰ is NH₂ and Y is —

C(O)—

N(CH₃)₂;

Z is H, R¹⁰ is NH₂ and Y is H;

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂ and Y is

Z is H, R¹⁰ is OH and Y is —

S(O)₂-Phenyl;

Z is H, R¹⁰ is NH₂ and Y is —

S(O)₂-Phenyl;

Z is H, R¹⁰ is OH and Y is —

C(O)—

N(CH₂CH₃)₂;

Z is H, R¹⁰ is NH₂ and Y is —

C(O)—

N(CH₂CH₃)₂;

Z is H, R¹⁰ is OH and Y is —

CH₃;

Z is H, R¹⁰ is NH₂ and Y is —

CH₃;

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂ and Y is

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂ and Y is

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂ and Y is

Z is H, R¹⁰ is OH and Y is —

C(O)—

CH₃;

Z is H, R¹⁰ is NH₂ and Y is —

C(O)—

CH₃;

Z is H, R¹⁰ is OH and Y is —

S(O)₂—

CF₃;

Z is H, R¹⁰ is NH₂ and Y is —

S(O)₂—

CF₃;

Z is H, R¹⁰ is OH and Y is —

S(O)₂—

CH₂—

CF₃;

Z is H, R¹⁰ is NH₂ and Y is —

S(O)₂—

CH₂—

CF₃;

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂ and Y is

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂ and Y is

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂ and Y is

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂ and Y is

Z is H, R¹⁰ is OH and Y is —

C(O)—

NH₂;

Z is H, R¹⁰ is NH₂ and Y is —

C(O)—

NH₂;

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂ and Y is

Z is Cl, R¹⁰ is NH₂ and Y is

Z is Cl, R¹⁰ is NH₂ and Y is —

S(O)₂—

CH₃;

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂ and Y is

Z is H, R¹⁰ is OH and Y is

or

Z is H, R¹⁰ is NH₂ and Y is

33. A compound according to claim 32 wherein said compound is of the formula:

wherein

Z is H, R¹⁰ is OH and Y is H;

Z is H, R¹⁰ is NH₂ and Y is —

S(O)₂—

CH₃;

Z is H, R¹⁰ is OH and Y is —

S(O)₂—

CH₃;

Z is H, R¹⁰ is OH and Y is —

C(O)—

N(CH₃)₂;

Z is H, R¹⁰ is OH and Y is —

C(O)—

CH₃;

or

Z is H, R¹⁰ is NH₂ and Y is —

C(O)—

CH₃.

36. A pharmaceutical composition comprising an effective amount of a compound according to claim 18 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

37. A method of inhibiting prenyl transferase in a subject in need thereof, which comprises administering to said subject an effective amount of a compound according to claim 18 or a pharmaceutically acceptable salt thereof.

38. A process for synthesizing a compound of formula 3, according to the scheme below, which comprises reacting a compound of formula 1, according to the scheme below, with an arylalkylmagnesium chloride of formula 2, according to the scheme below, in which case X³ is Cl—

Mg and p=1-2, or an aryllithium of formula 2, in which case X³ is Li and p=0, in an inert organic solvent, until the reaction is substantially complete,

wherein

P is a protecting group;

m, n, p, and q are each independently 0, 1 or 2;

T¹, T², T³ and T⁴ for each occurrence are each independently selected from the group consisting of CR²⁶R²⁷, S, O, C(O), S(O)₂ and NR²⁸;

Y is selected from the group consisting of H, CR¹⁴R¹⁵R¹⁶, S(O)R¹⁷, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹, C(S)NR²²R²³, C(O)OR²⁴, C(S)OR²⁵, S(O)NR²⁹R³⁰ and S(O)₂NR³¹R³²;

Z is selected from the group consisting of H, hydroxy, alkoxy, aryloxy, cyano, halo, CR¹⁴R¹⁵R¹⁶, S(O)R¹⁷, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹,C(O)OR²⁴, C(S)NR²²R²³, C(S)OR²⁵, S(O)NR²⁹R³⁰ and S(O)₂NR³¹R³², provided that when the optional bond connected to Z is present then Z is oxygen or sulfur;

R¹, R², R³, R⁴, R⁵, R⁶, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R²⁶ and R²⁷ for each occurrence are each independently selected from the group consisting of H, halo, hydroxy, thio and cyano, or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino and alkyl carbonyl amino;

or each pair of R¹ and R², R⁴ and R⁵, and R¹¹ and R¹² when on adjacent positions, is independently taken together to form a bivalent radical selected from the group consisting of —

O—

CH₂—

O—

, —

O—

CH₂—

CH₂—

O—

, —

O—

CH═

CH—

, —

O—

CH₂—

CH₂—

, —

O—

CH₂—

CH₂—

CH₂—

and —

CR³³═

CR³⁴—

CR³⁵═

CR³⁶—

;

R⁷, R⁸ and R⁹ are each independently H, halo, amino, cyano, hydroxycarbonyl, or an optionally substituted moiety selected from the group consisting of aryl, alkyl, alkyloxy, alkylthio, aryloxy, arylthio, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)₂-alkyl, cyanoarylalkyl and arylalkyl, provided that when R⁷, R⁸ or R⁹ is bound to one of the nitrogen atoms of the imidazolyl ring, R⁷, R⁸ or R⁹ is H or an optionally substituted moiety selected from the group consisting of aryl, alkyl, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)₂-alkyl, cyanoarylalkyl and arylalkyl;

R¹⁷ and R¹⁸, for each occurrence are each independently H, OH or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;

R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁸, R²⁹, R³⁰, R³¹ and R³² for each occurrence are each independently H or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;

or each pair of R²⁰ and R²¹, R²² and R²³, R²⁹ and R³⁰, and R³¹and R³² is independently taken together to form a bivalent radical selected from the group consisting of —

(CH₂)_r—

NR⁴⁰—

(CH₂)_s—

, —

(CH₂)_r—

O—

(CH₂)_s—

, —

(CR³⁸R³⁹)_t— and

—

(CH₂)_r—

NR⁴⁰—

(C(O))_u—

, where r and s are each independently 1 to 3, t is 2 to 6 and u is 1 or 2;

R³³, R³⁴, R³⁵, R³⁶, R³⁸ and R³⁹for each occurrence are each independently selected from the group consisting of H, amino, halo, cyano, alkyl, substituted alkyl, aryl, substituted aryl, alkyloxy, aryloxy, alkylthio, arylthio, mono- or di-alkylamino, arylamino, hydroxy, heterocyclyl and thio;

and R⁴⁰ is H, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹, C(S)NR²²R²³, C(O)OR²⁴, C(S)OR²⁵, S(O)₂NR³¹R³² or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl.

39. A process for synthesizing a compound of formula 2, according to the scheme below, which comprises reacting a compound of formula 1, according to the scheme below, with a chlorinating reagent until the reaction is substantially complete,

wherein

m, n, p, and q are each independently 0, 1 or 2;

T¹, T², T³ and T⁴ for each occurrence are each independently selected from the group consisting of CR²⁶R²⁷, S, O, C(O), S(O)₂ and NR²⁸;

X is N—

Y, O or S where Y is selected from the group consisting of H, CR¹⁴R¹⁵R¹⁶, S(O)R¹⁷, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹, C(S)NR²²R²³, C(O)OR²⁴, C(S)OR²⁵, S(O)NR²⁹R³⁰ and S(O)₂NR³¹R³²;

Z is selected from the group consisting of H, hydroxy, alkoxy, aryloxy, cyano, halo, CR¹⁴R¹⁵R¹⁶, S(O)R¹⁷, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹, C(O)OR²⁴, C(S)NR²²R²³, C(S)OR²⁵, S(O)NR²⁹R³⁰ and S(O)₂NR³¹R³², provided that when the optional bond connected to Z is present then Z is oxygen or sulfur;

R¹, R², R³, R⁴, R⁵, R⁶, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R²⁶ and R²⁷ for each occurrence are each independently selected from the group consisting of H, halo, hydroxy, thio and cyano, or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino and alkyl carbonyl amino;

or each pair of R¹ and R², R⁴ and R⁵, and R¹¹ and R¹² when on adjacent positions, is independently taken together to form a bivalent radical selected from the group consisting of —

O—

CH₂—

O—

, —

O—

CH₂—

CH₂—

O—

, —

O—

CH═

CH—

, —

O—

CH₂—

CH₂—

, —

O—

CH₂—

CH₂—

CH₂— and

—

CR³³═

CR³⁴—

CR³⁵═

CR³⁶—

;

R⁷, R⁸ and R⁹ are each independently H, halo, amino, cyano, hydroxycarbonyl, or an optionally substituted moiety selected from the group consisting of aryl, alkyl, alkyloxy, alkylthio, aryloxy, arylthio, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)₂-alkyl, cyanoarylalkyl and arylalkyl, provided that when R⁷, R⁸ or R⁹ is bound to one of the nitrogen atoms of the imidazolyl ring, R⁷, R⁸ or R⁹ is H or an optionally substituted moiety selected from the group consisting of aryl, alkyl, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)₂-alkyl, cyanoarylalkyl and arylalkyl;

R¹⁷ and R¹⁸, for each occurrence are each independently H, OH or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;

R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁸, R²⁹, R³⁰, R³¹ and R³² for each occurrence are each independently H or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;

or each pair of R²⁰ and R²¹, R²² and R²³, R²⁹ and R³⁰, and R³¹ and R³² is independently taken together to form a bivalent radical selected from the group consisting of —

(CH₂)_r—

NR⁴⁰—

(CH₂)_s—

, —

(CH₂)_r—

O—

(CH₂)_s—

, —

(CR³⁸R³⁹)_t— and

—

(CH₂)_r—

NR⁴⁰—

(C(O))_u—

, where r and s are each independently 1 to 3, t is 2 to 6 and u is 1 or 2;

R³³, R³⁴, R³⁵, R³⁶, R³⁸ and R³⁹ for each occurrence are each independently selected from the group consisting of H, amino, halo, cyano, alkyl, substituted alkyl, aryl, substituted aryl, alkyloxy, aryloxy, alkylthio, arylthio, mono- or di-alkylamino, arylamino, hydroxy, heterocyclyl and thio;

and R⁴⁰ is H, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹, C(S)NR²²R²³, C(O)OR²⁴, C(S)OR²⁵, S(O)₂NR³¹R³² or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl.

40. A process for synthesizing a compound of formula 3, according to the scheme below which comprises reacting a compound of formula 2 with anhydrous liquid ammonia or an inert organic solvent saturated with anhydrous ammonia when n, p and q are each 0, or ammonium hydroxide when n, p and q are each not 0, until the reaction is substantially complete

wherein

m, n, p, and q are each independently 0, 1 or 2;

T¹, T², T³ and T⁴ for each occurrence are each independently selected from the group consisting of CR²⁶R²⁷, S, O, C(O), S(O)₂ and NR²⁸;

X is N—

Y, O or S where Y is selected from the group consisting of H, CR¹⁴R¹⁵R¹⁶, S(O)R¹⁷, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹, C(S)NR²²R²³, C(O)OR²⁴, C(S)OR²⁵, S(O)NR²⁹R³⁰ and S(O)₂NR³¹R³²;

Z is selected from the group consisting of H, hydroxy, alkoxy, aryloxy, cyano, halo, CR¹⁴R¹⁵R¹⁶, S(O)R¹⁷, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹, C(O)OR²⁴, C(S)NR²²R²³, C(S)OR²⁵, S(O)NR²⁹R³⁰ and S(O)₂NR³¹R³², provided that when the optional bond connected to Z is present then Z is oxygen or sulfur;

R¹, R², R³, R⁴, R⁵, R⁶, R¹¹, R¹², R¹³,R¹⁴, R¹⁵, R¹⁶, R²⁶ and R²⁷ for each occurrence are each independently selected from the group consisting of H, halo, hydroxy, thio and cyano, or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino and alkyl carbonyl amino;

or each pair of R¹ and R², R⁴ and R⁵, and R¹¹ and R¹² when on adjacent positions, is independently taken together to form a bivalent radical selected from the group consisting of —

O—

CH₂—

O—

, —

O—

CH₂—

CH₂—

O—

, —

O—

CH═

CH—

, —

O—

CH₂—

CH₂—

CH₂—

, —

O—

CH₂—

CH₂—

CH₂—

and —

CR¹³═

CR³⁴—

CR³⁵═

CR³⁶—

;

R⁷, R⁸ and R⁹ are each independently H, halo, amino, cyano, hydroxycarbonyl, or an optionally substituted moiety selected from the group consisting of aryl, alkyl, alkyloxy, alkylthio, aryloxy, arylthio, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)₂-alkyl, cyanoarylalkyl and arylalkyl, provided that when R⁷, R⁸ or R⁹ is bound to one of the nitrogen atoms of the imidazolyl ring, R⁷, R⁸ or R⁹ is H or an optionally substituted moiety selected from the group consisting of aryl, alkyl, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)₂-alkyl, cyanoarylalkyl and arylalkyl;

R¹⁷ and R¹⁸, for each occurrence are each independently H, OH or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;

R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁸, R²⁹, R³⁰, R³¹ and R³² for each occurrence are each independently H or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;

or each pair of R²⁰ and R²¹, R²² and R²³, R²⁹ and R³⁰, and R³¹ and R³² is independently taken together to form a bivalent radical selected from the group consisting of —

(CH₂)_r—

NR⁴⁰—

(CH₂)_s—

, —

(CH₂)_r—

O—

(CH₂)_s—

, —

(CR³⁸R³⁹)_t— and

—

(CH₂)_r—

NR⁴⁰—

(C(O))_u—

, where r and s are each independently 1 to 3, t is 2 to 6 and u is 1 or 2;

R³³, R³⁴, R³⁵, R³⁶, R³⁸ and R³⁹ for each occurrence are each independently selected from the group consisting of H, amino, halo, cyano, alkyl, substituted alkyl, aryl, substituted aryl, alkyloxy, aryloxy, alkylthio, arylthio, mono- or di-alkylamino, arylamino, hydroxy, heterocyclyl and thio;

and R⁴⁰ is H, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹, C(S)NR²²R²³, C(O)OR²⁴, C(S)OR²⁵, S(O)₂NR³¹R³² or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl.